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


Lung adenocarcinomas are characterized by histologic heterogeneity; adenocarcinomas with a single pure or predominant histologic pattern are rare.[27] Cribriform architecture is not a characteristic pattern in lung adenocarcinoma and tumors displaying this unusual growth pattern are not included in the World Health Organization classification of lung tumors.[3] In the literature, cribriform adenocarcinomas of the lung, when mentioned, are grouped with the acinar subtype[5,28] and, according to the actual recommendations by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society, there are not sufficient data to separate them from other subtypes.[7] Because of their rarity, the presence of a predominant or exclusive cribriform growth pattern in a lung tumor of an adult or elderly patient generally raises the diagnostic possibility of a metastasis from another organ.

We have described 15 primary lung adenocarcinomas with a predominant cribriform architecture. The majority of the lesions were initially mistaken for examples of metastases to the lung from carcinomas from various other organs. Immunohistochemical studies coupled with thorough clinical investigation supported the primary lung origin of these tumors.

Primary lung tumors with a cribriform architecture resembling colorectal carcinomas were first described by Tsao and Fraser.[29] The tumors were characterized by a predominant component of neoplastic tall columnar cells admixed with goblet cells and Paneth cells, with occasional features of neuroendocrine differentiation. More recently, pulmonary intestinal-type adenocarcinomas have also been described by Yousem[30] and by Inamura.[31] The tumors described by Yousem were characterized by a garland-like architecture, central 'dirty' necrosis, and stratified tall columnar cells lacking significant goblet cell or signet-ring features lining the glands. The author remarked that the tumors closely resembled colorectal and sinonasal 'intestinal-type' adenocarcinomas. A cribriform arrangement of the neoplastic cells in which luminal spaces were filled with mucinous material and necrotic debris was a feature of those tumors. Based on the patterns of immunoreactivity, pulmonary adenocarcinomas with enteric features can be divided into those showing positivity for TTF-1/CK7 and negativity for CDX2/CK20 (ie, lung adenocarcinoma with enteric morphology),[30] and those showing CD20/CDX2 positivity and negative CK7/TTF1 (ie, lung adenocarcinoma with enteric differentiation).[31,32] The majority of the enteric-type tumors, however, appear to exhibit a primary lung phenotype and, thus, display only enteric morphology.

Some of the cases in our study showed some of the features described by Yousem[30] and Inamura[31] resembling colorectal carcinoma, but our series further expands the morphologic spectrum that these tumors can display. This is of importance for differential diagnosis as tumors other than colorectal adenocarcinomas demonstrating a prominent cribriform growth pattern are capable of metastasizing to the lung and can arise from diverse sites such as the gallbladder,[33] paranasal sinuses,[34] urinary bladder,[35] breast,[11] prostate,[10] pancreas,[36] salivary glands,[37] thyroid,[38] sweat glands, stomach, ovary,[39] uterus, and endocervix.[40]

Adenocarcinomas of the prostate and breast can metastasize to the lung and can often display a cribriform architecture with comedonecrosis.[3] In a study of 129 frozen sections from 121 patients with breast adenocarcinoma and lung nodules, Herbst et al[11] found that comedonecrosis within solid tumor nests and cribriform architecture favored a diagnosis of breast metastases. A study of metastatic adenocarcinomas from the prostate to the lung also showed that the most common features in such tumors were a cribriform growth pattern with comedonecrosis, blue mucin, and mild pleomorphism.[10] All of our cases with a prostate/breast cribriform pattern except for one were women, TTF-1 was diffusely positive, and none had a previous history or evidence of breast or prostate carcinoma.

Cystadenocarcinomas from the pancreatobiliary tract and the ovary can metastasize to the lung and show a cribriform pattern. Endometrioid adenocarcinomas from the uterus typically have a back to back cribriform arrangement, with cylindrical cells and occasional dirty necrosis in their lumens.[7,36] Application of immunohistochemical stains can be of help in this setting; although such tumors can show reactivity for CK7, pancreatic, endometrioid, and ovarian carcinomas are generally negative for TTF1.

Papillary carcinomas of the thyroid frequently metastasize to regional lymph nodes and the lung is the principal distant site affected. Distant metastases very rarely can be the first manifestation of the disease.[38] The cribriform-morular variant of papillary thyroid carcinoma is another tumor that can metastasize to the lung late in its course. This tumor is characterized by prominent cribriform architecture in association with squamoid morules. The tumor cells are cylindrical with vacuolated nuclei, nuclear grooves, prominent nucleoli, and occasional pseudoinclusions. Immunohistochemical stains are positive for TTF-1, CK7, and nuclear β-catenin. Up to 40% may show neuroendocrine differentiation.[34] Our thyroid-like cases shared the nuclear features of papillary thyroid carcinoma as well as having areas with a cribriform pattern; however, they lacked squamoid morules. Moreover, thyroglobulin stains performed in both cases were negative and physical and ultrasound examination of the head and neck did not reveal evidence of thyroid nodules or masses.

Finally, a more remote possibility in the differential diagnosis is the so-called 'fetal type' adenocarcinoma of the lung, a rare variant of primary lung adenocarcinoma seen mostly in young adults. Histologically, it is characterized by a prominent cribriform architecture with abundant clear glycogen-rich cytoplasm, subnuclear vacuoles, and the distinctive presence of squamoid morules located predominantly at the base of the glands. These tumors also stain strongly for TTF1 and may display aberrant nuclear positivity for β-catenin.[7,41] Four of our cases contained areas with clear cells; however, none of our cases showed the distinctive combination of back-to-back arrangement of glandular spaces, subnuclear vacuoles, and squamoid morules. Only one of our cases showed focally clear subnuclear vacuoles as well as non-squamoid solid areas resembling morules; however, the glands were not back to back, and the morule-like structures were not associated with the cribriform glands but were located within dilated glandular spaces at the periphery of the tumor.

The ALK, ROS, and RET gene rearrangements leading to constitutive kinase activity define a new molecular subtype of lung adenocarcinoma, and patients with ALK or ROS1 gene rearrangements demonstrate benefit from criztotinib. Two of our cases showed a gene rearrangement involving EML4-ALK or ROS1, both of which had thyroid-like morphology that simulated metastatic papillary thyroid carcinoma. Although previous reports have demonstrated that ALK and ROS1 gene rearrangements frequently occur in young, non-smoking patients with predominantly cribriform, solid, or signet-ring cell patterns, these features have no specific role in selecting patients for molecular testing; rather molecular testing is recommended in lung cancer patients with adenocarcinoma and mixed lung cancer with an adenocarcinoma component.[4,14,23,25,42–47] The KRAS codon 12 c.G35A (p.G12D) mutation was present in one case with a pure cribriform architecture. No activating EGFR mutations were identified in our cases.

In summary, we have described a group of primary lung adenocarcinomas that are characterized by a distinctive and predominantly cribriform histology. All except one occurred in older patients with a heavy smoking history and were initially suspected of representing metastases from various other organs. Careful clinicopathologic assessment and immunohistochemical studies helped establish the primary pulmonary origin of these tumors. Last, an activating KRAS mutation and alterations in both ALK and ROS1 were observed in a subset of the cases amenable to analysis. The spectrum of activating mutations and genetic variation observed in this series is similar in frequency and distribution to conventional lung adenocarcinoma and do not seem to identify a particular molecular signature or predictive therapeutic response in lung adenocarcinoma with cribriform histology. However, because of their distinctive morphology, awareness of this unusual histologic variant of lung adenocarcinoma is of importance to avoid misdiagnosis with a metastasis from an occult or distant primary.