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Page 4 of 26 Skorupan et al. J Cancer Metastasis Treat 2023;9:5 https://dx.doi.org/10.20517/2394-4722.2022.106

The poor response of PDAC to both chemo- and immunotherapies has most often been attributed to the
tumor’s unique microenvironment. PDAC typically has a desmoplastic stroma which makes up
[23]
approximately 70% of the tumor mass, leading to vascular collapse and hypoxia . This results in an
“immunologically cold” microenvironment that is mainly infiltrated by immunosuppressive myeloid cells
such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), tumor-
associated neutrophils (TANs), and FOXP3+ CD4+ regulatory T (Treg) cells, with exclusion of tumor-
restraining effector T cells (reviewed in ).
[24]

The genomic landscape of PDAC is well known. The four most commonly mutated genes are KRAS, TP53,
CDKN2A, and SMAD4, all of which have been considered “undruggable” until recently [25,26] . Notably,
[27]
mutations in KRAS are the primary driver of PDAC oncogenesis, occurring in > 90% of patient cases . No
other mutations occur more frequently than 10%. Around 5%-9% of PDAC tumors exhibit germline or
somatic mutations in homologous recombination (HR) repair-related genes such as BRCA1/2 or
[30]
PALB2 [28,29] , and these tumors have significant sensitivity to platinum chemotherapy . Treatment of these
tumors with platinum-containing regimens doubles patient survival [31-33] . These patients may also benefit
from maintenance treatment with olaparib, a PARP inhibitor .
[34]

Transcriptomic profiling has revealed two main PDAC subtypes - a less-aggressive, better differentiated
classical subtype, and a more aggressive basal (also called quasimesenchymal or squamous) subtype [35-37] . It is
important to note that some tumors fail to fall distinctly into a single transcriptomic category ,
[38]
transcriptomic subtype can be heterogeneous across individual tumors [39,40] , and transcriptomic subtype may
not be static as treatment or environmental factors may select for a particular subtype [41,42] .

ADENOSQUAMOUS CARCINOMA OF THE PANCREAS (ASCP)
Pathologic characteristics
Histology of ASCP
ASCP is a rare exocrine cancer that includes both a glandular and a malignant squamous component. It was
first reported by Herxheimer in 1907 as a “cancroide” tumor. Subsequently, other researchers have called it
[43]
mucoepidermoid carcinoma, adenoacanthoma, and mixed squamous and adenocarcinoma . ASCP is
defined by the presence of a malignant squamous component in at least 30% of cancer cells in a background
of malignant glandular epithelium [44,45] . The arbitrary cutoff of 30% has been disputed in the literature [45,46] ,
with opponents noting that the evaluation is subjective and highly dependent on sampling , especially
[47]
[48]
when fine-needle aspiration is used . This was further substantiated by a retrospective trial showing that
the percentage of cells below or above the 30% cutoff did not correlate with different clinical outcomes .
[49]
Conversely, a very high percentage of squamous cell component (> 60%) was associated with worse survival
in resectable patients .
[50]
Under light microscopy, ASCP is more likely to have increased necrosis, to be poorly differentiated and to
[51]
have increased vascular invasion compared to PDAC . Malignant glandular components of ASCP appear
similar to PDAC, while the squamous component has well-defined cell borders with intercellular bridges
and keratinization of the cytoplasm . Representative H&E-stained images of ASCP are shown in Figure 1.
[52]
Immunohistochemistry differs between the two components. The glandular component stains positive for
CK8/18, CK7, CEA, and CA19-9, similar to PDAC, while appreciable expression of CK5/6, p63, and p40 is
seen in the squamous component. The squamous area also exhibits frequent loss of E-cadherin and p16,
and increased EGFR and vimentin expression [52-55] . Positive nuclear p63 expression has been validated as a
more sensitive marker for ASCP in tumors that are difficult to classify by routine H&E stains . Others have
[53]
noted that metastases from an ASCP primary may appear as a pure adenocarcinoma, or even dedifferentiate