key: cord-1038852-afkclhx2
authors: Akhtar, Zaheer; Laageide, Leah; Robles, Julian; Winters, Christopher; Wall, Geoffrey C.; Mallen, James; Jawa, Zeeshan
title: Unusual presentation of lepidic adenocarcinoma in a healthy female
date: 2022-05-16
journal: BMC Pulm Med
DOI: 10.1186/s12890-022-01969-1
sha: f2520b883a8c6a16b03e9555dbe2df9543ddd8ae
doc_id: 1038852
cord_uid: afkclhx2

BACKGROUND: Lepidic adenocarcinoma represents a histologic pattern of non-small cell lung cancer that characteristically arises in the lung periphery with tracking alongside pre-existing alveolar walls. Noninvasive and invasive variants of lepidic adenocarcinoma are dependent on parenchymal destruction, vascular, or pleural invasion. The lepidic-predominant lung malignancies are collectively recognized as slow growing with rare metastasis and excellent prognosis. The World Health Organization classification of lung malignancies depends on molecular and histopathological findings. CT findings most commonly include ground-glass characteristics, commonly mistaken for inflammatory or infectious etiology. These tumors are generally surgically resectable and associated with better survival given infrequent nodal and extrathoracic involvement. Rarely these tumors present with diffuse pneumonic-type involvement associated with worse outcomes despite lack of nodal and distant metastases. CASE PRESENTATION: A 63-year-old Caucasian athletic immunocompetent female presented with 2 months of progressive shortness of breath, fatigue, loss of appetite and 15 pound weight loss. History was only notable for well controlled essential hypertension and hypothyroidism. Contrast computed tomography angiogram and positron emission tomography revealed diffuse hypermetabolic interstitial and airspace abnormalities of the lungs without lymphadenopathy (or distant involvement) in addition to right hydropneumothorax and left pleural effusion. Baseline laboratory testing was unremarkable, and extensive bacterial and fungal testing returned negative. Bronchoscopy and video-assisted thoracoscopic surgery was subsequently performed with pleural fluid cytology, lung and pleural biopsies returning positive for lepidic adenocarcinoma with 2% programmed death ligand 1 expression and genomic testing positive for PTEN gene deletion. Prior to treatment, the patient perished on day 15 of admission. CONCLUSION: We present a rare case of lepidic predominant adenocarcinoma with extensive bilateral aerogenous spread in the context of no lymphovascular invasion in a healthy, low risk patient. This case presentation may add to the body of knowledge regarding the different behavior patterns of lepidic predominant adenocarcinomas.

accounts for nearly 50% of cases generally associated with mutations in the kirsten rat sarcoma gene (KRAS), anaplastic lymphoma kinase gene (ALK), or epidermal growth factor receptor (EGFR) [3] . Primary group classification (preinvasive, minimally invasive and invasive adenocarcinomas) is dependent on growth pattern predominance of the neoplastic cells (defined as a percentage and recorded in 5% increments), size of lesion, or invasion [4] . All these groups can present in a purely lepidic or predominant lepidic-pattern (defined as columnar or cuboidal cell proliferation that characteristically tracks alongside intact alveolar walls without stromal or lymphovascular invasion). Prognostically, 70-90% of adenocarcinomas are diagnosed as invasive (defined as greater than 3.0 cm in size and/or greater than 0.5 cm of pleural, lymphatic, or vascular invasion), of which the lepidic pattern is considered favorable, while micropapillary or solid pattern are unfavorable [5] [6] [7] . Lepidic predominant adenocarcinoma (LPA), formerly called non-mucinous bronchoalveolar carcinoma, has CT findings of both ground glass and solid opacities which corresponds to the invasive component [8] . Histologically, LPA type cancers show non-mucinous, type II pneumocyte and/or Clara cell proliferation along alveolar walls with greater than 3 cm in size as well as vessel or pleural involvement [9] [10] [11] . In contrast to most adenocarcinomas, LPA primarily affects women and is rare with an incidence of 4%. Aerogenous spread of LPA is exponentially rarer. The most common presenting symptoms of LPA are weight loss (35-45%), dyspnea (37-45%), and weakness (34%) [1, 12] . We present an unusual case of this presentation in an immunocompetent 63-year-old female.

A 63-year-old, Caucasian and thin (BMI 17.06 kg/m 3 ) female presented to the emergency department for 2 months of progressively worsening shortness of breath, loss of appetite, and weight loss (15 pounds). She also reported worsening fatigue limiting her ability to exercise, and also dyspnea with mild-moderate exertion. The patient denied any additional constitutional symptoms. Medical history was notable for hypothyroidism secondary to Hashimoto thyroiditis and well-controlled essential hypertension. Patient was up to date on screening tests including a negative colonoscopy 3 months prior. Social history included intermittent social tobacco use (defined as using 1-2 cigarettes in a setting, while at parties or social gatherings over a 5-year period in her early 30 s). Additional pertinent history included occasional alcohol use, no illicit drug use, and a healthy lifestyle with focus on healthy eating and outdoor bicycling. Family history was only notable for type II diabetes mellitus and obesity.

One week before admission, the patient underwent primary care directed evaluation for symptoms noted above with a computed tomography angiogram (CTA). Results showed diffuse nodular opacities throughout the lungs bilaterally with areas of coalescence and no lymphovascular invasion (Fig. 1C, D) . On admission, the differential included infectious versus inflammatory processes, interstitial lung disease, or lymphangitic carcinomatosis. The patient was considered high risk for fungal and atypical mycobacterial infections due to living in mid-west and thin body habitus. Vitals upon admission included a temperature of 37.6 °C (99.6 Fahrenheit), blood pressure of 138/92 mmHg, heart rate of 116, respiratory rate of 39, and oxygen saturation of 97%. with 95% neutrophils. Urinalysis was negative and imaging was obtained as shown below (Fig. 1A) .

The patient was admitted to the pulmonology service for thorough diagnostic evaluation and started on empiric antibiotics. Respiratory film array including SARS-CoV-2, urine streptococcus and legionella antigens, cryptosporidium, cytomegalovirus, histoplasma, aspergillus, herpes simplex virus, and clostridium difficile were performed and were all negative. The patient subsequently underwent a bronchoscopy with right middle lung biopsy and bronchial washings showing lepidic predominant adenocarcinoma, interpreted as primary lesion without stromal or lymphovascular invasion ( Fig. 2A) . Patient subsequently developed an iatrogenic right apical pneumothorax picked up on post procedure chest X-ray (CXR) showing a right pneumothorax with 3.2 cm pleural separation and prominent diffuse bilateral interstitial alveolar opacities (Fig. 1B) . A 14 French right anterior chest tube was placed on suction. This was followed by a positron emission tomography (PET) scan showing diffuse hypermetabolic interstitial and airspace abnormality of the lungs without lymphadenopathy or distant metastatic lesions in addition to right hydropneumothorax and left pleural effusion (Fig. 1E, F) .

Due to the patient's atypical presentation and worsening hypoxemic respiratory failure requiring supplemental oxygen and persistent right apical pneumothorax, the patient underwent a video-assisted thoracoscopic surgery (VATS) along with talc pleurodesis and placement of a right apical and basilar chest tube. Surgical intervention included two right upper lobe wedge biopsies (3.4 cm and 1.9 cm at greatest length) and pleural peel biopsy (0.6 cm at greatest length) confirming lepidic predominant adenocarcinoma, moderately differentiated with positive parenchymal margins (invasion of visceral pleura). Programmed death ligand 1 (PDL-1) staining showed 2% expression. Advanced genomic testing showed a PTEN mutation.

Although the patient was being considered for trial of chemoimmunotherapy, the patient unfortunately perished from worsening respiratory failure on day 15 of hospitalization after family opted for comfort measures.

Above we have reported a case of a healthy female succumbing to a rapidly deteriorating respiratory status secondary to bilateral lung involvement with diffuse pneumonic type lepidic adenocarcinoma (DP-LPA). LPA are being encountered frequently as having ground glass appearance on CT, are associated with increased resectability, favorable prognosis and overall diminished ability for nodal migration and extra-thoracic involvement [13] [14] [15] . LPA could present as solitary or multi-focal ground glass lesions [16] . Prognostically, favorable CT findings include small size, ground-glass opacities and air bronchograms, while unfavorable elements include spiculations, pleural retractions and size larger than 3.0 cm [17] . Studies have shown lepidic adenocarcinomas are low grade, acinar and papillary tumors are intermediate grade, and solid and micropapillary tumors are high grade [5, 18] . Lepidic adenocarcinomas have an average 5-year survival rate of 90% after surgical resection [19] .

DP-LPA on the other hand is associated with worse prognosis but still maintains decreased predilection for nodal and distant metastases. Pneumonic-type involvement on imaging is defined as pneumonia like area of infiltrate or consolidation affecting a region of the lung; histologically these regions involve predominant lipidic growth pattern filling up portions of alveolar air spaces by mucin or tumor cells [20] .

Similar to our case, multiple (US and non-US) population-based observational studies have shown that these multifocal LPA occur most commonly in middle age women, majority being non-smokers [20] . Radiographic studies commonly but not always correlate well with the histological findings and there also exists some interobserver variability among pathologists in identifying predominant pattern among lung adenocarcinomas [21] . Multifocal LPA can be mucinous, non-mucinous or mixed in nature. Whether DP-LPA is a different entity altogether or culmination of multifocal LPA process remains unclear. Consistent with our case about 60% of the patients with DP-LPA present with bilateral disease, generally with lack of nodal and (Figs. 1, 2) . In certain circumstances this had led to utilization of double lung transplantation process. However, most patients would eventually suffer recurrence in the transplanted organ. Based on TNM staging our patient would be designated as T4 due to involvement of different lobes in one lung and M1a on accounts of contralateral lung/pleural involvement. Captured below in Table 1 are additional cases like ours representing scenarios of bilateral aerogenous-limited metastasis of lepidic adenocarcinoma. Such cases of DP-LPA have been associated by rapidly progressive acute respiratory failure with ARDS and succumb prior to receiving cancer directed therapy [22] [23] [24] [25] [26] .

We outline a case of bronchoscopy and VATS-diagnosed lepidic adenocarcinoma with aerogenous spread in an otherwise healthy 63-year old Caucasian female. Admission evaluation and workup was notable for 2 months of progressive dyspnea, fatigue, and 15 pound weight loss. Laboratory workup was largely unremarkable apart from mild hyponatremia, elevated CRP, ESR, ALT and alkaline phosphatase. Several imaging studies throughout the patient's hospital course identified bilateral lung involvement of diffuse micronodular opacities. All bacterial and fungal testing was negative and no improvement in constitutional symptoms were observed with a course of piperacillin-tazobactam, trimethoprimsulfamethoxazole, or 9 days of oral steroids in a 40-20 mg taper. Because typical lepidic adenocarcinoma follows the path of the alveoli and bilateral aerogenous limited metastasis have been associated with rapidly progressive acute respiratory failure with ARDS, this case highlights the unique constitution adenocarcinomas can assume, even in a healthy, immunocompetent patient. This case report is aimed to help broaden the knowledge base and treatment protocols of DP-LPA. 

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We would like to acknowledge and thank Dr. Kathleen Hansen of the Iowa Pathology Associates for graciously assisting in obtaining pathology images for this case report.

ZA: Writing and conceptualization. LL: Writing original draft and editing. JR: Writing and editing. CW: Writing. GW: Conceptualization, editing, and supervision, JM: Conceptualization, editing, and supervision, ZAJ: Conceptualization, editing, and supervision. All authors have read and approved this manuscript.

The authors received no financial support for this manuscript.

The data that support the findings of this study are available from EPIC but restrictions apply to the availability of these data, which is protected by HIPAA. For access to raw data, please contact Dr. Zaheer Akhtar, DO at zaheera-khtarmed@gmail.com.

Ethics approval and consent to participate Not applicable.

Written and informed consent was obtained from the patient's next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

The authors have no conflict of interest to declare. The authors received no financial support for this manuscript.