Pancreas

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2021, Case 31, and is acinar cell carcinoma of the pancreas. The information provided in this case was accurate and correct at the time of publication in 2021. Any changes in terminology since the time of publication may not be reflected in this case.

Microscopic evaluation of the tumor demonstrates a highly cellular proliferation forming vague lobules separated by thin fibrous strands. The tumor is well circumscribed and partially encapsulated. While there are areas displaying sheets and nests of tumor cells, back-to-back “acinar” arrangement is a predominant pattern throughout the tumor. The monotonous tumor cells have abundant eosinophilic granular apical cytoplasm, basal nuclei, and single prominent nucleoli. Mitoses are frequent. ​This is an example of acinar cell carcinoma.​ 

Acinar cell carcinoma of the pancreas is a malignant epithelial neoplasm with acinar cell differentiation. Acinar cell carcinomas comprise approximately 1% to 2% of pancreatic neoplasms in adults (mean age 62 years) and approximately 15% of pancreatic neoplasms in children. Males are more affected than females (M:F ratio of 2:1). It can arise in any portion of the pancreas, although most frequently in the head. In most cases, presenting symptoms including weight loss, nausea, vomiting, and abdominal pain, while jaundice ​is ​rare. Approximately 15% of patients, often those with metastatic disease, also present with subcutaneous fat necrosis and polyarthralgia as a result of lipase hypersecretion.  

Grossly, acinar cell carcinoma is usually a well-circumscribed, solid, fleshy, large mass (average 11 cm) with variable hemorrhage, cystic degeneration, and necrosis. An intraductal/papillary variant has been described that is associated with a less aggressive course. Microscopically, the tumor cells are arranged in highly cellular lobules with scant fibrous stroma. Patterns of growth include acinar (resembling normal acini), solid, trabecular, glandular, or papillary, with acinar and solid patterns being most common. The nuclei are round to oval, with only mild pleomorphism, single prominent nucleoli, and variable mitotic activity. The cytoplasm tends to be abundant, eosinophilic, and granular. PAS-positive, diastase-resistant cytoplasmic zymogen granules may be present. 

Acinar cell carcinoma is immunoreactive for trypsin and chymotrypsin (90%+), lipase (50%), and rarely, amylase. BCL10 immunostaining is highly specific and sensitive for acinar cell differentiation, because the antibody directed against the COOH-terminal of BCL10 protein recognizes the COOH-terminal of carboxyl ester lipase, an enzyme produced by pancreatic acinar cells. There is no hallmark genetic alteration in pancreatic acinar cell carcinoma. Mutations of KRAS, SMAD4, and TP53 found in pancreatic ductal adenocarcinoma (PDAC) are largely absent in acinar cell carcinoma. The prognosis is poor, with a 5-year survival rate of 25%. Only ​tumor ​stag​e​ has been proven to be an independent prognostic marker. Metastases are present at the time of diagnosis in approximately one half of cases. Regional lymph nodes and liver are the most common metastatic sites. 

​​Other entities in the differential diagnosis for a​cinar cell carcinoma​ include​ pancreatic neuroendocrine tumor, pancreatoblastoma, and solid pseudopapillary neoplasm​​​.​​ ​ 

Mixed acinar carcinomas are rare and are defined as neoplasms having more than 30% of each line of differentiation in addition to a major acinar cell carcinoma component. The most common is mixed acinar-neuroendocrine carcinoma, which is diagnosed on the basis of coexpression of acinar and neuroendocrine markers. The neuroendocrine features may not be evident morphologically and, therefore, the use of immunohistochemistry is mandatory. It is best regarded as a subtype of acinar cell carcinoma because of the shared clinical behavior and genomic features. Mixed acinar-ductal carcinomas as well as mixed acinar-neuroendocrine-ductal carcinomas have been reported; although data are evolving, both neoplasms are known to behave aggressively.  

Pancreatic neuroendocrine tumor is typically composed of nests or trabeculae of uniform cells with stippled chromatin. Therefore, the trabecular pattern of pancreatic acinar cell carcinoma characterized by ribbons of cells can strongly resemble those of pancreatic neuroendocrine tumor. While pancreatic acinar cell carcinoma can show patchy focal labelling with neuroendocrine markers like synaptophysin and chromogranin, pancreatic neuroendocrine tumors stain diffusely positive with neuroendocrine markers and are negative for BCL10, trypsin, and chymotrypsin.  

Pancreatoblastoma is the most common pancreatic neoplasm in childhood (first 10 years of life). The presence of squamoid nests in pancreatoblastoma is the histological hallmark that distinguishes it from acinar cell carcinoma. Because of multiple lines of differentiation, pancreatoblastoma can be immunoreactive for pancreatic enzymes (trypsin, chymotrypsin, and lipase) and BCL10 in the acinar component, neuroendocrine markers (synaptophysin and chromogranin) in the neuroendocrine component, and EMA in the squamoid nests.  

Solid pseudopapillary neoplasm occurs predominantly in young to middle-aged women (F:M ratio of 10:1). The most common pattern is solid nests of poorly cohesive cells forming pseudopapillae. The diagnosis can be established by nuclear expression of β-catenin and absent labelling for trypsin and BCL10. 

1. Which of ​the ​following is true regarding acinar cell carcinoma?
   
   
   1. It has an overall favorable prognosis.
   2. It is the most common pancreatic neoplasm in childhood.
   3. It typically affects young women.
   4. KRAS and TP53 mutations are common.
   5. The acinar pattern is reminiscent of normal acini.
2. Which one of the following immunostains is ​the most​ sensitive and specific for acinar cell carcinoma of the pancreas?
   
   
   1. Amylase
   2. β-catenin (nuclear)
   3. BCL10
   4. Chromogranin
   5. Lipase
3. A pancreatic neoplasm from a Whipple specimen from a 68-year-old woman is composed of homogenous solid sheets of malignant cells with amphophilic cytoplasm. Immunohistochemistry shows greater than 30% positivity for synaptophysin, chromogranin, chymotrypsin, and trypsin.
   This tumor is best diagnosed as which of the following?
   
   
   1. Acinar cell carcinoma
   2. Mixed acinar-neuroendocrine carcinoma
   3. Pancreatic ductal adenocarcinoma
   4. Pancreatic neuroendocrine tumor
   5. Pancreatoblastoma

1. Hackeng WM, Hruban RH, Offerhaus GJA, Brosens LAA. Surgical and molecular pathology of pancreatic neoplasms. Diagn Pathol. 2016;11(1):47:1-17.
2. Klimstra DS, Heffess CS, Oertel JE, Rosai J. Acinar cell carcinoma of the pancreas. A clinicopathologic study of 28 cases. Am J Surg Pathol. 1992;16(9):815-837.
3. Klimstra DS, Rosai J, Heffess CS. Mixed acinar-endocrine carcinomas of the pancreas. Am J Surg Pathol. 1994;18(8):765-778.
4. La Rosa S, Adsay V, Albarello L, et al. Clinicopathologic study of 62 acinar cell carcinomas of the pancreas: insights into the morphology and immunophenotype and search for prognostic markers. Am J Surg Pathol. 2012;36(12):1782-1795.
5. La Rosa S, Franzi F, Marchet S, et al. The monoclonal anti-BCL10 antibody (clone 331.1) is a sensitive and specific marker of pancreatic acinar cell carcinoma and pancreatic metaplasia. Virchows Arch. 2009;454(2):133-142.
6. Odze RD, Goldblum JR, eds. Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas. 3rd ed. Elsevier Saunders. 2015;1115-1117.
7. WHO Classification of Tumours Editorial Board. Digestive System Tumours. 5th Ed. IARC. 2019;333-346.
8. La Rosa S, Sessa F, Capella C. Acinar cell carcinoma of the pancreas: overview of clinicopathologic features and insights into the molecular pathology. Front Med (Lausanne). 2015;2:41.

1. The acinar pattern is reminiscent of normal acini (e)
2. BCL10 (c)
3. Mixed acinar-neuroendocrine carcinoma (b)