Lung Carcinoma Metastatic to the Breast: A Comprehensive Analysis of Clinical Presentation, Morphologic, and Molecular Features, With Emphasis on Diagnostic Pitfalls

Abstract

Lung carcinoma metastatic to the breast (bLM) or axillary lymph nodes (lnLM) may closely mimic primary triple-negative breast carcinoma (BC), leading to possible misdiagnosis. We characterized the clinical, morphologic, and molecular features of a series of lung carcinomas metastatic to breast and regional lymph nodes to identify diagnostic clues and pitfalls. The study cohort consisted of 30 patients (27 women, 3 men) with a median age of 72 years (range, 46-86); 21 patients (70%) reported a smoking history. At the time of the index biopsy, 4 patients (13.3%) had no history of lung carcinoma. Most tumors (n = 25, 83.3%) were bLM; 4 (13.3%) were lnLM, and 1 was a supraclavicular lymph node metastasis. In 7 of 23 cases (30.4%) with available paired imaging studies, the bLM was larger than the lung tumor. Of the 30 cases, 26 (86.7%) were adenocarcinomas, 2 (6.7%) were small cell carcinomas, and 2 (6.7%) were atypical carcinoids. Metastatic adenocarcinoma resembled BC with apocrine morphology in 16 of 30 cases (53.3%), 6 cases (20%) had vacuolated cytoplasm, and 6 (20%) had micropapillary features. One bLM closely mimicked ductal carcinoma in situ morphologically, and another case showed peripheral expression of CK5/14 and p63 mimicking myoepithelium around ductal carcinoma in situ. Initial diagnosis of BC had been rendered in 7 cases (6 adenocarcinomas and 1 small cell carcinoma). Molecular analysis of 18 cases showed that the most altered cancer genes were TP53 (44%), KRAS (44%), CDKN2A (33%), and MTAP (31%). Compared with a cohort of primary triple-negative BC, the bLM/lnLM exhibited a higher tumor mutation burden (P = .002), a lower rate of TP53 mutations, and more frequently harbored genetic alterations in KRAS, RBM10, CDKN2A, CDKN2B, SMARCA4, and STK11. In 10 of 18 cases, mutational signature analysis revealed a dominant smoking signature, providing evidence of lung origin. Our findings unveil diagnostic pitfalls that may warrant additional evaluation to avoid misdiagnosis of metastatic lung carcinoma as a primary BC.

Keywords: apocrine-like morphology; extramammary metastasis; lung carcinoma metastatic to the breast; lymphovascular invasion; smoking signature; tumor mutation burden.