Coexpression of ΔNp63/p40 and TTF1 Within Most of the Same Individual Cells Identifies Life-Threatening NSCLC Featuring Squamous and Glandular Biphenotypic Differentiation: Clinicopathologic Correlations

Abstract

Introduction Double occurrence of TTF1 and ΔNp63/p40 (henceforth, p40) within the same individual cells is exceedingly rare in lung cancer. Little is known on their biological and clinical implications. Methods Two index cases immunoreactive for both p40 and TTF1 and nine tumors selected from The Cancer Genome Atlas (TCGA) according to the mRNA levels of the two relevant genes entered the study. Results The two index cases were peripherally located, poorly differentiated, and behaviorally unfavorable carcinomas, which shared widespread p40 and TTF1 decoration within the same individual tumor cells. They also retained SMARCA2 and SMARCA4 expression, while variably stained for p53, cytokeratin 5, and programmed death-ligand 1. A subset of basal cells p40+/TTF1+ could be found in normal distal airways. Biphenotypic glandular and squamous differentiation was unveiled by electron microscopy, along with EGFR , RAD51B , CCND3 , or NF1 mutations and IGF1R , MYC , CCND1 , or CDK2 copy number variations on next-generation sequencing analysis. The nine tumors from TCGA (0.88% of 1018 tumors) shared the same poor prognosis, clinical presentation, and challenging histology and had activated pathways of enhanced angiogenesis and epithelial-mesenchymal transition. Mutation and copy number variation profiles did not differ from the other TCGA tumors. Conclusions Double p40+/TTF1+ lung carcinomas are aggressive and likely underrecognized non–small cell carcinomas, whose origin could reside in double-positive distal airway stem-like basal cells through either de novo-basal-like or differentiating cell mechanisms according to a model of epithelial renewal.

Challenging Metastatic Melanoma to the Lung With p40 Expression: A Diagnostic Pitfall, Case Report

“…Nevertheless, extremely rare cases of TTF-1 and p40 coexpression are described in the literature. 12 p40 is, however, not completely specific for squamous cell carcinoma. Its specificity of close to 100% has been demonstrated when the differential diagnosis is lung adenocarcinoma.…”

“…p40 and TTF-1 antibodies are usually never coexpressed; this can serve as internal quality control. Nevertheless, extremely rare cases of TTF-1 and p40 coexpression are described in the literature 12…”

Non‐small cell lung carcinomas with diffuse coexpression of TTF1 and p40: clinicopathological and genomic features of 14 rare biphenotypic tumours

“…In prior literature only five cases with diffuse dual expression of TTF1 and p40 were reported 8–11 . Key findings for these cases are summarized in Table 5 and a detailed summary is provided in Supporting information, Table S2.…”

“…Lung carcinomas with diffuse coexpression of TTF1 and p40 are extremely rare. Only five such cases have been described in the literature to date 8–11 . Therefore, more detailed study on their clinicopathological, immunohistochemical and genomic characteristics is needed.…”

“…Only five such cases have been described in the literature to date. [8][9][10][11] Therefore, more detailed study on their clinicopathological, immunohistochemical and genomic characteristics is needed. Here, as a tri-institutional effort, we present a collection of 14 cases with diffuse TTF1 and p40 coexpression; cases were collected in part through a highvolume consultation practice at Memorial Sloan Kettering Cancer Center (MSKCC).…”