key: cord-0036652-m0tjqvql
authors: Suren Arul, G.; Spicer, Richard D.
title: Surgical Complications of Childhood Tumors
date: 2008
journal: The Surgery of Childhood Tumors
DOI: 10.1007/978-3-540-29734-5_22
sha: 90c1874a3313f709f01834dcb5213004d48d083a
doc_id: 36652
cord_uid: m0tjqvql

Most childhood tumors will first present to a physician; some tumors will present in an atypical manner and may mimic a surgical condition. The diagnosis may be missed if the surgeon is not aware of the possibility of cancer. A very great number of rare presentations of childhood cancer have been described in the literature. It is important that the surgeon who is not experienced in the management of childhood cancer is aware that an apparently benign condition could be a manifestation of an underlying malignancy [71, 83] (Table 22.1).

Most childhood tumors will fi rst present to a physician; some tumors will present in an atypical manner and may mimic a surgical condition. Th e diagnosis may be missed if the surgeon is not aware of the possibility of cancer. A very great number of rare presentations of childhood cancer have been described in the literature. It is important that the surgeon who is not experienced in the management of childhood cancer is aware that an apparently benign condition could be a manifestation of an underlying malignancy [71, 83] (Table 22 .1).

Soft tissue problems are a common cause for surgical consultation on the oncology ward. Immunosuppression, steroid-induced skin changes, and prolonged immobilization all contribute to skin infections. Th ese may start as simple localized infections, which may quickly spread into life-threatening problems. Although the conditions outlined below are all related, they do have signifi cant diff erences, which are refl ected in their varying management. Careful clinical diagnosis in conjunction with relevant microbiological, hematological, and biochemical fi ndings is essential.

Usually soft tissue problems involve no more than simple local infections. However, as these children are oft en immunosuppressed, a localized infection can quickly spread to a life-threatening cellulitis. Any areas of erythema should be treated suspiciously with swabs of the area and blood cultures being sent. Antibiotics should be employed early in a suspected infection.

Proven cellulitis should be managed by marking the area of erythema so that any progress can be monitored. Intravenous antibiotics are mandatory and should be prescribed aft er discussion with the infectious disease specialists.

Conditions such as paronychia and superfi cial skin abscesses in the groin or axilla are relatively common. In patients with a normal neutrophil count the treatment of choice is incision and drainage of the area of maximum fl uctuation. In the cases of neutropenic patients most abscesses will not contain pus but watery fl uid containing no neutrophils. Th ese instances are best treated with antibiotics and granulocyte stimulating factor; any areas of fl uctuation can be aspirated with a fi ne needle to provide fl uid for culture and sensitivity testing oft en without the need for incision and drainage.

Children receiving radiotherapy may develop extensive erythema of the skin and skin necrosis. Th is was seen more commonly in treatment protocols that advocated large doses of radiation therapy to superfi cial areas in the body. Th is is no longer the case with current protocols ( Fig. 22.1 ).

Established cellulitis may progress to necrotizing fasciitis. Th e common forms of this disease are either [12, 14] Ganglioneurofi broma [96] Lymphoma [26, 115] Intestinal obstruction Leiomyoma [109] Esophageal leiomyoma [11] Intestinal fi bromatosis [17] Lymphoma Gastrointestinal bleeding Gastric teratoma [47] Typhlitis [48] Perianal caused by group A streptococcus or a mixed fl ora of anaerobic and aerobic bacteria. Th is later condition is known as Fournier's gangrene if it occurs around the perineum or Meleney's gangrene if it occurs on the abdominal wall (oft en associated with a recent operation wound). In this condition the patient is toxic and complains of severe localized pain. Th e aff ected area oft en has a necrotic appearance from the underlying ischemia. Crepitus may be detected on examination. Th e diagnosis is made clinically. Once diagnosis is established the treatment is broad spectrum antibiotics (aminoglycoside, penicillin, and metronidazole), intravenous fl uid resuscitation, and extensive surgical debridement. Numerous debridements are oft en required, the defect being closed at a later stage with tissue fl aps or skin graft s [94, 99] .

Neutropenic patients are at particular risk of developing a pseudomonas fasciitis known as ecthyma gangrenosum ( Fig. 22 .2) [6, 10, 31, 90] . Th e patient develops black necrotic ulcers on the buttocks and perineal region. Th ese are initially small but without treatment will spread and coalesce. Unlike necrotizing fasciitis, the treatment is primarily medical with an antibiotic regime including aminoglycoside with an antipseudomonal cephalosporin or penicillin; granulocyte colony stimulating factor (GCSF) may help to revive the neutrophil count [4] . Close observation must be kept on the patient. If large necrotic areas develop then late surgical debridement may be required. Occasionally a diverting colostomy may be necessary.

Compartment syndrome is a rare problem in childhood and so is oft en overlooked till a late stage. It can develop in the presence of severe septicemia and shock, particularly aft er pseudomonas septicemia in the neutropenic patient. In our experience a septic child may complain of lower limb pain; however, as the child is so systematically unwell this can be overlooked. On examination the foot is plantar fl exed with tight lower leg muscle compartments. Th ere may be reduced skin sensation over the foot or parasthesia. Th e pathognomonic sign is extreme pain on the slightest attempt to actively or passively move the foot. Loss of pedal pulses is a late fi nding. Th e diff erential diagnosis is deep vein thrombosis, lower limb cellulitis, or an ischemic arterial problem. Th e diagnosis is a clinical one; checking compartment pressures and Doppler ultrasound studies can be misleading [78] .

Despite the fact that these children are severely ill, surgical decompression under general anesthetic should be performed urgently. All four compartments should be opened right down over the ankle using a medial and lateral incision. Th e sooner this is done the better the chances of saving the muscles. Th ough muscle compartments expand markedly aft er release, use of a loose subdermal tacking suture allows apposition of the wound edge without increasing the compartment pressures. Th is reduces the need for skin graft ing and thus gives a much better cosmetic result. Hemostasis with bipolar diathermy must be done scrupulously as bleeding is a major problem postoperatively. Numerous debridements of dead muscle may be required, although this should be left until demarcation has occurred. Delayed primary closure, tissue fl aps, or skin graft may be used subsequently.

Surgeons may be consulted by oncologists for advice and surgical intervention in children with thoracic complications. Th e most common request is for biopsying of suspicious lesions on a chest radiograph following treatment -the usual histological fi nding is of a benign lung scar; however, diff use fibrosis secondary to chemoradiotherapy, recurrence of tumor, or fungal lesion are other important diagnoses. In addition, surgical consultation may be required to help with management of pleural eff usions or severe hemoptysis. Other complications that may arise from thoracic structures involved with tumor, or from iatrogenic procedures, e.g., central lines, biopsy, or thoracoscopy or mediastinoscopy include the following. Th is 3-year-old boy undergoing treatment of acute lymphoblastic leukemia became profoundly neutropenic 10 days aft er receiving chemotherapy. He developed a pyrexia and a hot erythematous penis and scrotum with areas of necrosis. Blood cultures and swabs of the area grew Pseudomonas aeruginosa. He was treated with antibiotics and G-CSF and recovered fully without the need for surgical intervention.

Th e patient is unduly distressed following a procedure on the neck, e.g., aft er insertion of a central venous catheter or a biopsy. Th ere is venous congestion of the face and neck with distended neck veins and petechial hemorrhage. Color Doppler ultrasound is useful to detect thrombosis in the great veins of the neck. Angiography via the catheter may demonstrate thrombus in the superior vena cava. Assessment at a low-radiation dose, 64-slice CT angiography has been helpful in diagnosing this condition [119] . Rarely, surgical intervention is indicated and most can be managed by supportive measures alone including heparin administration and removal of the central line from this location.

Th is syndrome results in tracheal compression from trauma, biopsy of tumor (e.g., lymphoma of the mediastinum), or aft er thoracomediostinoscopy. Rapid intubation and treatment with antibiotics is indicated until the syndrome subsides. Rarely, a tracheostomy is indicated if this syndrome develops rapidly and unsuspected.

Th e "Michelin man" can be a complication aft er thoracoscopy from damage to the lung or the airway. Th is can be treated with antibiotics and a chest drain if a tension pneumothorax results. In rare instances this can occur as a complication of high-pressure ventilation therapy with dissection of air into their interstitial spaces.

Cardiac tamponade may result aft er insertion of a central venous line and needs early recognition. Pericardiac drainage and replacement of a central line is needed.

Large malignant pleural eff usions may cause respiratory embarrassment. If they do not settle with the treatment of the underlying disease they may require pleurodesis. Very little information has been pub-lished concerning children with malignant eff usions; most pleurodesis has been undertaken for congenital lymphatic problems (chylothorax) or recurrent spontaneous pneumothorax. Walker-Renard, et al. reviewed all the literature on pleurodesis of malignant lesions [112] . Th ey found that response rates varied from 93% with talcum powder to 0% for etoposide. Doxycycline, tetracycline, and bleomycin all had success rates around 60-80%. Bacillus Calmette-Guérin (BCG) vacine, quinacrine, and thioptepa were not assessed because of the lack of published data.

Talcum powder may be inserted into the pleural cavity using insuffl ation; this technique is best done under general anesthetic with thoracoscopy [121] , although it can be inserted as a talcum slurry by tube thoracostomy under local anesthetic. Adult respiratory distress syndrome (ARDS), pulmonary edema, and granulomatous pneumonitis have all been described as complications developing postoperatively.

Opportunistic fungal infections are an important cause of morbidity and mortality in the immunosuppressed child. Fungal infections include those caused by Candida albicans, Aspergillus, zygomycetes Cryptococcus, and Mycobacterium avium [100] . Th e usual presentation of pulmonary fungal infection is fever, malaise, cough, or chest pain. Other problems which may develop include progressive respiratory distress or life-threatening hemoptysis.

Plain chest radiography may show a cavitating lesion, a mass, or pulmonary infi ltrates, followed by computed tomography (CT) scan to more accurately identify the lesion (Fig. 22.3 a,b) . Bronchoscopy with bronchioalveolar lavage may demonstrate fungal hyphae. Occasionally, either fi ne needle aspiration or an open biopsy of the lesion is necessary to achieve a defi nitive diagnosis. Th e most frequently identifi ed organism is aspergillus. Treatment begins with appropriate antifungal agents, usually amphotericin B. Removal of the bulk of infected lung tissue improves the chances of eradicating the disease [100] .

Th e development of tunneled silastic central venous catheters by Broviac and Hickman are among the most important milestones in the progress of pediatric oncology. However, as with all surgical procedures they are not without signifi cant complications if they are not performed with care by an experienced operator.

Central venous lines can be placed either percutaneously or at an open operation. Despite the more invasive procedure open placement is required for port insertion and may be actually safer as the vein is carefully identifi ed and hence complications such as accidental puncture of the lung and tearing of the vein are minimized. Most children will require general anesthetic whichever technique is employed. See Chap. 27 [61] .

It is important to remember that most operative deaths associated with tunneled catheters occur when they are removed. Th e reasons for this may be that it is considered a simple procedure oft en attempted on the ward under local anesthetic or in the anesthetic room by the most junior surgeon. We have heard of three deaths directly attributable to removal of tunneled long lines -in two cases the line was accidentally divided and then embolized, and once a septic thrombus was dislodged; in all three instances a fatal pulmonary embolus resulted. For this reason all our cuff ed line removals are done in the operating theater by the following technique. Unless the cuff is readily visible at the exit site a new incision is made proximal to the cuff and the fi brous tissue surrounding the line is dissected free. An incision is made in this fi brous casing in the long axis of the line to reduce the risk of severing the line. Th e distal part of the line can then be clipped and the line removed while a second person presses fi rmly over its point of insertion into the vein. Th e cuff can then be dissected out without risk of damaging the line or causing an air embolus. Th e incision and exit site are then sutured closed [30] . 

Th e development of the acute abdomen in a child being treated for neoplastic disease oft en provides the medical and surgical teams caring for that child with a diagnostic and therapeutic dilemma. Th e cause of the symptoms may be the same as those in a child of similar age without cancer or it may be related to the treatment of cancer. Even simple conditions may be confused by the immunodefi ciency, the use of steroids, or cytotoxic drugs and other factors associated with the cancer and/or its treatment. Th is may lead to localized conditions becoming generalized and the clinical signs of sepsis and infl ammation being masked. In addition, the management decisions are complicated by the fact that many of these children are seriously ill at presentation and wound healing may be impaired. Assessment of the risks of all possible causes is necessary to determine whether a laparotomy is required or if intensive medical treatment is preferable. Th e present thinking is that both have their place even for the ill child [87] , and hence the medical and surgical teams should work closely together in initial assessment and ongoing management. Table 22 .3 shows the likely causes of acute abdominal pain in children with cancer and a suggested structured approach to their treatment. Specifi c conditions are discussed in detail below.

Close cooperation with the radiology department is important for the diagnosis of the acute abdomen in children with cancer. While accurate diagnosis is essential, avoidance of invasive or time-consuming investigations is also important in these seriously ill children. Plain abdominal radiograph may show bowel dilatation, mucosal edema, a space-occupying lesion, free air (outlining the bowel wall), or pneumatosis intestinalis. An erect abdominal radiograph may show free air under the diaphragm though it may be normal in over 10% of bowel perforations; lateral decubitus abdominal radiographs (right side up) may be used in the severely ill patient.

Abdominal ultrasound is an excellent noninvasive method of assessing the bowel for intestinal wall thickness, free fl uid, and collections of fl uid within the abdomen. Normal colonic wall thickness is ≤2 mm [10] . It can also pick up appendicitis, cholecystitis, and pyelonephritis [39, 76] . Ultrasound examination is relatively inexpensive, avoids ionizing radiation, and can be performed at the bedside. However, it must be remembered that ultrasound is operator-dependent and that excessive bowel gas, especially in the older child, can adversely aff ect the images; hence a negative scan does not necessarily rule out intra-abdominal pathology.

A CT scan is also noninvasive and requires both intravenous and oral contrast. Restless children will require sedation or general anesthetic for the study. In the immunocompromised patient, CT may demonstrate intra-abdominal abscesses, pseudomembranous colitis, typhlitis, graft -versus-host disease, radiation enteritis, and appendicitis [23, 70] .

Contrast studies are benefi cial in the relatively well child with chronic symptoms especially for diagnosis of strictures or radiation enteritis [68] . However, care must be taken in patients with colitis because of the risk of bowel perforation [67, 111] ; for this reason we prefer to use water-soluble nonionic contrast medium.

Surgeons are frequently called on to perform either upper or lower gastrointestinal endoscopy on patients with unexplained abdominal symptoms. Th e number of causes of abdominal pain or bleeding are numerous and, together with judicious use of diagnostic imaging, endoscopy and relevant biopsies may be essential for accurate diagnosis [5, 65, 86, 88] .

Obtaining biopsies at endoscopy is not associated with signifi cant sepsis even in severely immunosuppressed patients [49] . Upper gastrointestinal endoscopy can be used to sclerose esophageal varices or Hypercalcemia of malignancy inject bleeding ulcers. Careful performance of colonoscopy in patients with viral colitis, typhlitis, and severe graft -versus-host disease is essential in order to avoid overdistension of the colon and reduce the risk of perforation.

1. Full history with particular reference to the time of onset of pain with regard to other treatments, changes in the neutrophil count and changes in other physiological parameters, i.e., pulse, temperature, blood pressure, respiratory rate. 2. Full examination with special regard to the abdomen looking for focal or generalized tenderness and signs of peritonism. Avoid rectal examination in neutropenic patients if possible. 3. Blood tests to include full blood count, urea, electrolytes, amylase, liver function tests. Clotting studies may reveal disseminated intravascular coagulation. Arterial blood gas sample may show signs of an unexpected metabolic acidosis suggesting ischemia or sepsis. Remember that white cell count, C-reactive protein, and erythrocyte sedimentation rate may all be normal in the presence of immunosuppression. 4. Septic screen to include urine, stool, blood cultures, and sometimes lumbar puncture. 5. Diagnostic imaging -see above.

Th is usually arises from two main metabolic disorders. 1. Hypercalcemia of malignancy. Th is can be caused by metastases, osteolytic bone tumors, or humoral factors secreted by endocrine tumors [51] , e.g., parathyroid hormone. Th e symptoms are those of hypercalcemia (weakness, brachycardia, constipation, polyurea, peptic ulceration, and pancreatitis). Fluid resuscitation and pamidonate is of value in the management of acute cancer-related hypercalcemia in children. 2. Tumor lysis syndrome. Th is was oft en observed in the treatment of bulky lymphomas following chemotherapy but can occur with any large bulky tumor undergoing necrosis. A rare complication of germ cell tumors and calcium levels should be monitored in all children with solid ovarian masses [62] . Th e metabolic upset includes hyperuricemia, hyperkalemia, and hyperphosphatemia with hypocalcemia. Th e patient presents with severe abdominal pain from uric acid crystal crisis, lethargy, and anuria [1, 9, 123] . Calcifi cation of the gastric mucosa has been reported in association with tumor lysis syndrome in a child with non-Hodgkin lymphoma [8] .

Th e management of such a high-risk patient includes intravenous hydration with at least 2-3 liters/m2 over 24 h using quarter strength saline, 5% dextrose, alkalization of the urine with sodium bicarbonate 100 meq/ liter titrating the urine to a ph of 7.0-7.5, drug therapy, allopurinol 300-500 mg/m2 for 3 days to prevent uric acid deposition, and careful monitoring of urine output, ph, urine electrolytes, and urea including calcium and phosphate. Occasionally, dialysis or hemofi ltration may be necessary. Recombinant urate oxidase (rasburicase) may be used for prevention and treatment of tumor lysis syndrome in patients with hematological malignancies [114] . Rasburicase is a safe, highly and rapidly eff ective agent in the treatment and prevention of malignancy-associated acute hyperuricemia and could be considered the treatment of choice to prevent tumor lysis syndrome in children at high risk [79] .

Vomiting in a child being treated for malignant disease is very common; however, this must be diff erentiated from the emesis observed in numerous surgical conditions. Obstruction is due to mechanical blockage of the bowel and is common aft er operation for tumor [84, 98] . Characteristically vomit is bile-stained (green) in mechanical obstruction and in adynamic paralytic ileus. Auscultation is an important denominator. Table 22 .4 shows the causes of intestinal obstruction.

It must be noted that sometimes a child presents with obstruction due to abdominal lymphoma. Th ere are two clinical scenarios to be aware of. Th e fi rst is with localized ileo-cecal disease causing the lead point of an intussusception. In this case localized resection with primary anastomosis is the treatment of choice; biopsy of suspicious mesenteric lymph nodes may also help in staging. If there is diff use disease then a biopsy alone with intense supportive management is suffi cient as the disease will rapidly resolve once chemotherapy is started [14] .

Clinical features. Acute systemic upset, with nausea, vomiting, diarrhea, abdominal pain, and gastrointestinal bleeding; commonly complicates radiotherapy to the abdomen and pelvis. Although these acute symptoms usually resolve relatively quickly, about 5% of patients progress to chronic complications aft er the completion of radiotherapy [35, 68, 117, 120] . Radiation damage to the bowel is dose dependent, although other factors such as previous operations, peritonitis, and concurrent chemotherapy (especially actinomycin-D) may all contribute to worsening the long-term problems [22] . More than one complication may occur and new lesions may develop at later stages; radiation enteritis should, therefore, be considered to be a progressive disease [35] . Complications related to the large bowel include proctocolitis, colorectal and anal strictures, rectal ulcers, spontaneous necrosis, and fi stulae to bowel, bladder, or vagina. Small bowel complications include bleeding, adhesions, strictures, malabsorbtion, spontaneous necrosis, fi stula, and poor anastomotic healing [117] . Bleeding and fi stula or perforation seem to represent the two ends of the spectrum of radiation enteritis suggesting that bleeding represents just mucosal trauma whereas full-thick-ness bowel wall damage must be present for perforation and fi stula formation [35] . Malabsorbtion of fat, vitamin B12, and calcium may also occur [22, 117] .

A history is important with regard to the time and dosage of radiation. An erect or supine abdominal radiograph may show features of obstruction or perforation. Th e most important investigations are contrast radiographs, and either small bowel studies or large bowel enemas. Radiological signs of small bowel disease include evidence of submucosal thickening, single or multiple stenoses, adhesions, and sinus or fi stula formation [68] . Large bowel strictures usually appear smooth and concentric in outline [117] .

Radiation enteritis causes severe villous blunting, distended lymphatics, and replacement of the normal columnar epithelium with cuboidal cells; a pattern consistent with the clinical fi ndings of malabsorption. Th e submucosal changes include perivascular adventitial fi brosis. Microscopic changes can be found in macroscopically normal bowel [22, 117] .

Treatment. Radiation enteritis is a progressive disease [120] . Many patients can be treated conservatively; 5-20% of patients may require surgical intervention [46, 35] . Th e main indication for surgery is perforation. Patients with strictures are best treated conservatively, initially with bowel rest and decompression followed by low residue diets [22, 120] . If obstruction or fi stula makes operative intervention necessary then great care must be taken to handle the bowel gently and avoid resection wherever possible. A high incidence of anastomotic leaks follows bowel resection of irradiated bowel due to a compromised blood supply and poor wound healing. Extensive dissection of adhesions should be avoided and a side-to-side bypass operation considered in some cases. When a resection is inevitable, for instance aft er perforation or in response to chronic severe blood loss, then more generous resections should be made and the bowel temporarily exteriorized to avoid an anastomosis [35, 120] .

Prophylaxis. Many techniques have been used to exclude bowel from the pelvis during radiation therapy for pelvic malignancy using omental slings, tissue expanders, and distension of the bladder or retroversion of the uterus. Th e use of pelvic vicryl mesh placed at the level of the sacral promontory seems to be the best option in children [69] . In a study of eight children undergoing pelvic irradiation for malignancy who had a pelvic mesh placed before radiotherapy, none suffered from radiation enteritis [69] .

Adhesive obstruction. Previous laparotomy, intra-abdominal or pelvic irradiation, and intraperitoneal 

Obstruction may occur in the advanced stages of childhood malignancy and although it may be a preterminal event, its management is important for symptom control. Traditional treatment includes stopping oral intake, insertion of a nasogastric tube, decompression, intravenous fl uids, and correction of electrolyte abnormalities. Medical management includes anticholinergics, antiemetics, and analgesics. Th e role of steroids to reduce the degree of perineoplastic infl ammation is controversial. Octreotide is a somatostatin analog that stimulates water and electrolyte absorption and inhibits water secretion by the small intestine. It may be useful in the treatment of obstruction and enteric fi stulae [113] . Operative intervention with colostomy or bypass procedure may be justifi ed. However, it may be more appropriate to manage these patients with intravenous opiates alone.

Th ough this condition may aff ect any part of the bowel, the most common area to be aff ected is the distal ileum and cecum and hence the term " typhlitis" is oft en used. It describes the clinicopathological syndrome of necrotizing infl ammation of the cecum occurring in neutropenic patients. Th ough many cases of appendicitis complicating neutropenia had been described [27] . (usually with fatal results), it was not until 1961 that Amromin fi rst recognized that neutropenic enterocolitis of the cecum was a distinct entity [2, 63] .

Incidence. Exact incidence rates are diffi cult to collect because of the paucity of large studies and the diffi culties of defi ning the relevant population. Several series have suggested an overall incidence of approximately 5% in patients with acute leukemia [29, 72, 91] .

Etiology. Th e condition only develops in the presence of profound neutropenia. Th is may be disease induced [hematological malignancy, aplastic anemia and immunodefi cient diseases such as human immunodefi ciency virus (HIV)-induced acquired immunodefi ciency syndrome (AIDS)] or secondary to drug treatment (chemotherapy for malignancy and bone marrow transplantation). Th e condition appears to be more common in acute myelogenous leukemia than in other forms [72, 87] .

No defi nite cause has ever been identifi ed but several hypotheses exist. Damage to the bowel mucosa allows invasion by colonic fl ora. Septicemia can then develop unchecked by the depleted immune system. Later, shock may increase the ischemia and thus perpetuate the vicious cycle. Th e initial mucosal insult is probably multifactorial including a direct eff ect of cytotoxic drugs on the mucosa, profound neutropenia, mucosal hemorrhage due to associated thrombocytopenia, stasis, and by changes in the bacterial fl ora secondary to prophylactic antibiotics [3, 87, 111, 116] . Why the cecum is most commonly aff ected is not clear though stasis and a relatively poor blood supply are possible explanations.

Th e theory that leukemic infi ltrates of the bowel wall become necrotic in response to chemotherapeutic regimens causing damage to the mucosal wall and local hemorrhage appears plausible but there is little evidence, on microscopic examination, to support it.

Clinical features. Typically a patient undergoing induction chemotherapy is rendered neutropenic and develops problems between day 4 and 14. Symptoms and signs include diarrhea, vomiting, gastrointestinal bleeding, abdominal distension and sepsis. Examination usually reveals an ill patient with pyrexia, tachycardia, hypotension, and peritoneal irritation which may be diff use or limited to the right iliac fossa [29, 36, 67, 72, 80, 87, 91] .

Pathology. Grossly edematous cecum, mucosal ulceration, congested mesentery, and hemorrhagic mucosa progressing to full thickness necrosis of the bowel wall are seen at laparotomy. Th ree characteristic anatomical distributions are seen. First, the necrosis is sharply localized to the cecum with relative preservation of the ileum; second, the cecum is involved in extensive disease with other portions of the colon and small intestine; and third the cecum may contain ulcers which also occur sporadically throughout the intestine [111] .

Th e tissues are edematous and blood vessels are dilated and engorged. Tissue structures appear necrotic and frequently masses of organisms are seen within the lesions. Leukemic infi ltration is rarely seen but when present is readily identifi able. Th e usual microscopic pattern is one of hemorrhagic necrosis involving the mucosa and submucosa with a striking lack of acute infl ammatory reaction. Occasionally, an exudate resembling a pseudomembrane and consisting of fibrin and cell debris may be found overlying the most severely ulcerated mucosal surfaces. In later stages the process may progress to full thickness involvement of the bowel wall and perforation.

Diff erential diagnosis. Causes of acute abdominal pain in these patients include acute appendicitis, pseudomembranous colitis, intussusception, pancreatitis, and pelvic abscess [29] . However, studies have shown that the most likely cause of diff use or localized right iliac fossa abdominal pain in neutropenic patients is typhlitis [70, 72, 87, 111] .

Th e most common organism isolated in septic patients with typhlitis is Pseudomonas aeruginosa [67, 111] though other Gram-negative organisms such as Escherichia coli and Klebsiella are also commonly found [29, 87, 91, 92, 116] . Gram-positive bacteria and fungi are occasionally found [29, 36, 111] . It is important to send multiple stool samples for analysis of C. diffi cile and its toxins to rule out pseudomembranous colitis.

Investigations. Blood tests are of little help, except to confi rm neutropenia (neutrophils <0.5). Other markers of infection and infl ammation can be misleading due to the eff ects of steroids, cytotoxic drugs, and general bone marrow suppression.

Diagnostic imaging studies are essential. Plain radiographs of the abdomen may show a paucity of bowel gas in the right iliac fossa progressing to a right-sided, ill-defi ned soft tissue mass due to a fl uid-fi lled atonic cecum [111] . Other signs include small bowel ileus, ascites, and occasionally cecal pneumatosis which may not appear until the terminal stages of the disease process. Contrast enema fi ndings include thickened mucosal folds, "thumb-printing" due to edema of the mucosa and cecal contraction [67] . Filling of the appendix rules out acute appendicitis. Contrast enemas may precipitate perforation of the cecum in the debilitated child [70, 111] .

Th e investigation of choice is abdominal ultrasound [76, 92] . Sonographic features of typhlitis include the so-called target sign of a rounded mass with a highly echogenic center and a wide hypoechoic periphery. Remember that this sign is also seen in malignant tumors of the bowel, intussusception, and bowel infarction [67, 76, 92] .30,35,61 Appendiceal thickening may indicate an increased risk of serious complications from this disease process [64] .

If the ultrasound is not diagnostic or there is a suspicion of a more sinister cause then CT scan should be used. It can detect transmural infl ammation, cecal wall thickening, soft tissue mass, and pneumatosis [70, 92] .

Having ruled out intussusception, the fi nding of a soft tissue infl ammatory mass in the right iliac fossa by ultrasound or CT in a neutropenic patient with pain and sepsis should be considered diagnostic of typhlitis [39, 70, 92] .

Management. Management of these patients remains controversial, and both surgical [29, 72, 91, 110, 116] and conservative medical management have been advocated [36, 87] . Recently, large series have shown that aggressive medical treatment with bowel rest, fl uid resuscitation, and broad spectrum antibiotics together with selective surgical intervention are associated with good outcomes [87, 92] . Children are treated with intravenous fl uids and triple antibiotics (benzylpenicillin, netilmicin, and metronidazole) and closely observed with frequent reassessment by the surgical team, for signs of deterioration. Granulocyte colony stimulating factor (GCSF) has been employed to hasten the return of the neutrophils but thus far its benefi ts in typhlitis have not been confi rmed.

Th e main indication for surgical intervention is perforation; the other indications for operation include persistent gastrointestinal bleeding despite correction of thrombocytopenia and coagulation defects or clinical deterioration despite maximal supportive therapy. Th e child will benefi t from removal of the source of abdominal sepsis by resection of necrotic bowel and peritoneal lavage [28] . It is important to rule out surgically treatable causes such as intussusception or acute appendicitis. Prognosis is better if the patient is in remission at the time of the operation [29] .

Using a combination of aggressive medical and selective surgical management the two largest recent studies have shown a mortality of approximately 8% [87, 92] .

Pancreatitis may rarely develop in some children with cancer following treatment with L-asparaginase, azathioprine, thiazide diuretics, and corticosteroids [60] . In addition it can complicate raised intracranial pressure [25] . or hypercalcemia [60, 104] . Aft er L-asparaginase up to 6.5% of patients will develop pancreatitis [74] . L-asparaginase-induced severe narcotizing pancreatitis has been successfully treated with percutaneous drainage used to fl ush the infected necrotic parts [103] .

Clinical features include severe abdominal pain, vomiting, and shock. Diagnosis is confi rmed by a raised serum amylase or lipase level [93] . Full blood count, urea and electrolytes, serum calcium, liver function tests, clotting screen, and an arterial blood gas (ApO2) should be obtained. Chest radiograph can show signs of adult respiratory distress syndrome (ARDS). Th e abdomen should be assessed by either ultrasound examination or CT scan [76, 93] evaluated for edema, fl uid collection, hemorrhage, necrosis, and other complications of pancreatitis.

Treatment is essentially medical, aimed at correction of the shock-like state of the patient with aggressive fl uid resuscitation, nasogastric tube insertion, and drainage bowel rest. Intensive care is required if complications such as severe hypocalcemia, disseminated intravascular coagulation or respiratory distress associated with hypoxia develop [93] . Antibiotics may be required particularly in patients who are immunocompromised. Complications of pancreatitis include pancreatic abscess, which oft en requires urgent debridement and drainage. Pseudocysts may also occur but oft en will resolve, although in some instances may require drainage either percutaneously or by operative treatment. Octreotide has been used successfully in a child with L-asparaginase induced hemorrhagic pancreatitis [38] .

Th ough rare, cholecystitis should always be considered in the diff erential diagnosis of the acute abdomen. In particular acute acalculous cholecystitis is associated with stress, sepsis, and co-existing problems such as leukemia [105] . Th e usual presentation is with rightupper quadrant pain, pyrexia, and vomiting; jaundice and a palpable mass are sometimes found. Diagnosis is confi rmed by ultrasonograph demonstration of gallbladder distension, thickening of the gall bladder wall, pericholecystic fl uid collection, and lumen sludge. Patients with cholecystitis usually respond to conservative management with intravenous fl uids and antibiotics [105] . Unresponsive cases may require percutaneous drainage or cholecystectomy, either laparoscopically or by open surgery.

Occasionally the cause of the acute abdominal pain is the result of a ruptured tumor. Th is has been described in patients with Wilms' tumor, hepatoma, neuroblastoma, and B-cell lymphoma. Th is is oft en the result of trivial trauma in a child with an unsuspected neoplasm, but can occur spontaneously. Tumor rupture results in a more advanced stage of the disease process and requires more aggressive treatment. Godzinski found that survival aft er acute nephrectomy for ruptured Wilms' tumor was good but that this was achieved at the expense of long-term morbidity from using doxurubicin (adriamycin) and radiotherapy [42] (Fig. 22.4 ). An arteriovenous fi stula and hemorrhage has been reported as a complication following renal biopsy of a suspected bilateral Wilms' tumor [20] .

Surgeons are occasionally asked to evaluate children on the oncology unit with gastrointestinal bleeding. Th is can range from small specks of altered blood to frank life-threatening hemorrhage. A list of conditions associated with gastrointestinal hemorrhage is presented in Table 22 .5.

Gastric Antral Vascular Ectasia. Th is is a condition that is being increasingly reported in BMT patients. It was fi rst described by Rider1 back in 1953 but recently has been noted in patients undergoing transplantation [12, 42] . It causes acute and chronic blood loss, at endoscopy the appearance is of red patches within the stomach. Histology shows dilated submucosal capillaries, fi brin thrombi, and fi bromuscular hyperplasia. Th ere should be no evidence of GVHD, infection, or ulceration. Ohashi reported fi ve cases all of whom had received conditioning therapy with busulfan and all had a history of microangiopathy.3 Treatment was supportive but did not seem to respond to omeprazole in three of the fi ve patients. Selective angiography had suggested high venous pressures so they were tried on the cardio-selective beta blocker Metoprolol with good results.

Plain radiographs are rarely useful but may show toxic dilatation of the colon in acute colitis. Contrast studies should be avoided as they yield little useful information and prevent more useful investigations such as angiography.

Angiography and red cell scans are diffi cult to set up and time consuming and thus should be held in reserve until upper or lower gastrointestinal endoscopy fail to provide a diagnosis. Angiography has the advantage of accurately detecting the site of the bleeding if the rate exceeds 1.0 cc/min and can be used to embolize a bleeding point. Th e disadvantage of angiography is that it is an invasive procedure. Radiolabeled red cell scan, on the other hand, can be used in cases with a slower bleeding rate (0.5 cc/min) but provides less precise anatomical location of the bleeding point.

Upper and lower gastrointestinal endoscopy are the most rewarding procedures in detecting the site of bleeding. In a bleeding peptic ulcer endoscopic injection of the ulcer bed with epinephrine and heater probe coagulation may stop the bleeding. In rare instances of liver damage associated with portal hypertension, esophageal varices may be the cause of bleeding and can be injected with sclerosing agents or banded.

A recommended algorithm for the management of patients with gastrointestinal bleeding is shown in Fig. 22 .5.

Th e esophagus is a frequent site for infection in the immunosuppressed patient. Patients present with dysphagia, retrosternal chest pain, fever, and upper intestinal bleeding. Th e patient's symptoms, oropharyngeal cultures and esophageal contrast radiography are not predictive of the cause -therefore, accurate diagnosis depends on endoscopy, mucosal biopsy, and brushings of abnormal-appearing areas and cultures [65] . Endoscopic fi ndings range from discreet vesicles in herpes simplex virus (HSV) esophagitis to erosions and a spectrum of fi ndings from esophagitis to gross ulceration which may complicate any infection and is compounded by gastroesophageal refl ux. Th e most common infecting organism was HSV followed by cytomegalovirus (CMV). Fungal infection also occurs and is usually due to Candida albican [65] . Treatment is supportive with adequate analgesia and appropriate antiviral or antifungal therapy.

Immunocompromised patients are at high risk for development of opportunistic infections. Aff ecting agents include Candida albican, pneumocystitis carnii, C. diffi cile, cryptosporidia, giardia, CMV, HSV, rotavirus, astrovirus, and adenovirus. Cytomegalovirus infection is particularly associated with colitis and bowel perforation [43] . Investigation of diarrhea includes sending stool culture for anaerobic organisms, C. diffi cile toxin, and microscopy and culture looking for protozoa, fungi, or viral infestation. Viral infec- tion is of particular importance in the bone marrow transplant patients as clinically it is diffi cult to diff erentiate infection from acute graft -versus-host disease. Th e consequences of increasing the level of immunosuppression to treat graft -versus-host disease, when the patient is actually suff ering from viral colitis, can result in a fatality. Sigmoidoscopy or colonoscopy are useful in making the diagnosis by providing biopsies from aff ected areas of colon for histology [52, 122] . Histological examination of biopsies may show viral inclusion bodies or fungal colonies. Appropriate Clostridium-diffi cile-associated diarrhea is now a common problem in hospitals. Changes in the normal bacterial fl ora of the colon as a result of antibiotic therapy (especially clindamycin and in infants ampicillin) allows overgrowth of C. diffi cile with subsequent release of toxins that cause mucosal damage and infl ammation [50] . Clinical presentation includes mild to moderate diarrhea, antibiotic-associated colitis with or without pseudomembrane formation, and fulminant colitis (Fig. 22.6 ). Associated symptoms include abdominal cramps and bloody diarrhea. In instances of fulminating colitis the patient presents with an acute abdomen, fever, tachycardia, and lethargy. Toxic dilatation may develop. Diagnosis depends on demonstration of C. diffi cile toxins in the stool; sigmoidoscopy or proctoscopy and biopsies may be benefi cial as most disease is confi ned to the rectum or sigmoid. However, in 10 % of cases the colitis is limited to the proximal colon. Unfortunately, colonoscopy in these latter cases, in patients with fulminant colitis, may be complicated by perforation.

Th e treatment of C. diffi cile associated colitis is cessation of prior antibiotics, and treatment with vancomycin or fl agyl preparations is mandatory. Barrier nursing of infected patients is recommended. Th ough severe colitis can usually be controlled within 48-72 h with antibiotics and appropriate supportive treatment, in some cases this fails and perforation occurs. Emergency celiotomy is mandatory for instances of proven perforation or severe refractory cases unresponsive to nonoperative management [13, 50] colectomy, ileostomy and construction of a Hartman pouch are oft en required.

Perianal lesions include localized infections, abscesses, and other causes of infl ammation such as graft -versushost disease and radiation proctitis.

Measures to avoid perianal infections include the following points: 1. Avoid rectal examination and the use of suppositories and enemas. 2. Avoid constipation using laxatives/stool soft eners. 3. Avoid diarrhea. Clean perianal skin carefully with water (Sitz baths) and soft cloth. Barrier cream may reduce any skin reaction.

Symptomatic perianal infections are a relatively common occurrence in the neutropenic child, complicating 6% of hospitalized leukemic patients [44] . In the case of the profoundly neutropenic patient, no abscess will develop because of the lack of neutrophils to produce pus. Th e usual fi ndings are of a mixed culture of colonic organisms [4, 41] . Pseudomonas aeruginosa is particularly pathogenic in this region and may quickly progress to necrotizing fasciitis of the anorectal region [4] . Unlike the patient with an intact immune system where surgical incision and drainage of the abscess forms the basis of treatment, the immunocompromised patient should be treated primarily with broad spectrum antibiotics that cover anaerobic and Gram-negative organisms. Th e regime used includes intravenous benzylpenicillin, netilmicin, and metronidazole. Granulocyte colony stimulating factor may hasten the return of an immunological response though its role is yet to be proven. Constipation should be treated with stool soft eners and laxatives. Pain relief may be required. Th ese patients should be observed closely to make sure that no abscess develops when the neutrophil count rises and that the cellulitis does not spread resulting in a necrotizing fasciitis [4, 41, 75] . Indications for surgical intervention are obvious fl uctuation, a signifi cant amount of necrotic tissue, or progression to a necrotizing infection [44, 75] . Th ere appears to be no increased morbidity or mortality in those requiring operation [44, 75] . Th e usual procedure is drainage of the abscess.

Renal failure may be a complication seen aft er many years following treatment with cytotoxic agents and radiotherapy. Patients with neuroblastoma and Wilms' tumor are especially susceptible. Another complication seen in patients receiving therapy for bulky tumor is that of uric acid nephropathy discussed under metabolic causes of the acute abdomen (see "tumor lysis syndrome, " above).

Hemorrhagic cystitis is a complication resulting from cancer therapy. Several causes have been identifi ed, including alkylating agents, infections, and pelvic irradiation. Th e oxazaphosphorine alkylating agents, cyclophosphamide and ifosfamide, are the most important causes. Cyclophosphamide was fi rst introduced as an antineoplastic agent in 1957. Within 2 years Coggins, et al. had reported cases of signifi cant hemorrhagic cystitis ( Fig. 22.8 ) [19] . Acrolein, a liver metabolite of cyclophosphamide produced by microsomal enzymatic hydroxylation, has been identifi ed as the cause of the cystitis. Th e exact mechanism of action is unknown but contact of acrolein with the urothelium causes sloughing of epithelium, development of infl ammatory infi ltrates, regeneration of a thinner epithelium, and formation of new blood vessels.

Numerous infectious causes are known. Viral pathogens include BK virus, polyoma virus, adenovirus, and cytomegalovirus. Th ey are thought to be most signifi cant in bone marrow transplant patients who are immunosuppressed and already sensitized by cyclophosphamide. Th ese patients seem to develop a late hemorrhagic cystitis weeks or months aft er transplantation -there may be a link with graft -versus-host disease. Bacterial causes include E. coli, Klebsiella and Proteus, and fungal causes such as Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans are also implicated in immunosuppressed patients [97] .

Th e incidence of hemorrhagic cystitis ranges from 2% to 40% in adults; in children this complication seems to be less frequent at around 5-10% [55] . Th e complication appears to be more frequent during the summer, suggesting that there may be a link with dehydration.

Th e urological side-eff ects vary from transient irritative voiding symptoms, including urinary frequency, dysuria, urgency, suprapubic discomfort and stangury with microscopic hematuria, to life-threatening hemorrhagic cystitis [57, 95] . Late complications include bladder fi brosis, necrosis, contracture, and vesicoureteric refl ux. Th e onset of symptoms is variable and may occur during the course of therapy or for several months later [57] .

Th ough the severity of hemorrhagic cystitis does not appear to be dose-related, pediatric patients seem to develop cystitis at lower dosage and shorter duration compared with adults -this may be a consequence of the parenteral route of administration used in most children. Th ere is no correlation with age or sex [55, 95] . However, it is a common complication of allogenic blood and marrow transplantation. In a recent paper they concluded it is more prevalent in matched unrelated donors and unrelated cord blood transplantation than matched related donors [28] .

Th e diagnosis is oft en made clinically. Urine culture must be obtained to rule out infection. Excretory urograms may show anatomical defects and ultrasound can be diagnostic of hemorrhagic cystitis [53] . Urine cytology is frequently used in adults but has not been useful in children. Urine should be examined by electron microscopy for viral infection. Defi nitive diagnosis requires cystoscopy and biopsy, and can be useful in ruling out other causes.

Adequate hydration, diuresis, and frequent bladder voiding all reduce the concentration and the time for which the toxic urine is in contact with the bladder [57, 95] . Care must be taken not to cause overhydration as cyclophosphamide is known to cause damage to renal tubules and inappropriate water retention. N-Acetyl cysteine and more recently Mesna (2mercaptoethane sulfate) have been shown to reduce the incidence of cyclophosphamide-related cystitis [57, 97] by binding and inactivating the toxic acrolein (Table 22 .6).

Many diff erent therapies have been suggested over the last 40 years, few of which have been rigorously tested by randomized controlled trials. Several of the Ref.

Cessation of cyclophosphamide [57] Hyperhydration [57] Frequent or continuous bladder emptying Continuous irrigation [107] Correction of clotting and platelet abnormalities Intravesical therapy with formalin, alum or prostaglandin F2 [21, 37, 54, 56, 73, 82, 89] Cystoscopy with evacuation of clot and diathermy or laser of hemorrhagic areas [45] Open cystotomy, clot evacuation, and diathermy

Systemic estrogen [58] Antiviral therapy if urine cultures are positive

Cystectomy and neobladder substitution [77] management possibilities have only been described in adults (Table 22.7) . Fresh frozen plasma, platelets, and blood transfusion should be given as required. Levine and Richie [57] suggested an algorithm for treatment based on the severity of the disease. Mild acute disease simply requires cessation of cyclophosphamide with good hydration and oral analgesia [55] . More severe disease justifi es a more aggressive approach with cystoscopic evacuation of all mucosal clots followed by continuous bladder irrigation with 1-2% alum aluminum potassium sulfate for 2-3 days through a large-bore catheter; alternatively intravesical instillation of prostaglandin F2 followed by cystoscopy, diathermy of any bleeding sites, and instillation of 2.5-4% formalin. In very small children in whom only a very small cystoscope can be passed our experience has been that open cystotomy, clot evacuation, and diathermy of bleeding points can provide excellent control of symptoms and should be considered at an early stage. In unresponsive cases with massive hemorrhage, total cystectomy may be a life-saving procedure.

Th ough formalin is a well-described treatment, it must be used with extreme caution because of complications of fi brosis, stricture, and renal damage. Before it is used a micturating cystourethrogram must be done to exclude urinary refl ux. Formalin should not be used in the presence of refl ux.

A review of the presentations and management of children with hemorrhagic cystitis aft er bone marrow transplantation at Th e Royal Hospital for Sick Children, Glasgow during the period between 1990 and 1997 showed only six children who developed the disease. During this 8-year period 91 children received a bone marrow transplant. Th e mean age was 12 years (range 5-15 years); all had prophylaxis with hydration and Mesna. Th e presentation of hemorrhagic cystitis occurred on average 40 days aft er chemotherapy (range 26-40 days).

Hemorrhagic cystitis was heralded by a period of microscopic hematuria lasting 4-12 days (mean 9 days). Five patients required continuous irrigation, one with normal saline and his condition settled; the other cases failed due to clot retention and catheter blockage. Irrigation with prostaglandin and alum 1% was tried in two instances but failed to infl uence the course of the disease. Th ree children required formal suprapubic vesicostomy with wide stoma; one required temporary urinary diversion and bladder packing and one required emergency cystectomy for massive life-threatening bleeding. Further studies are required to see if earlier intervention during the phase of microscopic hematuria may aff ect the course of this serious complication. Fibrin glue applied suprapubically while visualizing and insuffl ating the bladder through a cystoscope achieved hemostasis [81] .

Although hemorrhagic cystitis secondary to cyclophosphamide therapy is usually self-limiting, it can have serious long-term eff ects especially with regard to bladder fi brosis leading to vesico-ureteric refl ux, bladder irritability and incontinence, and ureteric strictures. Renal function may be compromised by the outfl ow tract obstruction. Th e long-term problems in some of these patients may require cystectomy or augmentation.

Patients who received more than 50 g of cyclophosphamide probably require long-term surveillance with blood pressure, urinalysis, and assessment of renal function. In addition there is a 4-7% increased risk of bladder malignancy [97] . Th e risks are greatest in those patients receiving both cyclophosphamide and pelvic irradiation without any uroprotection with Mesna. Urine cytology can be used for early detection of new bladder malignancy [109] . Abnormal cytology or evidence of gross or microscopic hematuria requires further investigation with cystoscopy, bladder biopsy, and excretion urogram.

Renal involvement in non-Hodgkins lymphoma is associated with a poor prognostic factor and renal function should be monitored closely. Renal dysfunction caused by direct tumor involvement may complicate therapy and shorten survival [15] . Ureteral obstruction may be caused by L-asparaginase, an eff ective antileukemia and antilymphoma agent as it is toxic to many organ systems. Th is could be managed by a double J stent [18] . Children with leukemia may present with acute testicular swellings which can be mistaken for other acute scrotal conditions, e.g., torsion of the testes, epididymo-orchitis. Th ese children have leukemic infi ltration of the testes (Fig. 22.9 ) and a biopsy usually confi rms the presence of leukemic cells in the testes. Th is is oft en a presentation in boys who have had treatment for leukemia and have relapsed aft er their treatment is fi nished. Th e testis is considered a "sanctuary site" for tumor persistence and may require irradiation.

Graft -versus-host disease is one of the major complications of bone marrow transplantation. Th e concept behind transplantation of allograft bone marrow is that new T lymphocyctes will develop which will recognize the host as "self. " However, mature T cells may also be transplanted that have already learned what is "not self " and thus may attack host cells that are covered with "foreign" class I and II major histocompatibility antigens.

Most patients undergoing bone marrow transplantation will develop graft -versus-host disease without specifi c anti-graft -versus-host disease prophylaxis, at around 2-5 weeks posttransplant. Th e severity of disease depends on the closeness of the major histocompatibility match, whether the donor marrow has been T cell depleted, the degree of minor histocompatibility match (related to age, sex, race, etc.), and the type of prophylaxis used.

Th e skin, followed by the gastrointestinal tract ( Fig. 22.10) and liver, are the most commonly aff ected organs. Cutaneous manifestations include pruritus and a fi ne erythematous or maculopapular rash. In severe cases blistering and desquamation of the skin may occur. A punch biopsy of the skin is required for defi nitive diagnosis and grading (Table 22 .9) of the histological severity of the graft -versus-host disease. In severe disease, the lung can also be aff ected (though usually in the more chronic form).

Any area of the alimentary tract from the mouth to the anus can be aff ected. In one study MacGregor, et al. found that up to 70% of patients with graft -versus-host disease had some degree of intestinal involvement [59] .

Th e most common manifestations occur in the small bowel and refl ect direct eff ects on the intestine and secondary infections that develop as a consequence of graft -versus-host disease [24, 32, 66, 101, 108] . Symptoms include nausea, vomiting, abdominal cramps, and diarrhea. Th e diarrhea may be profuse and cause fl uid and electrolyte imbalance. Nutritional problems may occur due to malabsorption and a protein-losing enteropathy. Occasionally mucosal casts are passed per rectum. In severe graft -versus-host disease there can be generalized signs of adynamic ileus, 

Investigations include blood tests to assess the severity of electrolyte and serum protein levels with complete blood count and a coagulation profi le. Erect and supine abdominal radiographs may show signs of thumb printing, suggesting mucosal edema; pneumatosis may also be observed as erect chest radiographs (or decubitus abdominal radiographs) may show pneumoperitoneum. Contrast barium enema may show typical signs of gastrointestinal graft -versus-host disease but must be used cautiously in very sick patients because of the risks of perforation [33] .

Radiological signs include thickened and eff aced mucosal folds, thickened bowel wall and rapid transit. In subacute gastrointestinal graft -versus-host disease the contrast studies show a segmental patchy appearance of ulceration with normal and abnormal areas interspersed [33] . Use of CT scan shows fl uid-fi lled, dilated, poorly opacifi ed bowel loops and characteristic abnormally enhanced, thin mucosa.

Histology of intestinal graft -versus-host disease initially shows necrosis of individual intestinal crypt cells (apoptosis). Progression of disease leads to loss of whole crypts with mucosal denudation and ulceration. In extreme circumstances the entire mucosa may be sloughed off [34] .

Endoscopic examination can be very useful. Th e endoscopic appearance of graft -versus-host disease shows edema, erythema, and frank ulceration but these signs are nonspecifi c [34] . Mucosal biopsy, however, may be characteristic [101] and can help diff erentiate graft -versus-host disease from opportunistic infections and other causes of colitis [65, 5] . Upper gastrointestinal biopsies have a higher yield than biopsies from the colon or rectum. However, as the disease is patchy the most aff ected area of bowel should be examined. Invasive procedures such as endoscopy or biopsy should be undertaken because the benefi ts are oft en life saving and the actual risks of serious complication are relatively low [5, 49, 101] .

In addition to problems with the gastrointestinal tract, the surgeon is occasionally consulted for advice and requests for biopsies to help diagnose problems in patients with liver and respiratory problems. We recently reviewed liver and lung biopsies taken from bone marrow transplant patients at the Bristol Royal Hospital for Sick Children with undiagnosed fi ndings such as worsening liver function and increasing respiratory distress. Of eight liver biopsies (seven by Tru-cut and one by open operation) three were related to graftversus-host disease, two were due to viral infection, two were related to transfusion siderosis, and one was an aspergilloma. Two open lung biopsies showed one case of cytomegalovirus pneumonitis and one case of radiation fi brosis. Overall we found the complication rate to be low and a number of unsuspected diagnoses were made that altered future management.39

Once graft -versus-host disease is documented the treatment is essentially medical with administration of high-dose steroid immunosuppression. Th e prognosis of graft -versus-host disease is worse if skin, gut, and liver are all involved. Th e only indication for surgical intervention is perforation of the intestine. Severe hemorrhage is best treated by aggressive medical management with correction of clotting abnormalities, platelet transfusion, and endoscopy. Th e results of surgical resection in the acute phase are universally poor. Once the disease is quiescent the areas of sloughed intestinal mucosa may heal by forming a stricture that may require bowel resection.

Tumor lysis syndrome in children with non-Hodgkin lymphoma

Necrotizing enteropathy

Neutropenic enterocolitis treated by primary resection with anastomosis in a leukaemic patient receiving chemotherapy

Management of anorectal/perineal infections caused by Pseudomonas aeruginosa in children with malignant diseases

Role of surgical biopsies in the management of bone marrow transplant patients

Ecthyma Gangrenosum -A trap for the unwary

Wilms' tumor presenting as a varicocele

Calcifi cation of the gastric mucosa associated with tumor lysis syndrome in a child with non-Hodgkin lymphoma

Acute tumor lysis syndrome in solid tumours -A case report and review of the literature

Fournier's gangrene complicating aggressive therapy for hematologic malignancy

Esophageal leiomyoma in children: Two case reports and review of the literature

Colo-colic intussuception due to a hemangioma

Surgical aspects of Clostridium diffi cile colitis

Blue rubber bleb nevi as a cause of intussusception

Renal invovlement in non-Hodgkin's lymphoma and its prognostic eff ect in childhood

Embryonal rhabdomyosarcoma of the ampulla of Vater with long term survival following pancreaticoduodenectomy

Solitary intestinal fi bromatosis: A rare cause of intestinal obstruction in neonates and infants

Ureteral obstruction casued by L-asparaginase-induced pancreatitis in a child with acute lymphoblastic leukemia

Clinical pharmacology and preliminary evaluation of cytoxan (cyclophosphamide)

Arteriovenous fi stula: A complication following renal biopsy of suspected bilateral Wilms' tumor

Intravesical formalin for haemorrhagic cystitis: Analysis of therapy

Radiation enteritis in children. A retrospective review, clinicopathologic correlation, and dietary management

CT imaging of immunocompromised children with acute abdominal symptoms

Acute graft -versus-host disease in children: Abdominal CT fi ndings

Acute pancreatitis and increased intracranial pressure

Intussusception due to lymphoma

Temporary remission in acute leukemia aft er an attack of 'acute appendicitis

Hemorrhagic cystitis aft er allogeneic hematoppietic stem cell transplantation; Donor type matters

Management of the acute abdomen in children with leukaemia

Superior vena cava thrombus treated with low-dose, peripherally administered recombinant tissue plasminogen activator in a child: Case report and review of the literature

Pseudomonas aeruginosa cellulitis and ecthyma gangrenosum in immunocompromised children

Graft versus host disease

Gastrointestinal radiographic features of human graft -versus-host disease

Infl ammatory polyps as a manifestation of intestinal graft versus host disease

Th e natural history of clinically established radiation enteritis

Successful medical management of neutropaenic enterocolitis

Open instillation of formalin for cyclophosphamide-induced hemorrhagic cystitis in a child

Successful management with ocreotide of a child with L-asparagenase induced hemorrhagic pancreatitis

Colonic complication of acute lymphoblastic leukaemia

Neuroblastoma masquerading as congenital ureteropelvic obstruction

Anorectal infections in patients with malignant diseases

Primary nephrectomy for emergency in SIOP-9 Wilms' tumor patients

Perforation of the colon associated with cytomegalovirus infection

Anorectal disease in neutropenic leukemic patients. Operative vs. nonoperative management

Treatment of cyclophosphamide induced hemorrhagic cystitis with neodymium:YAG laser in pediatric patients

Th e spectrum of radiation enteritis. Surgical considerations

Gastric teratoma with gastrointestinal bleeding

Acute lymphoblastic leukemia presenting with typhlitis

Infectious complications of endoscopic procedures in bone marrow transplant recipients

Clostridium diffi cile colitis

Hypercalcemia and childhood cancer: A 7-year experience. Pediatr

Diagnostic imaging in children with acute chest and abdominal disorders

Th e sonographic appearance of cyclophosphamide-induced acute haemorrhagic cystitis

Prostaglandin E2 bladder instillation for the treatment of hemorrhagic cystitis aft er allogeneic bone marrow transplantation

Cyclophophamide-induced hemorrhagic cystitis in children with leukemia

Treatment of cyclophosphamide-induced hemorrhagic cystitis with intravesical carboprost tromethamine

Urological complications of cyclophosphamide

Treatment of radiation or cyclophosphamide induced hemorrhagic cystitis using conjugated estrogen

Acute graft versus host disease of the intestine. A surgical perspective

Drug-induced pancreatitis: A critical review

Th romboprophylaxis of central venous lines in children with cancer: Th e fi rst steps taken on the long road ahead

Severe malignancy-associated hypercalcemia in dysgerminoma

Typhilitis in childhood cancer

Signifi cance of appendiceal thickening in association with typhilitis in pediatric oncology patients

Th omas ED (1985) Esophageal infections in immunosuppressed patients aft er marrow transplantation

Intestinal and hepatic complications of human bone marrow transplantation. Part II

Typhilitis in acute childhood leukemia: Radiological features

Th e radiological features of chronic radiation enteritis

Prevention of radiation enteritis in children, using a pelvic mesh sling

Right lower quadrant pain in the immunocompromised patient: CT fi ndings in 10 cases

Complications in paediatric surgical oncology

Typhlitis: Selective surgical management

Alum irrigation for severe bladder haemorrhage

Serial sonograms to detect pancreatitis in children receiving L-asparaginase

Th e management of infectious and noninfectious anorectal complications in patients with leukemia

Abdominal ultrasound fi ndings during and aft er treatment of childhood acute lymphoblastic leukemia

Severe cyclophosphamide-induced hemorrhagic cystitis successfully treated by total cystectomy with ileal neobladder substitution: A case report

Compartment syndrome in children

Treatment and prevention of tumor lysis syndrome in children. Experience of Associazione Italiana Ematologia Oncologia Pediatrica

Typhlitis resulting from treatment with taxol and doxorubicin in patients with metastatic breast cancer

Application of fi brin glue to damaged bladder mucosa in a case of BK viral hemorrhagic systitis

Cutaneous vesicostomy with direct intravesical application of formalin: Management of severe vesical hemorrhage resulting from high dose cyclophosphamide in boys

Malignant tumors of childhood masquerading as acute surgical conditions

Surgical complications aft er nephrectomy for Wilms' tumor

Testicular enlargement as a presenting feature of monocytic leukemia in an infant

Simultaneous upper and lower endoscopic biopsy in the diagnosis of intestinal graft -versus-host disease

Medical and surgical management of typhlitis in children with acute non-lymphocytic (myelogenous) leukaemia

Gastrointestinal hemorrhage in the cancer patient

Prostaglandin F2-alpha bladder irrigation for control of intractable cyclophosphamide-induced hemorrhagic cystitis

Ecthyma gangrenosium: A rare cutaneous maifestation caused by pseudomonas aeruginosa without bacteraemia in a leukaemic patient -A case report

Right lower quadrant pain in young patients with leukaemia

Typhlitis in children with cancer: A 30-year experience

Fournier's gangrene: Report of 20 patients

Cyclophosphamide-induced hemorrhagic cystitis: A review of 100 patients

Colonic obstruction in a child with von Recklinghausen's neurofibromatosis

Haemorrhagic cystitis in children

Intussusception as a cause of postoperative intestinal obstruction in children

Fournier's syndrome

Th oracotomy for pulmonary mycoses in non-HIV-immunosuppressed patients

Th e role of endoscopic evaluation in patients with suspected intestinal graft -versus-host disease aft er allogeneic bone-marrow transplantation

Bone marrow transplantation

L-asparaginase-induced severe necrotizing pancreatitis successfully treated with percutaneous drainage. Pediatr

Drug-induced pancreatisis; An update

Acalculous cholecystitis in children

Haemangioendothelioma of the pancreas obstructing the common bile duct and duodenum

Prevention of hemorrhagic cystitis following allogeneic bone marrow transplant preparative regimens with cyclophosphamide and busulfan: Role of continuous bladder irrigation

What is graft versus host disease?

Congenital leiomyomatous tumor in a newborn simulating jejunal atresia

Typhilitis in acute leukaemia

Typhlitis, a complication of leukemia in childhood

Chemical pleurodesis for malignant pleural eff usions

Successful closure of intestinal fi stulae in an infant using the somatostatin analogue SMS 201-995

Recombinant urate oxidase (rasburicase) for the prevention and treatment of tumor lysis syndrome in patients with hematologic malignancies

Intussusception in the older child -Suspect lymphosarcoma

Successful surgical management of neutropenic enterocolitis in two patients with severe aplastic anemia. Case reports and review of the literature

Th e intestinal complications of radiotherapy

Pediatric superior vena cava syndrome: Assessment at low radiation dose 64-slice CT angiography

Surgical aspects of radiation enteritis of the small bowel

Video-assisted thoracoscopic surgery in the paediatric population

Colonoscopy for frank bloody stools associated with cancer chemotherapy

Use of pamidronate in the management of acute cancer-related hyercalcemia in children