Cellular organization and histogenesis of adenosquamous carcinoma of the pancreas: evidence supporting the squamous metaplasia concept

Abstract

Adenosquamous carcinoma of the pancreas (ASCAP) is characterized by conventional pancreatic ductal adenocarcinoma (PDAC) and squamous carcinoma components with at least 30% of the tumour showing squamous differentiation. To get further insight into the histogenesis of these lesions, we analysed the cellular organization of ASCAP compared to PDACs. Using Immunohistochemistry and triple immunofluorescence labelling studies for keratins, p63, p40, MUC1, MUC2, MUC5AC, Ki67, and EGFR we demonstrate that many ASCAPs contain a transitional zone between the K8/18-positive adenocarcinomatous component and the p63+ /p40+ /K5/K14+ squamous component initiated by the expression of p63 in K8/18+ adenocarcinomatous cells and the appearance of basally located p63+ K5/14+ cells. p63+ K5/14+ cells give rise to fully developed squamous differentiation. Notably, 25% of conventional PDACs without histologically recognizable squamous component contain foci of p63+ p40+ and K5/14+ cells similar to the transitional zone. Our data provide evidence that the squamous carcinoma components of ASCAPs originate from pre-existing PDAC via transdifferentiation of keratin K8/18-positive glandular cells to p63-, p40-, and keratin K5/14-positive squamous carcinoma cells supporting the squamous metaplasia hypothesis. Thus our findings provide new evidence about the cellular process behind squamous differentiation in ASCAPs.

Development and Validation of Nomograms to Predict Overall Survival and Cancer-Specific Survival in Patients With Pancreatic Adenosquamous Carcinoma

“…To date, the etiology of histogenesis of PASC was still unclear. The hypotheses to explain this phenomenon include the disputable collision tumor hypothesis, malignant squamous metaplasia of the ductal adenocarcinoma, and development from a progenitor cell (31)(32)(33)(34)(35)(36). As a result, the epidemiology and clinical course of PASC remain poorly understood.…”

Proteogenomic characterization of pancreatic ductal adenocarcinoma

“…Consistent with a previous report (Cancer Genome Atlas Research Network, 2017), some of these molecular classifications overlapped significantly, such as ''ADEX'' (Bailey) and ''exocrine-like'' (Collisson), ''Classical (Collisson)'' and ''pancreatic progenitor'' (Bailey), and ''squamous'' (Bailey), ''quasimesenchymal'' (Collisson) and ''basal-like'' (Moffitt) (p < 0.0001, Fisher's exact test). Notably, five adenosquamous carcinoma samples in our cohort were classified into ''squamous'' (Bailey), ''quasimesenchymal'' (Collisson), or ''basal-like'' (Moffit) groups, in line with the understanding for this histological pancreatic cancer subtype (Boecker et al, 2020;Lenkiewicz et al, 2020;Moffitt et al, 2015). Non-negative matrix factorization (NMF)-based proteogenomics subtyping using multiomics data from all 140 tumors revealed four clusters with significant overlap with RNA subtypes (Figures S7B and S7C; Table S7A).…”

Pancreatic acinar cell carcinoma with a ductal adenocarcinoma component: a case report and analysis of the histogenesis of the tumor

“…Pancreatic ductal cells can transform to squamous epithelium via metaplasia in conditions such as chronic pancreatitis. Recently, it has been reported that the squamous carcinoma component of pancreatic adenosquamous carcinoma originates from preexisting DAC via transdifferentiation [ 21 ]. Similarly, it is not surprising that ACC can transdifferentiate into DAC because acinar cells originally have the ability to transform into duct-like cells via acinar–ductal metaplasia.…”