Distinctive features of immunostaining and mutational load in primary pulmonary enteric adenocarcinoma: implications for differential diagnosis and immunotherapy

Abstract

BackgroundPrimary pulmonary enteric adenocarcinoma (PEAC) is an extremely rare variant of invasive lung cancer. It is highly heterogeneous while shares some common morphologic and immunohistochemical features with usual pulmonary adenocarcinoma (PAC) and colorectal adenocarcinoma (CRAC), making the differential diagnosis difficult. At present there are only limited studies about distinctive features of primary PEAC and the results are often inconsistent.MethodsWe retrospectively analyzed total 129 primary PEACs and 50 CRACs that were published since 1991 or diagnosed in our centre. Among them eight typical samples of primary PEACs and usual PACs were detected by targeted exome sequencing.ResultsThe combination of CK7+/CDX2+ acquires high sensitivity (71.3%) and specificity (82%) in differential diagnosis of PEACs from CRAC. The primary PEACs harbor a high incidence of KRAS mutation but almost absent of EGFR mutation. Moreover, compared with usual PACs, the primary PEACs have higher nonsynonymous tumor mutation burden and more frequent MMR mutation.ConclusionsThe combination of CK7+/CDX2+ immunostaining and the distinctive genetic signatures, including low incidence of sensitivity genes mutations and high tumor mutation burden, is an important supplementary to the clinical differential diagnosis of primary PEACs. Our findings thus have significant implications for development of individualized treatment strategy in these patients.

Clinical analysis of 23 patients pathologically diagnosed with primary and secondary pulmonary enteric adenocarcinoma

“…For immunohistochemistry, P-PEAC expresses at least one of the enteric differentiation markers (including Caudal Type Homeobox 2 [CDX2], cytokeratin [CK] 20, and mucin 2 [MUC2]), [2] with lung adenocarcinoma markers (such as CK7 and thyroid transcription factor 1 [TTF-1]) being consistently positive in almost half the cases. [3] CK20, MUC2, CDX2, Villin, CK7, TTF-1, and NapsinA were summarized as follows in our study: 36%, 0, 89%, 100%, 93%, 47%, and 39% in P-PEAC and 100%, 83%, 100%, 100%, 50%, 0, and 33% in S-PEAC. Our result implied Villin that also serves as a common marker for PEAC.…”

Pulmonary enteric adenocarcinoma: an overview

“…IHC features of PAED have been described by several authors, but data are often conflicting and inconclusive ( Refs 13,19,20,23,24,31,34). However, scientific societies agree in considering, as major pathological characteristics of PAED, the IHC positivity for at least one marker of colonic differentiation, among CDX2, CK20 and MUC2, as well as the presence of an entero-like tumour cell morphology in more than half sample (Travis 2013, Truini 2015).…”

“…When carrying out a research of the scientific literature pertinent to the topic, we realised that most studies included reports of isolated or few cases, some others described sporadic cases as part of a larger series of lung cancers lacking detailed clinical information. The only studies with the highest numbers of patients (over 10) have been published in the last 3 years (Refs 11, 12, 19, 20, 23, 24, 25, 26). Based on this experience, in this paper, we summarised current researches on PAED, focusing on its IHC and molecular features as potential tools for differential diagnosis, prognosis definition and therapeutic strategy choice.…”

Molecular and Morphological Profiling of Lung Cancer: A Foundation for “Next-Generation” Pathologists and Oncologists

“…The most common genetic abnormality in enteric carcinomas (EC) was KRAS mutation followed by EML4-ALK fusion, NRAS mutations and EGFR mutations [29,30]. Moreover, four out of five enteric ADCs had mutations in mismatch-repair genes, and tumor mutational burden (TMB) levels were higher than those seen in control ADCs [29].…”