Comprehensive Histologic Analysis of ALK-Rearranged Lung Carcinomas

Abstract

A subset (1% to 5%) of non-small-cell lung carcinomas harbors the EML4-ALK fusion gene. Data from previous studies on the histomorphology of ALK-rearranged lung cancer are inconsistent, and the specific histologic parameters that characterize this subset and how accurately such parameters predict underlying ALK abnormality remain uncertain. To answer these questions, we performed a comprehensive histologic analysis of 54 surgically resected, extensively sampled ALK-rearranged lung carcinomas and compared them with 100 consecutive resections of ALK-wild-type lung cancers. All 54 cases showed at least a focal adenocarcinoma component, and 3 and 2 cases had additional squamous and sarcomatoid differentiation, respectively. Solid or acinar growth pattern, cribriform structure, presence of mucous cells (signet-ring cells or goblet cells), abundant extracellular mucus, lack of lepidic growth, and lack of significant nuclear pleomorphism were more common in ALK-positive cancers. Two recognizable constellations of findings, a solid signet-ring cell pattern and a mucinous cribriform pattern, were present at least focally in the majority (78%) of ALK-positive tumors, but were rare (1%) in ALK-negative tumors. Multivariate analysis showed that a combination of these 2 patterns was the most powerful histologic indicator of ALK rearrangement. Characteristic histologies were present both in primary sites and in metastases. Thus, histologic findings may help to identify cases for ALK testing. However, none of the histologic parameters were completely sensitive or specific to ALK rearrangement, and histomorphology should not replace confirmatory molecular or immunohistochemical studies. ALK-positive cancers commonly showed coexpression of thyroid transcription factor-1 and p63, and its significance is currently unclear.

Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas

“…The majority of ALK þ lung adenocarcinomas in our study showed a solid-predominant architectural pattern, in agreement with previous reports from both Western and Asian patient cohorts. 11,15 We also found that micropapillary-predominant adenocarcinomas were significantly associated with ALK rearrangements. The presence of a micropapillary pattern in lung adenocarcinomas reportedly correlates with increased propensity for metastasis, pleural invasion, and decreased survival among stage I patients.…”

“…Tumors that showed both extracellular mucin and cribriform architecture were noted to have a mucinous cribriform component; these cases were recorded as a subcategory of tumors with a cribriform component. 15 We also noted the presence of necrosis and calcifications (including psammoma bodies). For each case, we also applied a three-tier scoring system for nuclear grade (low, intermediate, and high grade) and recorded the highest grade for the analysis.…”

“…Some features previously reported to be associated with ALK rearrangements include young age of onset, reduced smoking history, advanced stage at presentation, adenocarcinoma histology, and mutual exclusivity with activating mutations in EGFR and KRAS. 4,[7][8][9][10][11][12][13][14][15][16] In spite of the common findings among the above studies, the results of detailed pathologic analyses have varied. Previously, our microscopic analysis of 20 ALK þ lung adenocarcinomas revealed a strong association with a solid-predominant architecture and the presence of signet ring cells with intracytoplasmic mucin vacuoles and peripherally displaced and flattened nuclei.…”

Assessment of invasion in lung adenocarcinoma classification, including adenocarcinoma in situ and minimally invasive adenocarcinoma

“…17,28 In addition, certain histological subtypes have been associated with specific molecular alterations, such as KRAS mutation in mucinous adenocarcinoma, 29 EML4-ALK translocation in cribriform mucinous and signet ring type adenocarcinoma, 30,31 and b-catenin mutations in fetal type adenocarcinoma. 32 The main utility of enumerating invasive patterns remains one of pathological communication.…”

Diagnosis and Predictive Molecular Analysis of Non–Small-Cell Lung Cancer in the Africa-Middle East Region: Challenges and Strategies for Improvement

“…Of note, there is an association between some of these molecular abnormalities and histology. For example, ALK-positive tumours have been more commonly detected in solid or poorly differentiated adenocarcinomas with a cribriform or signetring cell morphology [21,22]. However, such associations should not be used in the selection of patients for testing.…”