key: cord-026025-xqj877en
authors: PETRAS, ROBERT E.; FRANKEL, WENDY L.
title: Large Intestine (Colon)
date: 2009-10-30
journal: Modern Surgical Pathology
DOI: 10.1016/b978-1-4160-3966-2.00023-0
sha: 
doc_id: 26025
cord_uid: xqj877en

nan

Normal large bowel gross anatomy and microscopic anatomy 1-3 are outlined here. The large bowel extends from the ileocecal valve to the anus and measures 120 cm to 150 cm in adults. It can be clinically useful to divide the large bowel into regions. The cecum, the most proximal saccular part of the large bowel, lies inferior to a horizontal line defined by the ileocecal valve. The cecum is completely invested by peritoneum and contains the opening of the vermiform appendix. The right colon, 15 cm to 20 cm in length, extends to the hepatic flexure. The right colon lacks mesentery and lies mostly in the retroperitoneum except for its anterior and right lateral serosa. The transverse colon averages 30 cm to 60 cm in length, runs from the hepatic flexure to the splenic flexure, and has a mesentery. The descending colon begins at the splenic flexure, becomes retroperitoneal, and extends for 20 cm to 25 cm. At the distal portion of the descending colon, the large bowel once again acquires a mesentery to become the sigmoid colon, which measures approximately 40 cm in length. The sigmoid colon arbitrarily becomes the rectum at approximately the level of the third sacral vertebra. The rectum, measuring 10 cm to 15 cm in length, ends at the anal canal. The upper one third of the rectum is covered by peritoneum; the lower two thirds lies in the retroperitoneum surrounded by the fatty mesorectum.

Beneath the mesothelium-covered serosa lies a subserosal layer of fibroadipose tissue. The muscularis externa of the large bowel is composed of an inner circular layer and an outer longitudinally running layer of smooth muscle that condenses into three longitudinally running taeniae coli, the mesocolic taenia and two antimesenteric taeniae. The taeniae unite at the base of the vermiform appendix. They flare at the rectum and incorporate into its external muscular layer. The inner and outer layers of muscularis externa are separated by the myenteric plexus of Auerbach. Appendages of subserosal fat typically hang from the large bowel to form the epiploic appendices.

Extending luminally from the muscularis externa lie the fibroadipose tissue, blood vessels, lymphatics, and nerves of the submucosa. The submucosa contains Meissner's plexus, which is usually found closely juxtaposed to the muscularis mucosae. The inner surface of the large bowel is characterized by horizontally oriented folds (plicae semilunares) and fine innominate grooves of the mucosa.

The proximal colon to the splenic flexure derives its blood supply from the superior mesenteric artery through the ileocolic, right colic, and middle colic branches. The remainder of the colon is supplied by the left colic and sigmoid branches of the inferior mesenteric artery. The inferior mesenteric artery and iliac vessels provide blood to the rectum. Veins accompany the arteries and share their names. The large bowel venous drainage enters the portal circulation except for the distal rectum, which drains into the systemic circulation through the middle and inferior rectal veins. In portal hypertension, this area can serve as a portalsystemic shunt and can be a site of varices. The lymph node drainage is divided into those lymph nodes close to the bowel wall (e.g., pericolic, perirectal) and those that follow the blood vessels (e.g., mesenteric).

The vagus nerves supply stimulatory nervous activity to the right colon and proximal transverse colon. The remainder of the large bowel is supplied by pelvic postganglionic parasympathetic nerves. The inhibitory nervous activity is derived from the superior and inferior mesenteric plexuses.

The large bowel mucosa is composed of a single-cell layer of colorectal epithelium covering the lumen and lining the crypts, the supporting lamina propria and a small smooth muscle band referred to as the muscularis mucosae. The normal colorectal luminal surface of the mucosa is straight; the glands are made up of tubules (crypts) that are tightly packed, parallel, nonbranching, and closely approximating the muscularis mucosae ( Fig. 23-1) . The appearance of the colonic tubules is similar to rows of test tubes placed in a rack. Goblet cells interspersed between colorectal absorptive cells line the colonic tubules. Scattered neu-roendocrine cells can be observed usually near the base of the crypt and contain basally oriented eosinophilic cytoplasmic granules. The lamina propria contains a modest amount of mixed inflammatory cells including plasma cells, lymphocytes, eosinophils, mast cells, and macrophages. Intraepithelial lymphocytes are present normally but usually are fewer than 6 per 100 colorectal epithelial cells. The muscularis mucosae is arranged into two layers (an inner circular and outer longitudinally running layer) and is usually thin and regular. The submucosa is typically devoid of inflammatory cells. Scattered mucosal and submucosal lymphoid follicles are normally encountered, especially in younger individuals. In areas of mucosal lymphoid follicles, the mucosal architecture may be distorted and the muscularis mucosae can be incomplete. Flattened epithelial cells known as M cells overlie the mucosal lymphoid aggregates. The epithelium of the M-cell zone typically contains numerous intraepithelial lymphocytes. [1] [2] [3] Paneth cells with their basal nuclei and luminal cytoplasmic refractile red granules are seen in the base of colonic crypts but are considered normal only in the cecum and proximal right colon. 2, 3 Mucosal biopsy interpretation can be hampered by changes associated with bowel preparation and with the trauma of the biopsy procedure itself. Changes ascribed to bowel preparation include decreased intraepithelial mucin, increased numbers of mitotic figures, surface apoptosis with karyorrhectic debris in the superficial lamina propria, and small numbers of neutrophils and eosinophils in surface or crypt epithelium. [2] [3] [4] [5] [6] [7] Edema and recent hemorrhage into tissues not associated with other degenerative or inflammatory changes most likely represent biopsy-related trauma.

Muciphages (foamy macrophages containing faintly periodic acid-Schiff [PAS]-positive material) are often present in the lamina propria of the large bowel, especially the rectum, where they most likely represent a nonspecific response to mucosal injury (i.e., trauma). 8, 9 Muciphages should be distinguished from xanthelasma/xanthomatous polyp, which can also occur in the large intestine ( Fig.  23 -2).

An adenoma, defined as a benign intraepithelial neoplasm composed of epithelial cells exhibiting cytologic dysplasia, is considered the precursor lesion of most colorectal carcinomas. 1, [10] [11] [12] Dysplasia is characterized by decreased intraepithelial mucin, epithelial nuclear enlargement with hyperchromasia, nuclear stratification, and increased numbers of mitotic figures. Large bowel adenomas are highly prevalent in Western societies. The frequency of these tumors markedly increases after age 40 years and reaches a peak at age 70 years. Adenomas are usually asymptomatic but large ones may bleed.

Adenomas usually produce a raised endoscopically or grossly detectable abnormality, generally a protrusion or polyp that can often be further subclassified as sessile or pedunculated. Some adenomas appear flat; some may cause mucosal depressions. Adenomas occur singly or can be multiple. Multiple (≥10) adenomas may indicate a genetic syndrome such as familial adenomatous polyposis (FAP), attenuated FAP, or MYH-associated polyposis syndrome. 13 Most adenomas are small, measuring less than 10 mm.

Adenomas should be classified histologically based on the pattern of growth as tubular, villous, or tubulovillous following the World Health Organization (WHO) guidelines. 1, 14 Adenomas in which simple tubules make up more than 80% of the area are classified as tubular. Adenomas with greater than 80% of their area showing a villiform configuration are called villous adenomas ( Fig. 23-3) ; all others should be reported as tubulovillous adenomas. 1 Once discovered, adenomas are characteristically removed by endoscopy or surgery because they are an important precursor lesion to colorectal carcinoma. There-fore, it is not surprising that occasionally a resected polyp thought to be a benign adenoma may contain an area of carcinoma.

The various nomenclatures applied to colorectal adenomas, dysplasia, and malignant polyps can be confusing. Unfortunately, no unified accepted guidelines exist. [10] [11] [12] 14 Most surgical pathologists use variations of the 1989 WHO terminology. 11 In this system, the terms dysplasia, adenocarcinoma in situ, intramucosal adenocarcinoma, and invasive adenocarcinoma are accepted. Each has a precise meaning when applied to colorectal polyps and appropriate patient care requires that the endoscopist, surgeon, and surgical pathologist understand the significance of each of these terms.

All adenomas demonstrate at least low-grade epithelial dysplasia. Without dysplasia, an adenoma cannot be recognized and distinguished from normal colonic mucosa. Lowgrade dysplasia is characterized by a slight decrease in the amount of intracellular mucin, mild nuclear enlargement with hyperchromasia, some nuclear stratification, and an increased number of mitotic figures (Fig. 23-4) . Increasing degrees of dysplasia (low-grade to high-grade) show progressive loss of intracellular mucin, progressive increase in nuclear size with stratification, and a loss of nuclear polarity. Adenocarcinoma in situ describes the next step in the dysplasia-carcinoma sequence. Here, the atypical glands assume a complex cribriform or back-to-back gland configuration but the basement membrane remains intact (Fig. . Some experts consider adenocarcinoma in situ as part of the spectrum of high-grade glandular dysplasia and report both under the same term. 12 When carcinoma cells infiltrate into the lamina propria or muscularis mucosae only, terms such as high-grade glandular dysplasia and adenocarcinoma in situ are technically no longer applicable because both require an intact basement membrane. There- fore, the term intramucosal adenocarcinoma is more accurate (Fig. 23-6 ). 1, 11 Finally, when carcinoma cells have invaded the submucosa (or beyond) the lesion is labeled invasive adenocarcinoma. Invasion is invariably associated with an infiltrative pattern to neoplastic glands associated with tumor desmoplasia (Fig. 23-7) . This tumor desmoplasia is extremely helpful in recognizing invasion of at least the submucosa, especially in small biopsy specimens. The nomenclature controversy principally centers on the observation that in the colon and rectum, infiltrating carcinoma cells do not become clinically significant (i.e., able to metastasize) until they have invaded the submucosa. 1, 12, 15, 16 Only polyps containing invasive adenocarcinoma require a decision for additional treatment on the part of the clinician. Adenoma, adenocarcinoma in situ, and even intramucosal adenocarcinoma lack metastatic capability and are considered adequately treated by polypectomy alone. 1, 11, 13, 14, 16 As a result, some pathologists advocate modification of the nomenclature to account for clinical behavior and promulgate use of the term high-grade glandular dysplasia to encompass high-grade dysplasia, adenocarcinoma in situ, and even intramucosal adenocarcinoma. 10, 14 Although the 1989 WHO guidelines accepted and defined two (low-grade, high-grade) or three (mild, moderate, severe) grades of dysplasia, adenocarcinoma in situ, and intramucosal adenocarcinoma, the authors of those guidelines recommended a similar behavior-based modification for intramucosal carcinoma and stated that "… intramucosal adenocarcinoma of the colon has not been shown to metastasize, and for this reason 'carcinoma in situ' is more appropriate." 11 The 2000 version of the WHO classification added little clarification and introduced new and even more confusing terms. 14 The authors stated that the defining feature of colorectal adenocarcinoma is invasion through the muscularis mucosae into the submucosa. However, once defined, worrisome lesions not fulfilling this criterion become difficult to describe. For example, the 2000 WHO classification defines adenocarcinoma in situ and intramucosal adenocarcinoma as lesions with morphologic characteristics of "adenocarcinoma" confined to the epithelium or that "invade" the lamina propria alone and lack invasion through the muscularis mucosae. The WHO goes on to state that these lesions have virtually no risk of metastasis. According to the WHO, the term "… high-grade intraepithelial neoplasia is more appropriate than adenocarcinoma in situ and … intramucosal neoplasia is more appropriate than intramucosal adenocarcinoma." In the 2000 version, the WHO believes that use of these terms will help avoid overtreatment. 14 The problems with this classification are many. The inaccurate use of the term invasion to describe lesions that are not by definition invasive carcinoma is confusing. The lesser lesion of high-grade intraepithelial neoplasia sounds worse than the term used to describe intramucosal adenocarcinoma (intramucosal neoplasia). Furthermore, all adenomas, strictly speaking, are intraepithelial neoplasia. An effort to achieve consensus (largely between Eastern [Japanese] and Western pathologists) [17] [18] [19] [20] resulted in the Vienna classification of gastrointestinal (GI) neoplasia, 20 presented in Table  23-1. Problems with the Vienna system include the following: (1) inaccurate use of the word invasion; (2) category 4 "noninvasive" high-grade neoplasia including potentially dangerous lesions (e.g., suspicious for invasive adenocarcinoma); and (3) category 5 "invasive neoplasms" including intramucosal adenocarcinoma, which is widely accepted to be clinically benign in the colon and rectum. It is unlikely that this system of categories without clinical correlation will ever gain widespread acceptance.

As modified from the 1989 WHO classification, low-grade dysplasia, high-grade dysplasia, adenocarcinoma in situ, and intramucosal adenocarcinoma exist and can be recognized by pathologists. 1, 11 This nomenclature remains attractive because it can be applied throughout the GI tract. If one chooses to diagnose high-grade dysplasia, adenocarcinoma in situ, and intramucosal adenocarcinoma in colorectal biopsy specimens, specific mention in the report that these lesions lack metastatic potential is helpful to clinicians.

Because infiltrating carcinoma cells in a colorectal polyp do not become clinically significant (i.e., able to metastasize) until they have invaded the submucosa, 1,14-16,21-48 only a polyp containing invasive adenocarcinoma (invasion of at least the submucosa) should be considered malignant. Only invasive adenocarcinoma requires a decision regarding additional treatment. Therefore, the presence or absence of invasive adenocarcinoma should be specifically mentioned in the pathology report. To comply with the American College of Gastroenterology (ACG), the U.S. Multi-Society Task Force on Colorectal Cancer, and the American Cancer Society guidelines, 13, 28, 49 a villous component (villous or tubulovillous adenoma) and high-grade dysplasia should be reported because these features require more frequent surveillance. Carcinoma in situ and intramucosal adenocarcinoma can be reported parenthetically as high-grade dysplasia. Most mistakes that pathologists make in reporting colorectal adenomas, dysplasia, and malignant polyps occur in three major categories: (1) the pathology report is not clear (nonspecific or noncommittal terms are used or the presence or absence of invasive adenocarcinoma is not clearly stated); (2) mispositioned glands (pseudocarcinomatous invasion) are misinterpreted as invasive adenocarcinoma; and (3) the margin of excision is either not identified or not discussed.

A common problem concerns differentiating invasive carcinoma complicating a colorectal adenoma from pseudocarcinomatous invasion (pseudoinvasion). Pseudoinvasion describes a situation in which neoplastic glands of the adenoma are mispositioned, presumably by trauma, into or beneath the muscularis mucosae. [50] [51] [52] [53] [54] [55] [56] [57] [58] Pseudoinvasion is relatively common, reported in 3% to 10% of resected colorectal polyps. 50, 52, 53 Distinguishing this epithelial mis- placement from invasive adenocarcinoma can be difficult. Some reported series of "malignant polyps" have included and even illustrated polyps with pseudoinvasion as examples of invasive adenocarcinoma associated with adenoma. 51 Histologic features favoring pseudoinvasion include the lack of an infiltrative pattern, the lack of tumor desmoplasia, the presence of lamina propria around mispositioned glands, the lack of increased atypia in mispositioned epithelium as compared with the surface epithelium of the adenoma, and the presence of hemorrhage or hemosiderin deposits in nearby connective tissue ( Fig. 23-8) .

Occasionally, the misplaced glands of pseudoinvasion can become cystic, can rupture, and can be associated with dissection of mucus into the connective tissues of the polyp. In this case, the distinction between mucinous adenocarcinoma and misplaced glands can be extremely difficult. [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] Table 23 -2 illustrates histologic features that can aid in this differential diagnosis. Examination of additional sections can help in difficult cases because almost all mucinous adenocarcinomas contain at least small foci of typical nonmucinous-type adenocarcinoma.

A rational decision concerning management of a patient with an endoscopically removed malignant colorectal polyp (one containing invasive adenocarcinoma) requires weighing the chances of finding residual or metastatic cancer with a follow-up surgical excision (whom do I help?) against the risk of surgical mortality and morbidity (whom do I hurt?). Some investigators have advocated surgical resection for all patients. 60 Currently, however, almost all surgeons and gastroenterologists embrace a more conservative approach and use certain gross and histologic features as indications for follow-up colectomy. 1, 58 These features include sessile growth, 16, 21 residual villous adenoma, a short stalk (<3 mm), 22 stalk invasion, 23 level 4 invasion, 16, 21 lymphatic or vascular permeation, 44 lack of a residual adjacent adenoma (so-called polypoid carcinoma), poor differentiation, 24, 25, 42, 43 and invasive carcinoma at or near a margin of resection. 24, 25, 42 We and others 24, 25, 29, 42 believe that two features identify patients likely to avoid an adverse outcome defined as residual or metastatic adenocarcinoma in a subsequent colectomy specimen or during clinical follow-up. Patients with favorable histology (defined as well-or moderately differentiated adenocarcinoma with a 2-mm tumor-free margin of resection in the polypectomy specimen) experienced no adverse outcome and are considered adequately treated by polypectomy alone. Similar, although not identical, therapeutic recommendations have been adopted by the ACG. 27, 28 These guidelines consider colonoscopic polypectomy definitive treatment for a patient with a malignant polyp if the following criteria are fulfilled: (1) the polyp is considered completely excised at endoscopy, (2) the specimen is properly processed by the pathology laboratory, (3) the cancer is not poorly differentiated, (4) no histologic evidence of vascular or lymphatic involvement exists, and (5) the resection margin is not involved by carcinoma.

Lymphatic or venous invasion, proposed as an indication for follow-up colectomy, remains controversial. 16, 22, 26, 34, 35, 39, 44, 60 Only a few malignant polyps with these features have been reported and almost all have had positive margins, contained poorly differentiated invasive carcinoma, or both. We think that lymphatic or venous invasion is not a reliable criterion because the distinction from retraction artifact is frequently difficult. Cooper and colleagues 44 encountered significant interobserver variation in assessing this feature. Furthermore, no guidelines exist that establish the extent to which a pathologist must go to diagnose lymphatic or venous invasion (e.g., number of sections or use of immunostains). Although patients can be stratified into high-risk and low-risk groups based on margin status and grade of invasive adenocarcinoma, 42 and lymphatic or 28 and in deference to these guidelines, the presence or absence of angiolymphatic invasion should be reported.

As a guide for therapy, the major studies of endoscopic polypectomy for malignant polyps have shown that the chance of finding residual or metastatic cancer in a subsequent colon resection specimen or during follow-up in the "favorable histology" group is less than 1%. Weighing these odds against the published operative mortality rates for colectomy that range between 2% and 8%, [38] [39] [40] it seems that subsequent major surgical resection should be avoided in the "favorable histology" subgroup. 25, 42 If a decision for subsequent colorectal resection is made, a cancer operation is recommended rather than a more limited procedure because cancer was the indication for surgery. Residual carcinoma in a follow-up resection specimen can be expected in only 10% of cases. These cases of residual or metastatic carcinoma that are discovered within this subset of pT1 lesions are overrepresented by cases containing poorly differentiated carcinoma.

Evaluation of the resection line is critical to proper patient management; therefore, correct handling of the polypec-tomy specimen is of utmost importance. 24, 25, 30, 42 The entire polyp should be immediately placed into fixative. Following adequate fixation, a polyp with a stalk should be trimmed on either side of the stalk as illustrated in Figure 23 -9. The section of the polyp with stalk and margin can be embedded in a block, to maintain the correct anatomic relationship. The remainder of the polyp should be submitted in separate blocks. For polyps without stalks (sessile growths or those in which the stalk has retracted), look for the effect of cautery on the gross specimen. This will appear as a lightercolored area or a defect on the external surface of the polyp. Carefully trim on either side of this defect (Fig. 23-10 ) and place this tissue in a block. Again, the remaining tissue should be submitted in separate blocks. Routine examination of a minimum of three step-sections stained with hematoxylin-eosin (H&E) from each block is recommended.

In the pathology report, the presence or absence of invasive carcinoma must clearly be stated. With malignant polyps, the grade of carcinoma must be noted, the resection line must be identified and assessed, and the status of that resection line must be clearly stated in the pathology report. A distance measurement of carcinoma-free margin should be included in the report. In deference to the ACG, the presence or absence of angiolymphatic invasion should be investigated and reported. 28 The treating physician must individualize the decision for follow-up colorectal excision by weighing the patient's wishes against the estimated cancer recurrence risk and the predicted operative morbidity and mortality. 40 Advances in laparoscopic resection of the colon and rectum could drastically reduce the morbidity and mortality of operative resection that now constitutes the major contraindication for surgery. These newer surgical techniques may require reassessment of the current management recommendations for malignant colorectal polyps. 61

More than 150,000 new cases of colorectal carcinoma occur in the United States each year and account for approximately 52,000 deaths annually. The peak incidence occurs between the ages of 60 and 79 years; fewer than 20% of cancers occur in patients less than 50 years of age. Risk factors for carcinoma include diets rich in animal fat, sedentary lifestyle, and coexisting inflammatory bowel disease (IBD).

At least five separate but overlapping molecular pathways to colorectal cancer may exist. 62 Approximately 80% of colorectal carcinomas occur sporadically, whereas 20% appear to have a genetic basis. 1, 63 The genetic group includes the 3% of cases related to Lynch's syndrome (hereditary nonpolyposis colon cancer syndrome [HNPCC] ) and the 1% associated with FAP and its variants. The other 16% of cases show strong familial clustering but a specific genetic cause has yet to be found. Colorectal carcinoma can also be viewed another way. Approximately 85% of colorectal cancers are thought to originate through the chromosomal instability pathway. These tumors typically demonstrate DNA aneuploidy and have abnormalities of chromosomes 5, 17, and 18 and contain mutational changes in APC gene, K-ras proto-oncogene, DCC tumor suppressor gene, and p53 tumor suppressor gene. 64 FAP colorectal carcinomas arise through this pathway. Approximately 15% of colorectal carcinoma appears to arise in the so-called mutator phenotype. These cancers tend to be DNA diploid and are associated with microsatellite instability (MSI). The cancers related to Lynch's syndrome are associated with the mutator phenotype.

DNA integrity is essential for normal cell function. DNA insults can result from the direct effects of chemicals or radiation and are usually corrected through the excision repair system. DNA replication errors are of two types: (1) simple mispairing of nucleotides, the most common type; and (2) "slipping" errors, in which genes may contain too many or too few copies of repeat short DNA nucleotide sequences known as microsatellites. Normally, these errors are recognized, the cell cycle is arrested, and the mismatched segment is corrected. For those errors not immediately corrected by DNA polymerase, the mismatch repair (MMR) system acts as a backup for additional proofreading of DNA. Failure to repair mismatches allows the error (mutation) to persist and to become the template for subsequent DNA replication. 65 The known MMR genes and their relative frequency in Lynch's syndrome are presented in Table 23-3. MSI is best viewed as an epiphenomenon found in colorectal tumor DNA but not in non-neoplastic tissues. It indicates that extensive mutation exists in the nonencoding repetitive DNA sequences that are particularly prone to replication error, the microsatellites. The majority of MSI is linked to somatic inactivation of hMLH1 through hypermethylation inactivation of the promotor region, but it can also be detected in persons with germline MMR gene mutations, the definition of Lynch's syndrome. 65 MSI is detected in 15% of colorectal cancers overall and is present in more than 95% of the cancers found in patients with Lynch's syndrome.

Because patients with Lynch's syndrome have a germline mutation of an MMR gene, they are at increased lifetime risk for colorectal (≈80%) and other cancers. 63, 66 These cancers develop at significantly younger ages (e.g., average age for colorectal carcinoma ≤44 years). 66 Other tumors related to Lynch's syndrome include cancers of the endometrium, ovary, stomach, biliary tract, urinary tract, kidney, central nervous system, small bowel, and skin. 66 Patients and families with Lynch's syndrome can sometimes be identified by taking a careful patient and family medical history, can be suggested from the pathologic findings of excised tumors, and can be detected by direct evaluation of the MMR system. Pathologic features of colorectal cancer that suggest MSI/Lynch's syndrome include right-sided location, synchronous or metachronous large bowel cancers, large and bulky polypoid tumors with circumscribed pushing margins, tumors showing prominent lymphoid infiltrate, and cancers of poor differentiation (medullary or undifferentiated carcinoma) or mucinous and signet ring cell histologic pattern (Figs. 23-11 and 23-12) . 1, 63, 67 The diagnosis of Lynch's syndrome is evolving. Originally, the Amsterdam criteria were used to identify HNPCC clinically including patients with Lynch's syndrome. 68 The original Amsterdam criteria included (1) three or more relatives with colorectal cancer with at least one first-degree relative, (2) colorectal carcinoma in two generations, and (3) one or more colorectal carcinomas occurring in a person less than 50 years of age. To increase the sensitivity, the Amsterdam criteria were modified (Amsterdam II criteria) to include (1) three or more relatives with any carcinoma related to Lynch's syndrome, (2) colorectal carcinoma in two generations, and (3) and one or more carcinomas related to Lynch's syndrome in a person younger than 50 years of age. 69 Detecting Lynch's syndrome based on the Amsterdam criteria alone poses many problems. Patient histories are less useful now than in the past because of 72 requires than just one of the following criteria be met: (1) colorectal cancer before age 50 years, (2) synchronous or metachronous colorectal or other tumor related to Lynch's syndrome regardless of the patient's age, (3) colorectal cancer with MSI-high pathology (MSI-H) in a patient less than 60 years old, (4) person with colorectal cancer and a first-degree relative with colorectal adenoma or carcinoma or other Lynch's syndrome-related tumor (cancer <50 years; adenoma <40 years), and (5) colorectal cancer with two or more relatives with colorectal or other Lynch's syndrome-related tumor regardless of age.

The American Gastroenterological Association position states that genetic testing should be performed on (1) families meeting Amsterdam criteria, (2) any affected person meeting the modified Bethesda guidelines, and (3) any firstdegree relative of those with known mutations of MMR genes. 63 These guidelines suggest that after pretest genetic counseling and written informed consent, immunohistochemical analysis for MMR gene products or MSI testing by PCR be performed on tumor tissue. The international guidelines for evaluation of MSI by PCR recommend use of consensus markers: BAT25, BAT26, D5S346, D2S123, and D17S250. If two or more markers are abnormal, the carcinoma is considered MSI-H. If one marker is abnormal, the tumor is classified as MSI-low (MSI-L). If no markers are abnormal, the cancer is referred to as MSI-stable (MSS). Laboratories using more than five loci modify this classification with 30% to 40% or more abnormal defined as MSI-H, less than 30% to 40% as MSI-L, and none abnormal as MSS. Immunohistochemistry can be used to detect MSI. Almost all MSI-H cancers can be identified if the antibody panel includes MLH1, MSH2, PMS2, and MSH6 (Figs. 23-13 and 23-14) . 73, 76 Immunohistochemical analysis and MSI analysis by PCR have specific advantages and limitations. PCR requires a molecular laboratory and usually requires normal tissue for comparison. Immunohistochemistry is more widely available but can be limited by poor tissue fixation or poor technique rendering interpretation difficult. Immunohistochemistry may be superior because the findings can direct gene sequencing and MSI is not always seen in Lynch's syndrome kindred with MSH6 germline mutation. 66 Patients with MSI-H cancer should undergo additional genetic testing including gene sequencing. MSS and MSI-L tumors require no further testing. 63 Additional genetic evaluation may be considered if the clinical history is compelling.

The clinical significance of identifying Lynch's syndrome is that affected individuals and at-risk persons are recognized and can be screened and treated with correct surgical procedures. Subtotal colectomy is usually recommended to treat colon cancer related to Lynch's syndrome because of the high likelihood of synchronous or metachronous cancers. Partial colectomy with colonoscopy every 1 to 2 years is a reasonable alternative. 66 Furthermore, clinicians can institute proper screening such as colonoscopy at a young age (beginning at age 25 or 5 years younger than the youngest cancer history in the family), periodic endometrial sampling (every 1 to 2 years starting at age 25 years), pelvic ultrasound, CA125 serum testing, and urine cytology or molecular testing for urinary tract carcinoma. Many experts screen all resected colorectal cancers for MSI initially by PCR. Immunohistochemical analysis is a useful alternative and some prefer this as the initial test because an abnormality in protein expression correlates almost invariably with MSI-H by PCR. In cases showing normal MMR proteins or equivocal staining by immunohistochemical analysis, MSI testing by PCR should be done in clinically suspicious cases to exclude a germline mutation that can yield an antigenic protein that is biologically inactive.

MSI testing in sporadic colorectal carcinoma is a subject of considerable contemporary interest and debate. Much like their counterparts in patients with Lynch's syndrome, sporadic MSI-H carcinomas have a predilection for the right colon, mucinous histologic features, and a prominent lymphoid infiltrate. 77 Strong arguments exist for routine testing for MSI in all resected colorectal carcinomas including the lower mortality rate independent of tumor stage. 78 Sporadic MSI-H cancer can also be associated with an increased rate of metachronous tumors with subsequent clinical implications for cancer surgery, surveillance, and follow-up. MSI status may also have implications for chemotherapy. Improved survival is reported in patients with MSS and MSI-L stage II and stage III cancers who are treated with fluorouracil-based regimens. 79, 80 Finally, routine MSI testing could increase the detection of Lynch's syndrome because 44% of probands were more than 50 years old and up to 22% of patients with Lynch's syndrome did not fulfill Amsterdam or Bethesda guidelines. 76 colorectal serrated polyps and the serrated pathway to colorectal cancer

Hyperplastic polyps are the most common benign polyps of the large intestine. 1, 81 These polyps are usually small (<5 mm), sessile, and are often about the same color as the surrounding colonic mucosa. Histologically, evenly distributed absorptive and goblet cells line crypts that are elongate and dilated (Fig. 23-15 ). Inhibition of normal apoptosis is thought to be the underlying mechanism for polyp formation and because more epithelial cells are present per unit area than normal, the cells must pseudostratify, thus imparting a serrated or micropapillary appearance. Characteristically, the basement membrane under the surface epithelium is thickened and hyalinized. Regenerative epithelial changes, mitotic figures, and active inflammation can be quite prom- 

C D inent at the crypt bases. This regenerative area can occasionally cause diagnostic confusion with dysplasia and carcinoma, especially in a variant referred to as inverted hyperplastic polyp. 82, 83 In this inverted variety, the regenerative epithelium of the crypt base is misplaced into or beneath the muscularis mucosae. Most examples of inverted hyperplastic polyp are now probably best classified as sessile serrated polyp (see later) and are easily recognized if one is cognizant of its existence and also notes the overall architectural and cytologic similarity to hyperplastic polyp/sessile serrated polyp. The entity is distinguished from invasive adenocarcinoma by the lack of infiltration and tumor desmoplasia. The differential diagnosis between hyperplastic polyp and tubular adenoma can be difficult, especially in a diminutive polyp that has been treated by hot biopsy (so-called thermal polyp). Useful features in the differential diagnosis are found in Table 23-4. When the choice between hyperplastic polyp and tubular adenoma is difficult, as long as an adenoma diagnosis is not going to result in surgical resection (e.g., right colonic adenoma incompletely excised), we err on the side of adenoma to ensure that the patient will receive more frequent surveillance. Mixtures of hyperplastic polyp, sessile serrated polyp, and adenoma occur. 84, 85 Mixed polyps and serrated adenomas are considered in more detail later.

Rare examples of patients with colons carpeted by hyperplastic-like polyps (hyperplastic polyposis) have been described ( Fig.  23-16 ). The WHO defines hyperplastic polyposis as (1) 5 or more hyperplastic polyps proximal to the sigmoid colon of which 2 are larger than 1 cm, (2) any number of hyperplastic polyps proximal to the sigmoid colon if the person has a first-degree relative with hyperplastic polyposis, and (3) more than 30 hyperplastic polyps of any size and any Molecular events involved in the serrated polyp family are now recognized. Methylation-induced inactivation of MMR genes occurs in both hyperplastic polyps and carcinoma. As shown in Table 23 -5, methylation inactivation of genes and certain gene mutations (especially BRAF) appear to be involved in the serrated pathway to carcinoma. 99, 100 These molecular events have been verified. [101] [102] [103] [104] [105] [106] Hyperplastic polyps associated with carcinoma have been unusually large and right-sided lesions. They have been reported using numerous synonyms, including giant hyperplastic polyp, sessile serrated adenoma, sessile serrated polyp, inverted hyperplastic polyp, and polyp with epithelial serrated proliferation.

It is becoming clear that several different pathologic entities have been called hyperplastic polyps in the past. This serrated polyp family includes conventional hyperplastic polyp, mixed hyperplastic/sessile serrated polyp/adenoma ( Fig. 23-18 ), serrated adenoma (epithelial dysplasia defined, usually pedunculated and left sided, having eosinophilic cytoplasm and showing gastric foveolar change and often referred to as the traditionally defined serrated adenoma) ( Fig. 23-19) , and hyperplastic-like polyps with unusual features that have been referred to as sessile serrated polyps or sessile serrated adenomas. 84, 91, [93] [94] [95] [96] Sessile serrated polyps appear related to serrated adenomas and mixed polyps and could be the specific precursor lesion to sporadic MSI-H carcinoma. Transitions from sessile serrated polyps to areas of dysplasia and carcinoma with loss of hMLH1 protein expression have been described . 97, 98 Sessile serrated polyps as the name implies are sessile, large (frequently ≥1 cm), right sided, and often show poor endoscopic circumscription. Numerous cytologic and architectural abnormalities have been reported in sessile serrated polyps, especially those associated with carcinoma. 92, 95, 97, 98 The abnormal proliferation or dysmaturation features include persisting nuclear atypia with large nuclei and nucleoli high (upper third) in the crypts, high (upper third of the crypt) mitotic figures, and irregular distribution of dystrophic goblet cells. Architectural abnormalities include basal crypt dilatation, horizontally oriented crypts, crypt branching, an increased epithelial-to-stromal ratio (>50%), inverted crypts, prominent serration, increased surface villosity or papillations, and the lack of a surface basement membrane thickening typical of conventional hyperplastic polyps. Some authors suggest that a diagnosis of sessile serrated polyp requires the presence of at least four of the architectural and abnormal proliferation features mentioned earlier (Figs. 23-21 and 23-22) . 102 Once recognized, the sessile serrated polyp creates a patient management dilemma. Calling them "sessile serrated adenomas" may not be an appropriate default. First and foremost, these lesions do not show the cytologic dysplasia that should be definitional for adenoma. Sessile serrated adenoma is often confused by gastroenterologists and surgeons with serrated adenoma or villous adenoma. It is unknown whether colonic resection (which is typically done for incompletely excised adenomas) should be recommended for sessile serrated polyps that are incompletely excised at endoscopy. Furthermore, endoscopic follow-up for serrated adenoma would typically be in 3 years (if the clinician considers serrated adenoma or sessile serrated adenoma a variant villous adenoma) or in 5 years. In a cohort of 91 patients with sessile serrated polyps preceding MSI-H carcinomas, 19 predated the carcinomas by less than 3 years. 95 We think that these lesions should be diagnosed as sessile serrated polyps and that they should be treated by complete endoscopic excision if possible. Until more is known, a shorter surveillance interval (e.g., 1 to 2 years) rather than resection seems prudent for these types of polyps that are incompletely excised or associated with additional, endoscopically similar polyps that have remained unsampled. [93] [94] [95] [96] 

Colorectal carcinoma occurs more often in men (male-tofemale ratio, 3 : 2), with a median age of 62 years. 1 Most patients present with rectal bleeding, anemia, change in bowel habits, bowel obstruction, or less often perforation. 1 Patients with right-sided colon carcinoma are more likely to present with anemia and fatigue, whereas left-sided car-cinoma is more likely to produce melena, constipation, and change in bowel habits. Approximately half of all large bowel carcinomas occur in the rectum, 25% occur in the sigmoid colon, and the rest are evenly distributed throughout the remainder of the colon. 1 That said, with increased use of colonoscopy with removal of adenomas, clinicians have seen a right-sided migration of carcinomas since the late 1970s. Carcinomas of the right colon tend to produce large, exophytic tumors (see Fig. 23 -11) . Carcinomas of the descending colon are more likely to be stenotic and produce the so-called "napkin ring" tumor. Carcinomas anywhere can be fungating, ulcerated, or necrotic masses; the most common macroscopic appearance is an ulcer with raised, indurated edges (Fig. 23 The following features adversely affect prognosis: advanced stage, extensive local spread, lymph node involvement, aggressive histologic type, high histologic grade, extramural venous invasion, and free mesothelial surface invasion. 1, 67, [107] [108] [109] Although useful information is gleaned through these classic grading and staging exercises, the process is not without problems and controversy. No general agreement exists on staging or grading and all current schemes have shortcomings. [109] [110] [111] Using current systems, most fall into a moderate-stage, moderate-grade category in which the probability of survival is roughly 50/50.

The CAP considered and commented on the multitude of reputed prognostic factors in a consensus statement 67 and concluded that certain factors have been definitively proved to be of prognostic import, including local extent of tumor (pT), regional lymph node metastases (pN), blood or lymphatic vessel invasion, and residual tumor following surgery with curative intent. Other factors that have repeatedly been shown to be of prognostic importance include tumor grade, radial margin status, and residual tumor in specimens following neoadjuvant therapy. 67 The CAP recommends that these additional features should also be included in pathology reports. Although customarily included in pathology reports, parameters such as tumor size and gross configuration have been well studied and are of no prognostic significance. 67 That still leaves an incredibly large group of factors that may be considered prognostic but have not yet been sufficiently studied.

This discussion focuses on controversial areas in classic staging and grading including methods of lymph node dissection and assessment of histologic grade and type. Additionally, the role of flow cytometric analysis, markers of proliferative activity, and other ancillary testing will be examined.

The single most important factor related to patient prognosis is the presence or absence of lymph node metastases. No doubt exists that searching for lymph nodes in a resection specimen is tedious. The lymph node yield per case is directly proportional to the dissector's enthusiasm and skill. As a general rule, a standard resection specimen for carcinoma of the sigmoid colon or rectum should contain 10 to 25 lymph nodes, although we all have had cases in which the dissector found far fewer. Minimum numbers of lymph nodes harvested is increasingly considered a measure of quality. 112, 113 Therefore, the routine use of clearance techniques for lymph node dissection has been debated. Certainly, clearance techniques have advantages. One is likely to find more lymph nodes in a specimen and the lymph node yield will no longer depend solely on the dissector's ability and enthusiasm. However, the clearance process is time consuming and it may delay reporting. 114, 115 Clearing is relatively expensive because of the large volumes of clearing agents used and the prolonged technologists' or pathologists' time. Common clearing agents are often flammable and toxic.

Cawthorn and colleagues 114 showed that clearance techniques increase the yield of lymph nodes per specimen when compared with routine dissection. However, the proportion of stage 1, 2, and 3 cases did not change. The number of positive lymph nodes found was similar between cleared and noncleared groups. This finding was later confirmed. 113 Clearance techniques are considered unnecessary for routine cases. 67, 116 Additional controversy is added by consideration of nontraditional methods of lymph node examination such as the following: immunohistochemical analysis for carcinoembryonic antigen (CEA), cytokeratins, and epithelial membrane antigen; PCR testing looking for tumor DNA or RNA; and sentinel lymph node examination. The biologic significance of these nontraditional methods lacks validation, 67, [117] [118] [119] [120] [121] and "positive" nodes found by these techniques may have no effect on prognosis. 122 Currently, the CAP recommends that all grossly identified lymph nodes be sectioned (without multiple levels) in a routine fashion. 67, 121 Pathologists should find as many lymph nodes as possible and should recognize that the rules of representative sampling and probability apply. 112 As a general rule, 12 negative lymph nodes usually correlate with true pN0 status. 112, 121, 123, 124 Extramural tumor nodules of any size with smooth con- tours are counted as replaced regional lymph nodes. 111 Sentinel lymph node examination does not accurately predict either conventionally defined nodal metastasis or micrometastasis and is not considered useful in the study of patients with colorectal carcinoma. 125 

Pathologists admit that grading is more art than science. Grading is subjective and prone to interobserver and intraobserver variation. One multicenter trial noted 3% welldifferentiated adenocarcinomas from one institution, whereas another hospital reported 97% well-differentiated cases. 111 Marked heterogeneity exists within a given tumor. Some observers grade on the average, whereas others assign a grade corresponding to the least-differentiated area. Many grading systems are used for colorectal carcinoma. 111, [126] [127] [128] [129] [130] [131] [132] All employ slightly different criteria that are poorly defined. Some use three grades and others four. Some exclude mucinous carcinoma altogether and others include it as grade IV or grade III. Criteria for mucinous carcinoma are hardly ever defined.

We follow the guidelines of Dukes and Bussey 132 and use a three-grade system. 1 Well-differentiated adenocarcinoma (grade I), which should account for 10% to 20% of cases, shows tubular differentiation; the nuclear polarity is easily discerned, and nuclei are generally uniform in size . Approximately 70% of adenocarcinomas are moderately differentiated (grade II) exhibiting a more complex and irregular tubular pattern, and the polarity of nuclei is lost or is only barely discernible ( Fig. 23-25 ). The remaining poorly differentiated adenocarcinomas (grade III) consist of highly irregular glands or may show an absence of glandular architecture. Nuclear polarity is lost ( Fig. 23-26 ). When variability exists within a given tumor, the grade is determined by the worst area no matter how small. Mucinous carcinoma and signet ring cell carcinoma are considered poorly differentiated or grade III. 133 Jass and colleagues 111 investigated grading using a Cox regression analysis model in 447 resection specimens. The only grading parameters associated with prognosis were the amount of tubule configuration, the pattern of growth (expanding versus infiltrative), and the degree of lymphocytic infiltration. When stage-related parameters were added into the Cox regression model, only three factors emerged as significant: (1) lymph node involvement, (2) local spread (i.e., the components of stage), and (3) the amount of lymphocytic infiltration in the neoplasm (i.e., a reflection of MSI status). This study provided the scientific verification of the original observation by Dukes and Bussey 132 that grade was subservient to stage in prognosis and re-emphasizes the need for careful specimen dissection and examination to determine the amount of local spread and lymph node status.

Many clinicians believe that mucinous carcinoma and signet ring cell carcinoma are associated with significantly worse prognosis than nonmucinous adenocarcinoma. Unfortu- nately, the definitions of mucinous and signet ring cell carcinoma vary. 1, 67, [134] [135] [136] [137] [138] Work by Sasaki and colleagues 137 and Umpleby and associates 138 verified that mucinous and signet ring cell carcinomas are associated with a worse prognosis, but these tumors manifest at high stage and are associated with extensive local spread.

Sasaki and colleagues 137 scrutinized a large cohort of mucinous, signet ring cell, and nonmucinous carcinomas using a Cox multiple regression model. According to this study, the only significant adverse prognosis-related independent variables were the presence of lymph node metastases and the extent of local spread (i.e., the components of stage), along with an infiltrative growth pattern and minimal lymphocytic infiltration. Sasaki and colleagues 137 and Umpleby and associates 138 concluded that mucinous carcinoma (>75% to 80% by volume) and signet ring cell carcinoma (>50% cells with signet ring morphology) ( Fig.  23-27 ) are more aggressive. These histologic features were not, however, significantly associated with poor prognosis when they were controlled for stage.

Flow cytometry for examination of DNA content in human tumors involves cells or isolated nuclei stained in suspension with a fluorescent dye that binds stoichiometrically with double-stranded DNA. These stained cells or nuclei are then passed one by one through an excitor light source (laser). The amount of fluorescence produced by the bound dye is detectable by a photoelectric cell, and the information is stored electronically. With this technique, thousands of measurements can be made in seconds and displayed on a histogram. The position of peaks on the x-axis is proportional to the amount of DNA per cell, and the height of the peaks on the y-axis is proportional to the number of cells demonstrating a particular DNA content. Using this method, diploid cell populations can be distinguished from nondiploid (including DNA aneuploid) cell populations.

Studies of paraffin-embedded and fresh colorectal carcinoma specimens have demonstrated an inconsistent association between DNA aneuploidy and survival. 134, 139 In at least one of these studies, 139 stage was retained as a strong independent variable associated with prognosis after mul-tiple regression analysis. Other investigators showed no independent association between DNA aneuploidy and prognosis in a large group of patients with colorectal carcinoma, with stage as the only independent variable associated with prognosis. 140 DNA content analysis by flow cytometry is of no proved clinical value. 67 The technology and methods lack standardization, and the results among groups generally are not comparable. Most published studies have employed paraffin-embedded material. This may not be optimal because DNA fragments and partial nuclei tend to stick together, thus leading to increased yields of pseudoaneuploid histograms. 133 The proportion of cases showing aneuploid peaks is lower when fresh intact cells are used. In terms of interpretation, control histograms are easy to read but tumor histograms are less clean and interpretations are subject to interobserver variation. In a cohort of 165 patients with colorectal carcinoma prospectively studied, results of flow cytometric analysis showed no correlation between DNA aneuploidy and any standard staging or grading parameter and had no independent association with prognosis. 133, 141 The CAP believes that DNA analysis has not been adequately studied for determination of prognostic value and the data are insufficient to recommend a specific technologic method. 67 Various proliferation markers have been studied in colorectal carcinoma. For example, a cohort of 122 patients with colorectal carcinoma were studied using an antibody that recognizes Ki-67, a nuclear antigen expressed in all phases of the cell cycle except G 0 . 108 No correlation was found between Ki-67 scores and stage, grade, or prognosis. Stage, growth pattern, and lymphocytic infiltration were the only factors independently associated with prognosis. The CAP believes that data are insufficient to recommend inclusion of proliferation indices in pathology reports for prognostic information. 67 Early Nonpolypoid Colorectal Carcinoma Early invasive colorectal carcinoma (pT1-invasive carcinoma limited to the submucosa) warrants special mention given the advent of endoscopic techniques allowing gastroenterologists and surgeons to resect some carcinomas locally either surgically or through the endoscope (e.g., endoscopic mucosal resection [EMR]). Because lymph node status is the strongest prognostic factor in colorectal carcinoma, the question asked, particularly by surgeons, is whether local excision or EMR is enough or should definitive surgical resection be performed for pT1 lesions. The issue is further complicated by the low rate of lymph node metastases in pT1 colorectal carcinoma, estimated at 3% to 17%. 132, [142] [143] [144] [145] This dilemma prompted evaluation of histologic parameters and molecular markers that correlate with positive lymph node status in excised pT1 colorectal carcinoma.

Features that consistently correlate with positive lymph node status in pT1 colorectal carcinoma include angiolymphatic invasion, poor differentiation, tumor budding (Fig. [23] [24] [25] [26] [27] [28] , and SM3 invasion (invasion of the deepest third of the submucosa). [144] [145] [146] [147] [148] Although various immunostains and molecular markers have not been significantly associated with lymph node status, 144 gene expression profiling could improve the prediction of patients likely to have positive lymph nodes and could improve outcomes. 149 

Cetuximab is a chimeric monoclonal antibody that binds to epidermal growth factor receptor (EGFr). It has clinical significant activity when given alone or in combination with irinotecan in patients with advanced irinotecan-refractory colorectal carcinoma. [150] [151] [152] Approximately 85% of colorectal cancers express EGFr on immunohistochemical analysis but that expression does not correlate with gene amplification. 153 Immunohistochemical analysis for EGFr is sometimes used as a selection criterion for cetuximab. 154 The threshold for positive staining results has been extraordinarily low (1+ staining in >1% of cancer cells) and neither the proportion of positive tumor cells nor the intensity of staining has correlated with clinical response. Some patients who tested negative for EGFr responded to cetuximab and many patients who tested positive did not. Consequently, the National Comprehensive Cancer Network guidelines for colorectal cancer management recommend against using EGFr expression based on immunohistochemical results to select patients for cetuximab therapy. 151, 155 Patients with colorectal cancer bearing mutated K-ras do not benefit from cetuximab. 155a Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF), which is critical in the regulation of angiogenesis. This monoclonal antibody added to fluorouracil-based chemotherapy regimens resulted in significant improvement in patients with advanced colorectal carcinoma. 156, 157 VEGF is expressed in approximately 50% of colorectal carcinomas. 157 Neither microvessel density determination, which is prone to significant methodologic variation, 158 nor VEGF determinations by immunohistochemical analysis were considered a selection criterion.

Before 2000, fluorouracil, a thymidylate synthase inhibitor, was the only effective treatment for advanced colorectal cancer and because leucovorin (folinic acid) enhances the effect by stabilizing the bond between fluorouracil and thymidylate synthase, both agents are often given together. 152, 159, 160 Other cytotoxic drugs such as irinotecan, an inhibitor of topoisomerase I, and oxaliplatin, which distorts DNA by cross-linking into adducts, are now approved for treatment for advanced colorectal carcinoma. 152, 159, 160 Irinotecan has efficacy as a first-line treatment for advanced colorectal cancer but lacks efficacy as adjunct therapy. Irinotecan is hydrolyzed into an active metabolite (SN-38) by hepatic carboxyl esterase. SN-38 is converted into an inactive form by uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1). In patients with polymorphisms of UGT1A1, the toxicities of irinotecan (diarrhea, nausea, vomiting, myelosuppression, alopecia) are more severe. Although results indicate that UGT1A1*28 polymorphisms have some relevance to toxicity, especially hematologic toxicity with the first cycle of chemotherapy, 161 determination of the polymorphism seems to have marginal clinical implications. The observed toxicities can be managed clinically, other UGT1A enzymes may play a role as well, 162 and data do not support dose reduction based on a molecular test.

Cisplatin and its analogues (oxaliplatin) are particularly toxic and molecular markers to identify patients likely to respond have been investigated. Oxaliplatin adducts are repaired by the nucleotide excision repair complex. ERCC1 (excision repair cross-complementation group 1) is 1 of 16 genes that encode proteins of this complex. 163 Polymorphisms that reduce levels of ERCC1 correlate with clinical sensitivity to oxaliplatin 163, 164 and could be used for patient selection.

The medullary variant of colorectal carcinoma occurs predominantly in women and usually occurs in the cecum and right colon. 1, 14 Histologically, it is composed of uniform polygonal cells arranged in a nesting or trabecular pattern with minimal gland formation. Immunohistochemistry is often employed to rule out neuroendocrine carcinoma or melanoma. Other characteristic features of medullary carcinoma include a prominent lymphoid component that can either be peritumoral, often described as Crohn's diseaselike, or intratumoral with tumor-infiltrating lymphocytes (more than five per high-power field; see Figs. 23-11 and 23-12) . 165 Medullary carcinoma is seen with increased frequency in MSI-H colorectal carcinoma whether sporadic or in association with Lynch's syndrome.

Adenosquamous carcinoma, defined by having a malignant glandular and squamous component, occurs rarely as a primary carcinoma in the colon and rectum (Fig. 23-29 ). The possibility of metastasis must always be considered. Adjacent adenoma can help to confirm a primary tumor. Adenosquamous carcinoma has been described in patients with ulcerative colitis (UC), FAP, schistosomiasis, and endometriosis. Occasionally, squamous differentiation can be found in adenomas (Fig. 23-30 ). Pure squamous colorectal carcinoma outside of the anal canal is extremely rare. The possible diagnosis of metastasis must be excluded. Squamous carcinoma has been reported in fistulas, in association with radiation, and in patients with IBD, tuberculosis, and schistosomiasis. 1,14,166 Occasional case reports of microglandular goblet cell adenocarcinoma (goblet cell carcinoid) identical to that seen in the vermiform appendix have been described in the large bowel. These tumors are composed of trabeculae and nests of well-differentiated adenocarcinoma cells showing differentiation toward goblet cells. Scattered or no endocrine differentiation is characteristically seen by immunohistochemical analysis for chromogranin and synaptophysin. Although cytologically bland, these carcinomas are often aggressive in the colon and rectum. 1 carcinosarcoma Carcinosarcoma is often referred to as spindle cell carcinoma or metaplastic carcinoma and can occur rarely in the large bowel. Frequently, a high-grade squamous or glandular component is detected. The mesenchymal component can be undifferentiated or can show striated or smooth muscle differentiation or areas of cartilage or bone. These tumors are associated with a poor prognosis. 1, 167, 168 

Giant cell carcinoma and choriocarcinoma can occur purely or as focal components of an otherwise typical high-grade adenocarcinoma or carcinosarcoma. In choriocarcinoma, the giant cells express beta human chorionic gonadotropin (HCG). Carcinomas with giant cells that fail to stain for beta HCG are referred to as giant cell carcinomas. 1, 169, 170 

Endocrine tumors involving the colon and rectum can be classified into three types based on morphology: (1) carcinoid tumor (well-differentiated neuroendocrine tumor), (2) intermediate-grade neuroendocrine carcinoma, and (3) high-grade neuroendocrine carcinoma, which can be further subdivided into small cell and large cell types. 1, 14 Rightsided endocrine tumors are usually large, whereas rectal endocrine tumors manifest as small polyps, most being solitary and less than 1.0 cm in greatest cross dimension.

Rectal carcinoids are quite common. They most often exhibit hindgut patterns of growth with trabeculae, small acini, and tubular structures that may contain luminal mucin and that must not be confused with goblet cell carcinoid (microglandular goblet cell adenocarcinoma) . Mitoses are rare. The cytoplasm of the carcinoid tumor cells may be clear or eosinophilic and can sometimes appear granular. Nuclei are regular and ovoid and contain granular chromatin. Neuroendocrine differentiation can be proved with immunohistochemical analysis for chromogranin and synaptophysin. Hormonally inactive carcinoids that are less than 2.0 cm in greatest cross dimension without angiolymphatic invasion act in a clinically benign fashion. 1, 171 Intermediate-grade neuroendocrine carcinoma acts more aggressively and is often characterized by angiolymphatic invasion, more frequent mitotic figures, nuclear pleomorphism with open nuclear chromatin, increased apoptotic bodies, and areas of necrosis ( Fig. 23-32 ). 1 Transitions from low-grade to intermediate-grade and high-grade neuroendocrine carcinoma can be observed in rare cases.

High-grade neuroendocrine carcinoma is important to recognize because of its particularly poor prognosis and because of chemotherapeutic considerations. 1, 172 The small cell variant is composed of sheets of densely packed small to intermediate-size cells with dark hyperchromatic nuclei, inconspicuous nucleoli, frequent mitoses, and very little cytoplasm with molding ( Fig. 23-33 ). Foci of squamous and glandular differentiation can be seen in high-grade neuroendocrine carcinoma. Large cell neuroendocrine carci-noma shows an endocrinoid growth pattern but contains larger cells that are round or polygonal and contain more abundant cytoplasm. The nuclei show a coarse chromatin pattern and in contrast to small cell carcinoma are often nucleolated ( Fig. 23-34 ). Large cell carcinoma and small cell carcinoma of the colon and rectum have a poor prognosis.

Virtually any subtype of lymphoma or leukemia can involve the colon and rectum. The reader is directed to the section covering the hematolymphoid system for more detailed discussions of these entities. Use of the WHO classification for tumors of the hematopoietic and lymphoid tissues is recommended. 173 This discussion focuses on the most common lymphoproliferative disorders affecting the colon and rectum.

Approximately one half of extranodal lymphomas involve the GI tract. Diffuse large B-cell lymphoma makes up the majority of these cases and is usually easily identified by the surgical pathologist as malignant. 174 B-cell lineage should be confirmed with CD20 immunostaining. An immunohistochemical panel to rule out undifferentiated carcinoma, melanoma, and high-grade neuroendocrine carcinoma is helpful in practice. Differentiation of germinal center type (better prognosis) from nongerminal center type of diffuse large B-cell lymphoma should be made using immunostains for CD10, bcl-6, and MUM-1. 175 Burkitt's lymphoma and Burkitt-like lymphoma can involve the colon and rectum. 1, 173, 174 These lymphomas are composed of relatively uniform medium-sized cells with coarse chromatin and prominent nucleoli. B-cell lineage should be confirmed with CD20 immunostain and, as described earlier, other high-grade neoplasms should be excluded. Most investigators recommend the workup of Burkitt's and Burkitt-like lymphoma with MIB-1 immuno- staining, which should highlight at least 90% of cells. 174 Burkitt's lymphoma cells also characteristically stain positive for CD10 and bcl-6.

Lymphoid hyperplasia must be distinguished from follicular lymphoma involving the colon and rectum. This is especially true in the setting of low rectal or anorectal lymphoid hyperplasia (so-called anorectal tonsil) and in defunctioned bowel seen in the setting of primary IBD. Localized lymphoid hyperplasia of the anorectal area can manifest with bleeding, prolapse, or anorectal discomfort. The endoscopic appearance can vary from a sessile polyp, which can measure up to 5.0 cm in greatest dimension, to mere thickening of the mucosa resembling cobblestoning. Histologically, one sees lymphoid hyperplasia with germinal center formation and scattered interfollicular collections of pale-staining histiocytes. 1 Distinction from follicular lymphoma can usually be made with standard H&E-stained sections but immunostaining for bcl-2, which is overexpressed in follicular lymphoma because of the t(14;18) translocation, can be an extremely helpful adjunct. Positive bcl-2 staining is seen in neoplastic follicles but not in reactive germinal centers. 174 Up to 40% of cases of multiple lymphomatous polyposis are caused by follicular lymphoma (Fig. 23-35 ). 176 Mantle cell lymphoma usually manifests with widespread lymphadenopathy and frequent bone marrow involvement. Overt GI tract involvement occurs in 10% to 20% of patients and clinically occult disease can affect up to 80% of patients. 177 Colonic involvement can manifest as a mass, a polyp, diffuse mucosal thickening, or multiple lymphomatous polyposis. 1 Approximately one third of patients with lymphomatous polyposis have mantle cell lymphoma. 176 The histologic pattern of mantle cell lymphoma typically shows mucosa and submucosal infiltrates by small atypical lymphocytes surrounding germinal centers with effacement. The lymphoma cells express the B-cell marker CD20 and often coexpress CD5. The t(11;14) translocation causes overexpression of cyclin D-1, which is now considered defining. 173, 174 Extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type can involve the colon and rectum and is responsible for up to 25% of cases manifesting as multiple lymphomatous polyposis. 1, 176 Similar to its appearance in the stomach, colorectal marginal zone B-cell lymphoma of MALT type creates destructive lymphoepithelial lesions and produces an expansive proliferation of marginal zone lymphocytes. An appropriate immunohistochemical profile includes positive staining for pan B-cell markers and negative staining for CD3, CD5, CD10, CD31, and cyclin D-1. Gene rearrangement studies by PCR can be helpful in difficult cases. 1, 173, 174 

Mesenchymal tumors involving the colon and rectum are unusual and include GI stromal tumors (GISTs), true smooth muscle tumors, neural tumors, inflammatory fibroid polyp, fatty tumors, fibrohistiocytic tumors, tumors of skeletal muscle, and vascular lesions (see later). 1 Primary mesenchymal tumors of the colon and rectum must be distinguished from mesenchymal differentiation within a high-grade carcinoma. The reader is directed to the section on soft tissues for more detailed discussions of these entities.

GISTs of the colon and rectum are rare and usually show high-grade features using the National Institutes of Health consensus approach for classification. 178 Approximately 75% of colon and rectum GISTs have shown aggressive clinical behavior. 179 Overexpression of c-kit using CD117 immunostaining must be ascertained, preferably as part of a panel of immunostains that includes CD34, smooth muscle actin, desmin, cytokeratin, S-100 protein, and melan A to verify GIST and to exclude other differential diagnostic possibilities. 180 Schwannoma in the colon and rectum is rare and is usually encountered in the absence of a predisposing condition. Schwannomas are rarely seen in patients who have neurofibromatosis syndrome or multiple endocrine neoplasia type IIB (MEN2B) and must be distinguished from GISTs in that setting. 1, 181, 182 Neurofibromas can manifest as an isolated mass lesion or nodule but are more commonly seen as a diffuse infiltration of the bowel wall in the setting of neurofibromatosis. 1 Care must be taken to distinguish neurofibroma from schwannoma and GIST, which also occur in neurofibromatosis. 1, 183, 184 Granular cell tumor can manifest as a polyp or nodule frequently in the distal rectum and anal canal where it can mimic a hemorrhoid. The tumor is composed of masses of histiocytic-like cells with granular eosinophilic or amphophilic cytoplasm, which can sometimes be spindled . The cytoplasmic granules stain positive on PAS and stain intensely for S-100 protein. 1, 185 True smooth muscle tumors are rare but leiomyomas of the muscularis mucosae are commonly encountered in biopsy specimens. 1 These tumors are usually small, less than 5 mm to 10 mm in greatest cross dimension, and are composed of smooth muscle cells. Atypical mitoses and necrosis typical of leiomyosarcoma are not seen and the reported behavior has been benign. 186 Primary glomus tumors of the colon and rectum are exceptionally rare 187, 188 and can manifest as a polyp or mucosal thickening. Microscopically, these tumors are composed of lobules of small round cells intimately related to vascular spaces and usually show positive immunoreactivity for smooth muscle actin and vimentin. The cases reported so far have acted in a benign fashion.

Lipohyperplasia of the ileocecal valve, which can be accentuated in obese persons, is the most common fatty tumor of the colon. 1, 189 Occasionally, the fat may produce a more localized tumor. Patients are usually asymptomatic and the degree of lipohyperplasia generally correlates with body weight.

Lipomas are frequently encountered during colonoscopy. These tumors are composed of benign adipose tissue. Most are small and asymptomatic but larger ones can bleed, can be subject to trauma or prolapse, cause abdominal pain, and may lead to resection ( Fig. 23-37 ). Lipomas are usually recognized at colonoscopy by their yellow color and pliability (pillow sign). Atypical lipomas and even liposarcoma have rarely been described. 1 Rare examples of malignant fibrous histiocytoma, rhabdoid tumor, and rhabdomyosarcoma have been reported in the large bowel. 1

Numerous classifications for intestinal vascular lesions have been proposed. 190, 191 We find it useful to divide the vascular lesions into two groups, those isolated to the GI tract and those associated with recognized clinical syndromes (Tables 23-6 and 23-7). 1 

Vascular ectasia of the right colon has numerous synonyms, including angiodysplasia, arteriovenous malformation, and the type I lesion of Moore and colleagues. 1, 190, 192, 193 Vascular ectasia of the right colon is a well-defined clinicopathologic entity with a distinct type of lesion and pathogenesis. Patients are typically elderly and present with episodes of recurrent low-grade lower GI bleeding. Approximately 15% of patients present with massive GI hemorrhage. The lesions nearly always manifest in the cecum or right colon and are often multiple. Vascular ectasia of the right colon is usually not associated with other conditions. Reports linking vascular ectasia of the right colon to aortic valvular disease have been criticized. 194, 195 However, bleeding vascular ectasias may be associated with aortic stenosis and associated abnormalities in von Willebrand factor (deficiency of the largest multimers). 196 Colonoscopic and radiographic examination will show almost all lesions. Endoscopically, vascular ectasias appear as erythematous mucosal macules or papules measuring 0.1 mm to 10 mm in diameter ( Fig. 23-38 ). They may be round, oval, or stellate. A "feeding" vessel may be visible. Angiographic signs of vascular ectasia include the densely opacified, slowly emptying vein, an opacified vascular tuft, early opacification (filling) of a draining vein, or, rarely, extravasation of contrast media into the lumen. Vascular ectasia is usually treated primarily by the endoscopist (heat probe or other endoscopic ablation technique) or by the radiologist (vasopressin infusion or transcatheter embolization) at the time of diagnosis. 197, 198 The typical curative surgery, right hemicolectomy, is rarely performed and is often reserved for those cases in which endoscopy or radiography could not be performed or treatment was not successful or for perforative complications of endoscopic or angiographic treatment. Vascular ectasia is notoriously difficult to identify by standard pathologic techniques in resection specimens. Demonstration of the lesion usually requires some form of vascular injection. Boley and Brandt's technique employs injection of the fresh specimen vasculature with a silicon rubber compound. The specimen is then fixed in formalin, dehydrated in graded alcohols, and cleared with methylsalicylate. 192 This technique produces a transparent specimen in which the vasculature can be examined by epi-illumination and transillumination under a dissecting microscope. Using this technique, the vascular ectasias appear as "coral reef-like" arrangements measuring 0.1 cm to 2.0 cm in diameter contrasted against the honeycombed pattern of the normal colonic mucosal vasculature. Histologic examination reveals abnormal thin-walled ectatic veins, venules, and capillaries localized to the mucosa and submucosa. The lesions are thought to result from repetitive partial obstruction to venous drainage caused by contraction of the muscularis propria. Wall tension is directly proportional to lumen diameter, a finding that may explain the lesion's predilection for the right colon, where the diameter is the greatest. Obviously, vascular injection techniques require preparation in terms of materials. If caught unprepared, one may still demonstrate larger ectasias by carefully and gently washing off the mucosal surface of the specimen with water. Sometimes, a blood clot adheres to the bleeding point and this may direct the histologic sectioning. We have been disappointed with injection of contrast media and specimen radiography but have had success demonstrating right-sided vascular ectasia by injecting brightly colored ink into the ileocolic artery. Some investigators have reported success by bluntly dissecting the mucosa from the muscular wall of the formalin-fixed bowel followed by dehydration and transillumination. 199 hemangiomas Many isolated hemangiomas may be classified on the basis of the predominant vessel type as capillary, cavernous, venous, arteriovenous, or mixed. 1 Capillary hemangiomas are typically small, rarely multiple, and composed of small, closely packed capillaries. These lesions may be found in the colon but are usually encountered in the small intestine, appendix, and perianal skin. 200 Some lesions reported as capillary hemangiomas may, in fact, be vascular ectasias (see earlier). Capillary hemangiomas rarely cause clinical symptoms. Cavernous, venous, arteriovenous, and other mixture hemangiomas occur in localized or diffuse forms [201] [202] [203] [204] and have the same clinical significance regardless of vessel type .

Cavernous hemangiomas are composed of blood-filled, sinus-like spaces supported by connective tissue. 191, 201 The stroma occasionally contains smooth muscle. Cavernous hemangiomas can occur in the small bowel but have a predilection for the colon and rectum. Patients may present with symptoms of a mass or with rectal bleeding. Localized cavernous hemangiomas can be treated by excision, fulguration, or sometimes radiation therapy, whereas diffuse forms of hemangiomas may be unresectable and treatment must be directed toward controlling complications.

A lesion composed of abnormal proliferating veins and arteries with evidence of arteriovenous shunting is referred to as an arteriovenous hemangioma. 1 Venous hemangiomas are characterized by large, thick-walled vessels that resemble normal veins but occasionally have more disorganized smooth muscle in their walls. Arteriovenous and venous hemangiomas have the same distribution and significance as cavernous hemangioma. 191 Rare reports have noted tumors composed of admixtures of dilated vascular chan- nels and lymphatics. These tumors can be referred to as hemangiolymphangiomas, lymphaticovenous malformations, or even generically as vascular malformations. 1, 205 These lesions have the same clinical significance as cavernous hemangiomas.

Pure lymphangioma of the large bowel is extremely rare. Depending on size and location, these lesions may be asymptomatic or they may cause pain, diarrhea, or bleeding. 206 Reported size has varied to up to 10 cm. Microscopically the lesions are composed of thin-walled, anastomosing endothelial-lined channels that are bloodless but usually contain eosinophilic material.

The term phlebectasia defines a non-neoplastic venous varicosity. 191 These lesions may occasionally cause severe GI bleeding. The most frequent site of bleeding caused by phlebectasias associated with portal hypertension is the lower esophagus. Other sites have been reported, especially the rectosigmoid colon 207 and rarely the small intestine. 191 We have also seen cases of idiopathic colonic varices in children. Because phlebectasias are encountered rarely, if ever, in surgical specimens, they are not considered further. Hereditary hemorrhagic telangiectasia (HHT) is inherited as an autosomal dominant trait. 191, 208 Two disease-causing genes have been identified, endoglin and ALK-1. 209 Vascular lesions occur in the skin, mucous membranes, and internal organs, including liver, genitourinary tract, meninges, eyes, and spinal cord. The mucocutaneous lesions appear in the second and third decades of life. Many patients present with recurrent epistaxis in childhood. Approximately 15% of patients with HHT, usually older patients, have GI bleeding. The histopathologic pattern of the colorectal lesion is simple dilatation of normal vascular structures (i.e., telangiectasia) and in general resembles the lesions of right-sided vascular ectasia ( Fig. 23-40 ).

Progressive systemic sclerosis can be associated with GI tract telangiectasias. 191, 210 A predilection exists for the stomach, rectum, and colon. Intestinal bleeding develops only rarely.

The blue rubber bleb nevus syndrome can occur as an autosomal dominant trait or in a sporadic form. The characteristic histologic lesion is a cavernous hemangioma that can involve the skin, GI tract, and other viscera. [211] [212] [213] The skin lesion is typically blue and tender and ranges in size from 0.1 cm to 2.0 cm. The lesion empties on digital pressure to leave a wrinkled blue sac that in time refills with blood. The preferred site of involvement in the GI tract is the small intestine but colorectal lesions have been reported.

Turner's syndrome is characterized by numerous somatic abnormalities associated with a 45 XO karyotype. Telangiectasias of the small and large intestine have been described in this disorder and may cause GI bleeding. 214

Klippel-Trenaunay-Weber syndrome occurs sporadically. Patients demonstrate unilateral soft tissue and bony hypertrophy associated with a port-wine hemangioma. GI cavernous hemangiomas have been described in these patients. 191, 215 Pseudoxanthoma elasticum shows marked clinical and genetic variability. 191 Clinically, "plucked-chicken" skin and angiomatoid streaks in the retina have been described. Bleeding in the GI tract may occur from ruptured blood vessels caused by the abnormalities in elastic structure. Patients usually bleed from the stomach. 216 Arteriovenous hemangiomas have also been described. 191, 217 

The term Ehlers-Danlos syndrome describes more than 11 subclasses of metabolic disorders associated with abnormal collagen synthesis. 218 Most patients demonstrate hyperelasticity of skin and joints (i.e., the circus rubber man). Vascular ectasias or proliferative vascular lesions have not been described, but spontaneous arterial or intestinal rupture has been reported in some forms (especially type IV [vascular Ehlers-Danlos syndrome with mutations of COL3A1 gene 219 ]) of Ehlers-Danlos syndrome. [218] [219] [220] [221] [222] [223] [224] 

Kaposi's sarcoma characteristically cause pigmented skin nodules predominantly on the lower extremities. Currently, an aggressive variant of Kaposi's sarcoma in patients with acquired immunodeficiency syndrome (AIDS) is most commonly seen [225] [226] [227] and has been linked to infection with human herpesvirus 8. 228 The GI tract of patients with AIDS is frequently involved by Kaposi's sarcoma. 227 Investigators have estimated that about half of the patients with cutaneous or lymph node Kaposi's sarcoma have concomitant GI tract involvement. [229] [230] [231] Rarely, the GI tract can be involved without skin lesions. GI tract Kaposi's sarcoma is typically asymptomatic but occasional GI Kaposi's sarcoma can cause bleeding, obstruction, perforation, or protein-losing enteropathy. 1, 232 GI Kaposi's sarcoma has numerous appearances grossly and endoscopically. 1 Although red macules have been described, Kaposi's sarcoma more characteristically causes a red or purple nodule or plaque measuring 15 mm or more. 229 Some patients with GI Kaposi's sarcoma have large tumors. Despite the vascular nature of the neoplasm, lesions can be sampled for biopsy and in most instances bleed surprisingly little. The diagnostic yield with biopsy has been notoriously low 227 ; in one report, only 13% of upper GI specimens and 36% of sigmoidoscopic specimens tested positive. 229 Usually, the low yield is attributed to the preferential submucosal location of Kaposi's sarcoma that may not be sampled in an endoscopic biopsy specimen. That said, examples of Kaposi's sarcoma are easily overlooked by even experienced pathologists, because the sarcoma is subtle and can be dismissed as granulation tissue.

In positive biopsy specimens, Kaposi's sarcoma typically causes an expansion of lamina propria by a spindle cell proliferation that may not be very atypical. The spindle cells are usually not extremely mitotically active and at first glance may suggest granulation tissue (although macrophages and mononuclear inflammatory cells are typically absent) or the fibromuscular obliteration of the lamina propria associated with the solitary rectal ulcer syndrome (prolapse or trauma-related change). Generally, GI Kaposi's sarcoma is histologically similar to Kaposi's sarcoma seen elsewhere. 227 The histologic pattern shows spindle cells, vascular clefts, extravasated red blood cells frequently associated with hemosiderin deposits, and occasionally tumor necrosis ( Fig. 23-41 ). Kaposi's sarcoma cells usually stain with antibodies directed against factor VIII-related antigen but more consistently stain positive with endothelial markers such as CD34 and CD31.

As mentioned earlier, the changes are subtle and diagnosis can be difficult. Important clues to the proper diagnosis include (1) knowledge of the clinical situation, (2) knowledge of the endoscopic appearance, (3) recognition of crowding and hyperchromasia in the spindle cell nuclei, (4) recognition of slits and spaces containing red blood cells, and (5) recognition of the tendency for Kaposi's sarcoma cells to overrun or obliterate the muscularis mucosae. 1 Aggressive antiretroviral therapy is now considered the first-line treatment for GI Kaposi's sarcoma. 233, 234 Other forms of treatment are reserved for symptomatic tumors. 232 Surgical procedures are performed for obstruction or severe bleeding. Chemotherapy approaches have improved but the treatment is risky in an already immunocompromised patient. These therapies offer palliation at best. Treatment with zidovudine (formerly azidothymidine [AZT]) does not have an effect on GI Kaposi's sarcoma. 235, 236 Immunomodulation has been tested but is not used. 232, 237, 238 The addition of taxanes (paclitaxel and docetaxel) to aggressive antiretroviral therapy appears promising. 239, 240 Angiosarcoma Angiosarcomas are only rarely encountered in the colon and rectum. 241 The varied histologic spectrum ranges from wellformed vascular structures to sheets of malignant polygonal or spindle cells. Grossly and endoscopically, angiosarcomas form red-gray polypoid masses. An immunohistochemical panel including CD31 and factor VIII-antigen can be useful in diagnosis.

The term Dieulafoy's lesion refers to an inappropriately large artery located directly beneath the mucosa where it can erode and cause profuse bleeding. Although typically described in the stomach, similar lesions are found in the colon and rectum. 242

Metastatic neoplasia to the colon and rectum come principally from the lung, breast, ovary, and skin (melanoma). 1 Advanced prostate carcinoma can cause confusion with primary rectal carcinoma or with neuroendocrine carcinoma. Sometimes perirectal lymph node metastases in resections performed for colorectal carcinoma contain metastatic deposits from prostate carcinoma.

FAP is inherited as an autosomal dominant trait. Bussey recognized that 100 or more colorectal adenomas (recognized grossly) phenotypically identified patients with FAP and distinguished them from patients with multiple adenomas in whom inheritance was not seen. 243, 244 In typical FAP, hundreds to thousands of adenomas develop within the colon ( Fig. 23-42 ). The adenomas begin to appear in the second or third decades of life and are surprisingly asymptomatic considering their usually large numbers. Symptom-atic patients present with signs and symptoms of increased bowel motility and the passage of blood or mucus, or both, which often heralds the onset of carcinoma. The average age of patients with colon cancer and FAP is 39 years. 66 Two thirds of patients with these so-called propositus cases present with carcinoma and nearly one half of them have more than one carcinoma in the colon. This high risk of invasive cancer in symptomatic patients forms the basis for polyposis registries and the extensive screening of asymptomatic kindred at risk for FAP.

Screening recommendations have evolved with increased genetic information. Genetic testing should be considered for FAP, attenuated FAP, and mutY homologue (MYH)-associated polyposis (MAP) when 10 or more colorectal adenomas are found in a patient during a single examination or over time. 66 Screening of first-degree relatives of affected individuals should begin at the age of 10 years. 63 In the absence of genetic testing, endoscopic screening is still useful to detect FAP. All affected patients have adenomas within the range of a flexible sigmoidoscope. It is therefore recommended that screening sigmoidoscopy begin at age 14 years with re-examination every 2 years. The diagnosis of FAP must be confirmed with biopsy because lymphoid polyposis and hyperplastic polyposis can mimic FAP grossly and endoscopically. Once a diagnosis of FAP has been established, prophylactic proctocolectomy is recommended. Most investigators recommend sigmoidoscopy for mutation-negative kindred at age 12 years just in case the genetic test is erroneous. Thyroid examination for associated thyroid lesions (usually papillary carcinoma with cribriform pattern 245 ) and determination of serum alpha fetoprotein (to screen for hepatoblastoma) are recommended.

Regular upper endoscopy should also be performed. Gastric and duodenal polyps develop in 30% to 90% of patients with FAP. 246 The gastric lesions are usually fundic gland polyposis, whereas the duodenal polyps are usually adenomas. The fundic gland polyps can develop a peculiar surface epithelial atypia called foveolar dysplasia, 247 but progression to carcinoma is extremely rare. 229 The incidence of duodenal adenomas in FAP increases with increasing age. Duodenal adenomas have a propensity to develop in the periampullary region. Adenomas anywhere in the GI tract can proceed through the dysplasia-carcinoma sequence. The relative risk of duodenal or periampullary carcinoma in patients with FAP is approximately 125 to 350 times that seen in the general population, and duodenal or periampullary carcinoma has become the major cause of morbidity and mortality in patients with FAP in the post-prophylactic colectomy era. 248 The gene responsible for FAP (APC gene) has been localized to the long arm of chromosome 5 (5q21-q22) and has been cloned. [249] [250] [251] [252] [253] Some APC gene mutation-negative cases may be caused by mutation of MYH (see later). 254 Mutation in most patients with FAP creates a stop codon resulting in a truncated protein product. The APC gene is a tumor suppressor gene and the APC protein is part of the Wntsignaling pathway 66, 255 involved in cell growth control. When the APC gene is mutated, beta-catenin accumulates, thus altering expression of certain genes affecting proliferation, differentiation, migration, and apoptosis. 256 Most patients are now diagnosed by DNA sequencing, which has largely replaced the assay to detect the truncated APC protein (PTT). 63, 256 Monoallelic mutation analysis (MAMA) examines the two APC alleles independently and can detect more than 95% of patients with FAP. Another test, multiplex ligation-dependent probe amplification (MLPA), is useful in detecting large deletions. 256 More than 700 disease-causing APC gene mutations have been reported. 256 Localization of mutations within the APC gene locus correlates with phenotype. For example, germline mutations between codon 1250 and codon 1464 are associated with very large numbers of colonic adenomas, whereas mutations elsewhere, especially near the 5′ end or the 3′ end of the APC gene and an area of exon 9, yield lesser numbers of colonic adenomas (see the later discussion of attenuated FAP). 63, [256] [257] [258] In Gardner's variant, in addition to colonic adenomas and upper GI polyps, patients can exhibit extraintestinal manifestations such as osteomas, epidermal inclusion cysts and other benign skin tumors, desmoid tumors of the abdomen or abdominal wall, fibrosis of mesentery, dental abnormalities, carcinoma of the periampullary region or duodenum, and carcinoma of the thyroid. Patients with Gardner's syndrome have APC gene mutations; however, no particular APC mutation distinguishes FAP from Gardner's variant. Even within a "Gardner's family," Gardner's stigmata can be variably expressed and can skip generations. 253 Therefore, some unknown disease-modifying factors are required for phenotypic expression of the extraintestinal manifestations.

Turcot's syndrome has been the subject of some controversy. In many investigators' zeal to publish, the phenotypic spectrum has been unduly broad with colonic manifestations ranging from a single adenoma to a virtual carpeting of the colonic mucosa with polyps. Furthermore, the brain tumors have comprised almost every histologic type. Molecular studies done on 14 families with Turcot's syndrome have clarified the situation. 259 Families with Turcot's syndrome and germline mutations of the APC gene have a typical FAP colonic phenotype and develop medulloblastomas. Other patients originally thought to have Turcot's syndrome have mutations in the DNA MMR genes that are characteristic of Lynch's syndrome. The brain tumors in this group have varied, with many reported as glioblastoma.

Mutations of the APC gene near the 5′ end and 3′ end and in a particular region of exon 9 66 result in fewer adenomas (<100; average, 30), a tendency for the adenomas to be macroscopically flat, and a propensity for these adenomas to cluster in the right colon. Originally reported as hereditary flat adenoma syndrome, this form is now more accurately referred to as attenuated FAP (AFAP). 63, 258 As in typical FAP, these patients can develop fundic gland polyposis, duodenal adenomas, and periampullary carcinoma. The risk of colorectal carcinoma is increased in these patients albeit to a lesser degree than in the other form of FAP and the cancers tend to occur later in life (average age, 49 years).

Inherited variants of a base-excision repair gene MYH have been associated with colorectal polyposis with an autosomal recessive mode of inheritance. 254, 260, 261 Some cases phenotypically resemble FAP or attenuated FAP and are referred to as MYH polyposis or MAP. 254 Of those patients with a phenotype typical of FAP or suspected AFAP in whom an APC gene mutation is not found, 10% to 20% will have mutation of the MYH gene. 66 Approximately 80% of affected persons have one of two specific MYH mutations (Y165C or G382D). If one is found, then sequencing is done to find the mutation on the other allele because MAP is biallelic. 66 These patients should be treated and followed similarly to patients with FAP.

Juvenile polyps can occur in a sporadic form or can be part of juvenile polyposis syndrome. In the sporadic form, juvenile polyps have their peak prevalence in children between 1 and 7 years of age. Some evidence indicates that juvenile polyps once formed can regress; they can certainly be seen in adults. Sporadic juvenile polyps typically occur singly but patients can have up to five, usually located in the rectum. Juvenile polyps typically range in size up to 2 cm and can be associated with overt prolapse (Fig. 23-43 ). 262 Because these polyps are often attached by a small pedicle, they are prone to autoamputation. Histologically, typical juvenile polyps consist of a hamartomatous overgrowth of the lamina propria accompanied by elongation and cystic dilatation of colonic crypts lined by nondysplastic colonic epithelium ( Fig. 23-44 ). 66 Osseous and cartilaginous stromal metaplasia can occur ( Fig. 23-45 ). The inflammatory component of juvenile polyps can be quite prominent with neutrophils and lymphoid follicles within the lamina propria. Frequently, the distinction between juvenile polyps and inflammatory polyps of primary IBD cannot be made on histologic grounds alone and requires clinical correlation. Nonsyndromatic juvenile polyps appear to have no malignant potential. 263 Juvenile polyposis syndrome can be familial or nonfamilial and usually becomes clinically apparent within the first decade of life with painless rectal bleeding, prolapse, iron deficiency anemia, or passage of an autoamputated polyp. 244 Patients are considered to have juvenile polyposis syndrome if they have six or more juvenile polyps in the colon and rectum, have juvenile polyps throughout the GI tract, or have any number of juvenile polyps in association with a positive family history. 262, 264 In the nonfamilial forms of juvenile polyposis syndrome (≈30% of the total), patients frequently have associated abnormalities, such as cardiac defects, hydrocephalus, gut malrotation, undescended testes, and skull abnormalities. 244 Patients with the familial forms usually lack these extraintestinal manifestations. Inheritance has varied although almost all are considered autosomal dominant with variable penetrance. 244 Familial forms of juvenile polyposis syndrome appear to be associated with an increased risk of colorectal carcinoma. 264 Prophylactic colectomy may be prudent in juvenile polyposis syndrome. Patients may also have an increased risk of gastric, small intestinal, and pancreatic carcinoma. 265 Juvenile polyposis syndrome coexisting with HHT (Osler-Weber-Rendu syndrome) is rarely reported. 265 The number of polyps in juvenile polyposis syndrome typically ranges from a few dozen to several hundred ( Fig.  23-46) . Phenotypically, juvenile polyposis syndrome appears to occur in three varieties: (1) polyps limited to the colon, (2) polyps limited to the stomach, and (3) polyps throughout the entire GI tract. [266] [267] [268] The mucosal polyps found in the context of juvenile polyposis syndromes are often unusual histologically. In addition to the typical juvenile polyps described earlier, one can find juvenile polyps with atypical features such as more epithelium than lamina propria. In addition, mixture polyps (juvenile polyps with areas of adenoma or dysplasia) are quite frequent. 244 265, [271] [272] [273] seen in 25% of cases. One should consider genetic testing for juvenile polyposis syndrome when three or more juvenile polyps have occurred in one individual or when juvenile polyps are found outside the colon. 66 MADH4 and BMPR1A are both components of the signaling pathway for transforming growth factor-b and the bone morphogenetic proteins. Patients with MADH4 gene mutation are more likely to have gastric juvenile polyposis. 265, 274, 275 Juvenile polyps can be found in patients with other hamartomatous syndromes of the colon, such as intestinal ganglioneuromatosis or ganglioneurofibromatosis (see later), [276] [277] [278] although some of these syndromes are now best classified as PTEN (phosphatase and tensin homologue) syndrome (see later).

Patients can sometimes be managed with endoscopy and polypectomy (every 1 to 3 years); however, colectomy must be considered for patients with large numbers of polyps or polyps with dysplasia or for patients with complications (e.g., bleeding, obstruction). Screening colonoscopy every 3 years should commence with symptoms or in the early teenage years in an asymptomatic patient. 66, 279 Upper endoscopy is also recommended in patients with juvenile polyposis syndrome. Esophagogastroduodenoscopy and small bowel examination (every 2 years) should begin at age 15 years. 66, 279 Ruvalcaba-Myhre-Smith Syndrome (Bannayan-Zonana Syndrome,

Ruvalcaba-Myhre-Smith syndrome consists of macrocephaly, mental deficiency, unusual craniofacial appearance, pseudopapilledema, pigmented macules on the penis, and hamartomatous polyps in the GI tract. The syndrome appears to be passed on as an autosomal dominant condition. 280 The GI polyps have been indistinguishable from juvenile polyps and in rare instances intestinal ganglioneuromatosis has also been described. The syndrome has been linked to mutations or deletions in the PTEN gene (10q23.3) 267, 271, 281 and with Cowden's syndrome and can be considered as one of the PTEN polyposis syndromes. 265

Peutz-Jeghers polyps can be found throughout the GI tract, either sporadically or as part of the Peutz-Jeghers syndrome. 1, 282, 283 The polyp itself is characterized by fairly normal epithelium and lamina propria lining an abnormal arborizing network of smooth muscle that represents hamartomatous overgrowth of the muscularis mucosae ( Fig.  23-47 ). 1, 282, 284 Peutz-Jeghers syndrome, usually inherited as an autosomal dominant trait, is the combination of skin hyperpigmentation and Peutz-Jeghers polyps in the GI tract. The diagnosis of Peutz-Jeghers syndrome is considered definitive if the patient has a Peutz-Jeghers polyp and at least two of the following criteria: (1) family history, (2) mucocutaneous hyperpigmentation, and (3) small bowel polyposis. 265, 283 The pigmentation consists of clusters of brown or black freckles about the lips, buccal mucosa, and perianal and genital region. Pigmented areas can occasionally be seen on the fingers and toes. The spots appear in the first year of life and tend to fade toward middle age. The polyps usually number only in the dozens and can be found throughout the GI tract. These polyps have a propensity to form in the small intestine where they often cause intussusception. In rare kindred, Peutz-Jeghers polyps have been limited to the large bowel. Cases of complicating GI carcinoma have been reported. 285, 286 Approximately 5% of female patients with Peutz-Jeghers syndrome have a peculiar ovarian tumor, sex cord tumor with annular tubules (SCTAT). 287 The rate of detection may increase if the ovaries are carefully examined, 287, 288 and some tumors may be associated with sexual precocity. 289 Male patients with Peutz-Jeghers syndrome occasionally have unilateral or bilateral Sertoli cell tumors of the testes. 290, 291 Adenoma malignum and pancreaticobiliary tract carcinomas are reported to occur at increased rates. 292 The Peutz-Jeghers syndrome has been linked to the STK11 (serine/threonine-protein kinase 11, also known as LKB1) gene on chromosome 19p13.3 [293] [294] [295] [296] and can be demonstrated in 70% of cases. 265 This is a tumor suppressor gene involved in transduction of intracellular growth signals. 66 Investigators have suggested that genetic testing be considered for Peutz-Jeghers syndrome when any Peutz-Jeghers polyps or typical perioral pigmentations are found. 66 Meta-analysis of cancer risk in an evaluation of patients with known mutations of the STK11 gene have shown increased lifetime risk for cancer of the esophagus, stomach, small bowel, colon, pancreas, and breast. 283, 297 Putting this into perspective, the risk for breast cancer in Peutz-Jeghers syndrome is similar to the risk seen in individuals with germline mutations of BRCA1 and BRCA2 and Peutz-Jeghers syndrome is the strongest known risk factor for pancreatic carcinoma except for hereditary pancreatitis. 283 Screening at-risk individuals (first-degree relatives of a patient with Peutz-Jeghers syndrome) should begin at birth with an annual history and physical examination to look specifically for melanotic spots, precocious puberty, and testicular tumors. Asymptomatic at-risk individuals without stigmata by age 8 years should be tested for STK11/LKB1 gene mutations. If mutation is not found in the family, small intestinal contrast radiography every 2 years until age 25 years is recommended. Other investigators suggest that upper and lower endoscopy with small bowel series should be done at ages 12, 18, and 24 years. 283 Esophagogastroduodenoscopy and upper GI radiographic series with small bowel follow through are recommended in patients with Peutz-Jeghers syndrome commencing at age 8 years and repeated every 2 years thereafter. 283, 298 Colonoscopy every 3 years is recommended starting with symptoms or by age 18 years if symptoms have not occurred. 66, 283 Testicular examination, pelvic examination by age 20 years, mammographic examination by age 25 years, and endoscopic ultrasound examination of the pancreas by age 25 to 30 years have been recommended. 229, 283 Annual transvaginal ultrasound examination and serum CA-125 determination are also recommended commencing at age 25 years. 283

Intestinal ganglioneuromatosis is defined as proliferation of ganglion cells, neurites, and supporting cells that can affect any layer of the GI wall ( Fig. 23-48 ). 280 These proliferations often manifest as mucosal polyps in the colon. Although these lesions most often occur as an isolated phenomenon, the importance of intestinal polypoid ganglioneuromatosis is in recognizing the other settings in which it can occur, such as von Recklinghausen's disease (NF1 gene mutation), MEN2B (RET gene mutation), Cowden's syndrome (PTEN mutation), Ruvalcaba-Myhre-Smith syndrome (PTEN mutation), and tuberous sclerosis (TSC1 [9q34] or TSC2 [16p13] mutation). [299] [300] [301] [302] [303] Intestinal ganglioneuromatosis can coexist with juvenile polyps although these patients may be better classified as having PTEN polyposis. [276] [277] [278] 

Cowden's syndrome describes an autosomal dominant multiple hamartoma syndrome in which patients have multiple orocutaneous hamartomas (e.g., facial trichilemmomas, mucosal papillomas, acral keratosis, subcutaneous lipomas), fibrocystic disease of the breast, an increased risk of breast carcinoma, thyroid abnormalities, and hamartomatous polyps in the stomach, small intestine, and colon. Polyps of the GI tract, when described, often have shown an abnormal proliferation of the smooth muscle in the lamina propria and generally have resembled the polypoid variant of solitary rectal ulcer syndrome. 304 Some juvenile polyp-like proliferations have been described. 265 Intestinal ganglioneuromatosis has also been reported. 302 Other associated abnormalities include macrocephaly, high arched palate, hypoplastic mandible and maxilla, microstomia, supernumerary nipples, pectus excavatum, hemangiomas, ovarian cysts, and uterine leiomyomas. 265, 303 The gene (PTEN) for Cowden's disease has been mapped to chromosome 10 (10q22-23). 272, 305, 306 Cowden's syndrome and Ruvalcaba-Myhre-Smith syndrome are sometimes referred to as the PTEN polyposis syndromes. Genetic testing is suggested when features of this syndrome are present. 66 Esophagogastroduodenoscopy and small bowel examination every 2 years beginning at age 15 years is recommended. 66

Cronkhite-Canada syndrome is an acquired nonfamilial syndrome characterized by intestinal polyposis, dystrophic changes of the fingernails, alopecia, and cutaneous hyperpigmentation. 307, 308 Patients first present with diarrhea, abdominal pain, and anorexia that progresses to weight loss and protein-losing enteropathy. Many patients complain of loss of taste (hypogeusia) and loss of smell. As a rule, the ectodermal changes occur weeks to months after the other symptoms. The nail dystrophy consists of thinning, splitting, and separation from the nail bed (onycholysis). Onychomadesis (complete loss of the nail) can also occur. The hair loss is rapid and may be seen in the scalp, eyebrow, face, axilla, or pubic region. The cutaneous hyperpigmentation ranges from small macules to confluent areas of hyperpigmentation that can be 10 cm or more. Histologically, the pigmented macules result from increased melanin in the basal layer.

Cronkhite-Canada polyps are found throughout the GI tract but are most commonly seen in the stomach and large bowel. Grossly, they are sessile; a few are pedunculated. The polyps tend to occur on a background of diffuse mucosal thickening ( Fig. 23-49) . Histologically, the polyps themselves are identical to juvenile polyps. However, the mucosa between polyps is abnormal and shows edema, congestion, and inflammation (chronic inflammation often with prominent eosinophils) of the lamina propria coupled with glandular ectasia (Fig. 23-50) . Carcinomas of the colon and stomach have been described rarely in patients with Cronkhite-Canada syndrome. The malabsorption in this syndrome is usually progressive and with no specific therapy available, the prognosis is generally poor. Death results from anemia, septic shock, bleeding, or postoperative complications. Treatment consists of supportive therapy, antibiotics, corticosteroids, and surgery. Within the stomach, Cronkhite-Canada syndrome closely mimics Ménétrier's disease. Ménétrier's disease, however, is confined to the stomach and has no associated ectodermal changes.

Heterotopic gastric, pancreatic, sebaceous, and salivary gland tissues have been described in the colon and rectum. These ectopic tissues can be found throughout the GI tract but are most often seen in the rectum where they can cause a plaque, polyp, or mass ( Fig. 23-51 ). [309] [310] [311] 

Inflammatory fibroid polyp is most commonly found in the stomach but can be encountered throughout the GI tract including the colon and rectum. 1,312-314 Symptoms include abdominal pain and bleeding. The polyp is usually solitary. It can be sessile or pedunculated and typically has a solid pale tan cut surface.

Microscopically one sees a loose myxoid fibrous tissue background containing regularly distributed blood vessels, some of which show hyalin change in their walls. The fibrous tissue can layer in a whorl-like fashion around these vessels in an onion-skin pattern. Most lesions are rich in inflammatory cells including plasma cells and eosinophils ( Fig. 23-52) . Scattered macrophages and Touton-type giant cells can also be seen. The stroma in most lesions is positive for CD34 but negative for CD117. Mutations in plateletderived growth factor receptor alpha gene have been described. 314a The mucosa overlying these typically submucosal tumors can be ulcerated, presumably by trauma, and can show areas of inflamed granulation tissue. The ulcerated surface can contain bizarre stromal cells, which are also seen in a variety of inflammatory polyps with chronic ulceration (e.g., IBD, trauma or prolapse, and radiation injury). The inflammatory fibroid polyp is benign and typically does not recur.

Malakoplakia, an abnormal immune response to gramnegative bacteria, can cause a tumor or polyp in any site of the GI tract, including the large bowel. Histologically, it is characterized by xanthogranulomatous inflammation accompanied by the pathognomonic Michaelis-Gutmann body (Fig. 23-53 ). 1 The partially digested bacteria accumulate in macrophages and lead to deposition of calcium and iron on the residual bacterial glycolipids. 315 An association between colorectal malakoplakia and colorectal neoplasia may exist. 315

Defined as the presence of endometrial glands or stroma usually with hemorrhage and hemosiderin deposits in an extrauterine location, endometriosis tends to affect sites closest to the female genital tract such as the sigmoid colon and rectum. 1 Symptoms include episodic abdominal pain. Hematochezia can occur with mucosal involvement. Endometriosis usually involves the serosa and muscularis externa and can cause smooth muscle proliferation and stricture. Mucosal and submucosal involvement can cause mucosal polyps. 316 Endometriosis must be distinguished from müllerian adenosarcoma and endometrial stromal sarcoma. The glandular component can be confused with colitis cystica profunda and adenocarcinoma. Immunohistochemical analysis for CD10, which highlights endometrial stromal cells, can be helpful in the differential diagnosis as can recognition of ciliated epithelial cells. Differential cytokeratin immunostaining can also help because endometriosis commonly stains positive for CK7, whereas colorectal epithelium usually expresses CK20. Examples of malignant transformation (mostly endometrioid carcinoma and clear cell carcinoma) in endometriosis have been reported. 316

Injection of materials containing lipid bases into the lower rectum and anus can cause a mass or polyp referred to as an oleogranuloma. The lesion is composed of lipidcontaining cysts surrounded by a foreign body giant cell reaction. 1

Benign fibroblastic polyps and perineurioma have been described in the colon and rectum where they may represent the same or a similar lesion. 317-319 These mucosal polyps are usually solitary but can be multiple and have been reported throughout the GI tract, most commonly in the colon and rectum. Histologically, these polyps contain proliferations of small tightly packed spindle cells within the lamina propria that often orient themselves parallel to the muscularis mucosae. This lesion frequently coexists with hyperplastic polyp-like epithelial proliferations, and indeed the polyp could represent a trauma-related change seen in the otherwise typical hyperplastic polyp or sessile serrated polyp ( Fig. 23-54) . The spindle cells test negative for immunoreactive S-100 protein and other neuromarkers; they can express immunoreactive epithelial membrane antigen by immunohistochemical analysis.

Areas of increased elastin fibers in the submucosa and muscularis mucosae are referred to as elastosis or elastofibromatous change and can cause polyps in the colon and rectum. Histologically, the elastosis appears as finely granular or fibrillar amphophilic material usually with a fibrous component and is often centered around prominent blood vessels (Fig. 23-55) . The change could also be a manifestation of mucosal trauma or prolapse. Elastosis can be confused with amyloid deposits but results of Congo red stains have been negative. 320 

Benign spindle cell proliferations that express immunoreactive S-100 protein can manifest as mucosal polyps in the colon and rectum and are usually termed mucosal neuromas 1 or Schwann cell hamartomas. Care must be taken not to overlook ganglion cells, which would indicate a ganglioneuroma. These lesions can be seen in patients with neurofibromatosis but most occur sporadically and are unassociated with syndromes. 321 

With increased availability of total colonoscopy and flexible sigmoidoscopy, pathologists can expect an ever-increasing number of colorectal biopsy specimens. The pathologist plays a critical role in the diagnosis and management of patients with colitis and suspected colitis.

When evaluating a colorectal biopsy specimen, it is useful to scan the tissue at low magnification and ask several questions. Are abnormalities present? If present, are the changes diffuse or focal? Is the luminal border of the specimen straight or irregular? Is intraepithelial mucin (the goblet cell population) preserved or depleted? If intracellular mucin is depleted, is this change focal or diffuse? Are inflammatory cells increased in the lamina propria or epithelium? Is this increase diffuse or focal? What kind of inflammatory cells are they? Is the lamina propria obliterated by fibrous or fibromuscular tissue? Are crypt abscesses present? Are colonic tubules straight? Do the colonic tubules reach the muscularis mucosae or are they short, branched, or budded? With careful consideration of the features outlined earlier, one can often recognize a pattern of abnormality that when coupled with clinical and endoscopic information can lead to a fairly specific diagnosis in a large number of patients.

The following patterns of inflammation can be identified in mucosal biopsy specimens: chronic colitis, diffuse active colitis, focal active colitis, ischemic-type injury, traumarelated change, apoptotic colopathy, and intraepithelial lymphocytosis. Identification of an inflammation pattern can be helpful in assessing patients by creating a clinically relevant differential diagnosis.

Quiescent UC best typifies the chronic colitis pattern of injury. The predominant features are mucosal atrophy and architectural distortion (Fig. 23-56) . [322] [323] [324] [325] The luminal border is often irregular and the number of crypts decreased. The remaining crypts typically appear short (i.e., they do not touch the muscularis mucosae), they lose their parallel arrangement, and they become branched and budded. The goblet cell population is usually preserved. Chronic inflammatory cells including plasma cells are increased in the lamina propria. Paneth cells may be present. The muscularis mucosae is usually hypertrophied. The foregoing changes, although consistent with a diagnosis of chronic UC, must be interpreted in light of the clinical, radiologic, and endoscopic findings because similar changes can be seen in focal, healed, or healing areas of other chronic colitides such as Crohn's disease, ischemia, chronic irradiation injury, tuberculosis, and schistosomiasis.

Care must be taken when interpreting biopsy specimens obtained from the normal mucosa adjacent to lymphoid follicles, from normal mucosa containing the innominate groove, and from the lower portion of the rectum near the transition zone. These areas normally show some loss of crypt parallelism and should not be misinterpreted as evidence of chronic colitis. 2, 7 Conversely, histologically normal biopsy specimens must not be reported as showing "chronic nonspecific inflammation" consistent with UC. Unless one or more of the features discussed in the preceding para- graph are also present, it is a good rule not to diagnose primary IBD based only on an evaluation of inflammatory cells within the lamina propria.

The term active colitis describes inflammatory conditions in which neutrophils are present within the lamina propria, within epithelial cells (cryptitis), or within the lumen of crypts (crypt abscesses). Included under this heading are UC in an active phase, most examples of Crohn's disease, and infectious colitis or acute self-limited colitis. 326, 327 UC in an active phase represents the prototype diffuse active colitis. Biopsy specimens usually demonstrate diffuse abnormalities, meaning that changes are of approximately the same intensity in all areas of the tissue submitted from a particular region of the colon. The luminal border of the mucosa is irregular. [323] [324] [325] [326] [327] [328] [329] Increased numbers of chronic inflammatory cells are present in the lamina propria and may occasionally spill over into the superficial portion of the submucosa. Intracellular mucin in goblet cells is diffusely depleted. 330 Cryptitis and crypt abscess formation are often prominent (Fig. 23-57 ). It is surprising that even in UC of extremely short overt clinical duration, atrophy, branching, and budding of crypts are already apparent in many specimens. 7, [324] [325] [326] [327] [328] [329] This crypt distortion coupled with basal plasmacytosis, which is defined as increased plasma cells in the lower fifth of the mucosa, has been proposed as the most useful histologic criterion to differentiate primary IBD from infectious colitis or acute self-limited colitis. 323, [326] [327] [328] Remember, the most a pathologist can conclude from a biopsy specimen showing this pattern of injury is that the changes are consistent with UC in an active phase. The diffuse active colitis pattern of injury can also be seen in some examples of Crohn's disease 324, 328 and in some cases of documented infectious colitis, 331 although we think it is likely that these cases represent an infectious exacerbation of an underlying, albeit clinically latent, primary IBD. The diffuse active colitis pattern of injury has been reported in a form of colitis associated with diverticular disease. 332 However, this entity can be distinguished from classic UC by virtue of its rectal sparing and the presence of inflammation only in areas of diverticula.

The focal active colitis pattern of injury refers to the patchy distribution of architectural or acute inflammatory change in mucosal biopsy specimens. Chronic colitis showing diffuse chronic changes as described earlier, coupled with patchy acute inflammation, is not considered focal active colitis but is classified as chronic colitis showing mild activity. The focal active colitis pattern consists of limited areas of increased inflammatory cells sometimes coupled with focal minimal architectural distortion (Fig. 23-58) . Characteristically, some areas of the biopsy specimen from a region of the colon must maintain an essentially normal appearance. The focal active colitis pattern of injury is usually not seen with UC and when present suggests Crohn's disease, 7, 333, 334 injury related to nonsteroidal anti-inflammatory drugs (NSAIDs), or infectious colitis or acute self-limited colitis (see later). 7, 323, 327, 330, 334, 335 The focal active colitis pattern of injury, however, can be seen in resolving UC under active medical management. 330, 336 Areas previously involved in the colon and rectum in UC can return to an almost normal histologic appearance with therapy.

Granulomas typically found in Crohn's disease should be sought in all biopsy specimens, but especially those showing the focal active pattern. Although serial sectioning of biopsy specimens is advocated by some investigators for the detection of granulomas, 337 in our experience, granulomas are rarely missed. That said, germinal centers, tangential cuts of blood vessels, tangential cuts of the pericryptal fibroblastic sheath, and an inflammatory reaction to extravasated mucin (so-called mucin granulomas) are often misinterpreted as the granulomas of Crohn's disease. In the absence of true granulomas, biopsy specimens from patients with Crohn's disease often show the focal active colitis pattern of injury without neutrophils in the lamina propria. Some examples of Crohn's colitis can be indistinguishable from resolving mucosal UC in biopsy specimens. 323, 328 A fibrinopurulent exudate in the specimen overlying but separate from the mucosa is always abnormal. The clinician should be informed that ulcers are likely to be present in a more proximal location in the bowel. On a practical note, all inflammatory exudates should be examined under high magnification for trophozoites of Entamoeba histolytica, because this is their preferred location and these organisms are easy to overlook.

The definitive classification of colonic inflammation depends on clinical pathologic correlation. In our opinion, the task of the pathologist is to convey the histologic pattern of injury to the clinician who then collates that information with the clinical history and data obtained from endoscopic, radiologic, and laboratory examination.

Antineutrophil cytoplasmic antibodies (ANCAs) have been identified in patients with IBD. [338] [339] [340] The immunofluorescence pattern (perinuclear) differs from the diffuse cytoplasmic reaction detected in patients with Wegener's granulomatosis. Although initially thought to be specific for UC, ANCAs more likely reflect inflammatory conditions involving the colon. In one study, up to 70% of patients with presumed UC had ANCA positivity with a 46% prevalence in patients with colonic Crohn's disease and a 5% prevalence in patients with infectious-type colitis. 328 Another antibody, anti-Saccharomyces cerevisiae antibody (ASCA), has been closely linked to Crohn's disease. ASCAs can be identified in up to 60% to 70% of patients with Crohn's disease, as opposed to 10% to 15% in UC and 5% of controls. 341, 342 Some investigators have proposed the use of ANCA and ASCA together to increase specificity. 343 These tests clinically have demonstrated low sensitivity (≈50% to 60%) but have been reported to be highly disease specific. These tests may have value in classification of indeterminate colitis but this remains to be proved. 344 

The following histologic appearances have been described in culture-proved or toxin-proved infectious colitis: normal colon, nonspecific increases in chronic inflammatory cells, the diffuse active colitis pattern of injury 331 (although these likely represent infectious exacerbations of an underlying primary IBD), ischemic-like changes, 345, 346 and the focal active colitis pattern of injury. Although colonic mucosal biopsy appearance in infectious colitis can vary greatly, many specimens have the focal active colitis pattern. In general, invasive organisms cause greater changes in morphology than those producing their effects by toxins.

Histologic evaluation, although helpful in suggesting infection and ruling out primary IBD, can only rarely suggest a specific cause. The definitive diagnosis of infectious colitis requires laboratory identification of the serologic features of the offending organism.

Even after extensive microbiologic workup, a subset of patients presumed clinically to have infectious colitis will experience spontaneous recovery in less than 6 months and will have biopsy specimens that demonstrate the focal active colitis pattern of injury without an identifiable infectious cause. The term acute self-limited colitis has been used to describe such patients. [326] [327] [328] 330 We prefer the term infectious-type colitis to acute self-limited colitis because some examples of acute self-limited colitis may not be self-limited. 7 Other investigators prefer the term nonrelapsing colitis. 327, 329 the ischemic pattern

The characteristic pattern of acute ischemic-type injury consists of hemorrhage into the lamina propria associated with superficial epithelial coagulative necrosis, with relative sparing of the deep portions of the crypts (Fig. 23-59) . 3, 346, 347 These changes can occasionally be associated with more extensive necrosis of epithelium with inflammatory pseudomembrane formation. Surprisingly, acute and chronic inflammatory cells, especially plasma cells, are typically scant in ischemic-type damage and this feature can help differentiate ischemic-type damage from primary IBD.

The differential diagnosis of ischemic-type damage is wide and includes all causes of true ischemia such as inadequate perfusion, narrowing of blood vessels, obstructing lesions of the bowel, and bowel distention. Ischemictype change is also associated with a variety of drugs, including vasopressors, oral contraceptives, NSAIDs, cocaine, and glutaraldehyde, which is sometimes used to clean endoscopes. [348] [349] [350] [351] Some infectious agents typically cause ischemic-type damage, including cytomegalovirus (CMV), Clostridium difficile, Clostridium septicum, and the enterohemorrhagic Escherichia coli (EHEC). 346

Trauma-type histologic changes frequently coexist clinically with mucosal ulcers or erosions. The characteristic traumatype histologic pattern is found in the mucosa adjacent to ulcers or in polypoid mucosa areas and consists of fibro- muscular proliferation within the lamina propria associated with mucosal architectural distortion and intramucosal capillary ectasia (Fig. 23-60 ). [352] [353] [354] [355] The trauma-type histologic features can be seen in the solitary rectal ulcer syndrome, localized colitis cystica profunda, inflammatory cloacogenic polyp, the mucosa adjacent to orifices of colonic diverticula, 356 and inflammatory cap polyposis 357 and are frequent findings adjacent to neoplasia and in the vicinity of the ileocecal valve. 358

Surface colonic epithelial apoptosis and karyorrhectic debris within the superficial lamina propria are commonly seen in mucosal biopsy specimens and are widely attributed to bowel preparation. Apoptotic bodies in the deep crypt are only rarely seen (<1 per 20 crypts) outside of pathologic conditions. Increased deep apoptotic bodies can be seen in ischemic-type damage, CMV infection, chemotherapy or radiation, and in association with mycophenolate mofetil (CellCept) (Fig. 23-61 ). 359 Although associated with a variety of injurious agents, apoptosis is the characteristic form of cell death in cell-mediated immune cytotoxicity as demonstrated in graft-versus-host disease (GVHD), 360 other immune deficiency syndromes 361, 362 and thymic neoplasia. 363 Many patients with AIDS with diarrhea demonstrate deep apoptosis in the absence of pathogens, a finding suggesting that primary immune-mediated apoptotic colopathy may cause some of the diarrhea and wasting seen in AIDS. 364, 365 intraepithelial lymphocytosis

The term collagenous colitis, first coined by Lindström in 1976, 366 describes a distinct clinicopathologic syndrome causing watery diarrhea, predominantly in middle-aged or older (mean age, 59 years) women (male-to-female ratio, 1 : 7.5). 367, 368 Results of colonoscopic and barium enema examination in these patients are usually normal. Therefore, diagnosis depends on recognition of characteristic changes in biopsy specimens. The primary histologic change of collagenous colitis consists of a patchy increase in the thickness of the subepithelial collagen plate (Fig. 23-62) . 367, 368 The normal colonic epithelial collagen layer measures approximately 5 µm in thickness, but in collagenous colitis it may increase to 10 µm or more. We use 15 µm as a morphologic cutoff point for collagenous colitis. A mild to moderate increase in chronic inflammatory cells including plasma cells and eosinophils expands the lamina propria. Patchy injury to the surface epithelium characterized by increased numbers of intraepithelial lymphocytes, epithelial degeneration, and sloughing also occur. Atrophy, mucosal architectural distortion, and acute inflammation are usually not present or are minimal. 367, 369, 370 Read and colleagues 371 introduced the term microscopic colitis to describe patients with chronic watery diarrhea of unknown origin occurring in middle-aged (mean, 54 years) patients. As in collagenous colitis, the colonoscopic appearance and the barium enema were usually described as normal. Biopsy specimens demonstrated increased inflammatory cells in a pattern not specific for any established entity. 371 Since this initial report, investigators have refined the clinical and especially the histologic diagnostic criteria of lymphocytic colitis. 370, 372 The histologic changes include increased chronic inflammatory cells in the lamina propria and surface epithelium, degenerative changes of the surface epithelium, minimal architectural change, and minimal acute inflammation (Fig. 23-63) . The changes of lymphocytic colitis in general resemble the surface epithelial and lamina propria changes of collagenous colitis, and indeed changes identical to lymphocytic colitis are seen in biopsy specimens from patients with collagenous colitis when areas where the collagen plate is not well developed are sampled.

The similarities between lymphocytic colitis and collagenous colitis are striking. They share similar symptoms and endoscopic findings. The histologic similarities include increased intraepithelial lymphocytes, surface epithelial damage, and increased chronic inflammatory cells within the lamina propria. 369, 370, 373 Both collagenous colitis and lymphocytic colitis can be associated with other autoimmune phenomena such as thyroid disease, enteropathic arthritis, rheumatoid arthritis, myasthenia gravis, and celiac sprue. 374, 375 Some cases of lymphocytic colitis demonstrate thickening of the subepithelial collagen plate, and distinguishing lymphocytic colitis from collagenous colitis may not be so clear-cut in all cases. 373 It appears likely that lymphocytic colitis and collagenous colitis are either the same or very similar conditions, perhaps representing different morphologic phases of one disease process. 370, 374 Some minor differences between lymphocytic colitis and collagenous colitis deserve mention, however. Collagenous colitis has been reported predominantly in women, whereas lymphocytic colitis affects men and women equally. 370, 376 Differences in human leukocyte antigen (HLA) haplotypes between collagenous colitis and lymphocytic colitis have been described. 376 Finally, collagenous colitis and lymphocytic colitis differ histologically with the presence of the thickened collagen plate.

Lymphocytic colitis and collagenous colitis are associated with net fluid secretion in the colon that is responsible for the diarrhea. 377 Several investigators could find no association between the thickness and extent of the collagen plate and the amount of diarrhea. 373 Therefore, most investigators conclude the damage to the surface epithelial cells and the inflammation, rather than the collagen deposits, cause diarrhea. The presence and thickness of the subepithelial collagen plate appear unrelated to the patient's age or the duration of disease. 373 Some patients have also demonstrated evidence of small bowel dysfunction such as salt wasting, fatty acid malabsorption, small bowel net secretion, and rarely a small bowel villous lesion that resembles celiac sprue (see later). 376 

Spontaneous resolution of collagenous and lymphocytic colitis has occurred, thus rendering evaluation of therapeutic regimens difficult. 378 A few patients with these colitides have presented with relatively mild diarrhea and have achieved medical control with dietary restriction (elimination of caffeine and lactose-containing foods), bulking agents, and antimotility drugs (loperamide hydrochloride, diphenoxylate hydrochloride, atropine). A trial of bismuth compounds is worthwhile. Many times, symptomatic therapy has failed, thus necessitating the addition of antiinflammatory agents. Approximately 80% to 90% of patients eventually respond to therapy with sulfasalazine, prednisone, or budesonide. 368, 378, 379 Etiology and Pathogenesis NSAIDs and ticlopidine have been linked to some occurrences of collagenous colitis, 380, 381 and lymphocytic colitis has been reported in patients receiving Ruscus extract (Cyclo 3 Fort), 382 ranitidine, 383 ticlopidine, and flutamide. 381 However, most cases cannot be linked to drug ingestion and the bulk of the evidence suggests that lymphocytic and collagenous colitis share common immune-mediated etiology and pathogenesis. Both conditions have a striking histologic similarity to celiac sprue, a condition known to be autoimmune and possibly having a viral or infectious trigger. 370 In addition, both lymphocytic and collagenous colitis have been linked to other conditions thought to have autoimmune pathogenesis such as Crohn's disease, hypothyroidism, hyperthyroidism, inflammatory arthropathies, pernicious anemia, small bowel villous atrophy, iritis, diabetes mellitus, and myasthenia gravis. 374, 384, 385 Both conditions respond dramatically to anti-inflammatory agents. 378, 379 The finding of "lymphocytic colitis-like" histologic features reported in an epidemic outbreak of Brainerd diarrhea linked to a water tank aboard a cruise ship supports an infectious trigger for some cases of lymphocytic colitis (see later).

The association between lymphocytic colitis or collagenous colitis and celiac sprue and spruelike lesions deserves special attention. In the experience of DuBois and associates 386 and Wolber and colleagues, 387 approximately 25% of patients with "celiac sprue" who had colonic biopsies also showed changes of lymphocytic colitis. Colonic microscopic abnormalities in patients with celiac sprue occur after experimental exposure to wheat or gliadin enemas, a finding suggesting that the entire intestinal tract may be susceptible to gluten-induced injury. It is possible that in some patients with true celiac sprue (responsive to gluten withdrawal), occult dietary gluten reaches the colon and induces the histologic changes of lymphocytic colitis. However, approximately one half of the patients with spruelike small bowel lesions and lymphocytic colitis have not responded to gluten withdrawal. The term lymphocytic enterocolitis has been coined to describe this refractory spruelike condition associated with colonic intraepithelial lymphocytosis. 386 

As more cases are investigated, it is not unusual to see variations in histologic pattern commingled with the classic changes of lymphocytic and collagenous colitis. These variations include architectural change, cryptitis, Paneth cell metaplasia, ulcers, and inflammatory membranes. [388] [389] [390] [391] Approximately one third of patients demonstrate cryptitis. Rarely, one encounters inflammatory pseudomembranes. Neither histologic pattern correlates strongly with infection. Approximately 2% of patients have ulcers, and architectural abnormalities have been reported in 5% of patients. Paneth cell metaplasia is seen in 14% to 44% of patients, most often in collagenous colitis in which it may correlate with increased severity of diarrhea. Acute inflammation is seen with increased frequency in patients taking antibiotics. Ulcers have been linked with concomitant NSAID usage. Some investigators have suggested that the "stiff" colon seen in collagenous colitis could be at increased risk for the development of ulcers and perforation during colonoscopy. 388 Other variants with subepithelial giant cells have been described (Fig. 23-64 ). 392 Histologic features, aberrant or otherwise, do not seem to correlate with symptoms, results of medical treatment, or outcome. 393 No patient with unusual histologic features, including architectural change and Paneth cell metaplasia, has yet to develop primary IBD (e.g., Crohn's disease or UC).

The term Brainerd diarrhea has been applied to outbreaks of diarrhea of unknown origin characterized by acute onset and prolonged duration. 394 The disease was named after Brainerd, Minnesota, where in 1984 122 residents developed watery diarrhea after drinking unpasteurized milk. A second outbreak occurred in Henderson County, Illinois in 1987, when 72 people developed watery diarrhea associated with drinking contaminated well water at a roadside restaurant. In each outbreak, patients underwent extensive diagnostic evaluations including comprehensive microbiologic studies of their stool and the implicated exposure site. Despite the workup, no causative agent was identified. The clinical and epidemiologic characteristics were typical of point-source epidemic infectious diarrhea. However, unlike in typical infectious diarrhea, these patients developed a chronic watery diarrhea syndrome with symptoms lasting longer than 6 months and often lasting for years.

In general, the small bowel biopsy specimens from patients with Brainerd diarrhea were histologically normal. Colonic biopsy specimens revealed surface epithelial lymphocytosis without distortion of mucosal architecture, surface degenerative changes, or thickened subepithelial collagen plate. The degree of surface epithelial lymphocytosis was similar to that seen in cases of collagenous and lymphocytic colitis. 370, 394, 395 Many experts believe that patients with the clinical syndrome of chronic watery diarrhea of unknown origin and patients reported as having lymphocytic colitis represent a heterogeneous group that may contain persons with unrecognized Brainerd diarrhea. With long-term follow-up, cases of Brainerd diarrhea appear to be self-limited, and patients recover in less than 3 years. From a practical standpoint, surface epithelial lymphocyte counts should be performed on all colonic biopsy specimens from patients with chronic diarrhea, especially chronic watery diarrhea. Currently, Brainerd diarrhea cannot be recognized outside the setting of an epidemic.

The solitary rectal ulcer syndrome, localized colitis cystica profunda, inflammatory cloacogenic polyp, prolapsing mucosal folds in areas of diverticular disease, and inflammatory cap polyposis are closely allied conditions that have been linked to large bowel mucosal prolapse and trauma. [352] [353] [354] [355] [356] [396] [397] [398] [399] [400] Affected patients with solitary rectal ulcer, localized colitis cystica profunda, and inflammatory cloacogenic polyp often demonstrate abnormal function of the anal and pelvic floor musculature during defecation 352,401,402 that leads to rectal mucosal prolapse or even intussusception. The resulting trauma is thought to cause the clinical symptoms and the pathologic changes. The term solitary rectal ulcer syndrome is quite a misnomer because the ulcers are often multiple, a preulcer polypoid phase is reported, and similar lesions occur in the anal canal and proximal colon. 352, 356, 396, 397 The terms colitis cystica profunda and inflammatory cloacogenic polyp are also misnomers. Because all three conditions share a common histologic appearance, clinical presentation, clinical course, and pathogenesis, we prefer to consider them together under the heading mucosal prolapse syndromes.

Patients with mucosal prolapse syndrome range in age from 10 to 83 years with the majority presenting in the third and fourth decades of life. The condition occurs more commonly in women. All patients report difficulties in defecation. Other common symptoms include rectal bleeding, passage of mucus, anal and abdominal pain, and intermittent bowel habits in which periods of constipation interrupt bouts of loose stools. Furthermore, surprising numbers of patients admit to the use of digital manipulation, spoons, or other instruments to assist in rectal evacuation.

The diagnosis of mucosal prolapse syndromes can be difficult because the history often suggests primary inflammatory or ischemic bowel disease. In addition, mucosal prolapse is often covert requiring special techniques such as evacuation cine proctography and defecography to demonstrate abnormalities in these patients. 352, 356, 401, 403 Ulcers, when present, typically occur on the anterior or anterolateral wall of the rectum, are irregular in shape, and often appear well demarcated. In patients without ulceration, the mucosa appears polypoid, roughened, or erythematous. Inflammatory cloacogenic polyp 398,399 involves the lower rectum and anal transition zone. The clinical impression in patients with mucosal prolapse syndromes is often incorrect and includes ulcer, Crohn's disease, nonspecific proctitis, carcinoma, and villous adenoma. 355 The characteristic histopathologic changes are found in the mucosa adjacent to the ulcers or in the polypoid areas and consist of fibromuscular obliteration of the lamina propria associated with mucosal architectural distortion often with a hyperplastic or villiform appearance (see Fig.  23 -60). [352] [353] [354] [355] 397 Inflammation is typically mild or absent and mucosal capillaries can be ectatic. Superficial erosions occasionally occur and can be associated with acute inflammation and the formation of inflammatory pseudomembranes. On occasion, colonic glands may be misplaced into the muscularis mucosae or submucosa, a histologic pattern referred to as localized colitis cystica profunda. Submucosal vessels may also be ectatic and hyalinized. The histologic features of specimens obtained from ulcerated areas appear nonspecific and usually show fibrinopurulent debris, fibrosis, and granulation tissue.

Differential diagnostic considerations include mucinous adenocarcinoma, chronic UC, Cowden's disease, and ulcers resulting from ergotamine suppositories. The misplaced glands of mucosal prolapse syndrome (colitis cystica profunda) simulate pseudoinvasion seen in adenomas; these glands can be associated with dissecting mucous pools and easily can be mistaken for invasive mucinous adenocarcinoma. Table 23 -2 illustrates histologic features that aid in this differential diagnosis.

The mucosal abnormalities of mucosal prolapse syndrome also closely mimic chronic UC. Knowledge of the clinical picture and recognition of the characteristic fibromuscular obliteration of the lamina propria (not usually present in IBD) are helpful in this distinction. The histologic appearance of colorectal polyps from patients with Cowden's disease appears identical to the histologic features seen in mucosal prolapse syndrome. 304 Mucosal prolapse syndrome and Cowden's disease must be separated on clin-ical grounds. Clinical history is also required to separate the rectal ulcers associated with the use of ergotamine suppositories from mucosal prolapse. These lesions can be grossly and microscopically identical to those seen in mucosal prolapse syndrome. 404 The few studies with long-term follow-up report a chronic, stable appearance to the lesions. 352, 396, 405 Most patients with mucosal prolapse syndrome tolerate their symptoms following reassurance that they do not have cancer, the addition of fiber to the diet, and instruction to reduce straining and to avoid digital manipulation. The rare patient with severe bleeding or obstruction requires excisional therapy. Medical remedies such as sulfasalazine, local or systemic corticosteroids, and antibiotics are useless. 352, 355, 396 Unusual patients with severe, incapacitating symptoms have been treated by resection, diverting colostomy, or rectal prolapse repair. Results of these operations have varied and because approximately 100 different operations have been described for mucosal prolapse syndrome, comparisons are difficult.

Inflammatory conditions of the colon can be caused by specific agents or conditions, such as bacteria or ischemia, or can be nonspecific. After specific causes of colitis have been ruled out, one is left with a group of diseases referred to as nonspecific or primary IBD. These include UC, Crohn's disease, and IBD type indeterminate (unclassified colitis). In most cases, careful examination of gross and microscopic features will allow categorization of these nonspecific IBDs into either UC or Crohn's disease. 406 Approximately 10% of cases will cause significant differential diagnostic problems by illustrating ambiguous features. These cases are best classified as IBD type indeterminate (see later).

Evolving surgical techniques have changed the pathologist's role in the analysis of IBD. Patients with UC have several surgical options that either create continence through ileostomy (Kock ileostomy) or preserve anal sphincter function and restore continuity to the bowel (ileal pouch-anal anastomosis). [406] [407] [408] These operations have in common the creation of a pouch or reservoir formed by interconnecting loops of terminal ilium. In general, these pouch procedures are contraindicated in patients with Crohn's disease because of increased morbidity such as fistula and abscess. 409 Furthermore, complications requiring pouch removal can result in loss of considerable lengths of small bowel, sometimes enough to cause short-bowel syndrome. In our experience, there is nothing quite like a pouch to bring out the Crohn's disease in someone. These cases highlight the limitations of the current pathologic classification especially in the setting of fulminant clinical disease.

Accurate pathologic diagnosis of colonic IBD contributes greatly to patient care. In patients who have had subtotal colectomy, relaxed and thorough pathologic examination of the colectomy specimen to rule out Crohn's disease is pos-sible. A staged resection of the large bowel is still the safest and most advisable approach for patients with severe or fulminant colitis, even though it requires an additional operation to remove the rectum and a period with a temporary ileostomy. Although pathologic assessment and interpretation are more difficult in fulminant disease, the two-stage procedure still allows for a complete examination of the colectomy specimen before any contemplated pouch construction with ileal-anal anastomosis. Some surgeons do not consider two-stage proctocolectomy necessary for selected patients with colonic IBD. The one-stage operative approach therefore requires accurate preoperative diagnosis and emphasizes the importance of clinical evaluation, radiologic examination, endoscopic analysis, and proper interpretation of mucosal biopsy specimens (see earlier). 406 Pouch complications include inflammation, fistula, obstruction, incontinence, and anastomotic leaks. 406, 407 Although many complications result from surgical and mechanical difficulties, and others relate to the development of "primary" inflammation in the pouch (see "Pouchitis," later), some of these complications represent pouch recurrence of initially unrecognized Crohn's disease. These cases illustrate the inability to differentiate UC from Crohn's disease reliably in severe colitis, even after thorough examination of the colectomy specimen. 410 All reports of surgical experience with ileal pouch-anal anastomosis for presumed UC contain approximately 2% to 7% of patients in whom the final diagnosis proves to be Crohn's disease. 406, [409] [410] [411] [412] We recommend use of a three-tiered classification system for primary IBD in colon resection specimens: UC, Crohn's disease, and IBD of indeterminate type. The definitive diagnosis of UC requires all the following features: diffuse disease limited to the large intestine, involvement of the rectum, more proximal colonic disease occurring in continuity with an involved rectum (i.e., no gross or histologic skip lesions), the absence of deep fissural ulcers, the absence of mural sinuses, and the absence of transmural lymphoid aggregates or granulomas (Fig. 23-65) . 406, 413, 414 The definitive diagnosis of Crohn's disease requires histologic verification with the demonstration of transmural lymphoid aggregates in an area not deeply ulcerated or the presence of non-necrotizing granulomas (Figs. 23-66 and 23-67). 406, [413] [414] [415] [416] When the gross and clinical features suggest Crohn's disease by the presence of skip lesions, linear ulcers, cobblestoning, fat wrapping, or terminal ileal inflammation, extensive histologic sampling to find the definitive histologic features of Crohn's disease is suggested (Fig. 23-68) .

The term primary IBD of an indeterminate type is used for cases of idiopathic colonic IBD that have ambiguous pathologic features in the resection specimen and are inconclusive for a diagnosis of UC or Crohn's disease. 406, 410, [413] [414] [415] [416] [417] [418] The classification system has prognostic significance. The pouch failure rate in indeterminate colitis (≈19%) is intermediate between that seen with Crohn's disease (≈48%) and that reported in UC (≈8%). Even so, patients without clinical, endoscopic, or radiologic evidence suggestive of Crohn's disease in whom the final pathologic results are indeterminate generally are considered suitable for ileal pouch-anal anastomosis. 406, 414, [418] [419] [420] [421] [422] [423] 

Colon and rectum surgically placed out of circuit acquire histologic changes associated with defunctioning alone, regardless of the original reason for diversion. [424] [425] [426] [427] The changes reflect a physiologic response to stasis and the loss of trophic factors in the feces, most notably short-chain fatty acids. 428 Most patients are asymptomatic. The mucosa of the diverted segment appears erythematous, granular, and friable ( Fig. 23-71 ). Histologic changes include marked lymphoid hyperplasia with germinal center formation, usually accompanied by mild colitis with crypt abscess formation (Fig. 23-72) . These changes may be indistinguishable from follicular proctitis (ulcerative proctitis or localized UC). 429 With time, the muscularis mucosae hypertrophies, the submucosa shows fatty and fibrous tissue infiltration, the muscularis propria thickens, and the lumen becomes progressively smaller. 406 The mucosal lymphoid hyperplasia may be accompanied by lymphoid aggregates scattered in the deep submucosa and muscularis externa and may occur in diverted segments in patients without IBD. Care must be taken not to base a diagnosis of primary IBD, especially Crohn's disease, solely on the histologic changes seen in diverted specimens. In many patients, the rectum is placed out of circuit during an operation for primary IBD. In these instances, the rectum can show changes of both IBD and diversion. The histologic changes in a defunctioned rectum do not correlate with the original diagnosis or clinical outcome. 430 

A late complication of Kock pouch and ileal pouch-anal anastomosis is the development of "primary" inflammation in the pouch with its associated clinical syndrome termed pouchitis. 431, 432 The reported incidence ranges from 8% to 46%. This wide range may be the result of the lack of an accepted case definition of pouchitis. Patients generally experience nausea, vomiting, malaise, fever, and abdominal cramping. The increased effluent/stool from the pouch may be watery, foul smelling, or grossly bloody. Patients frequently become incontinent. Pouch bacterial ecology is often altered and many patients respond to antibiotics such as metronidazole and ciprofloxacin, a finding that suggests a bacterial cause in some cases. Some patients have required 5-aminosalicylates, sulfasalazine, corticosteroids, immunomodulators, or even pouch excision to manage symptoms. 432 Pouch biopsy may be performed to confirm the presence of inflammation or to evaluate the possibility of Crohn's disease. 433 Pouch biopsy specimens from nondysfunctional pouches can show mild villus shortening and increased chronic inflammation with augmented crypt proliferation. Most specimens from pouches that are functioning well resemble normal terminal ileum. A few neutrophils within surface epithelium and within the lamina propria are commonly seen in pouches that are functioning well. [432] [433] [434] [435] [436] In contrast, pouches with classic pouchitis show decreased epithelial mucin and decreased or absent lymphoid follicles. The most consistent finding in this classic form of pouchitis has been ulcers with granulation tissue and patchy accumulations of neutrophils within crypt epithelium and within the lamina propria with deep crypt abscess formation. 432, 433, 435, 437, 438 To define pouchitis more precisely, Sandborn proposed the Pouchitis Disease Activity Index. 432, 434 In this system, up to 12 points are awarded for various clinical and endoscopic findings. The amount of neutrophilic infiltration and the degree of ulceration are graded on a scale of 1 to 3 points each. Histologic findings are weighted in this system because pouchitis is diagnosed in patients who have 7 or more points.

Many investigators report an inconsistent relationship between endoscopic and histologic changes in the pouch and patients' symptoms. Therefore, many clinicians diagnose pouchitis on clinical criteria and reserve endoscopic examination with biopsy for those patients with refractory pouchitis or possible Crohn's disease. 432, 433, 439, 440 Unfortunately, no reliable endoscopic or histologic criteria are available to differentiate most examples of pouchitis from a new onset or recurrence of Crohn's disease in the pouch. Confusion over pouchitis is easily understood when one considers that the clinical syndrome of pouchitis probably represents at least six different conditions (Table 23-8) . 406, 432, 433 The two variants of antibiotic-responsive pouchitis syndromes are classic pouchitis and jejunal bacterial overgrowth. 432, 433, 441 Classic pouchitis is associated with endoscopic and histologic findings that support the pouch as the source of clinical symptoms. [431] [432] [433] [434] 436, 439 Patients with classic pouchitis usually respond to antibiotics such as metronidazole and ciprofloxacin. Occasional patients with clinical symptoms of pouchitis have had endoscopically and histologically negative pouches but have responded to antibiotics. 431, 432 Although rare, some of these patients have had proximal jejunal bacterial overgrowth, 442 probably as a result of pouch distention causing an ileal brake phenomenon that decreases motility in the proximal intestine. 442, 443 This decreased motility may predispose some individuals to proximal small bowel bacterial overgrowth.

Pouchitis syndromes refractory to antibiotic therapy include irritable pouch syndrome, short-strip pouchitis ("cuffitis"), Crohn's disease, and chronic primary refractory pouchitis. 432, 433 Patients with irritable pouch syndrome may have severe clinical symptoms but demonstrate normal pouch endoscopy and histology. Some of these patients respond to dietary fiber supplements and antidepressant therapy. 432 To obtain a better-functioning pouch, many surgeons have abandoned rectal mucosectomy in the ileal pouch-anal anastomosis procedure. 432, 444 In short-strip pouch itis, clinical symptoms may be caused by exacerbation of UC in the small retained rectal segment. 432, 445 Many patients with this form of pouchitis have responded to topical corticosteroids or mesalamine. Although debated, 446 missed Crohn's disease is likely to manifest as a late pouch fistula or abscess rather than as refractory pouchitis. In occasional reported cases of refractory pouchitis, pouch biopsy specimens contained granulomas or the excised pouch showed histologic criteria for Crohn's disease. 414, 433, 436 Invariably, the original colectomy showed either missed Crohn's disease or colitis of an indeterminate type. 414 These cases are best classified as Crohn's disease. 406, 414, 433 Patients with chronic pouchitis should be investigated with endoscopy and biopsy to rule out Crohn's disease or CMV infection, which has been linked to some cases of refractory pouchitis. 432, 447 Routine biopsy specimens of the pouch should be examined as well as biopsy specimens of the afferent limb. Afferent limb ulcers tend to correlate with Crohn's disease and, in patients who do not have Crohn's disease, with the use of NSAIDs. 448 We have seen cases of refractory pouchitis requiring surgical removal of the pouch. After careful pathologic evaluation, no specific infection and no criteria for Crohn's disease can be found in either the excised pouch or the original colectomy specimen. 414, 433, 436 These cases are best categorized as primary refractory pouchitis. The causes of classic pouchitis and primary refractory pouchitis are unknown but are probably related to a combination of stasis, bacterial overgrowth, the abnormal immune response of patients with IBD, or perhaps associated colonic-type metaplasia, which is reported to occur in a minority of pouches (see later). 432, 433, 449 Some investigators have identified histologic patterns of mucosal adaptation in pouches. [450] [451] [452] Approximately 50% to 60% of patients exhibit what has been called type A mucosa with normal small bowel biopsy histology or only mild mucosal atrophy with no or minimal inflammation. Type B mucosa, characterized by transient atrophy with temporary moderate to severe inflammation followed by normalization of intestinal mucosa, is seen in 30% to 40% of patients. Type C mucosa with permanent persistent atrophy and severe inflammation occurs in up to 10% of pouches. Colonic-type features have been reported at least focally in pouches of all types by routine morphology, mucin histochemistry, immunohistochemistry, lectin binding, or electron microscopy. This colonic-type change is best developed in type C mucosa but is not complete. All pouches seem to retain mostly small bowel properties regardless of mucosal type or the duration of the pouch.

With long-term follow-up, it appears that epithelial dysplasia can rarely develop in the pouch. This extremely rare complication seems to be limited to the subgroup of patients (<10%) in whom refractory pouchitis and colonic-type metaplasia develop (type C mucosa). [450] [451] [452] Most investigators suggest yearly pouch surveillance once type C mucosa is established. However, until further information on cancer risk is available, it would seem prudent to survey types A and B mucosa as well, perhaps every other year. 433, 453 Dysplasia can also develop in the small retained rectal segment (often incorrectly referred to as the anal transition zone) in patients who have had restorative proctocolectomy and stapled ileal pouch-anal anastomosis. 454 Annual endoscopic surveillance with biopsy for these retained rectal segments seems prudent. The incidence of dysplasia is rare (<3% of patients), correlates with the original colectomy specimen containing dysplasia or cancer, and can be safely treated by completion mucosectomy. [454] [455] [456] colostomy changes Specimens from colostomy revisions usually show changes associated with trauma and mucosal prolapse such as erosions, ulcers, hemorrhage, acute and chronic inflammation, and fibromuscular obliteration of the lamina propria. One often encounters peri-intestinal fibrosis and suture granulomas. Inflammatory polyps can be seen as well.

Infiltration of the large intestine by large numbers of eosinophils can be seen in eosinophilic gastroenteritis. These patients usually show peripheral blood eosinophilia and have a clinical history of atopy. [457] [458] [459] [460] The entity that has been termed allergic proctitis is in our opinion a form of UC. 461 Whenever large numbers of eosinophils are encountered in a colorectal biopsy specimen, this finding should prompt thorough search for parasites, especially Strongyloides species. The most common form of allergic proctitis or colitis occurs in infants as a result of dietary protein-related allergy. These children present typically with rectal bleeding, sometimes with diarrhea. 462, 463 Colorectal biopsy specimens show increased numbers of eosinophils within the lamina propria, occasionally with focal active colitis. Biopsy specimens that contain more than 60 eosinophils per 10 high-power fields are suggestive of this disease. 463

Allogeneic bone marrow transplantation can be complicated by acute or chronic GVHD. 360, [464] [465] [466] [467] The changes of acute GVHD (apoptotic colopathy) in mucosal biopsy have been described and various grading systems for acute GVHD are used. 360, 466, 467 Grade 1 acute GVHD correlates with increased apoptosis alone. Grade 2 changes include crypt abscesses as well as apoptotic bodies (see Fig. 23-61) . Total necrosis of crypts is classified as grade 3, whereas denudation of areas of bowel is considered grade 4. 360 Biopsy specimens should be carefully examined for CMV infection. CMV may also cause apoptotic change that can mimic GVHD and occasionally both conditions can coexist. 467 Apoptosis is seen with damage associated with chemotherapy and irradiation. Patients receiving bone marrow transplantation for malignant conditions are prepared with chemotherapy and irradiation; therefore, distinguishing the effects of therapy from GVHD without a clinical history is impossible. Histologic changes associated with chemotherapy and irradiation typically resolve in 7 to 10 days. 464, 466 Apoptotic colopathy identical to grade 1 GVHD can be seen in immunodeficiency syndromes, in patients receiving mycophenolate mofetil, and in primary AIDS-related colitis. Grade 4 GVHD cannot be distinguished from ischemic damage without a clinical history.

Chronic GVHD usually spares the colon but a few examples have been described. The pathologic changes include submucosal fibrosis, mucosal calcification, and fibrosis of the lamina propria. 360, 464, 467 Chronic colitis-like changes have been seen in a subset of patients with GVHD; the relationship between this condition and chronic GVHD requires more study. 468 

A localized form of UC with a better prognosis has been described as mucosal proctosigmoiditis, follicular proctitis, or ulcerative proctitis. [469] [470] [471] The gross and endoscopic mucosal appearance resembles that seen with more extensive forms of UC. Mucosal biopsy specimens typically show changes of UC but some have shown prominent mucosal lymphoid aggregates (follicular proctitis) (Fig. 23-73) . 429 Most patients respond to the local administration of corticosteroids or 5-aminosalicylates; approximately 10% of patients develop more extensive colitis. 469, 470 Some evidence suggests that patients with prominent lymphoid follicles are less likely to respond to treatment. 429

Inflammatory changes are relatively common in patients with diverticular disease and are often related to trauma or prolapse. 356 IBD and diverticular disease are both common and occasionally coexist. UC-like inflammation in association with diverticular disease has been described. 332 Crohn's disease and diverticular disease share similar features such as focal mucosal inflammation, stricture, and fistula. Frequently, the pathologist will ascribe all the changes to one disease (usually diverticular disease) and overlook the concurrent IBD (usually Crohn's disease). Features that suggest Crohn's disease in this setting are the presence of fissural ulcers, patchy active mucosal inflammation outside diverticula, granulomatous inflammation, and internal fistulas other than colovesical or colovaginal fistula. Approximately 15% to 20% of patients develop other bowel lesions of IBD on follow-up. [472] [473] [474] [475] [476] [477] 

Systemic mastocytosis is a rare disorder characterized by the infiltration of mast cells and eosinophils in the skin, bones, lymph nodes, and other organs such as the GI tract. [478] [479] [480] One group of investigators suggested that colorectal biopsy specimens showing more than 20 mast cells per high-magnification field as highlighted by CD117 or mast cell tryptase immunostain should be diagnosed as mastocytic enterocolitis, a disease best treated with antihistamines or mast cell stabilizers. 481 This controversial study did not control for thickness of immunohistochemically stained sections and lacked a treatment control group, thus making such conclusions premature. Mast cells coexpressing CD25 usually indicate neoplastic mast cells. 480

Patients with long-standing UC are at increased risk for colorectal carcinoma. 322 The prevalence of colorectal cancer in patients with UC is estimated to be 3.7% overall and 5.4% for those with pancolitis. 482 Those at greatest risk are patients with extensive colitis 483, 484 who have been afflicted for more than 8 to 10 years. The cumulative risk of cancer in a patient with UC is approximately 2% at 10 years, 8% at 20 years, and 18% at 30 years. 482, 485 Early age at onset of colitis, family history of colorectal cancer, histologic evidence of active inflammation, and sclerosing cholangitis may also increase the risk. [483] [484] [485] [486] [487] [488] [489] [490] [491] [492] [493] [494] [495] Colitis-associated carcinoma makes up only a small proportion of total colorectal cancer cases, but these tumors are particularly bothersome to the medical community. They frequently occur in young patients and often develop insidiously even while the patient is under active medical care. Many times the carcinomas are not clinically apparent until distant spread has occurred. 488, 489 Colitis-associated carcinomas are often flat and infiltrative and difficult to visualize with standard radiographic and endoscopic techniques. 1 Because the symptoms associated with carcinoma mimic those of colitis, diagnosis is often delayed.

The estimated risk of carcinoma complicating UC varies considerably. However, epidemiologic data suggest that patients with UC have 6 to 8 times the risk of developing carcinoma when compared with the general population, and looking at the subgroup of patients with UC who have extensive colitis, the risk is 15-to 19-fold. 483, 490 This increased risk poses a management dilemma for physicians caring for patients not sick enough to require colectomy.

Several management options are available. First, the physician can ignore the risk. Many physicians prefer this approach when dealing with an older patient or a patient who is not otherwise a surgical candidate, especially if the actual cancer risk is believed to be low. 491 A second management approach is prophylactic colectomy in patients with colitis for longer than 8 to 10 years. 491 This may be the best approach when dealing with a young patient because of the expected long duration of cancer risk and the possibility that surveillance can fail. 489 Furthermore, the results of ileal pouch-anal anastomosis are better in young patients. Although prophylactic colectomy theoretically eliminates the cancer risk, several factors have made this approach generally unacceptable. Patients with extensive colitis for more than 8 to 10 years are often asymptomatic or have only mild disease. Such patients often find it difficult to accept the risks associated with major surgery, the possible morbidity associated with mobilizing the rectum, or the social implications of a permanent ileostomy (in the event of a pelvic pouch failure). Besides, most studies suggest that prophylactic colectomy would have been unnecessary in the majority of patients because they would not have developed carcinoma. 1, 484 A third option is colonoscopic surveillance with biopsy. The strategy of such surveillance is to identify a marker that signals a subgroup of patients with colitis who are at increased risk for carcinoma or the detection of carcinoma in an early, curable phase. 1, 484, 491 Currently, recognition of dysplasia in surveillance biopsy specimens is used as such a marker. Dysplasia, the presumed precancerous epithelial change, has been regularly recognized in colectomy specimens both adjacent to and distant from colitis-associated carcinomas. 1, 322 Circumstantial evidence suggests that dysplasia may not only be the marker for carcinoma but also may itself be the carcinoma in a preinvasive phase. 1, 322 Dysplastic epithelium can occur in grossly flat mucosa, in mucosa with a villous or plaquelike configuration, or in a nodular growth resembling adenoma (Fig. 23-74 ). 1 Dysplasia is recognized by histologic examination of biopsy specimens using well-defined cytologic criteria that include nuclear enlargement with hyperchromasia, increased mitotic figures, and decreased intracellular mucin. 1, 322 Most colitisassociated dysplasia resembles adenomas seen in patients without colitis.

The pathologist should use the term dysplasia only as a synonym for intraepithelial neoplasia and not in reference to reactive or reparative changes seen with active inflammation. The distinction between repair and dysplasia can be difficult, requires experience, and in certain instances can be impossible. In general, cytologic abnormalities seen in the presence of active inflammation must be interpreted with caution. 1, 322 Similar features can be seen in repair and dysplasia and no one histologic feature is absolute in making the distinction. 1 Both conditions are associated with nuclear enlargement and hyperchromasia, increased mitotic figures, and decreased intracellular mucin. Some features favor repair over dysplasia. Although cells undergoing repair demonstrate nuclear enlargement with hyperchromasia, these nuclei are often evenly spaced and not crowded, round to oval with a smooth external nuclear contour, contain granular chromatin with a single or multiple chromocenter or nucleoli, and are remarkably similar to one another in size and appearance. In contrast to dysplasia, the nuclear-tocytoplasmic size ratio of regenerative cells is often actually decreased, especially in cells adjacent to ulcerated areas. During this phase, the cell cytoplasm is often eosinophilic. Nearby crypt abscesses or neutrophils within epithelium (cryptitis) help to confirm the diagnosis of repair. As a general rule, reparative epithelial change is limited to or accentuated in the crypt base and will not extend onto the surface of the crypt.

Features that favor dysplasia over repair are variable nuclear hyperchromasia, nuclear pleomorphism, irregular external nuclear contours, nuclear stratification with irregular nuclear crowding and overlap, and a loss of nuclear polarity. The changes of dysplasia usually extend onto the surface of the crypt. Major distortions of mucosal architecture also favor dysplasia.

The Inflammatory Bowel Disease-Dysplasia Morphology Study Group proposed a three-tiered classification for biopsy interpretation in IBD: positive, negative, and indefinite for dysplasia. 322 Our experience has shown that this classification is useful and reasonably reproducible. 1, 492 Biopsy specimens negative for dysplasia include normal colon and those biopsy specimens showing changes of active or quiescent UC. Positive biopsy specimens are reported as showing high-grade dysplasia or low-grade dysplasia. Most dysplasias histologically resemble adenomas seen in patients without colitis, although some do not. 1 Dysplasias in this latter group are easy to miss.

In low-grade dysplasia, nuclear changes such as crowding, pleomorphism, hyperchromasia, and increased mitotic figures are present, but in general, the nuclei are limited to the basal half of the cell (Fig. 23-75) . Usually, intracellular mucin is decreased, but on occasion intracellular mucin can be increased. Dystrophic or signet ring-type goblet cells are common in dysplasia although not pathognomonic. The general mucosal architecture should not be greatly disturbed.

The distinction between low-grade dysplasia and highgrade dysplasia is made largely on the degree of cytologic and architectural change. In high-grade dysplasia, hyperchromasia and pleomorphism are marked (Fig. 23-76) . Stratification with loss of nuclear polarity is often present. Nuclei may be found in the luminal portions of the cells. High-grade dysplasia is often associated with a distortion of mucosal architecture, most often taking the form of a villous growth similar to villous adenomas seen in patients without colitis.

Biopsy specimens are classified as showing changes indefinite for dysplasia when cytologic abnormalities are seen but these changes are of insufficient degree to warrant a diagnosis of true dysplasia. Indefinite changes are usually encountered in a background of active inflammation in which atypical epithelial changes could represent repair or regeneration rather than dysplasia. The indefinite category also includes odd mucosal patterns of growth that have not yet been observed to give rise to carcinoma (e.g., sessile serrated polyp-like change [ Fig. 23-77 ], epithelial changes that resemble gastric foveolar epithelium). The category, indefinite for dysplasia, is a legitimate diagnosis alerting the treating physician that worrisome changes are present that may place a patient in a higher risk category that requires more frequent surveillance. The Inflammatory Bowel Disease-Dysplasia Morphology Group originally subdivided indefinite dysplasia into three groups: probably inflamma-tory, probably dysplastic, and unknown. 322 Obviously, in a category that is already uncertain, subcategorization is cumbersome, subjective, and associated with marked interobserver and intraobserver variation. Therefore, subdivision of biopsy specimens in the indefinite category is not recommended. 1

The use of 5-aminosalicylate compounds decreases the risk of cancer by 53% to 75%, 485, 493 as does seeing the physician regularly and having more than one colonoscopy. 493 Most patients and physicians opt for lifelong annual or biannual colonoscopic surveillance. 1, 485 Current practice guidelines recommend two to four biopsy specimens obtained every 10 cm throughout the diseased bowel in addition to special sampling of macroscopic lesions. 494 Compliance with this recommendation has been inadequate. [495] [496] [497] [498] Patients whose biopsy specimens remain negative for dysplasia can probably safely continue regular surveillance. Most authorities recommend annual total colonoscopic examination for patients with extensive UC who have had their disease for more than 8 to 10 years. 1, 322, 492, 497 The surveillance interval can be increased to 2 to 3 years for patients with negative initial colonoscopy because in only 2% to 4% of these patients has disease been shown to progress. 489 Patients demonstrating epithelial changes indefinite for dysplasia should have shorter follow-up (e.g., 6 months to 1 year). 488, 498 They must not be ignored because 28% of patients in whom the initial biopsy results were indefinite progressed to high-grade dysplasia and 9% progressed to cancer. 489 Management recommendations for patients with low-grade dysplasia in a flat mucosa are difficult because of the paucity of long-term follow-up information. Some clinicians consider it safe to continue short-term follow-up (e. g., 3 to 6 months) for patients with low-grade glandular dysplasia; 488, 498 if dysplasia persists 1, 497, 499, 500 or is associated with any suspicious gross lesion or stricture (dysplasiaassociated lesion or mass [DALM]), colectomy should be considered. 1, 322, 484, 501 Forty-three percent of reported patients with DALM already had carcinoma in immediate colectomy specimens. 489, 501 Increasing numbers of experts have advo- cated immediate colectomy for low-grade dysplasia. [487] [488] [489] 502 These experts have stated that 19% of patients with lowgrade dysplasia already had complicating carcinomas, and they also have cited a very high rate of progression to highgrade dysplasia or carcinoma with follow-up (54%, St. Marks, London; 53%, Mt. Sinai, New York; 33%, Mayo Clinic, Rochester, Minn). 485 These data are questioned because of case selection bias. 489 If high-grade dysplasia is encountered, then colectomy should be recommended because the risk of concurrent carcinoma is estimated to be as high as 42%. 1, 489 Experience with surveillance biopsy interpretation has shown that truly negative results are rarely interpreted as dysplasia, and dysplasia, especially high-grade dysplasia, is rarely missed. 1, 492 That said, variations in interpretation do occur, 1,322,500,502-504 and in general confirmation of a biopsy diagnosis of dysplasia is desirable before colectomy. 1, 322 Any one or more of the following may be considered adequate confirmation: finding of dysplasia in a repeat biopsy from the same site, finding of dysplasia in one or more additional sites during the same endoscopic examination, or review and confirmation of the original dysplasia interpretation by another pathologist experienced with the classification system. 1, 322, 485 Surveillance endoscopy with biopsy has limitations. No compelling evidence proves that surveillance benefits the patient. 489, 491, 497, 503, 505 Participation in a surveillance program does not guarantee that lethal cancer will not develop. 488, 489, 491, 497, 500, 505, 506 Dysplasia is unusual and it is difficult for any one pathologist to acquire extensive experience. Therefore, errors in histologic interpretation can be expected. Dysplasia can be focal and is subject to tremendous sampling error. 1, 488, 492 Because most authorities consider dysplasia a neoplastic change, it is unlikely that it ever resolves spontaneously. Thus, a clinician should not be lulled into a false sense of security by negative follow-up biopsy results once true dysplasia has been identified. 1 Although not proved scientifically, it seems likely that patients benefit from surveillance programs because many carcinomas are detected in a curable phase. 1, 488, 497, 498, 500, 505 In addition, the incidence of carcinoma in patients whose biopsy specimen results have remained negative is low. 489, 497, 498 It is unclear whether this benefit justifies the large cost of surveillance endoscopy. 489, 507 Finally, surveillance programs are pointless unless the patient complies with regular surveillance and agrees to colectomy when the end point (dysplasia) has been reached. 507

Many groups have searched for other markers for precancer in UC. Sialomucins predominate in cancer and dysplasia in UC but the role of mucin histochemistry findings is debated. 508 Results of lectin binding, CEA immunohistochemical study, and immunohistochemical analysis for products of c-myc and ras oncogenes have produced variable results and could not reliably differentiate dysplasia from repair. 1 Several investigators described a correlation between DNA aneuploidy and dysplasia or carcinoma in UC. [509] [510] [511] However, only 80% to 90% of invasive carcinomas and 50% to 80% of dysplasia demonstrated DNA aneuploidy. This finding indicates that DNA analysis by flow cytometry could not be used alone in a cancer surveillance program. Many specimens (≥6%) interpreted as negative or indefinite for dysplasia showed DNA aneuploidy. 510, 511 This finding can be interpreted in several ways. It could indicate technical problems linked to false-positive results including failure to disaggregate nuclear clumps, prolonged exposure of the sample to higher temperatures, and debris in the sample. 511, 512 Alternatively, this test could identify a subgroup of patients different from the group identified by dysplasia that is showing objective chromosomal abnormalities in the absence of recognizable dysplasia. It is tempting to speculate that this DNA aneuploidy could be used as a marker of some carcinomas complicating UC, although other investigators concluded that the detection of DNA aneuploidy was not useful as a predictor of the presence of concurrent carcinoma in UC. [509] [510] [511] Until large prospective studies determine the usefulness of DNA aneuploidy in UC, histologic dysplasia is still the only reliable marker for cancer in a surveillance program. 1,513,514 DNA analysis could benefit some patients. Patients with diploid DNA content and no signs of dysplasia probably can be examined at longer surveillance intervals. 510, 511 Approximately 90% of patients would fall into this category and a longer interval surveillance could save considerable amounts of money and time.

A special problem concerns the occurrence of adenoma in patients with colitis. Colorectal adenomas and IBD are both relatively common. Therefore, there is probably no reason that both conditions could not coexist. Because most IBDassociated dysplasias resemble adenomas, 1 the distinction in practice is often impossible. Management of patients with UC and adenoma has been controversial. Does the lesion represent a harmless sporadic adenoma or is it a dangerous DALM? In general, a pathologic diagnosis of "adenoma" in a patient with IBD must be carefully evaluated by the treating physician and should at least prompt further consultation with the pathologist because the lesion could represent IBD-associated dysplasia, an ominous change that implies a substantial risk for the development of carcinoma or for coexisting cancer. 1, 515 adenoma versus dysplasia-associated lesion or mass Dysplasia in IBD can be broadly classified endoscopically as flat or raised. Raised lesions can be further subdivided into adenoma-like (i.e., discrete, well-circumscribed sessile or pedunculated lesions that resemble sporadic adenomas [see Fig. 23-74] ) or non-adenoma-like (i.e., irregular plaque or masslike) lesions (Figs. 23-78 and 23-79). 1, 516 Most experts recommend colectomy for flat high-grade dysplasia and endoscopically raised non-adenoma-like dysplasia lesions. Correct management of patients with UC who have endoscopically adenoma-like dysplasia is not clear. The differential diagnosis between conventional adenoma and dysplastic lesions in IBD has been the focus of several publications. Distinction based on pathomorphologic features has been proposed. 517, 518 Although lesions can be classified histologically using this system, to date this approach has not been clinically validated. The study of Torres and colleagues 517 suggested that an admixture of normal and dysplastic glands at the surface of the lesion could be used to distinguish IBD-associated dysplasia from conventional adenoma. Several drawbacks to this study limit its clinical usefulness. An association with carcinoma or flat dysplasia was definitional for IBD-associated dysplasia in this study. Furthermore, the study had limited clinical follow-up to determine whether the distinction based on this feature (admixture of normal and dysplasia at the surface) was clinically relevant in patients not yet known to have other areas of dysplasia or carcinoma. Many authorities believe that admixtures of normal and dysplastic glands are so highly prevalent in sporadic adenomas that this criterion is not helpful in practice.

Molecular analysis has been applied in an attempt to resolve this diagnostic problem. Odze and associates 519 reported a similar prevalence of 3p, APC, and p16 muta-tions in adenoma-like dysplasia lesions in UC and sporadic adenomas. However, non-adenoma-like dysplasia in UC showed significantly higher proportions of 3p and p16 mutation, a finding indicating different timing of molecular events in these lesions. 519 Although promising, these molecular approaches are technically difficult, are not generally available, and remain to be validated clinically.

Immunohistochemistry has also been used in an attempt to discriminate between conventional adenoma and IBDassociated dysplasia. 520,521 p53 overexpression by immunohistochemical analysis that generally correlates with mutation of the corresponding tumor suppressor gene appears to be the most promising. p53 gene mutations reportedly occur earlier in IBD-associated dysplasia than in conventional adenoma or carcinoma. Therefore, strong p53 overexpression tends to correlate with IBD-associated dysplasia. Unfortunately, only 30% of IBD-associated dysplasias overexpress p53 (versus 5% of sporadic adenomas). 520, 521 This p53 testing is probably not sensitive enough for routine practice. Combining p53 immunoreactivity with betacatenin expression (which exploits the relatively low prevalence of APC gene mutation in IBD-associated dysplasia) or bcl-2 immunohistochemistry (which is more often overexpressed in sporadic adenomas) does not appear to improve the sensitivity or specificity of this approach. 520,521 Immunohistochemistry is clearly technically easier and more widely available. However, as with the molecular approaches outlined earlier, diagnoses based on immunohistochemistry have not been clinically validated. practical guide to patient management Pathomorphologic, molecular, or immunohistochemical testing could eventually separate harmless sporadic adenomas from the more ominous DALMs in patients with IBD but this remains to be proved. In the meantime, follow-up information is sufficient to guide a careful physician facing this dilemma. The most important criterion for stratification is the topographic relation of the adenoma-like lesion to areas of colitis. Adenoma-like lesions occurring in areas not affected by colitis histologically or endoscopically have not been associated with a high risk of concurrent or subsequent carcinoma. These lesions should be considered conventional adenomas and treated by polypectomy alone. 1, 516, 517, 520, 522 Management of adenoma-like lesions occurring in areas involved by colitis is more challenging. As many as two thirds of patients have had concurrent or subsequent invasive carcinoma at follow-up. 1, 515, 517, 523 From a practical standpoint, we believe that it is prudent to consider all adenoma-like lesions occurring in areas involved by colitis as potentially IBD-associated dysplasia lesions. These lesions must be excised endoscopically and not merely sampled with biopsy. 523 The diagnosis of IBD-associated dysplasia alone in this unique setting (adenoma-like dysplasia in a macroscopic polyp) may not necessarily be an indication for immediate colectomy. 1, 323, 498, [515] [516] [517] 520, 524 Endoscopic polypectomy alone may be adequate treatment provided that careful patient selection criteria are applied, including the following: (1) the patient is in an adenoma age group (>40 years of age), (2) the adenoma-like lesion is discretely defined macroscopically and can be excised in its entirety, (3) excision of the lesion appears complete to the endosco- pist, (4) no flat dysplasia is identified in the colon, and (5) the colon is easy to survey (i.e., compliant patient without inflammatory polyposis). Current data suggest that the majority of patients managed in this fashion will follow a clinically benign course. 1, 515, 516, [522] [523] [524] However, these patients must receive careful short-term surveillance. A 3-to 6month initial surveillance interval can be increased to 6 months to 1 year following negative results of colonoscopy. 516 Colectomy should be recommended for patients not fulfilling these selection criteria. 515

Increasing epidemiologic and pathologic evidence suggests that patients with Crohn's disease are also at increased risk for the development of carcinoma. 1,525-527 Those patients who are younger than 21 years of age at the onset of Crohn's disease may be at even higher risk. 528 Colonic carcinomas in patients with Crohn's disease have in general developed after about 20 years of disease. 1, [525] [526] [527] [528] [529] [530] [531] [532] The diagnosis is usually made clinically because a gross intraluminal lesion can often be visualized (Fig. 23-80) . The colonic carcinomas have been better differentiated than their small bowel counterparts in Crohn's disease, with an increased prevalence of mucinous histologic features. 1, 525, 526, 531 Reports using current histologic criteria almost invariably note dysplasia in the epithelium adjacent to small bowel and colonic carcinomas in Crohn's disease. 1, [525] [526] [527] 531 Dysplasia distant from carcinomas has also been encountered in specimens exhibiting both colonic carcinoma and Crohn's disease. These features suggest that the dysplasiacarcinoma sequence similar to that proposed for UC also occurs in Crohn's disease. 1,526,531 A practice-based surveillance study of 259 patients with Crohn's colitis affecting at least one third of the colon for more than 8 years found that 16% of patients developed dysplasia or cancer at 16 years. 533

Opinions vary regarding cancer surveillance in patients with long-standing Crohn's disease. 1, [525] [526] [527] 529, 531, 534 It is possible that surveillance could benefit an occasional patient with colonic Crohn's disease by detecting dysplasia or early carcinoma, but the safety, necessity, and benefit of regular cancer surveillance are questioned. 535 Colonoscopy may be technically impossible or dangerous in some patients with Crohn's disease. Retained rectal stumps are often strictured and inaccessible. The absolute number of colon carcinomas reported in Crohn's disease is still low, so again the expected yield of positive cases in a surveillance program would be quite small. Some experts advocate a UC-like surveillance strategy for patients with at least 8 years of Crohn's colitis involving at least one third of the colon. 485 Rather than ignoring the risk in Crohn's disease, options are available for a cautious clinician. 1, 534, 535 A patient with recrudescence of colitis-like symptoms and a background of long-standing inactive Crohn's colitis should be thoroughly investigated for carcinoma. 526 Yearly surveillance of an out-of-circuit rectum seems reasonable considering that approximately 20% of the reported cases of large bowel cancer in Crohn's disease have occurred in such segments. 534, 535 It may, however, be better to advise removal of the defunctioned rectum, especially if reanastomosis is not planned, not possible, or contraindicated. The presence of dysplasia in a biopsy specimen from a patient with Crohn's disease must alert the physician to the possibility of coexistent invasive carcinoma. In this situation, management approaches similar to those proposed for dysplasia in UC are recommended. 1, 321, 526 Clinicians should also recognize that chronic fistula or anal stricture in Crohn's disease may be complicated by squamous carcinoma or adenocarcinoma. 1, 530 Any abrupt change in the volume or nature of a fistula discharge or the development of an area of induration or mass near a fistula should be investigated with biopsy. 535

So-called left-sided colonic diverticular disease commonly affects middle-aged and older individuals and shows a characteristic muscular abnormality of the bowel wall. 536 The abnormality is characterized by marked thickening of the inner circular layer of the muscularis externa that results in a narrowed lumen and a mucosa thrown up into prominent accordion-like folds. The mucosal abnormality and associated diverticula are most prominent within the sigmoid colon but they may extend proximally for a variable distance and may even involve the entire colon. Diverticula are not seen in the rectum. The diverticula are usually still enveloped by an intact longitudinal muscle layer. Diverticula usually manifest in two longitudinally running rows situated between the mesenteric and two anti-mesenteric taeniae. In severe cases of diverticular disease, diverticula can also be found between the antimesenteric taeniae. Similar clinical signs and symptoms occur regardless of whether objective inflammatory changes are present; therefore, the term diverticular disease is preferred rather than routinely making the distinction between diverticulosis and diverticulitis.

Diverticula are sometimes difficult to demonstrate in freshly resected specimens because of lost muscle tone and intraluminal pressure. As a result the diverticula often evert and are mistaken for polyps. The best way to demonstrate diverticula is to fix an intact specimen with formalin under pressure for at least 1 day before dissection (Fig. 23-81) .

Complications of diverticular disease include inflammation within the diverticula (diverticulitis), perforation of diverticula, adhesion, fistula formation, pericolonic abscess with inflammatory mass, hemorrhage, and obstruction. 537 Although colovesical and colovaginal fistula can occur in diverticular disease, other fistula combinations must raise the suspicion of coexisting Crohn's disease. Any granularity or ulceration of the luminal mucosa that is accompanied by microscopic findings of crypt abscesses or deep lymphoid aggregates away from inflamed diverticula must also raise the possibility of coexisting Crohn's disease (see earlier). Likewise, features of colitis distal to the zone of diverticula (e.g., at the distal resection margin) must also raise the question of coexisting Crohn's disease.

Right-sided diverticular disease is often isolated and usually unassociated with diverticula in the rest of the colon. Right-sided diverticula occur in younger patients and are frequently seen in Asians. [538] [539] [540] [541] Clinically, right-sided diverticular disease manifests with symptoms that mimic acute appendicitis. Some authors classify these diverticula as congenital if the outpouching contains all layers of the bowel wall or acquired if the diverticula resemble those seen in the left-sided diverticular disease. Complications include inflammation, hemorrhage, pericolonic abscess, and peritonitis. These diverticula have been implicated in some solitary nonspecific ulcers of the cecum and right colon.

The clinical diagnosis of ischemic bowel disease can be difficult. Patients usually present with nonspecific symptoms and routine radiographic examinations such as plain abdominal films or barium enemas are rarely of use. Even arteriography may not be helpful because of the poor correlation between angiographic findings and the ultimate diagnosis or clinical outcome. 542 Angiographic demonstration of patent mesenteric blood vessels does not exclude ischemia. Conversely, stenosis or occlusion of mesenteric arteries (even two of the three major vessels) does not establish a diagnosis of ischemia because these are frequent findings in asymptomatic patients. Therefore, the diagnosis of ischemic bowel disease requires a high index of clinical suspicion complemented by continued monitoring of clinical, laboratory, and radiographic information. The pathologist can play an important role in the diagnosis and management of ischemic bowel disease by recognizing the patterns of injury that suggest ischemia in biopsy and resection specimens.

At first glance, intestinal ischemia seems simple, but in reality the topic is almost impossibly complex; the ultimate outcome of the patient depends on complicated interrelationships among temporal, anatomic, and physiologic factors. 543 For example, gradual occlusion of large vessels rarely causes ischemic damage because adequate collateral circulation (e.g., arc of Riolan, marginal artery of Drummond) will develop. In contrast, acute arterial occlusion is likely to result in infarct. Considering anatomic factors, occlusion of a large vessel does not often result in ischemic damage because collateral circulation is usually adequate to protect the bowel. However, occlusion of smaller end arteries frequently results in segmental ischemic damage and infarct. 544 Finally, the mere existence of an entity referred to as nonocclusive intestinal ischemia emphasizes the importance of physiologic considerations. Systemic hypotension and bowel distention lead to marked decreases in splanchnic blood flow caused by vasoconstriction and arteriovenous shunting in the bowel wall. 544, 545 This phenomenon can result in widespread bowel infarct even in the presence of patent blood vessels.

Ischemic injury to the GI tract occurs whenever the oxygen or vascular supply cannot meet the metabolic demands of the tissue. GI ischemia has many causes, including inadequate perfusion, narrowing of blood vessels from any cause, bowel obstruction and distention, drug effects, and infections that can mimic ischemic damage. The list of differential diagnostic possibilities often overwhelms the pathologist and clinician. Keeping the diagnostic considerations in their proper perspective, almost all cases of mesenteric ischemia result from systemic hypotension or occlusion of a major blood vessel. 544 Knowledge of these relative frequencies can be invaluable in decreasing the pathologist's anxiety and frustration when dealing with these types of specimens and when interacting with the concerned clinician, patient, and family. Most ischemic episodes result from nonocclusive ischemic bowel disease (low-flow states) and in these cases no vascular lesion or specific cause for ischemia can be demonstrated on pathologic examination. Superior mesenteric artery embolism or thrombosis is usually diagnosed by radiography or at operation. Almost all significant superior mesenteric artery occlusions occur in the proximal 1 cm to 2 cm of the artery, 544 an area not likely to be present in a resection specimen; such occlusive plaques, thrombi, or emboli are either bypassed surgically or removed and submitted separately to the pathology laboratory. Mesenteric venous thrombosis is also diagnosed and identified at laparotomy and treated with thrombectomy. Low-flow states, superior mesenteric artery occlusion, and mesenteric venous thrombosis account for more than 95% of major ischemic events.

Ischemia can result in a wide range of pathologic changes depending on the cause, severity, and duration of the hypoxia. Thus, ischemia can cause little or no change, mucosal plaques or hemorrhages with erosion, discrete or serpiginous ulcers that mimic Crohn's disease, strictures, or at the severe end of the spectrum, hemorrhagic infarct with perforation. Any part or length of bowel can be affected depending on the cause and duration of hypoxia and the state of the collateral circulation. In general, those cases of ischemic bowel disease associated with narrowing of a blood vessel show pathologic changes in the bowel in the corresponding distribution. In contrast, nonocclusive intestinal ischemia causes patchy and irregular distribution of damage not necessarily corresponding to an area supplied by a specific blood vessel (Fig. 23-82) . Ischemic damage associated with reduced blood flow shows a propensity to affect "watershed zones" such as the splenic flexure, which is the boundary between the superior mesenteric and inferior mesenteric artery distributions. 3, 347 Acute, organizing, and healed phases of ischemia can be recognized histologically. 347 Acute ischemic damage can be focal or diffuse. The characteristic pattern of acute injury consists of hemorrhage into the lamina propria associated with superficial epithelial coagulative necrosis, often with sparing of the deep portion of the intestinal crypt (see Fig.  23-59) . 3, 347 The mucosal distribution of these changes can be explained by the existence of a countercurrent exchange mechanism that has been suggested for intestinal mucosa. In the mucosa, a central arteriole carries blood luminally in a direction parallel to but opposite to the direction of blood flow in the draining mucosal venule. This situation causes a gradient in oxygen tension to form, with the luminal aspect of the bowel relatively hypoxic when compared with the crypt base. 546, 547 The changes of acute ischemia can occasionally be associated with more extensive necrosis of the epithelium, often associated with an attached inflammatory pseudomembrane. Surprisingly, acute and chronic inflammatory cells are typically minimal in acute ischemic damage. This finding helps to differentiate ischemic damage from changes seen in primary IBD. Depending on the severity and duration of the hypoxia, the acute change can be reversible or can proceed to mucosal ulcers, at which point the histologic features become relatively nonspecific. 548 With increasing severity and duration, ischemia can lead to full-thickness infarct with hemorrhage and coagulative necrosis involving all bowel layers.

Granulation tissue and fibrosis with plump fibroblasts predominate in the organizing phase of ischemic damage. The histologic change becomes nonspecific. Ischemia should be suspected when an ulcer or area of organizing inflammation in the bowel appears quite bland and is not associated with a marked increase in chronic inflammatory cells with plasma cells and lymphoid aggregates so characteristic of primary IBD. Often, the mucosa of the ulcer edge shows changes similar to those seen in acute ischemic damage, and extensive samplings of these areas can help in diagnostic problem cases. The presence of hemorrhage and hemosiderin deposits in the connective tissues, although not pathognomonic, strongly suggests an ischemic origin.

During the healing phase, the colonic mucosa often assumes an architectural appearance similar (if not identical) to chronic UC with atrophy, shortened crypts, and branched and budded glands. 3, 347 These changes usually have a patchy distribution in healed ischemic damage but are diffuse in UC. Ischemia usually does not show the basal plasmocytosis of primary IBD. Healed phases of ischemia are often complicated by fibrous stricture in which fibrosis can affect all the layers of the bowel wall including the muscularis externa. Fibrosis of the muscularis externa is distinctly unusual in primary IBD and its presence should raise the suspicion of ischemic bowel disease. Again, hemosiderin deposits can be a helpful clue in recognizing the ischemic nature of the injury.

Most ischemic bowel lesions result from a combination of atherosclerosis and low-flow states and are referred to as nonocclusive ischemic bowel disease. 544 Specimens showing ischemic damage or infarct are usually resected on an emergency basis and include relatively short segments of mes- entery. Large segments of infarct or ischemic damage are usually caused by an occlusive lesion in a proximal segment of a large artery or vein. In other words, the offending vessel is not likely to be present in the resection specimen. Although one is unlikely to see specific vascular abnormality in the resection specimen, the blood vessels should be carefully dissected and many cross sections examined microscopically to detect vascular lesions such as atherosclerosis, embolus, thrombosis, or inflammation (vasculitis). The significance of vascular inflammation in areas of active ulcer and infarct is questionable because this "vasculitis" may be secondary. However, acute inflammation in vascular walls associated with fibrinoid necrosis found in apparently viable areas separated from an ulcerated and necrotic area by a margin of normal tissue may indicate systemic vasculitis.

Polyarteritis nodosa is a multisystem disease characterized by random necrotizing inflammation involving small and medium-sized arteries. Because the distribution and severity of the vascular lesions are haphazard, polyarteritis nodosa produces protean clinical manifestations without pathognomonic signs or symptoms. Abdominal pain, fever, leukocytosis, hypertension, and neuropathy are common in patients with polyarteritis nodosa. 549 According to the American College of Rheumatology, the presence of 3 of the following 10 criteria are considered diagnostic of the disease 550 : weight loss, livedo reticularis, testicular pain or tenderness, myalgia or myopathy, neuropathy, hypertension, renal impairment, hepatitis B infection, abnormal arteriogram, and positive biopsy results.

The diagnostic histopathologic change of polyarteritis nodosa is necrotizing panarteritis with inflammation involving intima, media, and adventitia. The inflammatory infiltrate is composed of neutrophils, eosinophils, plasma cells, and lymphocytes and is often associated with a deposition of fibrin. 551, 552 The vascular lesions are usually seen in various stages of development and healing. Disruption of the internal elastic lamina weakens the vascular wall and can lead to aneurysm formation, an important sign used in radiographic diagnosis.

Of patients with polyarteritis nodosa, 14% to 70% have GI tract involvement 553 such as duodenal or gastric ulcer, melena, hematemesis, or small bowel infarcts. GI tract involvement is usually a manifestation of systemic polyarteritis nodosa. However, a growing body of literature has described polyarteritis nodosa apparently limited to one organ, most commonly the skin, gallbladder, or vermiform appendix. [551] [552] [553] [554] [555] Only a rare patient with polyarteritis nodosa that is initially diagnosed in the gallbladder or appendix develops systemic vasculitis 552, 553, 556, 557 and those who do frequently have elevated serum rheumatoid factor or antinuclear antibodies.

Phlebitis, Churg-Strauss angiitis, small vessel vasculitis, Buerger's disease, and giant cell arteritis can manifest initially in the GI tract and cause ischemic injury. 553, 557 Phlebitis and small vessel vasculitis are frequently associated with drugs and medications and are often self-limited. 553, 558 Special consideration should be given to an entity referred to as intra-abdominal (lymphocytic) phlebitis. Rare cases of ischemic damage to the colon have been linked to a curious form of phlebitis reported under numerous synonyms including lymphocytic phlebitis, necrotizing and giant cell granulomatous phlebitis, idiopathic myointimal hyperplasia of mesenteric veins, mesenteric inflammatory veno-occlusive disease, intramural mesenteric venulitis, and idiopathic colonic phlebitis. 553, [558] [559] [560] [561] [562] [563] [564] [565] [566] [567] [568] Since the original descriptions, approximately 40 additional cases have been described. The patients have ranged in age from 30 to 77 years, and no gender predilection is apparent. Most cases involve the small intestine and colon but involvement of other organs such as the gallbladder, omentum, and stomach have been described. 553, 568 Four patients received treatment with the drug rutoside.

Microscopically, specimens show phlebitis and thrombophlebitis mostly involving the submucosal veins and venules ( Fig. 23-83) . The most prominent lesion is infiltrative lymphocytic phlebitis. In approximately half of these patients, the phlebitis has been necrotizing, and in about one third a granulomatous component has been visible. In approximately half of the patients, myointimal proliferation has been described. 559 Some investigators have proposed that myointimal hyperplasia represents an end stage of lymphocytic phlebitis. 561 Immunohistochemical analysis has been performed on a few cases and demonstrates a mixture of T cells and B cells with a few macrophages. 559, 565 Some of the T cells express the cytotoxic granule-associated protein TIA-1 and granzyme B, findings supporting the contention that the lymphocyte-mediated vascular damage is a central event in the pathogenesis. 565 So far, cases in the literature have had a favorable clinical outcome. The disease usually has been diagnosed and treated by resection in these patients. No patient to date has required repeat resection, nor has any patient developed systemic vasculitis. Some patients con- tinue to have abdominal pain, and at least one report noted recurrent phlebitis documented by biopsy. 559

Other entities considered part of the spectrum of ischemic bowel disease include necrotizing enterocolitis of the neonate, neutropenic enterocolitis (typhlitis), intestinal Behçet's disease, late irradiation enterocolitis, uremic colitis, stercoral ulcer associated with bowel obstruction, potassium chloride-induced ulcer, stress ulcer and ulcers associated with drugs (e.g., NSAIDs and chemicals), certain infections such as Clostridium difficile-associated colitis, and EHEC infection. The pathologic features of these disorders resemble ischemic bowel disease and are generally indistinguishable without knowledge of clinical and laboratory information.

Necrotizing enterocolitis is a serious form of intestinal injury that resembles ischemic bowel disease. Although many investigators think it part of the spectrum of ischemia, increasing evidence supports a role for infectious agents in the pathogenesis of the lesion. 569 Necrotizing enterocolitis of the neonate generally affects low-birth-weight or premature infants. The disease usually occurs in babies younger than 10 days of age and symptoms usually develop after feeding has begun. The lesions resemble acute ischemic damage. 569, 570 Ulcers that can be patchy or diffuse occur and in general may affect any part of the GI tract. Preferred sites of involvement include the terminal ileum, right colon, and stomach. Histologically bland transmural necrosis occurs and may be associated with gas cysts within the bowel wall (pneumatosis cystoides intestinalis [PCI]) ( Fig. 23-84) . Babies surviving the acute episode may later develop fibrous strictures.

Neutropenic enterocolitis goes by numerous synonyms, including hemorrhagic necrosis of the GI tract, necrotizing enterocolitis, agranulocytic colitis, typhlitis, and the ileocecal syndrome. [571] [572] [573] [574] The condition is fulminant segmental colitis that is often seen in patients with lymphoma or leukemia receiving immunosuppressive drug therapy, but it has also been seen in association with other chemotherapyinduced or non-neoplastic-induced neutropenias such as cyclic neutropenia. Many investigators consider this disorder a form of ischemic bowel disease, but increasing evidence implicates bacteria, especially Clostridium septicum, as causative agents. [575] [576] [577] [578] The pathogenesis is unclear but is likely to be multifactorial with neutropenia, altered mucosal integrity, ischemia, and infection all playing a role. The lesion can occur anywhere in the GI tract, but the preferred sites are cecum, right colon, and terminal ileum. The histologic picture combines infarct necrosis with profound secondary bacterial or fungal overgrowth and is often associated with a paucity of acute inflammatory cells. The prognosis is grave; however, reports of successful surgical and medical management have been published. 571, 572, 574, 575, 579 nonspecific ulcers of colon Investigators have reported benign cecal ulcers and segmental necrosis of the right colon in which the pathologic features are nonspecific or resemble ischemia. [580] [581] [582] The cause of many of these ulcers remains unclear. 580 Some may represent inflammatory changes or bleeding vascular lesions in right-sided diverticula. 582, 583 Many are associated with endstage renal disease, hemodialysis, renal or cardiac transplantation, and corticosteroid therapy. Some are clearly related to ischemia caused by low-flow states, which are known to occur in patients undergoing hemodialysis. 581 However, a strong correlation exists among cecal and terminal ileal ulcers, renal or cardiac transplantation, immunosuppression, and CMV infection. 584 The possible role of CMV in these ulcers is unknown. The exact cause of many colonic ulcers cannot be determined at present. 585 NSAID use should also be investigated. 586

The term Behçet's disease describes the clinical triad of aphthous stomatitis, genital ulcers, and relapsing iritis. Behçet's disease is seen worldwide, but most cases have been reported from the Mediterranean basin, the Middle East, and Japan. 587 Male patients are twice as commonly affected as female patients and the mean age of onset is in the third decade. 587, 588 Behçet's disease is a systemic disorder; only 10% to 15% of patients demonstrate GI tract involvement, [587] [588] [589] usually in the form of intestinal ulcers. The ulcers of intestinal Behçet's are described as multiple, deep, and punched-out with a preferential localization in the ileum and cecum. The ulcers often perforate. [588] [589] [590] [591] The primary clinical differential diagnosis is Crohn's disease. Intestinal Behçet's disease differs from Crohn's disease in several ways. Behçet's disease is usually not associated with strictures or granulomas. Free perforation, common in Behçet's disease, occurs rarely in Crohn's disease.

Details of histologic pattern in intestinal Behçet's are difficult to find. 590, 591 The inflammatory infiltrate of Behçet's ulcer appears nonspecific. The lesions of so-called acute Behçet's ulcer closely resemble acute ischemic bowel disease. The chronic lesion of Behçet's disease resembles Crohn's disease except the transmural lymphoid aggregates in Behçet's disease contain more germinal centers, the bowel wall can be fibrosed, and granulomas are not usually encountered. Some authors have reported mononuclear cell infiltrates around capillaries and venules with some areas of fibrinoid necrosis. 588, 590 Indeed, large vessel inflammation with occlusion and aneurysm formation have been described in 3% to 25% of patients with Behçet's disease. 591, 592 Vasculitis may be the common underlying factor producing the GI lesions of Behçet's disease. 590

Late complications of irradiation can occur weeks to years after therapy and include colitis, stricture, ulcer, and fistula ( Fig. 23-85) . 593, 594 Many of these abnormalities may be related to ischemia as a result of the effect of radiation on blood vessels. Histologically, the mucosa appears atrophic and similar (often identical) to that seen in chronic UC. Having said that, the basal plasmacytosis in the lamina propria characteristic of primary IBD is usually but not always absent. Ectatic mucosal capillaries with thrombosis and hyalinization are important histologic signs that can point to irradiation effect ( Fig. 23-86 ). Irradiation may be associated with fibrosis of any of the layers of the bowel wall. The fibrosis can appear dense and hyalinized and may contain large, atypical radiation fibroblasts. Vascular changes are often prominent. Blood vessels may be ectatic in the mucosa and submucosa. More commonly, however, one encounters marked intimal fibroplasia with hyaline thickening of the blood vessel walls that leads to luminal stenosis.

Sharply demarcated ulcers sometimes with secondary bacterial overgrowth can often be seen in the colon and rectum proximal to obstructing lesions such as invasive carcinoma, or they can be seen in patients with intractable constipation and fecal impaction. 544, [595] [596] [597] The ulcer, bland in appearance, is thought to result from ischemia caused by a combination of pressure injury related to the hard fecal mass and the physiologic effects of bowel distention. 544, 598 

Many drugs or chemicals have been associated with ischemic-type changes in the colon, including hydrogen peroxide and glutaraldehyde (used to clean endo scopes), 349 NSAIDs, 350, 586, 599 cocaine, 350,600,601 oral contraceptives, and estrogen compounds. 348

Colitis can be caused by a host of bacteria including Campylobacter species, Shigella species, Salmonella species, Neisseria gonorrhoeae, Yersinia species, Mycobacterium species, and Aeromonas species. Although the histologic features of colonic mucosal biopsy specimens can vary greatly in these infections from essentially normal to lesions mimicking idiopathic IBD, large numbers of specimens show active colitis, as outlined earlier in the chapter, that when seen should suggest infectious-type colitis. 3, 323, 324, [326] [327] [328] [602] [603] [604] [605] [606] [607] [608] The histologic finding usually consists of the focal active colitis pattern of injury with relative preservation of mucosal architecture except for edema. The active inflammation is associated with little or no mucin depletion. Neutrophils can be present within the lamina propria and scattered cryptitis and crypt abscess formation, sometimes with luminal accentuation, can be seen. The definitive diagnosis of infectious colitis requires laboratory documentation by culture, PCR on the paraffin block, or serologic examination. Histologic evaluation, although helpful in suggesting infection, can only rarely point to a specific agent. True granulomas can be seen in tuberculosis, syp hilis, Chlamydia species infection, and Yersinia pseudotuberculosis infection. Microgranulomas are described in infection with Salmonella species, Campylobacter species, and Yersinia enterocolitica. Isolated mucosal giant cells are nonspecific but have been described in Chlamydia trachomatis infection. 330, 607 Some bacterial infections cause little inflammation but can be diagnosed by observation of adherent organisms such as with intestinal spirochetosis and adherent E. coli species. Although intestinal spirochetosis (infection with Brachyspira aalborgi or Brachyspira pilosicoli) can be seen in patients with human immunodeficiency virus (HIV) infection or AIDS, 609, 610 it is more frequently encountered in immunocompetent patients in whom its significance remains controversial. 609, [611] [612] [613] [614] The microscopic appearance is subtle, consisting of a thickening or accentuation of the colonic brush border that stains deeply with hematoxylin. This effect is caused by adherent spirochetes that align in parallel and embed themselves in the absorptive cells. Identification can be enhanced by use of a Warthin-Starry (or other silver) stain. The organism also cross-reacts with Treponema species immunostains. Adherent E. coli infections, described in HIV/AIDS under the term diarrheogenic bacterial enterocolitis, are discussed later.

GI involvement with Mycobacterium avium-intracellulare complex (MAIC) is seen in HIV/AIDS usually as part of disseminated infection. The organism is easily cultured from stool and even blood. MAIC can affect any part of the GI tract, including the large bowel. 615, 616 The characteristic histologic feature is infiltration of the lamina propria by foamy macrophages that can mimic muciphages. In addition, MAIC stains positive with PAS, a finding further adding to the possibility of misdiagnosis. MAIC is easily diagnosed with an acid-fast stain.

Cryptosporidium parvum infection can occur in immunocompetent persons but is more often seen in HIV/AIDS 617, 618 and occasionally can be seen in the colon (Fig. 23-87) . In biopsy specimens, cryptosporidial organisms are identified as basophilic dots measuring approximately 3 µm attached to the surface of the colonocyte. Immunocytochemical methods for identification have been described. 619 Amebiasis (infection with E. histolytica) is quite common worldwide and is seen in HIV/AIDS. 620 Clinical disease varies widely from asymptomatic conditions to fulminant colitis. Early lesions consist of a slight mucosal depression and erosion with adherent exudate containing trophozoites of E. histolytica (Fig. 23-88 ). Focal active colitis can also be seen. 608 More severe disease can cause ulcers that have been described as flask-shaped because they undermine the adjacent mucosa. E. histolytica is easily distinguished from the much larger Balantidium coli, which is only rarely seen in humans. 621 In addition, the trophozoite of B. coli is ciliated, the nucleus is much larger and kidney-shaped, and the cytoplasm contains vacuoles.

Schistosoma species infestation is a major cause of colitis worldwide but is rarely seen in North America. The adult worms elicit no inflammatory response. The colitis and the symptoms are caused by the marked inflammatory response to the eggs that can lead to mucosal ulcers ( Fig. 23-89) . Chronic colitis and inflammatory polyps can be seen in areas of endemic infection. 622 Strongyloidiasis is usually a self-limiting infection with adult worms residing in the proximal small bowel; the eggs develop into rhabdoid larvae in the lumen that pass in the stool. In immunocompromised patients, the rhabdoid larvae may develop into the infective filiform larvae. These infective larvae may invade intact colonic mucosa or perianal skin and set up a cycle of infection referred to as autoinfection. Many such infections are severe and often fatal. In colorectal biopsy specimens the infective larvae can be seen usually associated with marked infiltration of mucosa with the eosinophils (Fig. 23-90) . 622 Sometimes an eosinophilic and granulomatous reaction can be seen in biopsy and resection specimens. 623 Occasionally intraluminal worms are encountered in the colonic lumen and are removed at colonoscopy. These parasites are usually identified as Trichuris (whipworm) or Enterobius (pinworm) by examination of the worm and egg morphology. 622 

Common viral pathogens include adenovirus, rotavirus, coronavirus, echovirus, enterovirus, astrovirus, and Norwalk virus. Colorectal biopsy is rarely performed in the setting of viral gastroenteritis; therefore, histologic changes are not well documented. Norwalk virus and rotavirus are not known to cause morphologic changes in the colon. Adenovirus can cause diarrhea in HIV/AIDS. 608 Histologic changes affecting epithelial cells include cellular disorder with loss of orientation and degeneration. Eosinophilic viral intranuclear inclusions can be seen in surface goblet cells but are quite subtle. Immunohistochemical analysis can be performed as an aid to diagnosis.

CMV infection is extraordinarily common in patients with HIV/AIDS and in other immunosuppressed patients such as those receiving transplants. The characteristic inclusions are seen in endothelial cells, fibroblasts, and smooth muscle cells and are only rarely encountered in epithelial cells. 624 Severe infection can lead to vascular thrombosis and ischemic-type damage with ulcers (Figs. 23-92 and 23-93) .

Herpes simplex virus infection is associated with painful ulcers in the distal rectum and perianal skin. 625, 626 The pathologic changes (ulcer, neutrophils in the lamina propria, cryptitis, and crypt abscess formation) may suggest infec- 

Invasive candidiasis can be seen in severely debilitated patients and in patients with HIV/AIDS. This disorder is rarely encountered in colorectal biopsy specimens. Colorectal histoplasmosis can be seen in immunocompetent patients and in immunocompromised patients such as those with HIV/AIDS. 627, 628 In disseminated forms one can see collections of foamy macrophages. Some patients demonstrate granulomatous inflammation, which is sometimes suppurative. Diagnosis can be made using Gomori methenamine silver or other fungal stains.

Administration of any antibiotic that favors the growth of toxin-producing C. difficile can lead to pseudomembranous colitis. 629, 630 Early studies linked clindamycin and lincomycin to pseudomembranous colitis, but in terms of absolute numbers, most cases are linked to ampicillin, penicillin, the cephalosporins, and the fluoroquinolones (especially the C-8-methoxyfluoroquinolones gatifloxacin, and moxifloxacin) because of their far more prevalent use. 630, 631 Currently, the second-and third-generation cephalosporins and the fluoroquinolones are the leading instigators of C. difficileassociated colitis. [630] [631] [632] Pseudomembranous colitis has even been associated with antineoplastic chemotherapeutic agents that have antimicrobial activity. 633 In many cases, the source of Clostridium difficile infection is the patient's own gut flora. Alterations of the gut flora allow the patient's own C. difficile organisms to multiply. However, the spore-forming organism C. difficile is widely distributed in nature. Although cases may be acquired by these routes, increasing evidence indicates that C. difficile is often acquired in hospitals. 630, 632, 634 Indeed, reports of a previously uncommon strain of C. difficile, the NAP1 strain, showed that it is responsible for severe hospital outbreaks and serious disease in otherwise healthy individuals. 630, [635] [636] [637] [638] These reports of close-contact transmission, high recurrence rate, young age, bloody diarrhea, and lack of antibiotic exposure suggest changing epidemiologic features.

Advanced age is a risk factor; patients who are older than 65 years old have an approximately 20 times greater risk of developing C. difficile infection. 630 Statistically, C. difficile is associated with only a minority of cases of antibioticassociated diarrhea. In GI diseases other than primary IBD, isolation rates are about the same as in healthy adults. C. difficile is more frequently identified in patients with IBD and may be linked to exacerbations of IBD and fulminant colitis. 639, 640 Symptoms of pseudomembranous colitis usually develop during the administration of antibiotics but in up to one third of patients, the onset of symptoms can be delayed for up to 4 to 6 weeks; occasionally, no antibiotic exposure has occurred. 630, 636, 641, 642 The characteristic endoscopic and histologic lesion is found early in the course of the disease and only in some individuals. The surface of the mucosa is covered by a plaquelike, cream-colored to yellow pseudomembrane ( Fig. 23-94) . The intervening mucosa frequently appears normal but can be hyperemic or edematous. 345 With increasing severity, the membranes can become confluent and linear ulcers can develop. Usually the pseudomembranes are evenly distributed throughout the colon but in up to one third of patients, the pseudomembranes can be confined to the right colon. This finding emphasizes the need for total colonoscopy to make an endoscopic diagnosis.

Histologically, patchy necrosis of the superficial colonic crypts is evident that is not unlike that seen in ischemia. The affected crypts become dilated near the surface and an inflammatory exudate erupts from the surface aspect of the degenerating crypts in an explosive or mushroom-like configuration. The pseudomembrane may cover adjacent virtually normal colonic mucosa (Fig. 23-95 ). The karyorrhectic debris and neutrophils in the pseudomembranes tend to orient in a curious linear fashion within the fibrin and mucus. Early lesions of C. difficile and occasionally the mucosa between diagnostic pseudomembranes can show the focal active colitis pattern of injury frequently described in acute infectious-type colitis (acute self-limited colitis). 326, 327, 345 Left untreated, some cases of C. difficileassociated colitis progress and can become indistinguishable from ischemic bowel disease. Toxic megacolon and perforation can occur.

Treatment falls into three major categories: (1) nonspecific therapy, (2) specific therapy, and (3) therapies aimed at altering the gut flora. Nonspecific treatments include discontinuance of the offending antibiotic, supportive measures, enteric precautions to retard the spread of C. difficile outbreaks, and surgery. Surgical excision may occasionally be indicated 327 for patients too sick to take oral antibiotics (the specific therapy), as well as for some patients with relapses and for nonresponders. Toxic megacolon and perforation also require surgical treatment.

Specific therapies include the oral administration of antibiotics such as vancomycin, metronidazole, bacitracin, and the toxin binder cholestyramine. Vancomycin, the preferred treatment, is relatively expensive. 630 Bacitracin and metronidazole appear to be as effective as vancomycin and are less expensive. Theoretical disadvantages to metronidazole therapy include stool levels of the drug that appear far lower than those of vancomycin and the finding that metronidazole has occasionally been implicated as a cause of pseudomembranous colitis.

Treatment or prevention of pseudomembranous colitis by altering the gut flora with the introduction of such agents as Lactobacillus and Saccharomyces boulardii 630, 643, 644 has been studied. Saccharomyces boulardii was shown to decrease the incidence of antibiotic-associated diarrhea but did not change the rate of C. difficile colonization. Another provocative approach to prevention is to restrict the use of newer antibiotics such as third-generation cephalosporins and fluoroquinolones in the hospital setting. 632, 638 Patients with C. difficile-associated pseudomembranous colitis who are treated specifically show a 95% to 100% response rate usually with defervescence in 1 to 2 days and resolution of diarrhea in 5 days. However, 5% to 50% of patients have a relapse and relapse treatment can be challenging. Most investigators recommend a second course of the same antibiotic (metronidazole or vancomycin) for 14 days. 645 For a second recurrence, tapered-pulsed vancomycin is advised. 630 For a third or subsequent recurrence, a probiotic or toxin binder is added to tapered-pulsed vancomycin therapy. Newer treatments for recurrences include passive immunoglobulin therapy, toxin receptor decoys (e.g., tolevamer), and active immunization against toxin A. 645 Stool culture for C. difficile is usually not recommended but some investigators report a significantly higher yield of positive results based on fecal culture followed by toxin assay on positive colonies. 646 Cell culture assay for toxin B is not routinely performed. Results of latex agglutination tests have been disappointing. 647 Enzyme-linked immunoassays (EIAs) that detect toxin A (Meridian Diagnostic, Vitec, BD, and Cambridge) or toxin A and toxin B are widely used. 630 These assays have a 90% to 95% positive correlation with cell culture assay. Commercially available tests that detect toxin A and toxin B are preferred because 1% to 2% of C. difficile strains produce only toxin B. 629, 630 An alternative and more sensitive but slower approach is to perform an EIA for the detection of common antigen (a highly sensitive marker for C. difficile) followed by a cytotoxic assay if the results of the EIA are positive. 630 Various gene probes and PCR techniques that detect toxin at the DNA level are available for research purposes. 648 enterohemorrhagic escherichia coli-associated colitis

The clinical syndrome of hemorrhagic colitis is characterized by abdominal cramping, bloody diarrhea, and either no fever or low-grade fever. 346, 649 Patients typically demonstrate right-sided colonic edema, erosion, and hemorrhage and the absence of conventional enteric pathogens. In 1983, investigation of hemorrhagic colitis outbreaks occurring in Oregon and Michigan implicated a then-rare serotype of E. coli, O157:H7, as the cause of the syndrome. 650 Subsequently, investigations of several additional outbreaks confirmed the association between hemorrhagic colitis and the verocytotoxin-producing E. coli, the most important of which is E. coli O157:H7. 651 Patients with hemorrhagic colitis typically present with the sudden onset of crampy abdominal pain occurring 3 to 4 days after ingestion of contaminated food, usually undercooked hamburger. Outbreaks have also been linked to other foods, drinking water, and swimming pools. 652 Watery diarrhea, nausea, and vomiting follow within hours. One to 2 days later, grossly bloody diarrhea replaces the watery diarrhea. In almost all patients, the disease resolves spontaneously, usually within 8 days. Investigation of the epidemic outbreaks of E. coli O157:H7 infection revealed that not all patients acquire the full syndrome of hemorrhagic colitis. Rather, a clinical spectrum exists ranging from asymptomatic carrier or self-limited nonbloody diarrhea to severe cases complicated by hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura. 651, 653, 654 E. coli O157:H7 produces several toxins active against vero cells (verocytotoxins) and HeLa cells that have been termed Shiga-like toxins because their mode of action is similar to that of the toxin produced by Shigella dysenteriae type I. The toxins interact with the membrane receptor globotriosyl ceramide, are apparently absorbed into epithelial and endothelial cells, and cause damage or cell death by interfering with protein synthesis. 651, 655 Colonic histologic features in EHEC infection are the best documented of the diarrheogenic E. coli organisms because EHEC infection can lead to hospitalization and it clinically mimics ischemia and primary IBD, thus prompting colonoscopy with biopsy. 346, 656, 657 Colonoscopy typically demonstrates patchy erythema, edema, and surface ulceration of the colon (Fig. 23-96) . The cecum and right colon are usually described as markedly abnormal, whereas the descending colon typically has mild or no changes. Histologically, specimens usually show hemorrhage and edema within the lamina propria. Specimens most often show focal necrosis associated with hemorrhage and acute inflammation within the superficial mucosa with preservation of the deep colonic crypts, similar to the pattern of injury described in acute ischemic colitis. Specimens from many patients show neutrophils infiltrating the lamina propria and crypts resembling the focal active colitis pattern of injury seen in infectious colitis or acute self-limited colitis ( Fig. 23-97 ). Rarely patients also demonstrate inflammatory pseudomembranes. This combination of ischemic-like and infectious-like injury with capillary thrombi should at least suggest EHEC-associated colitis in biopsy specimens.

Routine stool culture media do not enable one to distinguish E. coli O157:H7 from other strains of E. coli normally found in the stool. Physicians suspecting hemorrhagic colitis caused by E. coli O157:H7 should specifically request that stools be screened for this organism. Specimens may be examined using sorbitol fermentation as a strain marker; unlike most E. coli organisms, E. coli O157:H7 strains test negative for sorbitol or have delayed positive results. 658 Colonies that test negative for sorbitol at 24 hours can be screened with commercial O157 antisera. Additional biochemical tests and H-antigen determinations can be performed later. 346 DNA hybridization techniques, PCR, direct immunofluorescence, and latex agglutination techniques have also been described for identification. Procedures for detection of free fecal verocytotoxin and more sensitive methods for screening stool cultures for verotoxinproducing E. coli using polymyxin B on colony sweeps have been reported. 651, 652 other escherichia coli pathogens E. coli organisms are the predominant components of the gut microflora. Although most of these organisms are harmless or even beneficial, at least six categories of E. coli intestinal pathogens are recognized (Table 23-9) . 659, 660 Much is known about the microbiology, pathogenic mechanisms, virulence factors, molecular genetics, and epidemiology of intestinal E. coli infections. However, surprisingly little is known about the histopathologic features of the human gut infection. Information remains scant because most infectious diarrheas, being self-limited, do not require specific treatment even when an infectious organism is identified. Therefore, sophisticated diagnostic tests such as organism identification, virulence factor determination, and endoscopy with biopsy are reserved for outbreaks or for cases with unusual features (e.g., severe or protracted diarrhea, systemic symptoms, need for hospitalization, or a differential diagnosis including serious diseases such as primary IBD or ischemia).

Analysis of the information available yields limited numbers of reaction patterns in E. coli-associated infection that have been described in the human gut or inferred from in vitro models or from human infection with other organisms having similar virulence factors. These include the following: no histologic change ( ETEC organisms are thought to adhere to and colonize the surface of the small bowel where they elaborate their toxins. 659 It is possible that a serendipitously obtained small bowel biopsy specimen may contain adherent surface bacteria. Histologic appearances of the small bowel and colon are inferred from ETEC's close relationship with Vibrio cholerae, which does not cause histologically recognizable lesions in the small bowel or the colon. Therefore, normal colon would be expected in ETEC-associated diarrhea. It is possible that ETEC could cause some acute self-limited colitis. Recognizing the difficulty in identifying pathogenic E. coli in routine stool culture, it is possible that EIEC and EHEC could otherwise be responsible for some cases of acute self-limited colitis.

As stated earlier, diffuse active colitis was also seen in some examples of documented cases of infectious colitis. These infectious colitis cases were associated with an epidemic outbreak of Shigella dysentery. Because the pathogenic features of Shigella species are virtually identical to those of EIEC, it is possible that EIEC may on rare occasions cause the diffuse active colitis pattern of injury. That said, EIEC infection with this pattern of injury may represent an infectious exacerbation of underlying primary IBD.

The ability to adhere to and colonize host enterocytes or colonocytes is requisite for human infection for all six recognized categories of diarrheogenic E. coli. However, EPEC, EAEC, and DAEC, which are traditionally referred to as the enteroadherent E. coli, are best differentiated on the basis of their adherence patterns to HEp-2 cells in culture. These patterns include localized adherence (EPEC), aggregative adherence (EAEC), and diffuse adherence (DAEC). 659 The human gut histopathologic features in EPEC in vivo have been described 661, 662 and are similar to those seen in experimental animal models. 663 Jejunal biopsy specimens have demonstrated variable villous abnormalities without acute inflammation. 661, 662 Adherent bacteria could be identified on routine H&E-stained sections on the luminal surface. Adherent surface bacteria have also been seen in colorectal biopsy specimens. 661 The characteristic attaching and effacing lesion can be recognized only by the use of electron microscopy. 659, 661, 662 The bacteria intimately adhere to the host cell by an attachment pedestal and cause effacement of the adjacent microvilli.

Human histopathologic features associated with EAEC and DAEC infection can be inferred only from animal models and in vitro studies. 659, [664] [665] [666] Presumably, bacteria adhere to the surface epithelium of the small intestine and the colon. 667 EAEC and DAEC infection may be associated with variable villous abnormalities. Electron microscopic study has shown adherent bacteria in cell culture with a normal microvillous structure. In the colon, EAEC produces cytotoxic effects ultrastructurally (microvillous vesic- ulation, enlarged crypt openings, creation of intercrypt crevices, and mucosal epithelial cell extrusion). 667 The most detailed description of human ileal and colorectal infection with EPEC, EAEC, and possibly DAEC probably is found in a published review of patients with AIDS. 668 Unfortunately, the exquisite light and electron microscopic descriptions of these diarrheogenic bacterial enterocolitides were not complemented by microbiologic studies. Therefore, identification of these organisms as E. coli rests on the pathologic similarity to other reported cases and preliminary isolation studies that have shown that at least some of these cases were caused by EAEC and DAEC. 668 The colonic histologic pattern showed surface epithelial degeneration with adherent bacteria (some extremely subtle) without colonic architectural distortion or significant inflammation. Electron microscopic examination demonstrated three patterns: (1) typical adhering and effacing lesions (as with EPEC), (2) a loosely adherent pattern with effacement (as with EAEC), and (3) an intercalated pattern with effacement in which vertically oriented bacteria were seen burrowing between intact microvilli. The intercalated pattern could be DAEC in vivo because it is similar to the pictures and descriptions of DAEC in other in vitro and animal models. 666 

The term intestinal pseudo-obstruction describes a disorder in which patients present with signs and symptoms of intestinal obstruction and in whom no mechanical obstructive lesion can be demonstrated. 669 Intestinal pseudoobstruction can be associated with a heterogeneous group of conditions some of which can affect the colon. [669] [670] [671] Systemic lupus erythematosus, dermatomyositis, and scleroderma can cause fibrosis of the muscularis externa. 669, 671 Amyloid deposits can also affect colonic motility. 672 Visceral myopathies can occasionally be identified in the colon. Recognized variants of familial visceral myopathy demonstrate differences in the mode of inheritance (autosomal dominant versus recessive), site of gut involvement, clinical symptoms, and extraintestinal manifestations. Visceral myopathies also occur in sporadic form. 673 The intestinal pathologic changes of many familial and sporadic visceral myopathies are identical and consist of muscle cell degeneration, muscle cell loss, and fibrosis of the muscularis externa. The degenerative fibers appear swollen and rarified. Collagen may encircle the residual muscle fibers in areas of muscle fiber dropout and impart a vacuolated appearance. 671, 673, 674 These changes are often limited to, or are more severe in, the external layer of the muscularis externa.

The differential diagnosis of these forms of visceral myopathy includes other entities that cause fibrosis of the muscularis externa and encompasses ischemia, tuberculosis, and scleroderma. Ischemia usually is associated with a fibrous stricture and hemosiderin deposits. Tuberculosis typically causes strictures and granulomas, often with central necrosis. Progressive systemic sclerosis is associated with more patchy bowel involvement than are the visceral myopathies. The fibrosis is often denser and replaces all the muscle layers of the muscularis externa or is accentuated in the inner layer ( Fig. 23-99 ). Vacuolar change is usually not seen with progressive systemic sclerosis. 671

The visceral neuropathies 675-681 form a complex group of unusual entities that vary in their pattern of inheritance, the extent of intestinal and extraintestinal involvement, and the nature of the histologic changes in the neural plexuses of the gut. Many of the neuronal and axonal changes are subtle; with the exception of inflammatory neuropathies 675 and some neuropathies associated with intranuclear or intracytoplasmic inclusions (e.g., red cytoplasmic inclusions in ganglion cells of mitochondrial neurogastrointestinal encephalomyopathy), 677 they cannot be recognized in routine H&E-stained sections. Difficult and unusual cases should probably be referred for consultation to pathology departments with particular expertise in the evaluation of visceral neuropathies. That said, referral is rarely indicated clinically. Some sporadic cases demonstrate mononuclear inflammation in the myenteric plexuses, and these cases can be identified by routine light microscopy. 678, 679 Some of these cases are manifestations of paraneoplastic syndromes often linked to small cell carcinoma of the lung. 680 Others are postinfectious. 675 The inflammatory neuropathies can sometimes cause acquired aganglionosis and can be associated with circulating antibodies, such as anti-Hu, (ANNA-1, antineuronal nuclear antibody-1), anti-Ri, and anti-Yo (Purkinje cell cytoplasmic autoantibody). 680, 681 An acquired form of hypoganglionosis associated with buserelin-induced formation of anti-GnRH (anti-gonadotropin-releasing hormone) antibodies has been reported. 682 Investigators now recognize the role interstitial cells of Cajal (ICCs) play as gut pacemakers and as mediators of neurotransmission. 683, 684 ICCs stain specifically with the tyrosine kinase receptor c-kit. 685 Immunohistochemical analysis for c-kit (CD117) and for CD34 (which reacts with many c-kit receptors) represents a relatively easy way to study severe constipation and intestinal pseudoobstruction. Streutker and colleagues 685 described completely absent or markedly reduced numbers of ICCs in some cases of intestinal pseudo-obstruction. Reduced volumes of ICCs have also been described in some patients with slow-transit constipation. [685] [686] [687] [688] [689] Although the observations could be an epiphenomenon, they could form the basis of an alternate classification system for these cases.

Severe intestinal malabsorption for whatever reason (e.g., celiac sprue, cystic fibrosis) can be associated with dark brown or orange-brown discoloration of the bowel wall, 690, 691 owing to deposits of a granular material that has the characteristics of lipofuscin in the smooth muscle of the muscularis externa and to a lesser degree the muscularis mucosae ( Fig. 23-100 ). This excessive accumulation of lipofuscin is termed ceroidosis or the brown bowel syndrome. Whether this pigment deposition adversely affects muscle function is debated; however, damage to smooth muscle mitochondria has been described, and several reports have linked ceroidosis to intestinal pseudo-obstruction. 692 Because of the name brown bowel syndrome, ceroidosis may be confused with melanosis coli (discussed in the next section).

Melanosis coli is a condition in which macrophages filled with lipofuscin-like pigment are found within the lamina propria or deeper in the wall of the colon (Fig. 23-101) . 693, 694 These macrophages may be of such numbers as to impart a brown or black color to the colonic mucosa ( Fig. 23-102) . Melanosis coli has been associated with increased apoptosis, which is often linked to ingestion of purgatives of the anthracene group (Cascara sagrada, aloe, rhubarb, senna, frangula). [695] [696] [697] One group of patients has severe and persistent constipation with no apparent cause (idiopathic constipation or morbid obstipation). These patients, usually women, can have as little as one bowel movement every 1 to 4 weeks, 673 and many of these patients are so uncomfortable that they require colectomy for relief. [698] [699] [700] [701] Because these patients almost invariably take laxatives, melanosis coli is usually found. What is so frustrating to the pathologist is that by H&E staining, the neuronal plexus and smooth muscle in these patients appear normal. Distinctive abnormalities of the myenteric plexuses (e.g., loss of "argyrophilic" neurons) have been reported using special silver staining techniques. 673, 693, 701, 702 These tests are best performed by pathology departments with expertise in this area. Reduced volumes of ICCs have been described in some patients with severe constipation. 685, 689 Cathartic colon is the name given to end-stage idiopathic constipation in which the bowel can no longer contract effectively. The mucosa has the gross appearance of snakeskin and histologically shows melanosis coli. The muscularis propria is thin and atrophic, and neurons are decreased in Auerbach's plexus.

Hirschsprung's disease (aganglionic megacolon) has a predilection for boys and men. Approximately 90% of patients present in infancy with constipation, abdominal distention, vomiting, and delay of meconium stool; diarrhea may occur 703 and some patients may even be affected by lifethreatening enterocolitis. Reports suggest that many cases of Hirschsprung's disease have a genetic basis. Both Hirschsprung's disease and MEN2 are associated with mutations of the RET proto-oncogene. [704] [705] [706] In cases of MEN2, the mutations are activating and enhance the function of the coded protein, whereas in Hirschsprung's disease the mutations are inactivating. Several cases of familial Hirschsprung's disease have been linked to mutations of the endothelin receptor-B (ENDRB) gene. 707 At least nine additional genes have been implicated in the pathogenesis of Hirschsprung's disease: NTN (seen only with RET mutations), GDNF, EDN3, ECE-1, SOX10, PHOX2B, ZFHX1B, L1CAM, and 7DHCR. 706 Despite this progress, mutations of one or more of the known genes are detected in only half the patients with Hirschsprung's disease.

In the typical clinical picture of Hirschsprung's disease, the anus is normal. The anal canal and rectum are usually small and devoid of stool. In classic cases, these physical findings are confirmed by barium enema study. The contrast material flows into an unexpanded distal segment, then passes through a cone-shaped area, and finally passes into the dilated proximal bowel (Fig. 23-103) .

The pathologic change is aganglionosis. The narrowed distal segment shows loss of ganglion cells in both the submucosa and myenteric plexuses, usually accompanied by hypertrophy of the muscularis mucosae and muscularis externa and increased numbers of nerve fibers in the submucosa and between the muscle layers of the muscularis externa. 708 Hypertrophied nerve fibers (>40 µm) derived from the extrinsic and sensory fibers are observed in many but not all cases of Hirschsprung's disease. In the tapered or cone-shaped region, the number of ganglion cells may be decreased (hypoganglionosis).

Historically, histologic diagnosis was based on fullthickness rectal biopsy specimens. However, this procedure requires general anesthesia and risks the development of stricture and perforation. Because the submucosal and myenteric plexuses stop at about the same level in Hirschsprung's disease, 708, 709 suction biopsy that samples the mucosa and submucosa is now considered the method of choice for the diagnosis. All rectal biopsy specimens for suspected Hirschsprung's disease should be serially sectioned throughout the block and each section examined. 708, 710 If no ganglion cells are found, then some comment should be made concerning the adequacy of the specimen. Biopsy specimens devoid of ganglion cells, but in which the amount of submucosa is less than the thickness of the mucosa, should be considered insufficient to diagnose Hirschsprung's disease. 708 If the biopsy specimen contains epithelium of the anal canal, this specimen should also be considered inadequate, because the anal canal and distal 2 cm of rectum are normally hypoganglionated or aganglionated.

Many pathologists prefer to examine frozen section slides stained for acetylcholinesterase in addition to standard H&E-stained sections. In Hirschsprung's disease, examination using the acetylcholinesterase stain demonstrates increased acetylcholinesterase-positive nerve fibers in the lamina propria and muscularis mucosae. The utility of this technique as an adjunct to diagnosis is debated. False-positive and false-negative reactions have been reported, and the use of this method is a matter of personal preference. [711] [712] [713] Occasionally, ganglion cells may be difficult to identify using light microscopy alone, especially in the neonate. 708 In such cases, a positive immunohistochemical reaction for neuron-specific enolase can be valuable in documenting ganglion cells. 714 We have been successful in performing immunohistochemical analysis for neuron-specific enolase on sections after they have been stained with H&E and examined. Other immunostains such as cathepsin D, PGP 9.5 (protein gene product 9.5), RET, BMPR1A (bone morphogenetic protein receptor type 1A), and bcl-2 decorate ganglion cells. 710, 715 Frozen section is often used as an adjunct to visual inspection to select the site for colostomy. However, use of the frozen section to establish a primary diagnosis of Hirschsprung's disease is best avoided because of the high rate of incorrect interpretations. 716

In 90% of patients with Hirschsprung's disease, the aganglionic segment of colon is less than 40 cm in length. The remaining patients have longer aganglionic segments that may extend even into the small intestine. 673 Microscopically, the hypertrophied nerve trunks of short-segment Hirschsprung's disease are absent, but increased numbers of acetylcholinesterase-positive mucosal nerve fibers are usually but not always seen. 717

Ultrashort-segment Hirschsprung's disease (segments <2 cm) reportedly exists but is impossible for a pathologist to document by routine H&E stains of the rectal mucosa and submucosa alone because this segment of the colon is relatively hypoganglionated or aganglionated even in physiologically normal individuals. Rectal manometry may be used in the diagnosis of this lesion. Recognition of acetylcholinesterase nerve abnormalities similar to those seen in Hirschsprung's disease may complement that study. Some patients may have internal sphincter achalasia with abnormalities of nitric oxide-induced sphincter relaxation. Regardless of pathogenesis, some patients benefit from sphincterotomy.

Hypoganglionosis is regularly observed in the cone-shaped transition zone between normal and aganglionic bowel in Hirschsprung's disease. 673 Some authors believe that diffuse hypoganglionosis of the colon may give rise to megacolon similar to that observed in Hirschsprung's disease. 708, 718 No accepted definition of hypoganglionosis exists; however, guidelines were offered by Meier-Ruge. 717 This study suggested that a decrease by a factor of 10 in the number of ganglion cells per centimeter of bowel as compared with normal (40 to 80 myenteric plexus neurons/cm bowel) is diagnostic of hypoganglionosis. 717 Other investigators have accepted much higher numbers of ganglion cells as evidence of hypoganglionosis. 719 In general, the condition has not been well characterized and many reports lack quantitation. 673 Diverse abnormalities have been described by special silver staining in cases that would have been called hypoganglionosis by H&E staining results, 720 and some cases of "hypoganglionosis" may be similar to those cases reported as severe idiopathic constipation or cathartic colon.

Intestinal neuronal dysplasia is characterized by hyperplasia of the myenteric plexuses, increased acetylcholinesterase activity in nerves of the lamina propria and submucosa, and increased numbers of ganglion cells with the formation of giant ganglia. 719, [721] [722] [723] These giant ganglia, typically containing more than 7 to 10 neurons (normal ganglia contain 3 to 5), make up only 3% to 5% of all ganglia seen in a given case and are usually not seen in the distal 7 cm of the rectum. 724 Occasionally, ganglion cells may be found within the lamina propria but this feature should not be considered diagnostic for intestinal neuronal dysplasia because it can be seen in physiologically normal individuals. 725, 726 The condition may give rise to signs and symptoms similar to those seen in Hirschsprung's disease. Intestinal neuronal dysplasia may occur in a localized or disseminated form. Similar lesions sometimes referred to as ganglioneuromatosis can be observed in patients with von Recklinghausen's disease or MEN2B. 673, 722, 723 Although some clinicians diagnose intestinal neuronal dysplasia based on abnormal acetylcholinesterase staining in specimens containing ganglion cells, others believe that one cannot rely on acetylcholinesterase staining alone for the diagnosis. 727 Diagnostic criteria for intestinal neuronal dysplasia and even its very existence are challenged 727,728 because 95% of infants so diagnosed experience normalization of gut motility within 1 year. Therefore, many of the observed "abnormalities" could be within normal range and in general the diagnosis should be reserved for florid pathologic cases. 729

In zonal aganglionosis or skip-segment Hirschsprung's disease, ganglion cells are found distal to one or more aganglionic segments. [729] [730] [731] Evidence suggests that zonal aganglionosis is rare and is likely to be acquired by ischemia (e.g., necrotizing enterocolitis), viral infection, or some other (e.g., immunologic) injury. The problem is that a rectal biopsy specimen may yield ganglion cells in spite of an authentic Hirschsprung's disease-like aganglionic lesion. Immaturity of ganglion cells 673, 717 and hypogenesis of myenteric plexuses 717, 718 have been reported to cause signs and symptoms similar to those seen in Hirschsprung's disease. Immunostains for bcl-2 may be helpful in detecting immature ganglion cells. 719 

The GI tract is a common site for amyloid deposits; such deposition has been documented in 70% of primary amyloidosis cases and in half of secondary cases. 672, 732, 733 Occasionally the deposition is symptomatic and causes ischemic manifestations such as bleeding diarrhea or infarct, sometimes referred to as amyloid colitis. On rare occasions, the deposits can be localized and form a tumor. 734 The AA (secondary) type of amyloid primarily deposits in the lamina propria and walls of blood vessels; the AL (primary or myeloma-associated) type tends to accumulate preferentially in blood vessel walls and in the muscularis externa. 672, 735 Amyloid can be subtyped using immunohistochemical analysis. 736 Although subcutaneous biopsy or aspiration is an easy way to obtain tissue for diagnosis, rectal biopsy is still widely used to diagnose amyloidosis. 735, 737 

The term pneumatosis cystoides intestinalis (PCI) describes the occurrence of gas-filled cysts within the bowel wall. The large intestine is a common site of involvement; benign and fulminant forms have been described. 738, 739 The fulminant form of PCI is most often seen in infants as a complication of ischemia. PCI in this setting is caused by mural invasion by gas-forming bacteria and subsequent formation of cysts (see Fig. 23-84) . The fulminant form can be seen in adults sometimes in association with drugs such as antineoplastic chemotherapeutic agents or in pseudomembranous colitis. 739 Histologically, one sees ischemic change, bacterial overgrowth, and gas cysts predominantly within the submucosa. It is easy to dismiss the gas cysts as cutting artifact because an endothelial or histiocytic lining is rarely seen in this form of PCI.

The benign form of PCI is most often seen in adults and is usually asymptomatic, 738 although diarrhea, constipation, and rectal bleeding have been documented. 738, 740 Benign PCI is often seen with comorbid conditions that either increase intraluminal pressure or provide a breach in mucosal integrity by which the gas can enter the bowel wall. These conditions include chronic obstructive pulmonary disease, emphysema, diverticular disease, appendicitis, cholelithiasis, peptic ulcer disease, abdominal trauma, Crohn's disease, and GI tract surgery. 738, 739 At endoscopy, mucosal broadbased elevations that are sometimes semitranslucent have been described. Resection specimens often show crepitance. Microscopic analysis demonstrates occasional tears in the submucosal connective tissues, but more often one sees dilated spaces lined totally or partially by endothelium, inflammatory cells, histiocytes, and marked foreign body giant cell reaction (Fig. 23-104 ). 741 The principal differential diagnostic consideration is the entity referred to as pseudolipomatosis. 742, 743 Pseudolipomatosis resembles fatty infiltration of the lamina propria but ultrastructural study convincingly demonstrates that the spaces are, in fact, gas cysts ( Fig. 23-105 ). Pseudolipoma-tosis has been associated with air inflation used to distend the bowel during colonoscopy. Some investigators have implicated cleaning agents used to disinfect colonoscopes.

The term fibrosing colopathy has been applied to colonic strictures seen in some patients with cystic fibrosis. 744, 745 The pathologic change is submucosal fibrosis, which can sometimes extend into the muscularis externa. Fibrosing colopathy has been linked to administration of high-dose pancreatic replacement therapy.

Large bowel agenesis and atresia are extremely rare. 746, 747 Congenital atresia and stenosis are associated with failure to pass meconium, abdominal distention, and vomiting. These conditions are often seen on a background of other congenital anomalies. Pathologically, one can see an imperforate septum, a portion of the colon replaced by fibrous cord, or the absence of a segment of colon and associated mesentery.

Colonic malrotation occurs with malrotation of the small bowel and is associated with abnormal anatomic relationships and fibrous bands; it may predispose patients to volvulus. 747, 748 Mispositioning of the cecum and appendix may lead to delayed diagnosis of acute appendicitis. 

Congenital duplications and diverticula are located within the mesentery and often occur in combination with other congenital malformations. 749, 750 Sometimes, the duplications are tubular, represent doubling of the bowel, and run parallel to the colon and rectum. Other duplications can become cystic and are often referred to as enterogenous cysts. Patients may have associated spine abnormalities. We classify tubular duplications that communicate with the lumen at one end as congenital diverticula. Small duplications and diverticula are usually asymptomatic. Larger ones may cause mass lesions, abdominal pain, constipation, or bleeding. Hindgut duplications may be associated with complex genital and urinary tract abnormalities.

Duplications and congenital diverticula usually have organized layers of smooth muscle sometimes with a nerve plexus within their walls. Mucosal linings if present resemble colon, respiratory epithelium, or gastric mucosa. As lesions enlarge to become cystic, the lining and the wall can become atrophic. 751 The retrorectal space is a relatively common location for developmental cysts that can become symptomatic in adults. [752] [753] [754] Epidermoid or dermoid cysts are unilocular, are lined by squamous epithelium, and may contain adnexal structures (dermoid cyst) and lack smooth muscle in the wall. Rectal duplications can become cystic. Rectal duplications are also unilocular, are lined by colonic, gastric, or respiratory epithelium, and have an organized muscular wall that recapitulates the muscularis externa. The retrorectal cystic hamartoma is often referred to as a tailgut cyst. This lesion manifests as a multilocular cystic and solid tumor ( Fig. 23-106) . The variably sized cysts can be lined by squamous, transitional, or glandular epithelium. Disorganized bundles of smooth muscle are found within the wall. Inflammatory changes such as a foreign body giant cell reaction are quite common. Developmental cysts in the retrorectal space are susceptible to infection and fistula, and associated malignancy has been reported. 754 Therefore, total excision is recommended.

The histologic changes associated with acute chemotherapyor radiation-induced colitis are similar. Necrosis, ulcer, and inflammation occur usually within 2 weeks of the cessation of therapy. 593, 755, 756 Epithelium lining the colonic tubules often shows marked enlargement with large atypical nuclei and loss of intracellular mucin (Fig. 23-107 ). Apoptotic bodies similar to those seen with grade 1 GVHD may be prominent. 757 Typically, the acute changes subside in 1 to 2 months. 755, 758 The epithelial atypia seen as a result of acute irradiation and chemotherapy can be alarming and may mimic the appearance of glandular dysplasia and carcinoma. Features favoring chemotherapy or radiation effect over dysplasia or carcinoma include (1) overall preservation of mucosal architecture, (2) bizarre atypia, (3) maintenance of a relatively low nuclear-to-cytoplasmic size ratio despite cellular enlargement and nuclear atypia, (4) a paucity of mitotic figures, (5) recognition of similar atypia in nearby fibroblast and endothelial cells, and (6) lack of an infiltration pattern in tumor desmoplasia. 759 The taxanes can cause epithelial changes that can mimic high-grade glandular dysplasia 760 similar to the changes seen with colchicine toxicity. 761 The histologic changes include increased apoptosis, increased mitotic figures, and "ringed" mitotic figures that correlate with metaphase arrest (Fig 23-108 ). The nuclear stratification and loss of polarity can mimic dysplasia. 760, 761 

Late complications of radiation-induced change are better documented than are antineoplastic chemotherapy effects and may occur weeks to years after therapy. 593 These late complications of radiation include chronic colitis, stricture, ulcers, and fistula. 594 The histologic pattern resembles that of ischemic damage with mucosal atrophy and architectural change. Mucosal and submucosal blood vessels can become ectatic. Fibrosis occurs and often resembles hyalin. Fibrosis can affect any bowel layer, including the muscularis externa. Atypical radiation-type fibroblasts can persist for years. Other vascular changes include intimal fibroplasia, accumulation of foamy macrophages in blood vessel walls, and luminal stenosis.

Epiploic appendices are pedunculated, serosa-covered accumulations of adipose tissue seen on the lateral aspects of the colon. They can become very large in obese individuals. The pedicles of epiploic appendices are thin and prone to torsion, a feature that can cause infarct and even amputation. Infarcted epiploic appendices can appear as fine, graywhite nodules attached to the bowel or even can be found loose within the abdomen at surgery. These appearances can mimic metastatic carcinoma or foreign body. The subsequent biopsy specimen can be confusing to the pathologist who is asked to identify the frozen section. Microscopically, these lesions show a central zone of infarct with mummification of the adipose tissue surrounded by a variable amount of fat necrosis and calcification. The outermost portion usually shows fibrosis. 762

Pacinian corpuscles occur in many areas of the body. Although most are noted in the skin, they occur in the base of the mesentery. For unknown reasons, these intraabdominal pacinian corpuscles can enlarge up to 1.0 cm or more and thus can mimic tumor implants or carcinomatosis. 763, 764 They also may be a source of confusion to the surgical pathologist asked to identify them at frozen section and are often misinterpreted as nematodes. Histologically, this specialized end organ resembles its cutaneous counter-part. A central blood vessel and nerve are surrounded by tortuous, roughly concentric lamellae (Fig. 23-109 ).

Extravasation of barium sulfate used in radiologic examination outside the lumen of the colon and rectum may elicit an inflammatory response often referred to as a barium granuloma. These lesions are usually encountered coincidentally in resection specimens in biopsies performed for IBD. Rarely, this inflammatory reaction can produce a polypoid mass or ulcerated lesion that mimics neoplasm. 765 Microscopically, barium sulfate appears olive green and is refractile, especially with the microscopic condenser lowered (Fig. 23-110 ). The small granular crystals do not bend polarized light and coalesce within connective tissue and macrophages. Water-soluble contrast media such as Gastrografin (sodium amidotrizoate and meglumine amidotrizoate) tend not to cause an exuberant inflammatory response. Gastrografin morphologically is composed of larger rectangular or rhomboidal light tan to pale yellow crystals.

Tumors of the Intestines. Atlas of Tumor Pathology

Histology for Pathologists

Mucosal biopsy of the rectum colon and distal ileum

Golytely lavage versus a standard colonoscopy preparation: Effect on normal colonic mucosal histology

Endoscope-induced colitis: Description, probable cause by glutaraldehyde and prevention

Morphological consequences of bisacodyl on normal human rectal mucosa: Effect of a prostaglandin E1 analog on mucosal injury

Guidelines for the initial biopsy diagnosis of suspected chronic idiopathic inflammatory bowel disease: The British Society of Gastroenterology Initiative

Muciprotein-containing histiocytes (muciphages) in the rectum

Histochemical and immunohistochemical characterization of foamy histiocytes (muciphages and xanthelasma) of the rectum

Nomenclature problems with gastrointestinal epithelial neoplasm

Histologic Typing of Intestinal Tumours

Dysplasia and early carcinoma in inflammatory bowel disease and colorectal adenoma

Guidelines for colonoscopy surveillance after polypectomy: A consensus update by the US Multi-Society Task Force on Colorectal Cancer and the

World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Digestive System

Distribution of human colonic lymphatics in normal, hyperplastic, and adenomatous tissue: Its relationship to metastasis from small carcinomas in pedunculated adenomas, with two case reports

Prognostic factors in colorectal carcinomas arising in adenomas: Implications for lesions removed by endoscopic polypectomy

Differences in the diagnostic criteria used by Japanese and Western pathologists to diagnose colorectal carcinoma

Problems arising from Eastern and Western classification systems for gastrointestinal dysplasia and carcinoma: Are they resolvable?

The Vienna classification of gastrointestinal epithelial neoplasia

The care of patients with colorectal polyps that contain invasive adenocarcinoma: Endoscopic polypectomy or colectomy?

Surgical pathology of endoscopically removed malignant polyps of the colon and rectum

Management of patients who have polyps containing invasive carcinoma removed via colonoscope

Histopathology and prognosis of malignant colorectal polyps treated by endoscopic polypectomy

When is endoscopic polypectomy adequate therapy for colonic polyps containing invasive carcinoma

Malignant colorectal polyps: Venous invasion and successful treatment by endoscopic polypectomy

Position paper polyp guideline: Diagnosis, treatment, and surveillance for patients with nonfamilial colorectal polyps

Polyp guideline: Diagnosis, treatment, and surveillance for patients with colorectal polyps

Malignant colon polyps: Cure by colonoscopy or colectomy?

Rational management of malignant colon polyps based on long-term follow-up

Endoscopic polypectomy of the large bowel: Management of cancer-bearing polyps

Management of patients with polyps containing malignancy removed by colonoscopic polypectomy

Colonoscopic polypectomy in diagnosis and management of cancerous adenomas: An individual and multicentric experience

The treatment of pedunculated adenomatous colorectal polyps with focal cancer

Definitive treatment of "malignant" polyps of the colon

Early colorectal cancer: Follow-up after endoscopic polypectomy

Patient management after endoscopic removal of the cancerous colon adenoma

Abdominal surgery

Epidemiology, management, and prognosis of malignant large bowel polyps within a defined population

The rationale for current practice in the management of malignant colonic polyps

Long-term prognosis of well-differentiated adenocarcinoma in endoscopically removed colorectal adenomas

Management and outcome of patients with invasive carcinoma arising in colorectal polyps

Significance of histologic criteria for the management of patients with malignant colorectal polyps and polypectomy

Endoscopically removed malignant colorectal polyps: Clinicopathologic correlations

Endoscopic polypectomy and management of colorectal adenomas with invasive carcinoma

Management of the malignant colorectal polyp: The importance of clinicopathological correlation

Long-term survival after treatment of malignant colonic polyps

Colorectal adenomas containing invasive carcinoma: Pathologic assessment of lymph node metastatic potential

Quality in the technical performance of colonoscopy and the continuous quality improvement process for colonoscopy: Recommendations of the U.S. multi-society task force on colorectal cancer

Pseudocarcinomatous invasion in adenomatous polyps of the colon and rectum

Adenomatous polyp with submucosal cysts

Epithelial misplacement in adenomatous polyps of the colon and rectum

Pseudocarcinomatous invasion in adenomas of the colon and rectum

Pseudocarcinomatous invasion of colonic polyps

Colitis cystica profunda

Adenomas and malignant polyps of the colon and rectum: Invasive carcinoma versus pseudocarcinomatous invasion

Pseudoinvasion with high-grade dysplasia in a colonic adenoma: Distinction from adenocarcinoma

Pathology of the malignant colorectal polyp

Distinguishing features of well-differentiated mucinous adenocarcinoma of the rectum and colitis cystica profunda

Endoscopic polypectomy: Inadequate treatment for invasive colorectal carcinoma

Clinical Outcomes of Surgical Therapy Study Group: A comparison of laparoscopically assisted and open colectomy for colon cancer

Classification of colorectal cancer based on correlation of clinical, morphological and molecular features

AGA technical review on hereditary colorectal cancer and genetic testing

Genetic alterations during colorectal tumor development

Molecular genetics of colorectal cancer

Genetic testing for inherited colon cancer

Prognostic factors in colorectal cancer

The International Collaborative Group on Hereditary Non-polyposis Colorectal Cancer

New criteria for hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC (ICG-HNPCC)

A National Cancer Institute workshop on hereditary nonpolyposis colorectal cancer syndrome: Meeting highlights and Bethesda guidelines

A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: Development of international criteria for the determination of microsatellite instability in colorectal cancer

Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability

Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: Parallel pathways of tumorigenesis

The colon cancer burden of genetically defined hereditary nonpolyposis colon

Population-based molecular detection of hereditary nonpolyposis colorectal cancer

Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer)

The hereditary nonpolyposis colorectal cancer syndrome: Genetics and clinical implications

Tumor microsatellite instability and clinical outcome in young patients with colorectal cancer

Tumor microsatellite instability status as a predictor of benefit from fluorouracil-based adjunctive chemotherapy for colon carcinoma

Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer

The prevalence of polyps of the large intestine in Oslo: An autopsy study

Inverted hyperplastic polyps of the colon

Inverted hyperplastic polyposis of the colon

Mixed hyperplastic adenomatous polyps/serrated adenomas: A distinct form of colorectal neoplasia

Hyperplastic polyps of the large bowel

World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Digestive System

Gastrointestinal polyposis: Clinical, pathological and molecular features

Neoplastic progression occurs through mutator pathways in hyperplastic polyposis of the colorectum

Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYHassociated polyposin

Hyperplastic polyposis and the risk of colorectal cancer

Sporadic colorectal cancers with microsatellite instability and their possible origin in hyperplastic polyps and serrated adenomas

Emerging concepts in colorectal neoplasia

Morphologic reappraisal of serrated colorectal polyps

Hyperplastic polyps and colorectal cancer: Is there a link?

Hyperplastic-like polyps as precursors of microsatelliteunstable colorectal cancer

Hyperplastic-like colon polyps that preceded microsatellite-unstable adenocarcinomas

Serrated polyps of the large intestine: A morphologic and molecular review of an evolving concept

Small colonic microsatellite unstable adenocarcinomas and high-grade epithelial dysplasias in sessile serrated adenoma polypectomy specimens: A study of eight cases

Sessile serrated adenomas with low-and high-grade dysplasia and early carcinomas: An immunohistochemical study of serrated lesions "caught in the act

Methylation patterns define two types of hyperplastic polyp associated with colorectal cancer

BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum

BRAF and KRAS mutations in hyperplastic polyps and serrated adenomas of the colorectum: Relationship to histology and CpG island methylation status

Demographic and pathological characteristics of serrated polyps of colorectum

Serrated pathway and APC (conventional)-type colorectal polyps: Molecular-morphologic correlations, genetic pathways, and implications for classification

High prevalence of sessile serrated adenomas with BRAF mutations: A prospective study of patients undergoing colonoscopy

The serrated polyp comes of age

Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points

The clinical significance of invasion of veins by rectal cancer

The prognostic value of substaging colorectal carcinoma: A prospective study of 1117 cases with standardized pathology

Ki-67 determined growth fraction versus standard staging and grading parameters in colorectal carcinoma: A multivariate analysis

A critical review of the classification and staging of colorectal cancer

The grading of rectal cancer: Historical perspectives and a multivariate analysis of 447 cases

Lymph nodes in colorectal carcinoma: The Poisson probability paradigm

A data management approach to quality assurance using colorectal carcinoma reports from two institutions as a model

Clearance technique for the detection of lymph nodes in colorectal cancer

Fat clearance method versus manual dissection of lymph nodes in specimens of rectal cancer

Pathologic studies in colorectal cancer: A guide to the surgical pathology examination of colorectal specimens and review of features of prognostic significance

The prognostic significance of immunohistochemically detected lymph node micrometastases in colorectal carcinoma

Restaging of colorectal cancer based on the identification of lymph node micrometastases through immunoperoxidase staining of CEA and cytokeratins

Micrometastases and survival in stage II colorectal cancer

Identification of occult micrometastases in pericolic lymph nodes of Dukes' B colorectal cancer patients using monoclonal antibodies against cytokeratin and CC49: Correlation with long-term survival

Key issues in reporting common cancer specimens: Problems in pathologic staging of colon cancer

Incidence and prognostic significance of occult tumor cells in lymph nodes from patients with stage IIA colorectal carcinoma

Detection of lymph node metastases in colorectal carcinoma before and after fat clearance

Accurate lymph-node detection in colorectal specimens resected for cancer is of prognostic significance

Analysis of micrometastatic disease in sentinel lymph nodes from resectable colon cancer: Results of Cancer and Leukemia Group B Trial 80001

Factors influencing prognosis in carcinoma of the rectum

Biopsy histology in the grading of rectal carcinoma

The classification of cancer of the rectum

Carcinoma of the rectum: An anatomicpathological study

Carcinomas of the large bowel

Histologic grading of rectal cancer

The spread of rectal cancer and its affect on prognosis

DNA ploidy and cell cycle analysis of colorectal carcinoma by flow cytometry: A prospective study of 137 cases using fresh cell suspensions

Mucoid adenocarcinoma of the colon and rectum

Mucinous colorectal carcinoma: Immunopathology and prognosis

Mucinous carcinoma of the colon and rectum

Mucinous carcinoma of the rectum

Peculiarities of mucinous colorectal carcinoma

The relative prognostic value of flow cytometric DNA analysis in conventional clinicopathologic criteria in patients with operable rectal carcinoma

Prognostic implications of proliferative activity and DNA aneuploidy in colonic adenocarcinoma

DNA ploidy analysis and survival in colorectal carcinoma: A prospective study of 165 patients

Factors influencing the prognosis of early cancer of the rectum

The relationship of histologic features in T1 resected colorectal adenocarcinoma and lymph node metastases: A multivariate statistical analysis

Correlation of histologic features, p53, MIB-1, BCL-1, BCL-X, cyclin-D1 and mismatch repair gene protein expression with lymph node status in T1 limited colorectal carcinoma

Histologic features associated with lymph node metastasis in T1 and superficial T2 rectal adenocarcinomas in abdominoperineal resection specimens: Identifying a subset of patients for whom treatment with adjuvant therapy or completion abdominoperineal resection should be considered after local excision

Tumour budding in colorectal carcinoma

Risk factors for an adverse outcome in early invasive colorectal carcinoma

Endoscopic mucosal resection: An evolving therapeutic strategy for non-polypoid colorectal neoplasia

Microarray versus conventional prediction of lymph mode metastasis in colorectal carcinoma

Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer

Clinical implications of the mechanism of epidermal growth factor receptor inhibitors

Advances in chemotherapy for colorectal cancer

Epidermal growth factor receptor expression and gene amplification in colorectal carcinoma: An immunohistochemical and chromogenic in situ hybridization study

Comparison of two antibodies for immunohistochemical evaluation of epidermal growth factor receptor expression in colorectal carcinomas, adenomas, and normal mucosa

National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology. Version 2: Colon Cancer

K-ras mutations and benefit from cetuximab in advanced colorectal cancer

Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer

Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: From the biology to the clinic

Morphology of angiogenesis in human cancer: A conceptual overview, histoprognostic perspective and significance of neoangiogenesis

Two steps forward in the treatment of colorectal cancer

Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer

The role of UGT1A1*28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer

Pharmacogenetics of uridine diphosphoglucuronosyltransferase (UGT) 1A family members and its role in patient response to irinotecan

ERCC1 measurements in clinical oncology

ERCC1 codon 118 polymorphism is a predictive factor for the tumor response to oxaliplatin/5-fluorouracil combination chemotherapy in patients with advanced colorectal cancer

Tumor-infiltrating lymphocytes are a marker for microsatellite instability in colorectal carcinoma

Adenosquamous and squamous cell carcinoma of the colon

Carcinosarcoma of the colon: Report of a case with morphological, ultrastructural and molecular analysis

Carcinosarcoma of the colon: Report of a case and review of the literature

Spindle and giant cell carcinoma of the colon

Choriocarcinoma of the colon: Report of a case and review of the literature

Prognosis and risk factors of metastasis in colorectal carcinoids: Results of a nationwide registry over 15 years

Neuroendocrine carcinomas of the colon and rectum

World Health Organization Classification of Tumours, Pathology and Genetics: Tumours of Haematopoietic and Lymphoid Tissues

Gastrointestinal lymphoproliferative disorders

Immunohistochemical classification of de novo, transformed, and relapsed diffuse large Bcell lymphoma into germinal center B-cell and nongerminal center B-cell subtypes correlates with gene expression profile and patient survival

Lymphomatous polyposis of the gastrointestinal tract, including mantle cell lymphoma, follicular lymphoma and mucosa-associated lymphoid tissue lymphoma

Gastrointestinal involvement in mantle cell lymphoma: A prospective clinic, endoscopic, and pathologic study

Diagnosis of gastrointestinal stromal tumors: A consensus approach

Clinical, pathologic, and immunohistochemical characteristics of gastrointestinal stromal tumors of the colon and rectum: Implications for surgical management and adjuvant therapies

Distinguishing gastrointestinal stromal tumors from their mimics: An update

Schwannoma of the gastrointestinal tract: A clinicopathological, immunohistochemical and ultrastructural study of 33 cases

Schwannomas in the colon and rectum: A clinicopathologic and immunohistochemical study of 20 cases

Gastrointestinal stromal tumors in patients with neurofibromatosis 1: A clinicopathologic and molecular genetic study of 45 cases

Intestinal neurofibromatosis is a subtype of familial GIST and results from a dominant activating mutation in PDGFRA

Granular cell tumors of the colon: Report of a case and review of the literature

Gastrointestinal stromal tumors, intramural leiomyomas, and leiomyosarcomas in the rectum and anus: A clinicopathologic, immunohistochemical, and molecular genetic study of 144 cases

Glomus tumour of the right colon

Case report: Glomus tumor of the colon

Lipohyperplasia of the ileocecal valve

Arteriovenous malformation of the gastrointestinal tract

Vascular anomalies of the gastrointestinal tract

Vascular ectasias of the colon: 1986

Angiodysplasia of the colon: Diagnosis and treatment

Aortic stenosis, idiopathic gastrointestinal bleeding and angiodysplasia: Is there an association? A methodological critique of the literature

Reassessment of the association between gastrointestinal arteriovenous malformations and aortic stenosis

Abnormal von Willebrand factor in bleeding angiodysplasias of the digestive tract

Detection and treatment of angiodysplasia

Angiodysplasia and lower gastrointestinal tract bleeding in elderly patients

Angiodysplasia of colon revisited: Pathologic demonstration without the use of intravascular injection technique

Large-bowel hemangiomas

Hemangiomas of the colon, rectum, and anus

Surgical management of diffuse cavernous hemangioma of the colon, rectum, and anus

Diffuse cavernous hemangioma of the rectum and sigmoid colon

Cavernous colorectal hemangioma: A rare cause of lower gastrointestinal bleeding and a review of the literature

Case records of the Massachusetts General Hospital: Case 5

Colorectal lymphangioma

Fatal hemorrhage from rectal varices: Report of two cases

Hereditary hemorrhagic telangiectasia and gastrointestinal hemorrhage

Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome)

Gastrointestinal telangiectasia as a cause of severe blood loss in systemic sclerosis

A 19-year-old female with blue rubber bleb nevus syndrome: Endoscopic laser photocoagulation and surgical resection of gastrointestinal angiomata

Blue rubber bleb naevus disease: An uncommon cause of gastrointestinal tract bleeding

Blue rubber bleb nevus syndrome presenting with recurrences

Serck-Hanssen A: Intestinal telangiectasia in Turner's syndrome

The Klippel-Trenaunay syndrome with colonic hemangioma

Management of upper gastrointestinal hemorrhage in patients with pseudoxanthoma elasticum

Pseudoxanthoma elasticum: Treatment of gastrointestinal hemorrhage by arterial embolization and observations on autosomal dominant inheritance

Type IV Ehlers-Danlos syndrome presenting as sudden infant death

Vascular Ehlers-Danlos syndrome

Surgical pitfalls in a patient with type IV Ehlers-Danlos syndrome and spontaneous colonic rupture: Report of a case

Understanding genetic disorders of collagen

Small bowel dilatation in Ehlers-Danlos syndrome: An unreported gastrointestinal manifestation

Spontaneous arterial perforation: The Ehlers-Danlos specter

Spontaneous carotidcavernous fistula and arterial dissections in type IV Ehlers-Danlos syndrome

Disseminated Kaposi's sarcoma in homosexual men

Kaposi's sarcoma in homosexual men: A report of 8 cases

Kaposi's sarcoma of internal organs: A multiparameter study of 86 cases

Identification of herpesviruslike DNA sequences in AIDS-associated Kaposi's sarcoma

Gastrointestinal Kaposi's sarcoma in patients with acquired immunodeficiency syndrome: Endoscopic and autopsy findings

Kaposi's sarcoma: A new staging classification

Kaposi's sarcoma: Gastrointestinal involvement and correlation with skin findings and immunologic function

Gastrointestinal and hepatobiliary neoplasms in AIDS

Hammer SM: Management of newly diagnosed HIV infection

Impact of highly active antiretroviral therapy on the presenting features and outcome of patients with acquired immunodeficiency syndrome-related Kaposi sarcoma

Zidovudine in patients with human immunodeficiency virus (HIV) infection in Kaposi's sarcoma: A phase II randomized placebo-control trial

Systemic treatment of AIDSrelated Kaposi's sarcoma: Results of a randomized trial

Interferon therapy for Kaposi's sarcoma associated with the acquired immunodeficiency syndrome (AIDS)

Beta-interferon therapy in patients with poor-prognosis Kaposi's sarcoma related to acquired immunodeficiency syndrome (AIDS): A phase II trial with preliminary evidence of antiviral activity and low incidence of opportunistic infection

Multicenter trial of lowdose paclitaxel in patients with advanced AIDS-related Kaposi sarcoma

Docetaxel in anthracycline-pretreated AIDS-related Kaposi's sarcoma: A retrospective study

Angiosarcoma of the colon and rectum: Report of a case and review of the literature

Endoscopic management of rectal Dieulafoy-like lesions: A case series and review of literature

Familial Polyposis Coli

The Pathogenesis of Colorectal Cancer

Cribriform-morular variant of papillary carcinoma: A distinctive variant representing the sporadic counterpart of familial adenomatous polyposis-associated thyroid carcinoma

Gastric and duodenal polyps in familial adenomatous polyposis: A prospective study of the nature and prevalence of upper gastrointestinal polyps

Fundic gland polyps in familial adenomatous polyposis: Neoplasms with frequent somatic adenomatous polyposis coli gene alterations

The risk of upper gastrointestinal cancer in familial adenomatous polyposis

Localization of the gene for familial adenomatous polyposis on chromosome 5

The gene for familial polyposis coli maps to the long arm of chromosome 5

Identification and characterization of the familial adenomatous polyposis coli gene

Identification of FAP locus genes from chromosome 5q21

Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients

The multiple colorectal adenoma phenotype and MYH, a base excision repair gene

Responsive colon cancer cell lines to the introduction of APC, a colon-specific tumor suppressor gene

Familial adenomatous polyposis

Correlation between the location of germ-line mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis patients

Attenuated familial adenomatous polyposis (AFAP). A phenotypically and genotypically distinctive variant of FAP

The molecular basis of Turcot's syndrome

Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH

MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps

World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Digestive System

Solitary juvenile polyps: Not a marker for subsequent malignancy

Juvenile polyposis: A precancerous condition

The hamartomatous polyposis syndromes: A clinical and molecular review

Familial juvenile polyposis coli: A clinical and pathologic study of a large kindred

Generalized juvenile gastrointestinal polyposis: A hereditary syndrome

Familial juvenile polyposis of the stomach

Clinical and molecular features of the hereditary mixed polyposis syndrome

Hereditary mixed polyposis syndrome: A zebra or a horse dressed in pinstripes

Castells A: MYH-associated polyposis: Adenomas and hyperplastic polyps

Mutations in the SMAD4/DPC4 gene in juvenile polyposis

Hamartomatous polyposis syndromes: Molecular genetics neoplastic risk, and surveillance recommendations

Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan-Riley-Ruvalcaba syndromes

Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis

Juvenile polyposis: Massive gastric polyposis is more common in MADH4 mutation carriers than BMPR1A mutation carriers

Familial ganglioneuromatous polyposis of the large bowel: Report of a family with associated juvenile polyposis

Mucosal ganglioneuromatosis associated with multiple colonic polyps

Ganglioneuromatosis proliferation associated with juvenile polyposis coli

Guidance on gastrointestinal surveillance for hereditary non-polyposis colorectal cancer, familial adenomatous polyposis, juvenile polyposis, and Peutz-Jeghers syndrome

Hereditary gastrointestinal polyposis syndromes

Localization of the Bannayan-Riley-Ruvalcaba syndrome gene to chromosome 10q23

Polyposis: The Peutz-Jeghers syndrome

Peutz-Jeghers syndrome and management recommendations

Hamartomatous polyps in Peutz-Jeghers syndrome: A light, histochemical and electron-microscopic study

Cancer and the Peutz-Jeghers syndrome

Increased risk of cancer in the Peutz-Jeghers syndrome

Sex cord tumor with annular tubules: A distinctive ovarian tumor of the Peutz-Jeghers syndrome

Ovarian sex cord tumor with annular tubules

A distinctive ovarian sex cordstromal tumor causing sexual precocity in the Peutz-Jeghers syndrome

Testicular tumors with Peutz-Jeghers syndrome

Feminizing Sertoli cell tumors in boys with Peutz-Jeghers syndrome

Adenoma malignum (minimal deviation adenocarcinoma) of the uterine cervix: A clinicopathological and immunohistochemical analysis of 26 cases

Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis

Fine mapping of a genetic locus of Peutz-Jeghers syndrome on chromosome 19p

Peutz-Jeghers syndrome is caused by mutation in a novel serine threonine kinase

Peutz-Jeghers syndrome: Molecular analysis of a three-generation kindred with a novel defect in the serine threonine kinase gene STK11

Relative frequency and morphology of cancers in STK 11 mutation carriers

Peutz-Jeghers syndrome

Colonic hamartomas in tuberous sclerosis

Ganglioneuromas of the gastrointestinal tract: Relation to von Recklinghausen disease and other multiple tumor syndromes

Intestinal ganglioneuromatosis: Mucosal and transmural types. A clinicopathologic and immunohistochemical study of six cases

Ganglioneuromatosis of the colon and extensive glycogenic acanthosis in Cowden's disease

Hereditable colon cancer syndromes: Recognition and preventative management

Colorectal polyps in Cowden's disease (multiple hamartoma syndrome)

Allelic imbalance, including deletion of PTEN/MMACI, at the Cowden disease locus on 10q22-23, in hamartomas from patients with Cowden syndrome and germline PTEN mutation

The genetic basis of Cowden's syndrome: Three novel mutations in PTEN/MMAC1/TEP1

The Cronkhite-Canada syndrome: An analysis of clinical and pathologic features and therapy in 55 patients

The pathology of Cronkhite-Canada polyps: A comparison to juvenile polyposis

Heterotopic gastric epithelium in the rectum: A report of three new cases with a review of 87 cases of gastric heterotopia in the alimentary canal

Heterotopic gastric and pancreatic tissue in the large bowel

Salivary gland heterotopia in the rectum

Inflammatory myofibroblastic tumors (inflammatory pseudotumors) of the gastrointestinal tract: How closely are they related to inflammatory fibroid polyps?

Vanek's tumor (inflammatory fibroid polyp): Report of 18 cases and comparison with three cases of original Vanek's series

Inflammatory fibroid polyps of the gastrointestinal tract: Clinical, pathologic, and molecular characteristics

Inflammatory fibroid polyps harbor mutations in the platelet-derived growth factor receptor alpha (PDGFA) gene

Malakoplakia outside the urinary tract

Polypoid endometriosis: A clinicopathologic analysis of 24 cases and a review of the literature

Fibroblastic polyp of the colon: Clinicopathological analysis of 10 cases with emphasis on its common association with serrated crypts

Intestinal perineuriomas: Clinicopathologic definition of a new anatomic subset in a series of 10 cases

Perineurioma versus fibroblastic polyp of the colon

Elastosis and elastofibromatous change in the gastrointestinal tract: A clinicopathologic study of 13 cases and a review of the literature

Mucosal Schwann cell hamartoma: Clinicopathologic study of 22 neural colorectal polyps distinct from neurofibromas and mucosal neuromas

Dysplasia in inflammatory bowel disease: Standardized classification with provisional clinical applications

Histopathological evaluation of colonic mucosal biopsy specimens in chronic inflammatory bowel disease: Diagnostic implications

Simple objective criteria for diagnosis of causes of acute diarrhea on rectal biopsy

Reliability of rectal biopsy in distinguishing between chronic inflammatory bowel disease and acute self-limited colitis

Rectal biopsy helps to distinguish acute selflimited colitis from idiopathic inflammatory bowel disease

Histopathology differentiates acute self-limited colitis from ulcerative colitis

First attack of inflammatory bowel disease and infectious colitis

Histological discrimination of idiopathic inflammatory bowel disease from other types of colitis

Mucosal biopsy diagnosis of colitis

Rectal histology in acute bacillary dysentery

Diverticular disease-associated chronic colitis

Colorectal biopsy in inflammatory bowel disease

A clinicopathologic study of 33 cases of focal active colitis: Does it ever represent Crohn's disease?

The clinical significance of focal active colitis

Effect of topical 5-aminosalicylic acid (5-ASA) therapy on rectal mucosal biopsy morphology in chronic ulcerative colitis

Rectal biopsy in the diagnosis of Crohn's disease: Value of multiple biopsies and serial sectioning

A distinct subset of antineutrophil cytoplasmic antibodies is associated with inflammatory bowel disease

Nuclear localization of the antigen detected by ulcerative colitis-associated perinuclear antineutrophil cytoplasmic antibodies

Segregation of pANCA antigenic recognition by DNase treatment of neutrophils: Ulcerative colitis, type 1 autoimmune hepatitis, and primary sclerosing cholangitis

Clinical value of the detection of antibodies in the serum for diagnosis and treatment of inflammatory bowel disease

Diagnostic accuracy of serological assays in pediatric inflammatory bowel disease

Anti-Saccharomyces cerevisiae mannan antibodies combined with antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease: Prevalence and diagnostic role

The value of serologic markers in indeterminate colitis: A prospective follow-up study

Pseudomembranous colitis

Escherichia coli O157:H7-associated colitis: A clinical and histologic study of 11 cases

The pathology of intestinal ischemia

Reversible ischemic colitis in young women: Association with oral contraceptive use

Glutaraldehyde colitis following endoscopy: Clinical and pathological features and investigation of an outbreak

Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestines in humans

Histologic spectrum of arterial and arteriolar lesions in acute and chronic cocaine-induced mesenteric ischemia: Report of three cases and literature review

Solitary" rectal ulcer syndrome: Are "solitary" rectal ulcer syndrome and "localized" colitis cystica profunda analogous syndromes caused by rectal prolapse?

Mucosal prolapse syndrome: A unifying concept for solitary ulcer syndrome and related disorders

Solitary rectal ulcer syndrome: Its clinical and pathologic underdiagnosis

Clinical and pathologic factors associated with delayed diagnosis in solitary rectal ulcer syndrome

Polypoid prolapsing mucosal folds in diverticular disease

Eroded polypoid hyperplasia of the rectosigmoid

Angiogenic polypoid proliferation adjacent to ileal carcinoid tumors: A nonspecific finding related to mucosal prolapse

Histologic features of mycophenolate mofetil-related colitis: A graft-versus-host diseaselike pattern

The Pathology of Bone Marrow Transplantation

Gastrointestinal pathology in patients with common variable immunodeficiency and X-linked agammaglobulinemia

Small intestinal lesion resembling graft-vs-host disease: A case report in immunodeficiency and review of the literature

Graft-versus-host disease-like syndrome in malignant thymoma

Enteropathy associated with the acquired immunodeficiency syndrome

Ultrastructural features of epithelial degeneration in rectal crypts of patients with AIDS

Collagenous colitis" with watery diarrhea: A new entity?

Collagenous colitis: Physiologic and histopathologic studies in seven patients

Collagenous colitis: A retrospective study of clinical presentation and treatment in 163 patients

Chronic colitis and thickening of the subepithelial collagen layer (collagenous colitis): Histopathologic findings in 15 patients

Lymphocytic ("microscopic") colitis: A comparative histopathologic study with particular reference to collagenous colitis

Chronic diarrhea of unknown origin

Lymphocytic colitis: A definable clinical and histological diagnosis

Subepithelial collagen table thickness in colon specimen from patients with microscopic colitis and collagenous colitis

Collagenous colitis

Collagenous colitis, enteropathic arthritis, and autoimmune diseases: Results of a patient survey

Lymphocytic ("microscopic") colitis: Clinicopathologic study of 18 patients in comparison to collagenous colitis

Collagenous colitis: Pathogenesis and management

Short-and long-term follow-up of treatment for lymphocytic and collagenous colitis

Systematic review: Microscopic colitis

Collagenous colitis in the setting of nonsteroidal anti-inflammatory drugs and antibiotics

Lymphocytic colitis: A distinct clinical entity? A clinicopathological confrontation of lymphocytic and collagenous colitis

Drug-induced lymphocytic colitis

Ranitidine, diarrhea, and lymphocytic colitis

Focal lymphocytic colitis and collagenous colitis: Patterns of Crohn's colitis?

Lymphocytic colitis: A retrospective clinical study of 199 Swedish patients

Lymphocytic enterocolitis in patients with "refractory sprue

Colonic lymphocytosis in patients with celiac sprue

Fractured colon: An endoscopically distinctive lesion associated with colonic perforation following colonoscopy in patients with collagenous colitis

Prevalence and significance of inflammatory bowel disease-like morphologic features in collagenous and lymphocytic colitis

Colonic ulcers accompanying collagenous colitis: Implication of nonsteroidal anti-inflammatory drugs

Pseudomembranous collagenous colitis

Microscopic colitis with giant cells

Sequential clinical and histopathological changes in collagenous and lymphocytic colitis over time

Colonic epithelial lymphocytosis associated with an epidemic of chronic diarrhea

Colonic epithelial lymphocytosis without a thickened subepithelial collagen table: A clinicopathologic study of forty cases supporting a heterogenous entity

Solitary ulcer of the rectum

The solitary ulcer syndrome of the rectum

Inflammatory collagenic polyp: A unique inflammatory lesion of the anal transition zone

Inflammatory coloacogenic polyp: Relationship to solitary rectal ulcer syndrome/mucosal prolapse and other bowel disorders

Colitis cystica profunda: Review of the literature

Anal rectal function in the solitary rectal ulcer syndrome

A common pathophysiology for full thickness rectal prolapse, anterior mucosal prolapse, and solitary rectal ulcer

The investigation of anorectal dysfunction in the solitary rectal ulcer syndrome

Anal rectal ergotism: Another cause of solitary rectal ulcers

Natural history of anterior mucosal prolapse

Intestinal complications of inflammatory bowel disease: Pathologic aspects

The Kock reservoir ileostomy: A review of its development, problems and role in modern surgical practice

Proctocolectomy without ileostomy for ulcerative colitis

Consequences of ileal pouch-anal anastomosis for Crohn's colitis

Indeterminate colitis predisposes to perineal complications after ileal pouch-anal anastomosis

Ileal pouch-anal anastomosis: Reoperation for pouch-related complications

Results of the pelvic-pouch procedure in patients with Crohn's disease

The importance of diagnostic accuracy in colonic inflammatory bowel disease

Indeterminate colitis: The real story

Indeterminate colitis in the spectrum of inflammatory bowel disease

Fulminant colitis in inflammatory bowel disease: Detailed pathologic and clinical analysis

Overlap in the spectrum of non-specific inflammatory bowel disease: Colitis indeterminate

Pathological subgroups may predict complications but not late failure after ileal pouch-anal anastomosis for indeterminate colitis

Indeterminate colitis: Long-term outcome in patients after ileal pouch-anal anastomosis

Ileal pouch-anal anastomosis for Crohn's disease

Ileal pouch-anal anastomosis in patients with indeterminate colitis: Long-term results

Analysis of the outcome of ileal pouch-anal anastomosis in patients with Crohn's disease

Long-term outcomes of restorative proctocolectomy for Crohn's disease and indeterminate colitis

Proctitis and colitis following diversion of the fecal stream

Diversion colitis: Pathologic findings in a resected sigmoid colon and rectum

Diversion colitis: A clinicopathologic study of 21 cases

Diversion colitis: Histologic features in the colon and rectum after defunctioning colostomy

Treatment of diversion colitis with short chain fatty acid irrigation

Lymphoid follicular proctitis: A condition different from ulcerative proctitis?

Histologic changes in defunctioned rectums in patients with inflammatory bowel disease: A clinicopathologic study of 82 patients with long follow-up

Inflammation in ileal reservoirs: "Pouchitis

A proposed classification of ileal pouch disorders and associated complications after restorative proctocolectomy

Role of the pathologist in evaluating chronic pouches

Pouchitis following ileal pouch-anal anastomosis: Definition, pathogenesis, and treatment

An assessment of inflammation in the reservoir after restorative procto-colectomy with ileal reservoir

Pouch ileitis

Medical therapy for induction and maintenance of remission in pouchitis: A systematic review

Restorative proctocolectomy with ileal reservoir: Pathologic and histochemical study of mucosal biopsy specimens

Pouchitis: Is it a wastebasket diagnosis?

Modified pouchitis disease activity index: A simplified approach to the diagnosis of pouchitis

Ileal ecology after pouch-anal anastomosis of ileostomy: A study of mucosal morphology, fecal bacteriology, fecal volatile fatty acids, and their inter-relationship

Enteric bacteriology, absorption, morphology, and emptying after ileal pouch-anal anastomosis

The "ileal brake" after ileal pouch-anal anastomosis

Manometric and functional comparison of ileal pouch-anal anastomosis with and without anal manipulation

Treatment of rectal cuff inflammation (cuffitis) in patients with ulcerative colitis following restorative proctocolectomy and ileal pouch-anal anastomosis

Bodzin JH: Crohn's-like complications in patients with ulcerative colitis after total proctocolectomy and ileal pouch-anal anastomosis

Misdiagnosis of specific cytomegalovirus infection of the ileoanal pouch as refractory idiopathic chronic pouchitis

Afferent limb ulcers predict Crohn's disease in patients with ileal pouch-anal anastomosis

Ileitis and pouchitis after colectomy for ulcerative colitis

Longterm appraisal of the histological appearances of the ileal reservoir mucosa after restorative proctocolectomy for ulcerative colitis

Long-term histomorphological surveillance of the pelvic ileal pouch: Dysplasia develops in a subgroup of patients

Neoplastic transformation of the pelvic pouch mucosa in patients with ulcerative colitis

Incidence of dysplasia in pelvic pouches in pediatric patients after ileal pouch-anal anastomosis for ulcerative colitis

Incidence, risk factors, and treatment of dysplasia in the anal transitional zone after ileal pouchanal anastomosis

Transanal mucosectomy

Dysplasia of the anal transitional zone (ATZ) after ileal pouch-anal anastomosis: Results of prospective evaluation after a minimum of 10 years

Eosinophilic gastroenteritis involving the ileocecal area

Eosinophilic ileocolitis: Expanding spectrum of eosinophilic gastroenteritis

Eosinophilic gastroenteritis presenting as ileocolitis

Colonoscopic features of eosinophilic gastroenteritis

Allergic proctitis: A clinical and immunopathologic entity

Food allergy: The major cause of infantile colitis

Allergy-related proctocolitis in infants: Diagnostic usefulness of rectal biopsy

Intestinal and hepatic complications of human bone marrow transplantation. Parts I and II

The pathology of bone marrow transplantation

Gastrointestinal graft-versus-host disease in man: A clinical pathologic study of the rectal biopsy

Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. II. Pathology working group report

Chronic mucosal changes of the colon in graft-versus-host disease

Emerging concepts of proctosigmoiditis

Observations on idiopathic proctitis

Diagnosis and treatment of ulcerative proctitis

Diverticular disease and chronic idiopathic inflammatory bowel disease: Associations and masquerades

Crohn's disease of the colon and its distinction from diverticulitis

Granulomatous inflammation in sigmoid diverticulitis: Two diseases or one?

Crohn's colitis-like changes in sigmoid diverticulitis specimens is usually an idiosyncratic inflammatory response to the diverticulosis rather than Crohn's colitis

Crohn's-like reaction in diverticular disease

Segmental colitis associated with diverticula: A prospective study

Gastrointestinal involvement in systemic mastocytosis

Systemic mastocytosis with review of gastrointestinal manifestations

Are gastrointestinal mucosal mast cells increased in patients with systemic mastocytosis?

Mastocytic enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea

The risk of colorectal cancer in ulcerative colitis: A meta-analysis

Ulcerative colitis and colorectal cancer: A population-based study

Precancer and cancer in extensive ulcerative colitis: Findings among 401 patients over 22 years

Diagnosis and management of dysplasia in patients with inflammatory bowel disease

Ulcerative colitis practice guidelines in adults (update): American College of Gastroenterology, Practice Parameters Committee

Ulcerative colitis and colon carcinoma: Epidemiology, surveillance, diagnosis, and treatment

Colonoscopic surveillance reduces mortality from colorectal cancer in ulcerative colitis

Are we telling patients the truth about surveillance colonoscopy in ulcerative colitis?

Colorectal cancer in ulcerative colitis: A cohort study of primary referrals from three centers

Colon cancer, dysplasia, and surveillance in patients with ulcerative colitis

Surveillance for colonic carcinoma in ulcerative colitis

Colorectal cancer prevention in ulcerative colitis: A case-control study

Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee

Physicians' perceptions of dysplasia and approaches to surveillance colonoscopy in ulcerative colitis

How gastroenterologists screen for colonic cancer in ulcerative colitis: An analysis of performance

Factors affecting the outcome of endoscopic surveillance for cancer in ulcerative colitis

Cancer surveillance in ulcerative colitis

Low-grade dysplasia: Non-surgical treatment

Surveillance in the routine management of ulcerative colitis: The prediction value of low-grade dysplasia

Dysplasiaassociated lesion or mass (DALM) detected by colonoscopy in long-standing ulcerative colitis: An indication for colectomy

The fate of low-grade dysplasia in ulcerative colitis

Observer study of the grading of dysplasia in ulcerative colitis: Comparison with clinical outcome

Inter-observer variation between general and specialist pathologists when grading dysplasia in ulcerative colitis

Colonoscopic surveillance for cancer in patients with chronic ulcerative colitis: Is it working?

Screening for colorectal cancer in ulcerative colitis: Dubious benefits and high costs

Failure of colonoscopic surveillance in ulcerative colitis

Value of mucin histochemistry and follow-up surveillance of patients with long-standing ulcerative colitis

DNA aneuploidy in ulcerative colitis

DNA aneuploidy in ulcerative colitis: Reproducibility, topographic distribution, and relation to dysplasia

DNA aneuploidy in colonic biopsies predicts future development of dysplasia in ulcerative colitis

Flow cytometric and histological progression to malignancy in Barrett's esophagus: Prospective endoscopic surveillance of a cohort

Dysplasia in ulcerative colitis: Aneuploidy versus morphology

Colonoscopic surveillance for cancer in patients with chronic ulcerative colitis: Is it working?

The significance of "adenomas" in ulcerative colitis: Deciding when a colectomy should be performed

Long-term followup after polypectomy treatment for adenoma-like dysplastic lesions in ulcerative colitis

Polypoid dysplasia and adenomas in inflammatory bowel disease: A clinical pathology and follow-up study of 89 polyps from 59 patients

Differential diagnosis of adenomas and dysplastic lesions in patients with ulcerative colitis

Genetic alterations in chronic ulcerative colitis-associated adenoma-like DALMs are similar to non-colitic sporadic adenomas

The differentiation of true adenomas from colitis-associated dysplasia in ulcerative colitis: A comparative immunohistochemical study

p53 and beta catenin expression in chronic ulcerative colitis-associated polypoid dysplasia and sporadic adenomas: An immunohistochemical study

Colonoscopic polypectomy in chronic colitis: Conservative management after endoscopic resection of dysplastic polyps

Sporadic adenoma in ulcerative colitis: Endoscopic resection is an adequate treatment

Treating polyps in ulcerative colitis: Adenoma-like lesions and dysplasia-associated mass lesions

Colorectal carcinoma in patients with Crohn's disease

Crohn's disease and intestinal carcinoma: A report of 11 cases with emphasis on associated epithelial dysplasia

Intestinal adenocarcinoma in Crohn's disease: A report of 30 cases with a focus on coexisting dysplasia

Crohn's disease and colorectal cancer

Lower gastrointestinal malignancy in Crohn's disease

Similarity of colorectal cancer in Crohn's disease and ulcerative colitis: Implication for carcinogenesis and prevention

Crohn's disease with adenocarcinoma and dysplasia: Macroscopical, histological, and immunohistochemical aspects of two cases

Colorectal adenocarcinoma in Crohn's disease

Screening and surveillance colonoscopy in chronic Crohn's colitis

The risk of cancer in Crohn's disease

Dysplasia and cancer in Crohn's disease

Elastosis in diverticular disease of the sigmoid colon

Diverticular disease of the colon

Diverticulitis of the right colon

Diverticular disease of the colon in Japan: A review of 615 cases

Diverticulitis of the right colon: Experience from Hong Kong

Acute diverticulitis of the right colon

Intestinal function and intestinal blood supply: A 20-year surgical study

Mesenteric ischemia: Acute arterial syndromes

Ischemic disorders of the intestines

Pathophysiologic effects of bowel distension on intestinal blood flow II

Countercurrent mechanisms in the mammalian gastrointestinal tract

Use of inert gases and carbon monoxide to study the possible influence of countercurrent exchange on passive absorption from the small bowel

Response of the intestinal mucosa to ischaemia

The clinical diagnosis of periarteritis nodosa

The American College of Rheumatology 1990 classification of polyarteritis nodosa

Polyarteritis nodosa presenting as acute cholecystitis

Polyarteritis nodosa presenting as acute cholecystitis

Localized vasculitis of the gastrointestinal tract

Necrotizing vasculitis of the gallbladder and appendix

Localized necrotizing arteritis: A report of two cases involving the gallbladder and pancreas

Polyarteritis nodosa (PAN) initially diagnosed in gall bladder resection specimens: A report of three cases

The primary vasculitides: A clinicopathologic correlation

Enterocolic lymphocytic phlebitis: Clinical, radiologic, and pathologic features

Enterocolic (lymphocytic) phlebitis: A rare cause of intestinal ischemic necrosis: A series of six patients and review of the literature

Necrotizing and giant cell granulomatous phlebitis of cecum and right colon

Idiopathic myointimal hyperplasia of mesenteric veins

Mesenteric inflammatory venoocclusive disease: A seldom recognized cause of intestinal ischemia

Chronic intestinal lymphocytic microphlebitis

Intramural mesenteric venulitis: A new cause of intestinal ischemia

Idiopathic enterocolic lymphocytic phlebitis: A rare cause of ischemic colitis

Enterocolic lymphocytic phlebitis: A case report

Veno-occlusive disease of the small bowel

Intra-abdominal veno-occlusive disease: A clinicopathologic and immunohistochemical study of five cases

Necrotizing enterocolitis

Neonatal necrotizing enterocolitis

The medical and surgical management of typhlitis in children with acute nonlymphocytic (myelogenous) leukemia

Surgical management of neutropenic enterocolitis

Typhlitis: An 18-year experience and postmortem review

Neutropenic enterocolitis: Clinical diagnosis and treatment

Neutropenic enterocolitis due to Clostridium septicum infection

Neutropenic enterocolitis and Clostridium septicum infection in patients with agranulocytosis

Neutropenic enterocolitis associated with Clostridium tertium

Neutropenic enterocolitis: Two unusual cases with review of the literature

Successful medical management of neutropenic enterocolitis

Benign cecal ulcers: Spectrum of disease and selected management

Necrosis of the right colon in chronic hemodialysis patients: Report of three cases

Nonspecific ulcers of the colon

Colonic angiodysplasia and true diverticula: Is there an association

The bleeding cecal ulcer in transplant patients

Idiopathic cecal ulcer: Diagnosis by colonoscopy followed by non-operative management

Use of anti-inflammatory drugs by patients admitted with small or large bowel perforations and hemorrhage

Behçet's syndrome

Intestinal Behçet's disease: Report of five cases

Intestinal involvement in Behçet's disease: Review of 136 surgical cases in the Japanese literature

The colitis of Behcet's syndrome

Colitis of Behcet's syndrome, radiologic and pathologic factors

Vasculo-Behcet's disease: A pathologic study of eight cases

Effects of radiation on the human gastrointestinal tract

The natural history and management of radiation induced injury of the gastrointestinal tract

Wrenn K: Fecal impaction

Stercoral ulceration

Stercoral perforation of the colon

Obstructive colitis: Ulceroinflammatory lesions occurring proximal to colonic obstruction

Colonic inflammation and NSAID administration

Medical complications of cocaine abuse

Intestinal ischemia induced by cocaine abuse

Pathology of salmonella colitis

Syphilitic proctitis

Chlamydia trachomatis proctitis

Acute diarrhoea: Campylobacter colitis and the role of rectal biopsy

Rectal biopsy in patients presenting to an infectious disease unit with diarrhoeal disease

Spectrum of rectal biopsy abnormalities in homosexual men with intestinal symptoms

Infective disorders of the gastrointestinal tract

Intestinal spirochetosis in homosexual men

Isolation and characterization of intestinal spirochaetes

Proposed pathogenic mechanism for the diarrhea associated with human intestinal spirochetes

Colorectal spirochetosis: Clinical significance of the infection

Colonic spirochetosis in children and adults

Human intestinal spirochetosis: Analysis of the symptoms of 209 patients

Mycobacterium avium complex infections in patients with acquired immunodeficiency syndrome

Continuous high grade Mycobacterium avium intracellulare bacteremia in patients with the acquired immune deficiency syndrome

Cryptosporidiosis in immunocompetent patients

An updated review on cryptosporidium and Giardia

Identification of cryptosporidium in paraffin-embedded tissue sections with the use of a monoclonal antibody

Gastrointestinal infections in AIDS

Parasitic diarrhea

Pathology of Infectious Diseases

Strongyloides stercoralis eosinophilic granulomatous enterocolitis

Alimentary tract biopsy lesions in the acquired immune deficiency syndrome

Herpes simplex virus proctitis in homosexual men: Clinical, sigmoidoscopic, and histopathological features

Severe acquired immunodeficiency in male homosexuals, manifested by chronic perianal ulcerative herpes simplex lesions

Colonic histoplasmosis presenting as colon cancer in the nonimmunocompromised patient: Report of a case and review of the literature

Gastrointestinal histoplasmosis in the acquired immunodeficiency syndrome: Report of 18 cases and literature review

Antibiotic-associated diarrhea

Clostridium difficile: Old and new observations

Review: Clostridium difficile-associated disorders/diarrhea and Clostridium difficile colitis: The emergence of a more virulent era

Antibiotics and Clostridium difficile

Clostridium difficile colitis associated with cancer chemotherapy

Nosocomial acquisition of Clostridium difficile infection

Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe

An epidemic, toxin gene-variant strain of Clostridium difficile

A predominantly clonal multiinstitutional outbreak of Clostridium difficile-associated diarrhea and high morbidity and mortality

The new Clostridium difficile: What does it mean?

Clostridium difficile-associated diarrhea: A role in inflammatory bowel disease

Changing epidemiology, diagnosis and treatment of Clostridium difficile toxin-associated colitis

Spectrum of antibioticassociated diarrhea

Isolation rates and toxigenic potential of Clostridium difficile isolates from various patient populations

Prevention of antibioticassociated diarrhea by Saccharomyces boulardii: A prospective study

Treatment of recurrent Clostridium difficile colitis with vancomycin and Saccharomyces boulardii

Laboratory diagnosis of Clostridium difficile-associated diarrhoea: A plea for culture

Evaluation of the latex agglutination test for detection of Clostridium difficile

Diagnosis and monitoring of Clostridium difficile interaction with the polymerase chain reaction

The epidemiologic, clinical, and microbiologic features of hemorrhagic colitis

Hemorrhagic colitis associated with a rare Escherichia coli serotype

The epidemiology of infections caused by Escherichia coli O157:H7, other enterohemorrhagic E. coli and the associated hemolytic uremic syndrome

Enterohemorrhagic E. coli-associated colitis

Escherichia coli O157:H7 diarrhea in a nursing home: Clinical, epidemiologic, and pathologic findings

A severe outbreak of Escherichia coli O157:H7-associated hemorrhagic colitis in a nursing home

The pathogenic mechanisms of Shiga toxin and the Shiga-like toxins

The histopathology of rectosigmoid biopsies from adults with bloody diarrhea due to verotoxin-producing Escherichia coli

The colonic pathology of Escherichia coli O157:H7 infection

H7 antiserum-sorbitol fermentation medium: A single tube screening medium for detecting Escherichia coli O157:H7 associated with hemorrhagic colitis

Diarrheogenic Escherichia coli

Escherichia coli diarrhea

A clinicopathologic study of enterocyte-adherent Escherichia coli: A cause of protracted diarrhea in infants

Adherence of bacteria to the intestine in sporadic cases of enteropathogenic Escherichia coliassociated diarrhea in infants and young children: A prospective study

Enteropathogenic Escherichia coli enteritis: Evaluation of the gnotobiotic piglet as a model of human infection

T84 cells in culture as a model for enteroaggregative Escherichia coli pathogenesis

Studies with enteroaggregative Escherichia coli in the gnotobiotic piglet gastroenteritis model

Localized, aggregative, and diffuse adherence to HeLa cells, plastic, and human small intestines by Escherichia coli isolated from patients with diarrhea

Enteroaggregative Escherichia coli: An emerging enteric pathogen

Diarrheogenic bacterial enteritis in acquired immune deficiency syndrome: A light and electron microscopy study of 52 cases

Chronic intestinal pseudoobstruction

Pseudo-obstruction: Current approaches

Progressive systemic sclerosis of the gastrointestinal tract and hereditary visceral myopathy: Two distinguishable disorders of intestinal smooth muscle

Gastrointestinal amyloid deposition in AL (primary or myeloma associated) and AA (secondary) amyloidosis: Diagnostic value of gastric biopsy

Pathology of neuromuscular disorders of the small intestine and colon

Pathologic features of familial visceral myopathy

Inflammatory neuropathies of the enteric nervous system

Chronic idiopathic intestinal pseudo-obstruction caused by a degenerative disorder of the myenteric plexus: The use of Smith's method to define neuropathology

Mitochondrial neurogastrointestinal encephalomyopathy: Diagnosis by rectal biopsy

Intestinal pseudoobstruction as the presenting manifestations of small-cell carcinoma of the lung: A paraneoplastic neuropathy of the gastrointestinal tract

An inflammatory axonopathy of the myenteric plexus producing a rapidly progressive pseudo-obstruction

Autoaggressive inflammation of the myenteric plexus resulting in intestinal pseudoobstruction

Acquired intestinal aganglionosis and circulating autoantibodies without neoplasia or other neural involvement

Chronic intestinal pseudo-obstruction due to buserelin-induced formation of anti-GNRH antibodies

A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract

Interstitial cells of Cajal direct normal propulsive contractile activity in the mouse small intestine

Loss of CD117 (c-kit)-and CD34-positive ICC and associated CD34-positive fibroblasts defines a subpopulation of chronic intestinal pseudo-obstruction

Decreased interstitial cell of Cajal volume in patients with slow transit constipation

Pan-colonic decrease in interstitial cells of Cajal in patients with slow transit constipation

Enteric nerves and interstitial cells of Cajal are altered in patients with slow-transit constipation and megacolon

Slow transit colon constipation is not related to the number of interstitial cells of Cajal

Intestinal ceroid deposition-"brown bowel syndrome": A light and electron microscopic study

Ceroidosis in the "brown bowel syndrome

The brown bowel syndrome: A possible smooth muscle mitochondrial myopathy

Pathologic changes in the colon produced by anthroquinone purgatives

Melanosis of the rectum in patients with chronic constipation

Melanosis coli is associated with an increase in colonic epithelial apoptosis and not with laxative use

Melanosis coli: A consequence of anthraquinone-induced apoptosis of colonic epithelial cells

Melanoses of the gastrointestinal tract

Results of colectomy for severe idiopathic constipation in women (Arbuthnot Lane's disease)

Colectomy as treatment for constipation in selected patients

Long-term follow-up of patients undergoing colectomy for colonic inertia

Pope CE II: Severe idiopathic constipation is associated with a distinctive abnormality of the colonic myenteric plexus

Pathology of cathartic colon

Pathogenic aspects of Hirschsprung's disease

The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung's disease

A common sexdependent mutation in a RET enhancer underlies Hirschsprung disease risk

Multiple endocrine neoplasia type 2B and Hirschsprung's disease

Hirschsprung's disease: Genetic mutation in mice and men

Rectal suction biopsy in the diagnosis of Hirschsprung's disease in infants

Ganglion cell distribution in the normal rectum and anal canal: A basis for the diagnosis of Hirschsprung's disease by anorectal biopsy

Can we stop looking? Immunohistochemistry and the diagnosis of Hirschsprung disease

Pathology of Hirschsprung's disease and related neuroenteric disorders

Acetylthiocholinesterase staining activity of rectal mucosa: Its use in the diagnosis of Hirschsprung's disease

Rectal mucosal biopsy in aganglionosis and allied conditions

Neuron-specific enolase as an immunohistochemical tool for the diagnosis of Hirschsprung's disease

Cathespin D in intestinal ganglion cells: A potential aid to diagnosis in suspected Hirschsprung's disease

The reliability of frozen-section diagnosis in the pathologic evaluation of Hirschsprung's disease

Morphological diagnosis of Hirschsprung's disease

Histologic studies of rectocolic aganglionosis and allied disease

Immunohistochemical studies of pediatric intestinal pseudo-obstruction: Bcl2, a valuable biomarker to detect immature enteric ganglion cells

Chronic intestinal pseudoobstruction in infants and children caused by diverse abnormalities of the myenteric plexus

Localized and disseminated forms of neuronal intestinal dysplasia mimicking Hirschsprung's disease

Particular forms of Hirschsprung's disease

Updated results on intestinal neuronal dysplasia

Histopathological criteria for intestinal neuronal dysplasia of the submucosal plexus (type B)

Colorectal intramucosal perikarya of ganglion cells

Intramucosal ganglion cells in normal adult colorectal mucosa

Intestinal neuronal dysplasia: Why does it only occur in parts of Europe?

Rectal biopsy for diagnosis of intestinal neuronal dysplasia in children: A prospective multicentre study on interobserver variation and clinical outcome

Aganglionosis and related disorders

Does zonal aganglionosis really exist? Report of a rare variety of Hirschsprung's disease and review of the literature

Zonal aganglionosis: An enzyme and immunohistochemical study of two cases

Primary amyloidosis: A review

Dahlin DC: Secondary amyloidosis

Amyloid tumors of the gastrointestinal tract: A report of two cases and review of the literature

The systemic amyloidoses

Immunohistochemical classification of amyloid in surgical pathology revisited

Value of rectal biopsy in the diagnosis of primary systemic amyloidosis

Pneumatosis cystoides intestinalis: A review of the literature

Pneumatosis intestinalis: A review

The mucosal changes and pathogenesis of pneumatosis cystoides intestinalis

Pneumatosis intestinalis: A challenging biopsy diagnosis

Mucosal pseudolipomatosis of the colon

A case of colonic pseudolipomatosis: A rare complication of colonoscopy?

The pathology of fibrosing colonopathy of cystic fibrosis: A study of 12 cases and review of the literature

Fibrosing colonopathy in cystic fibrosis: Results of a case-control study

Congenital absence of the colon and rectum

Newborn surgical emergencies: Gastrointestinal anomalies, abdominal wall defects

Anomalies of intestinal rotation in childhood: Analysis of 447 cases

Complete duplication of the colon

Cystic duplication of the rectum: Report of two clinical cases

Giant colonic diverticulum: Report of four cases and review of the literature

Tailgut cysts: Report of 53 cases

Retrorectal cysthamartomas: Report of two cases with adenocarcinoma developing in one

Retrorectal cystic hamartoma: Report of three cases, including one with a perirenal component

The effects of therapeutic radiation on colonic mucosa

The effects of 5-fluorouracil on rectal mucosa

Necrosis and apoptosis: Distinct modes of cell death with fundamentally different significance

Acute irradiation in proctitis in man: Development of eosinophilic crypt abscesses

Gastric epithelial atypia associated with hepatic arterial infusion chemotherapy: Its distinction from early gastric carcinoma

Gastrointestinal tract epithelial changes associated with taxanes: Marker of drug toxicity versus effect

Colchicine toxicity: Distinct morphologic findings in gastrointestinal biopsies

Pseudotumoral organization of a twisted epiploic fringe or "hard-boiled egg" in the peritoneal cavity

Enlarged intra-abdominal pacinian corpuscles simulating tumor implants

Intra-abdominal pacinian neuroma: A rare lesion in an unusual location

Intramural extravasation of barium simulating carcinoma of the rectum

We wish to acknowledge and thank Michele Dover for her tenacity and help in transcribing this manuscript. We also thank Drs. Jeff Kneile and Amber Petrolla for their contributions.