Integrated Analysis of Genomic and Immunological Features in Lung Adenocarcinoma With Micropapillary Component

BackgroundMicropapillary adenocarcinoma is one of the most aggressive histologic subtypes of lung adenocarcinoma (LADC), and even a minor proportion of micropapillary component (MPC) within the LADC could contribute to poor prognosis. Comprehensive analysis of genetic and immunological features of LADC with different percentages of MPC would help better understand cancer biology of this LADC subtype and direct future treatments.MethodsWe performed next-generation sequencing (NGS) for a discovery cohort of 43 LADC patients whose tumors were micro-dissected to separate MPC and non-MPC lesions and a reference cohort of 113 LADC patients. MPC-enriched genetic alterations that were detected in the discovery cohort were then confirmed using a validation cohort of 183 LADC patients. Immunological staining was also conducted on the MPC-containing samples in the discovery cohort.ResultsTumors with a higher percentage of MPC tended to harbor more tumor mutation burdens (TMBs) and chromosome instability (CIN). Some rare genetic events may serve as the genetic landscape to drive micropapillary tumor progression. Specifically, alterations in transcription termination factor 1 (TTF1), brain-specific angiogenesis inhibitor 3 (BAI3), mammalian target of rapamycin (MTOR), and cyclin-dependent kinase inhibitor 2A (CDKN2A) were cross-validated to be enriched in MPC-contained LADC. Additionally, tumors with a higher percentage of MPC were associated with a higher percentage of CD4+, CD8+, and PD-L1+ staining, and some genetic changes that were enriched in MPC, including MET amplification and MTOR mutation, were correlated with increased PD-L1 expression.ConclusionWe identified multiple novel MPC-enriched genetic changes that could help us understand the nature of this aggressive cancer subtype. High MPC tumors tended to have elevated levels of TMBs, T cell infiltration, and immunosuppression than low MPC tumors, implying the potential link between MPC content and sensitivity to immunotherapy.

HER2 Immunohistochemistry in Invasive Micropapillary Breast Carcinoma: Complete Assessment of an Incomplete Pattern

Context.— Invasive micropapillary carcinoma (IMPC) is a rare variant of breast carcinoma, composed of avascular morula-like tumor clusters surrounded by stromal spaces, which can affect the HER2 immunohistochemical (IHC) staining pattern. The 2013 American Society of Clinical Oncology/College of American Pathologists HER2 testing guideline (ASCO/CAP) suggests moderate to intense but incomplete (basolateral) staining be considered equivocal. Objectives.— To perform a detailed assessment of HER2 IHC staining patterns in IMPC. Design.— Hematoxylin-eosin and HER2 IHC slides were retrospectively reviewed to assess the morphology and HER2 IHC characteristics of IMPC. The 2018 ASCO/CAP guideline was applied. Results.— The cohort consisted of 187 IMPCs from 181 patients with median age of 58 years. Homogeneous (≥90%) micropapillary component was found in 40% (75 of 187) of cases. Receptor profile was as follows: 75% (140 of 187) ER+ HER2−, 19% (37 of 187) ER+ HER2+, 4% (7 of 187) ER− HER2+, and 2% (3 of 187) ER− HER2−. Of 26 cases with HER2 IHC 3+, 65% (17 of 26) showed a basolateral staining pattern with strong intensity. HER2 fluorescence in situ hybridization (FISH) showed amplification in 26% (17 of 66) of HER2 IHC equivocal cases: 76% (13 of 17) showed basolateral staining pattern and 24% (4 of 17) complete staining, with weak to moderate (2), moderate (14), or moderate to strong (1) intensity. Conclusions.— The most frequent staining pattern was basolateral, seen in 49% of cases, including 65% HER2 IHC positive and 76% HER2 IHC equivocal/FISH amplified. If a basolateral pattern and weak to moderate staining is observed in IMPC, alternative testing should be performed to confirm the HER2 status.