TTF-1/p63-Positive Poorly Differentiated NSCLC: A Histogenetic Hypothesis from the Basal Reserve Cell of the Terminal Respiratory Unit.

Daniela Cabibi,Nadia Barraco,Sandro Bellavia,Ada Maria Florena,Antonino Giulio Giannone,Vito Rodolico,Anna Martorana,Calogero Cipolla,Massimo Cajozzo

doi:10.3390/diagnostics10010025

Abstract

TTF-1 is expressed in the alveolar epithelium and in the basal cells of distal terminal bronchioles. It is considered the most sensitive and specific marker to define the adenocarcinoma arising from the terminal respiratory unit (TRU). TTF-1, CK7, CK5/6, p63 and p40 are useful for typifying the majority of non-small-cell lung cancers, with TTF and CK7 being typically expressed in adenocarcinomas and the latter three being expressed in squamous cell carcinoma. As tumors with coexpression of both TTF-1 and p63 in the same cells are rare, we describe different cases that coexpress them, suggesting a histogenetic hypothesis of their origin. We report 10 cases of poorly differentiated non-small-cell lung carcinoma (PD-NSCLC). Immunohistochemistry was performed by using TTF-1, p63, p40 (ΔNp63), CK5/6 and CK7. EGFR and BRAF gene mutational analysis was performed by using real-time PCR. All the cases showed coexpression of p63 and TTF-1. Six of them showing CK7+ and CK5/6− immunostaining were diagnosed as “TTF-1+ p63+ adenocarcinoma”. The other cases of PD-NSCLC, despite the positivity for CK5/6, were diagnosed as “adenocarcinoma, solid variant”, in keeping with the presence of TTF-1 expression and p40 negativity. A “wild type” genotype of EGFR was evidenced in all cases. TTF1 stained positively the alveolar epithelium and the basal reserve cells of TRU, with the latter also being positive for p63. The coexpression of p63 and TTF-1 could suggest the origin from the basal reserve cells of TRU and represent the capability to differentiate towards different histogenetic lines. More aggressive clinical and morphological features could characterize these “basal-type tumors” like those in the better known “basal-like” cancer of the breast.

Highlights

Identifying the correct type of lung cancer has become increasingly important due to the recent advances in “targeted” therapies
We examined a small casuistry of PD-NSCLC coexpressing both TTF1 and p63, with the aims of better characterizing their immunohistochemical and genetic profile and suggesting a histogenetic hypothesis about their origin
TTF1 and p63 immunohistochemical assays were repeated on new serial sections to confirm previous results, together with p40, CK5/6, cytokeratin 7 (CK7) and Immunohistochemistry was performed by a standard protocol on a BenchMark Ultra automated immunostainer according to the manufacturer’s instructions

Summary

Introduction

Identifying the correct type of lung cancer has become increasingly important due to the recent advances in “targeted” therapies. The morphological distinction between pulmonary adenocarcinoma (ADC) and squamous cell carcinomas (SCC) is sometimes difficult, mainly in cases of poorly differentiated tumors or when degenerative changes, necrosis and crushing may obscure the cell characteristics. Differentiated non-small-cell lung carcinomas (PD-NSCLC) are tumors. The combined use of antibodies TTF-1 and cytokeratin 7 (CK7) for ADC and p63 with high molecular weight keratins (CK5/6) for SCC provides a very reliable distinction between these two subtypes of non-small-cell carcinoma [1,2]. SCC shows positive immunostaining for CK5/6, p63 and p40 (∆Np63) (with strong and widespread nuclear reaction) and negative immunostaining for TTF-1 and CK7. ADC shows positive immunostaining for TTF-1 and CK7 and negative immunostaining for p63, p40 and CK5/6 [3,4]

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