Cribriform Adenocarcinoma of the Lung: Clinicopathologic, Immunohistochemical, and Molecular Analysis of 15 Cases of a Distinctive Morphologic Subtype of Lung Adenocarcinoma

Alexander C Mackinnon Jr; Arturo Luevano; Lisley C de Araujo; Nagarjun Rao; Min Le; Saul Suster


Mod Pathol. 2014;27(8):1063-1072. 

In This Article

Abstract and 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.


Non-small-cell lung carcinoma, particularly adenocarcinoma, remains the leading cause of cancer mortality in the United States.[1] According to the current World Health Organization classification of lung adenocarcinoma, the most frequent type is mixed adenocarcinoma, an invasive tumor with a combination of different histologic subtypes (bronchioalveolar, acinar, papillary, and solid with mucin).[2,3] Although the classification is widely applied, the subtyping has high interobserver variability[4,5] and lacks a reliable correlation with molecular characteristics.[6] The international multidisciplinary classification of lung adenocarcinoma recently published by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society proposes to classify these tumors according to the predominant histologic component in order to improve molecular and prognostic correlations.[7]

The acinar pattern of lung adenocarcinoma is defined as a neoplasm composed of small round glands, and according to the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification, it is the predominant component in 30–40% of cases.[6,8] A cribriform pattern of growth is not currently acknowledged in the histologic classification of lung adenocarcinoma, although some authors have regarded tumors with a cribriform morphology as a variant of the acinar pattern.[9] In primary lung tumors, a pure or predominant cribriform architecture is rare; most tumors displaying this type of architecture have been commonly regarded as metastases, particularly from the prostate, breast, and colon.[3,10,11]

Mutations in the epidermal growth factor receptor (EGFR) and the KRAS genes, and rearrangements in the anaplastic lymphoma receptor tyrosine kinase (ALK), the c-ros oncogene 1, receptor tyrosine kinase (ROS1) genes, and the RET proto-oncogene are among the most frequently observed molecular alterations in lung adenocarcinomas.[4,12] ALK, ROS1, and RET gene rearrangements occur exclusively of EGFR or KRAS mutations with rare exception.

The presence of activating mutations of the EGFR gene correlates with a better response to treatments with tyrosine kinase inhibitors (TKIs).[13–16] The most frequent type of ALK rearrangement is a fusion with the echinoderm microtubule-associated protein-like 4 (EML4). ROS1 gene rearrangements were first reported in 2007[17] and are present in 1–2% of lung adenocarcinoma. Similar to ALK-positive lung cancer, ROS1 gene rearrangements are more common in young, female, never smokers, and tumors harboring these rearrangements demonstrate more favorable response to crizotinib. RET gene rearrangements were recently described,[18–20] occur in 1–2% of lung adenocarcinoma, and may also show response to RET-targeted therapy.[21,22]

Recently, testing guidelines for properly selecting lung cancer patients for EGFR and ALK TKIs have been published.[23] The major recommendation to guide selection of appropriate targeted therapy is testing of all patients with advanced stage lung adenocarcinoma for activating EGFR mutations and ALK gene rearrangements regardless of clinical risk factors or tumor histology. KRAS mutations are present in 15–30% of lung adenocarcinomas and are regarded as a marker of resistance to TKI treatment. There are no recommendations for routine KRAS, ROS1, and RET testing in lung cancer.[7,16,24]

We report the clinical, histologic, and immunohistochemical status in 15 primary lung adenocarcinomas with a predominant cribriform histologic growth pattern, with special emphasis on the histopathologic differential diagnosis. We also describe the EGFR and KRAS mutational status and the ALK, ROS1, and RET rearrangements in six of these cases for which material was available for analysis, and we discuss the role of molecular testing in this group of tumors.