The first histological description of ASC reported in the literature was that of Herxheimer, in 1907, who defined this unusual entity as “cancroide” [6]. The characteristic cellular mixture of squamous and adenomatous cellular lines led other authors to various definitions of ASC, such as adenoacanthoma, mixed squamous and adenocarcinoma, or mucoepidermoid carcinoma [2, 3].

It was not until 2000 that the World Health Organization clearly indicated the presence of at least 30% squamous cell carcinoma differentiation as a mandatory criterion for the diagnosis of ASC (Fig. 13.1). Since then, tumors showing a lower squamous proportion are designated as PC with “squamous differentiation” [7].

Many theories have been proposed to explain the origin of ASC. In the “squamous metaplasia theory,” squamous metaplasia was postulated to occur as a result of ductal inflammation due to chronic pancreatitis or obstruction by an adenocarcinomatous tumor that ultimately became a malignant adenosquamous pancreatic tumor. A second theory, termed “the collision theory,” suggested that two histologically distinct tumors, adenocarcinoma and squamous cell carcinoma, arise independently from different sites and then fuse. According to the third theory, the “differentiation theory,” ASC reflects the malignant differentiation of a pluripotent ductal cell into two distinct histological types.

Currently, the most widely accepted theory postulates a metaplasia from a focal adenocarcinomatous cancer towards a squamous histotype [2, 8, 9] (Fig. 13.2). This consideration originates from a common observation during specimen examination, i.e., that only adenocarcinomatous foci show a characteristic cytological spectrum from ductal hyperplasia to carcinoma in situ, and are typically surrounded by squamous cell lines without a transitional margin [8, 9]. Furthermore, even ASC with a particular squamous predominance consistently contains KRAS2 gene mutations, similarly to the more common PC [8, 10–13].

The preoperative differential diagnosis between ASC and PC is often difficult. Similar to PC, ASC shows a slightly greater prevalence in males (M/F ratio: 1.5:1), with a mean age of 62 years. The most frequent symptoms at the time of presentation are weight loss, jaundice, and non-specific abdominal pain. Even the radiological and macroscopic appearance of ASC may completely mimic a typical PC [3, 8]. However, expression of the tumor markers CEA and CA 19-9 directly correlate with a more aggressive biological behavior and an advanced stage of disease [3, 8, 11, 14, 15].

Preoperatively, fine-needle aspiration (FNA) is a useful tool to obtain the correct diagnosis, although it requires careful pathological examination of the specimen in order to accurately distinguish the squamous cell cancer component from “atypical cells” (also referred to as “epidermoid”). The latter are also found in patients with chronic pancreatitis or in those undergoing endoscopic biliary stent placement [16, 17].

By the time symptoms occur, the vast majority of patients with ASC will present with advanced disease and thus succumb early, due to local or systemic dissemination. A potentially curative surgical resection (R0-R1) of the tumor, followed by adjuvant treatment (chemoradiation) is the only therapeutic option that can potentially lead to a significantly better survival [5, 8, 11].

Indeed, in a recent retrospective study by Voong et al. [5], based on a longterm follow-up of 38 patients who had undergone radical surgery for histologically confirmed ASC, the 1-, 2- and 5-year overall survival rates were 34, 11, and 5%, respectively. Furthermore, the authors found that adjuvant chemoradiation (5-FU or gemcitabine or capecitabine plus 5.040 Gy), but not other well-established prognostic determinants (T stage, nodal involvement, residual microscopic tumor), significantly correlated with a better median survival when compared to surgery alone (13.6 vs. 8.6 months respectively; p = 0.05). This favorable course was also confirmed in a series from our institution, in which four patients who had undergone pancreatic resection with negative resection margins (R0) plus adjuvant chemotherapy (5-FU, or gemcitabine plus or minus oxaliplatin) had a median survival of 14.5 months (R0; n = 2; 27 months; R1; n = 2; 13.5 months) [4].

Furthermore, alternative treatments such as intraoperative radiation therapy (IORT) for locally advanced ASC and surgery plus adjuvant locoregional chemotherapy also have been reported, although the results are controversial due to the small sample sizes [14, 18, 19]. Therefore, in the absence of further evidence, radical resection of the primary tumor plus adjuvant chemoradiation should be considered the gold standard approach in the multidisciplinary management of ASC.

ASC still represents a particularly aggressive disease associated with poor prognosis. For those patients suffering from locally advanced or metastatic ASC, the median overall survival rate is exceptionally dismal (4.5 months) [8, 11, 14, 20, 21].

Early studies published in the literature failed to document any significant improvement in survival comparing adjuvant chemotherapy with standard resection alone [3, 14, 21, 22]. However, these conclusions might have been biased by the small and heterogeneous samples and the lack of details regarding well-established prognostic factors, such as margin status and TNM stage [3, 8, 21]. Notably, more recent studies, in which detailed surgical and pathological data were included, reported a significantly more favorable outcome within the subset of patients undergoing radical surgery plus adjuvant chemoradiation, with a median overall survival comparable to that of patients with PCs of similar characteristics [5, 11].