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Page 2 of 26 Skorupan et al. J Cancer Metastasis Treat 2023;9:5 https://dx.doi.org/10.20517/2394-4722.2022.106

Keywords: Adenosquamous carcinoma of the pancreas, acinar cell carcinoma of the pancreas, rare exocrine
pancreatic cancer

INTRODUCTION
Pancreatic cancer is an aggressive malignancy with a 5-year overall survival rate in the United States of just
11% despite recent advances in systemic chemotherapy that have improved outcomes for patients with both
advanced and early-stage disease . While pancreatic cancer contributes only 3.2% of new cancer cases in
[1-5]
the US, the high mortality rate has made pancreatic cancer the third most common cause of cancer-related
death in the country . Since the incidence of pancreas cancer is increasing every year, it is projected to
[5]
[6]
overtake colorectal cancer as the 2nd most common cause of cancer death by 2030 . Pancreatic cancer has a
similarly grim prognosis and incidence trajectory globally .
[7]
Most pancreatic cancers arise from ductal and acinar cells involved in the exocrine functions of the organ.
Pancreatic ductal adenocarcinoma (PDAC) is the most common histology and represents > 90% of
pancreatic cancer cases. It is so common compared to other types of pancreatic cancer that mention of
pancreatic cancer can be assumed synonymous with PDAC unless otherwise specified. Tumors arising from
endocrine cells of the pancreas represent ~5% of all pancreas cancers are mostly less aggressive than
[8]
[9]
PDAC, and have entirely different standard-of-care treatment paradigms . Even less common than
pancreatic neuroendocrine tumors are rare tumors of the exocrine pancreas, such as adenosquamous
carcinoma, acinar cell carcinoma, mucinous cystic neoplasm, colloid carcinoma, and pancreatoblastoma.
These diseases are so rare that treatment paradigms for them are typically extrapolated from PDAC
standard of care even though their histology and molecular underpinnings may differ markedly from
PDAC.

In this review, we have described what the field presently knows about two rare exocrine cancers of the
pancreas: adenosquamous carcinoma and acinar cell carcinoma. We have defined their cellular and
molecular pathology, clinical characteristics, and prognosis. Basic and translational studies examining their
origins and behavior have been surveyed. Case studies and epidemiologic reports which provide insights
into fruitful treatment paradigms have been reviewed. It is important to note that there are no prospective
clinical studies reported in the literature that examine any aspect of these diseases. Significant differences
between these tumors and PDAC have been highlighted to provide insight into when clinicians should
diverge from established PDAC standards of care when treating these patients. In the end, we aimed to
identify the important unanswered clinical questions about these diseases, providing a guide for future
research that could allow clinicians to offer the first evidence-based advice to patients.

STANDARD OF CARE TREATMENT FOR PDAC
PDAC typically presents with non-specific symptoms such as back pain, unexplained weight loss, jaundice,
GI discomfort or thromboembolism [10,11] . Most patients already have distant metastasis (52%) or
locoregional disease (30%) at the time of diagnosis. Primary tumors are most commonly located in the
[12]
pancreatic head , while metastases are most often located in the liver, peritoneum and lung.
The staging for PDAC is shown in Table 1. Current standard of care for early-stage disease (Stage I and II,
or Stage III that is not T4) is upfront surgical resection followed by adjuvant chemotherapy. There is no
appreciable cure rate if chemotherapy is not given . Choices of adjuvant chemotherapy include single-
[13]
agent gemcitabine for those with poorer performance status, gemcitabine in combination with capecitabine,
or modified FOLFIRINOX for those with excellent performance status [2,4,13] . More than 50% of patients who