Clinical and Histological Basis of Adenosquamous Carcinoma of the Pancreas: A 30-year Experience.

An extensive review of our institutional database identified 23 patients with the diagnosis of ASC of the pancreas. ASC was more common in females (n=14, 61%), with a median age of 73 (interquartile range [IQR]=59–78) years at presentation. 39% and 65% of patients had diabetes mellitus and were smoker, respectively. The anatomical distribution of the tumor was the head of the pancreas (n=15, 65%), the body (n=6, 26%) and the tail (n=2, 9%). ( Table 1 ) The T clinical stages of the tumor according to the Tumor, Node, Metastasis (TNM) classification were: T2 (n=5), T3 (n=9), T4 (n=3) and unknown (n=6). Nodal disease was present on diagnostic interventions in 5 cases (21.7%). Clinical stage IV disease was documented in 3 cases (13%). Six patients (26%) were deemed to have resectable disease, three (13%) were borderline resectable (BLR) and eight (34.7%) were locally advanced (LA) or metastatic on presentation. Of note the median pre-treatment Carbohydrate antigen 19-9 (CA19-9) level for LA/metastatic disease was 2405 (IQR = 2130–15978) u/ml. ( Table 1 ) First-line treatment included pancreatic resection in eight cases (34.8%), neoadjuvant chemotherapy (NAC) in two (8.7%) and neoadjuvant chemoradiation (NACR) in three (13%). Ten patients (43.5%) underwent definitive non-operative treatment due to advanced disease or poor performance status. Pancreatic resection followed neoadjuvant treatment as a second-line intervention in 2 cases. Of the ten patients who underwent surgery, five underwent pancreaticoduodenectomy (Whipple procedure), four had distal pancreatectomy, and one patient received total pancreatectomy due to pancreatic atrophy. Two patients required vascular reconstruction of the superior mesenteric vein and portal vein. No postoperative pancreatic fistula, re-operation or 30-day mortality occurred. Adjuvant therapy was given in five cases (50%) when patients had acceptable postoperative performance status. ( Table 2 ) Most resected tumors had pathological T3 stage (80%). Pathological nodal disease was demonstrated in 60% of the operative cases. Margins were positive in 3 cases, in which one patient had positive peritoneal washing, and another who required vascular reconstruction following NAC. Complete pathological response was not perceived, although fibrosis presented in only once case (10%). Metastatic disease was noticed on final pathology in two cases: one in the cytology of the peritoneal washing at the time of resection and the other in a mesenteric nodule that was sent after committing to perform a distal pancreatectomy with splenectomy. ( Table 2 ) Follow-up revealed that 20 patients had developed metastatic disease with the most initial site of metastasis being the liver in 70% in cases. At the time of this publication, only three patients (13%) are alive. OS is 8.5 (IQR = 4.8–13.8) months.

After obtaining an approval by the Institutional Review Board, the histopathology database at our institute was interrogated to identify patients who underwent treatment for adenosquamous carcinoma of the pancreas. The pathology reports were carefully reviewed to confirm the squamous component or keratinizing feature. 29 cases presented at our comprehensive cancer center, of whom 23 patients received cancer care between 1990–2019. The histopathology reports of the biopsy or surgical specimens were reviewed in conjunction with clinical and radiological data. The nature of the clinical presentation was noted with a focus on the oncological staging and treatment interventions. Resectability and subsequent interventions performed in each case were reviewed. Patients were followed-up at our institute either in the surgical, medical or radiation oncology departments as appropriate and long-term outcomes including metastatic disease and overall survival (OS) were investigated.

Pancreatic cancer is a leading lethal malignancy accounting for half million newly-diagnosed cases worldwide every year.[ 1 ] Most are pancreatic ductal adenocarcinomas (PDAC) and only 0.4% to 4% are of the adenosquamous subtype.[ 2 – 7 ] Most cases to date have been reported in the Eastern hemisphere. The observation of squamous cell histology in the pancreatic tissue raised the query of metastatic disease from another primary lesion; however, the absence of primary squamous tumors and the presence of glandular component has complicated the picture.[ 8 ] The natural history of this cancer is poorly understood but many theories have been proposed to address the histopathogenesis of ASC. The first one was the pancreatic and biliary squamous metaplasia theory. This was thought, to some extent without sufficient evidence, to be related to the ductal inflammatory process associated with chronic pancreatitis, cholangitis or obstructive adenomatous neoplasm.[ 6 , 9 ] We know that 50% of pancreatic ASC cases are associated with synchronous subclinical chronic pancreatitis changes.[ 7 ] The second model examined the differentiation of a pluripotential duct cell into these two different malignant cellular lines, as evidenced by some immunochemical observations.[ 10 , 11 ] The collision theory suggested the coincidence rise of two independent histologically-distinct malignant cell populations that subsequently coalesce into one unique entity.[ 6 ] Although its rarity challenges to establish prognostic factors for ASC as entity, patients with pancreatic ASC has worse prognosis compared to those with PDAC.[ 7 , 12 , 13 ] They often present with obstructive jaundice, weight loss, nausea, and anorexia. Sectional Imaging, like computed tomography (CT) and magnetic resonance imaging (MRI), are the typical initial diagnostic methods.[ 14 ] ACS has the same stage and resectability status with twice tendency to present in the tail of the pancreas compared to PDAC.[ 12 ] It is also associated with more lymph node metastases and poorly differentiated histopathology compared to PDAC; 53% and 71% versus 47% and 45%, respectively.[ 12 ] Surgical resection, when applicable, has been the mainstay of treatment for ASC. Many case reports have incorporated adjuvant therapy to further improve resectability and survival. However, the heterogeneous nature of such therapeutic interventions and the rarity of pancreatic ASC challenge the interpretation of outcome data and formulation of guidelines. Herein we report our institutional experience in the management of ASC of the pancreas.

Adenosquamous carcinoma (ASC) of the pancreas represents a rare distinct and poorly understood histopathological variant of pancreatic malignancies.[ 7 ] Gotthold Herxheimer was the first to acknowledge this histology in 1907[ 15 ] when he referred to this tumor as “cancroide”, which subsequently evolved into many other names including mixed columnar adenocarcinoma, mixed squamous and adenocarcinoma, mucoepidermoid carcinoma, and adenoacanthoma.[ 6 ] ASC is known to present more frequently in organs where the glandular and squamous components are in vicinity, in particular, the lungs, esophagus, colon, anus, salivary glands and female reproductive system.[ 4 , 6 ] The majority of pancreatic ASCs presents in the head of the pancreas as demonstrated in our results (65% of cases). This distribution is similar to pancreatic ductal adenocarcinoma.[ 16 ] The medical literature includes few case reports and the management of this subtype of carcinoma has not yet been standardized. Most reported cases of pancreatic ASC are from the eastern hemisphere including Korea, Taiwan and Japan. It was primarily thought to favor the Asian populations; however current literature has broadened the ethnic spectrum of ASC.[ 7 ] Majority of ASC cases are diagnosed in the fifth-seventh decades with females being more affected than males 1.5:1 as demonstrated in our results.[ 6 ] Similar to ductal adenocarcinoma, tobacco is reported to share the same carcinogenic effect through the beta-arrestin-mediated activation of Src and Rb-Raf-1 pathways induced by nicotine.[ 17 ] 65% of our patients were smokers, which entitles a preventive opportunity in high-risk populations. Human papilloma virus (HPV) infection has not been shown to associate with ASC of the pancreas as seen in the head and neck and reproductive system malignancies.[ 7 ] The clinical presentation is diverse ranging from abdominal pain, weight loss, and anorexia to back pain, steatorrhea, pruritus and obstructive jaundice, mimicking periampullary cancer presentations.[ 18 ] However, symptoms tends to be more severe and tumor sizes are larger in ASC cases with 50% chance of metastatic disease upon initial presentation.[ 5 , 16 ] ASC has a more aggressive biological behavior compared to adenocarcinoma. The squamous component is believed to worsen the tumor prognosis, as malignant squamous cell grows at twice the rate of adenocarcinoma cells.[ 19 ] ASC is associated with advanced stage and evidence of angiolymphatic and perineural invasion. Approximately 60% of pancreatic ASC cases have regional lymph node involvement.[ 5 ] This is confirmed in our study as LA and metastatic disease was recorded in third of cases upon clinical presentation and nodal involvement was demonstrated in 60% of specimens. Liver enzymes and bilirubin are usually deranged indicating extrahepatic biliary obstruction. Carbohydrate antigen (CA) 19-9 and carcinoembryonic antigen (CEA) are beneficial tumor markers in 70% of patients, especially as seen in the LA/metastatic group in our cohort.[ 16 ] Paraneoplastic hypercalcemia has been reported in ASC tumors that secrete parathyroid hormone-related protein (PTH-rP).[ 20 , 21 ] Contrary to pancreatic ductal adenocarcinoma, ASC demonstrates contrast enhancement and hypervascularity on CT scan.[ 22 , 23 ] ( Fig 1a ) It appears avid on gallium 67 scintigraphy scan.[ 24 ] Invasive diagnostic modalities including endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasonography (EUS) guided biopsy have been utilized in the diagnostic method and treatment planning.[ 25 ] Historically, tissue obtained by biopsy was not obligatory for the surgical management of resectable pancreatic cancer. Although biopsies are needed to initiate neoadjuvant therapy, even in the setting of resectable disease. The diagnosis of ASC is established by microscopic examination, traditionally based on biopsy or resection specimens, with a growing role of cytology in recent decades.[ 26 ] ASC is defined as a lesion containing both adenocarcinoma and squamous cell carcinoma within the same tumor.[ 27 , 28 ] ( Fig 1b – d ) Adenocarcinoma forms glands or gland-like structures, often with intracellular or luminal mucin. Squamous differentiation is characterized by clusters or sheets of polygonal cells with dense eosinophilic cytoplasm, distinct cell borders, and varying degrees of keratinization. To qualify as ASC, the squamous component should be ≥30% of the neoplasm, admixed with variable proportions of adenocarcinoma.[ 27 , 28 ] The 30% cutoff is arbitrary, and several reports have argued against using strict criteria for the percentage of the squamous component in pancreatic ASC, citing that there have been no studies showing significant prognostic differences when using the 30% cutoff.[ 9 , 13 , 29 ] It has been shown that any degree of squamous differentiation portends a worse prognosis,[ 13 ] so it should be noted in the pathology report regardless of percentage. Pure squamous cell carcinoma of the pancreas and extrahepatic bile ducts are recognized entities, however, they are exceedingly rare, and investigators have questioned whether some cases represent undersampled ASC or metastasis from an occult primary.[ 9 , 28 ] Numerous studies have described the immunophenotype of ASC in the pancreas. The squamous component has been shown to express p63, p40, and CK5/6; identical to the immunophenotype of squamous cell carcinoma in other organs. The glandular component has been shown to express CA19-9, CEA, CK7, MUC1, and MUC5AC; all markers which are typical of PDAC.[ 9 , 30 , 31 ] A recent study by Boecker et. al. also described a transitional zone characterized by nuclear p63 expression and keratin 8/18 expression in malignant glandular cells, postulated to represent areas of squamous transdifferentiation.[ 30 ] Similarly, the squamous component has been reported to sometimes express markers more typical of PDAC such as CA19-9, CEA, and MUC5AC, albeit to a lesser degree.[ 9 , 30 ] EGFR expression appears to be more frequent in ASC of the pancreas than PDAC,[ 30 , 31 ] as does PD-L1; although PD-L1 expression may be selectively expressed by the squamous component.[ 32 ] Other studies have described nuclear p53 expression and loss of p16 and DPC4 in both components, which reflects molecular alterations shared by pancreatic ASC and PDAC.[ 30 , 31 , 33 , 34 ] Molecular studies of ASC in the pancreaticobiliary tract have mostly involved pancreatic cases. Almost all cases have KRAS mutations at codon 12, with frequent mutations in TP53 and SMAD4/DPC4;[ 31 , 33 – 35 ] very similar to PDAC. Among pancreatic neoplasms, mutations in the RNA surveillance gene UPF1 have been described as a unique molecular signature in ASC.[ 36 ] Fang et. al. also described distinct molecular alterations by using whole-genome and -exome sequencing to show a higher proportion of TP53 alterations in ASC, and chromosome 3p losses were found to be a distinct copy number alteration. That study also used laser capture microdissection to separate the adenocarcinoma and squamous cell carcinoma components in three cases of ASC, and found similar patterns of recurrent copy number alterations and crucial mutation events when comparing the two cellular components. This has been postulated to be evidence of a common progenitor tumor cell.[ 34 , 37 ] Radical surgical resection with negative margins (R0) remains the mainstay of cure in the management of ASC. Advanced unresectable ASC holds a very poor prognosis.[ 5 ] Analysis of 95 patients with ASC in the California Cancer Registry database reported a median overall survival of 12 months in resectable disease and 4.5 months in metastatic disease.[ 5 ] Smoot et al . demonstrated a median survival of 14.4 months and 8 months in patients who underwent R0 and R1 resection, respectively, compared to 4.8 months in patients who did not underwent surgical resection.[ 38 ] Due to the small number of our cohort, we are unable to make such sub-group analysis. Our median overall survival for both metastatic and resectable diseases in all comers is 8.5 months. Although no randomized trials have examined the advantage of perioperative therapy, neo- and adjuvant chemoradiation have been recommended to improve resectability and postoperative survival.[ 39 ] Although no standard treatment has been proposed, many chemotherapy regimens have been utilized, including Cisplatin, Vinblastine, Bleomycin, 5-Fluorouracil (5FU), or Gemcitabine-based regimens.[ 40 – 42 ] Knowing their efficacy in treating squamous cell carcinoma of other organ, these protocols were introduced in the pancreas, although none of them showed better survival than the others. The squamous component of ASC has deemed this tumor sensitive to radiation. Yamaue et al . has shown a 40 month free-recurrence survival in one patient with the use of intraoperative radiation and adjuvant chemoradiation utilizing external beam radiotherapy.[ 43 ] Voong et al . reported improved survival in resectable ASC cases followed by adjuvant chemoradiation, especially in the setting of squamous component ≥30% and lymph node involvement.[ 13 ] 75% of patients who lived beyond two years and all patients who survived beyond five years has had received adjuvant therapy.[ 5 , 13 ] It is wise to consider applying the results of the recently-published randomized phase III PREOPANC trial. This trial addressed the role of preoperative gemcitabine-based chemoradiotherapy versus immediate surgery for resectable and BLR pancreatic cancer in 16 centers.[ 44 ] Despite the insignificant overall survival benefit, R0 resection, disease-free survival and locoregional failure-free interval were improved in patients who received NACR.[ 44 ] This study opened the door to consider the applicability of NACR regimes in the setting of a newly diagnosed ASC of the pancreas.

Adenosquamous carcinoma of the pancreas is a rare and aggressive malignant phenotype and carry a worse prognosis. Histological characteristics include poor differentiation, keratin pearls and mucin production. Oncological resection remains the mainstay of treatment. Neoadjuvant chemoradiation has been proved to have a role in R0 resection and free-disease survival in pancreatic adenocarcinoma. Given the sensitivity of the squamous component of adenosquamous carcinoma, neoadjuvant chemoradiation might have a role in enhancing oncological outcomes. Such statement requires further investigation in the era of precision medicine.