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Cribriform adenocarcinoma of the lung: clinicopathologic, immunohistochemical, and molecular analysis of 15 cases of a distinctive morphologic subtype of lung adenocarcinoma

2014-01-03 16:02:20

Modern Pathology; 2014 January 3; doi:10.1038/modpathol.2013.227



Alexander C Mackinnon, Arturo Luevano, Lisley C de Araujo, Nagarjun Rao, Min Le and Saul Suster



Abstract



INTRODUCTION



Lung adenocarcinoma is characterized by marked heterogeneity and may be composed of an admixture of histologic growth patterns, including acinar, papillary, solid, and lepidic (bronchioloalveolar). Tumors displaying a prominent or predominant cribriform architecture are rare and most often confused for metastases from other organs. We report the clinical, histologic, immunohistochemical, and molecular features in 15 primary lung adenocarcinomas with a predominant cribriform histology. All patients were adults between 30 and 80 years of age (median: 64), and all but one reported a history of heavy cigarette smoking. All cases showed a predominant (>70%) cribriform architecture that resembled a variety of tumors arising in other organs, including breast, prostate, ovary, pancreas, uterus, colon, and thyroid. Immunohistochemical stains showed a phenotype consistent with a primary lung tumor (ie, TTF1+/CK7+), with negative results for other markers. Molecular analysis in six cases showed that none harbored an EGFR-activating mutation. KRAS mutation was detected in one case, and an ALK1 and ROS1 gene rearrangement were each detected in an additional two cases. Cribriform adenocarcinomas of the lung represent a distinctive histologic subtype of lung cancer that may be morphologically difficult to differentiate from metastases with a predominant cribriform architecture.



MATERIALS AND METHODS



15 cases were identified in a retrospective review of lung adenocarcinomas from the surgical pathology files of the Medical College of Wisconsin, Milwaukee, WI and the Ohio State University, Columbus, OH during 1990-2011. Criteria for inclusion were the presence of >70% cribriform growth pattern and an appropriate immunohistochemical profile consistent with primary lung adenocarcinoma (CK7/TTF1-positive; CK20/CDX2-negative). EGFR exons 18–21 sequencing analysis K-RAS real time PCR mutation analysis ALK/EML4 translocation analysis were performed in six cases.



RESULTS



Four cases resembled prostatic/breast adenocarcinoma, with nests with “roman bridges” separated by desmoplastic stroma. Two cases had cystic mucinous features
resembling adenocarcinoma of the pancreas or ovary. Cribriform structures lined the periphery of cystic spaces in a garland-like fashion with abundant mucinous eosinophilic secretions in the glandular lumina. Cells were elongated with some pseudostratification. Four cases resembled adenocarcinoma of the endometrium. The cells were columnar and all cases showed, at least focally, subnuclear vacuolation resembling early secretory endometrium. Three cases showed features of
intestinal-type, colorectal adenocarcinoma, with cystically dilated tumor islands with cribriform structures in a garland-like arrangement at the periphery and geographic necrosis, with adjacent areas of small confluent cribriform nests with dirty necrosis. Two cases displayed a papillary thyroid carcinoma-like pattern. The tumor cell nuclei showed chromatin clearing, occasional longitudinal grooves and rare intranuclear cytoplasmic inclusions. The lumina were filled with eosinophilic secretions with scalloping, and occasional psammoma bodies.



CONCLUSIONS



The tumors in this study occurred in older patients with a heavy smoking history and were initially suspected of representing metastases from other organs. Careful clinicopathologic assessment and immunohistochemical studies are important for establishing the primary nature of these tumors. The current classification of pulmonary adenocarcinoma relies on histology; however, the molecular profile can provide both predictive and prognostic information. Molecular data from this study demonstrated alterations in three major pathways indicating that this particular morphologic group does not appear to have a well-defined molecular fingerprint.



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