Pancreas

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2020, Case 06, and is acinar cell carcinoma in the pancreas.

The information provided in this case was accurate and correct at the time of publication in 2020.

Any changes in terminology since the time of publication may not be reflected in this case.

Histologic sections from the pancreatic tumor show an epithelial lesion with very little intervening stroma. The tumor cells are arranged in solid nests with an easily identifiable acinar pattern at some but not every foci. The tumor cells are large and polygonal, with large single nucleoli and open chromatin. The cytoplasm is scanty, granular, and eosinophilic. PASD-positive cytoplasmic granules are present. Immunohistochemically, the tumor cells are positive for CK18, BCL10, trypsin, chymotrypsin, and lipase, with focal nuclear staining for beta-catenin. Scattered positive cells for synaptophysin are also seen, although these account overall for fewer than 5% of the total tumor cells. Lastly, AFP is positive but CK7, CK19, CK20, chromogranin A, HepPar1, and arginase1 are negative. The routine and immunohistochemical profile of this lesion is that of acinar cell carcinoma of the pancreas. 

Acinar cell carcinoma (ACC) is a rare pancreatic malignancy of acinar origin, accounting for only 1% - 2% of adult exocrine pancreas neoplasms. It is even rarer in children, with the mean age of occurrence being 58 years. It is more common in men, with a male-to-female ratio of 3 to 4:1. There is no preferential site of origin within the pancreas, and unlike pancreatic ductal adenocarcinoma (PDAC), it tends to be well-circumscribed and can attain a large size at diagnosis without causing duct obstruction or jaundice. At diagnosis, metastasis is common, and patients may present initially with lipase hypersecretion syndrome. This syndrome results from release of lipase into the serum, often from hepatic metastases. The features of this syndrome, some of which are seen in the current case, include polyarthralgia, subcutaneous fat necrosis, and peripheral eosinophilia. Also, unlike PDAC, jaundice is an uncommon presenting feature, but patients can experience weight loss, back pain, nausea, vomiting, diarrhea, and other nonspecific symptoms, such as malaise and non-localizing abdominal pain. 

Some radiologic features of ACC are helpful in differentiating it from PDAC, as ACC is usually very large, bulky, and well-circumscribed, without evidence of pancreatic duct obstruction or dilation. ACC may have features of cystic degeneration and hemorrhage and may extend into adjacent duodenum, liver, spleen, or large vessels. When ACC has a prominent cystic pattern, with cysts lined by acinar cells, it is regarded as acinar cell cystadenocarcinoma, although its clinical behavior is believed to remain the same as typical ACC. 

The characteristic histologic features of ACC include typical acinar pattern of growth in many cases. This pattern is characterized by small acini with tiny lumina, lined by polarized uniform cells. These cells tend to have uniform nuclei, with or without large prominent nucleoli and rare/infrequent mitoses. However, other patterns exist, especially a solid pattern (as in the current case). This is often associated with more cytologic pleomorphism, mitoses and other atypical features. Rarely, true papillary features can be seen, but in most cases, irrespective of the predominating pattern, typical acinar foci are usually present with sufficient sampling. 

By immunohistochemistry, positive trypsin and chymotrypsin staining is the hallmark of ACC. These markers stain in an apical pattern in lesions with an acinar pattern but may be diffusely cytoplasmic in others. ACC is also positive for BCL10 and can express AFP, especially in younger patients. Unlike PDAC, ACC is usually negative for CK7 and CK19. Synaptophysin and/or chromogranin A expression is generally absent in ACC, but scattered individual cells staining for either or both neuroendocrine markers can be seen in some patients. When up to 30% of the tumor cells express neuroendocrine markers, a mixed acinar-neuroendocrine carcinoma (MANC) should be considered.  

Of all epithelial neoplasms of the pancreas, PDAC has the worst outcome. Although the prognosis of ACC is better than that for PDAC, the 3- and 5-year survival rates for ACC are dismal, being just 26.3% and 5% respectively in one of the largest reported series. The factors negatively affecting prognosis include high stage and incomplete surgical resectability. The treatment of choice is surgical resection with or without adjuvant or neoadjuvant chemotherapy. 

Because of its rarity, recognizing and differentiating ACC from other pancreatic neoplasms is important. The most likely lesion to be mistaken for ACC is pancreatoblastoma (PBM). Very importantly however, PBM, unlike ACC, occurs in a much younger age group, accounting for about 25% of all pancreatic neoplasms under the age of ten years. However, cases of adult PBM have been reported.  PBM may also have acinar features and react, albeit focally, for trypsin and chymotrypsin as well as AFP and also exhibit scattered synaptophysin and chromogranin A. In addition, PASD-positive cytoplasmic granules can be seen in PBM. Unlike ACC, PBM tends to have squamoid foci histologically, and it is more likely to stain for CK7 and CK19. When positive, trypsin and chymotrypsin are usually restricted to foci with acinar features, whereas these are more diffuse in ACC.  

PDAC is more common and has a poorer outcome than ACC, and it is important to distinguish between these tumors. The absence of acinar features, presence of desmoplasia, positive CK7 and CK19 and typically negative acinar markers (trypsin, chymotrypsin, and lipase) are helpful histological features that characterize PDAC. The table below highlights some key differences between ACC, PDAC, and PBM. 

ACC may occur in pure forms or with a histologically recognizable neuroendocrine component. To designate a tumor as a mixed acinar-neuroendocrine carcinoma (MANC), the neuroendocrine component has to be greater than or equal to 30% of the lesion. While the neuroendocrine component in MANC is most commonly poorly differentiated neuroendocrine carcinoma, well differentiated neuroendocrine tumors may also be encountered in this context. Pure pancreatic neuroendocrine tumors (PanNET) are also on the differential of ACC. PanNET are well-differentiated tumors with typical “salt-and-pepper” nuclear features. These lesions may be functional (eg, insulinoma, glucagonoma) or non-functional. Although some of the histological growth patterns may overlap, in general PanNET cells tend to be more diffusely positive for synaptophysin and/or chromogranin A. 

Solid-pseudopapillary neoplasms (SPN) are tumors of the pancreas of uncertain lineage that have a low malignant potential. They predominantly affect young women, with a female-to-male ratio of 10:1 and a mean age in the mid-30s. SPN share several radiologic features with ACC, including large size and hypodensity on CT scan. Histologically, however, these lesions differ from ACC in having more papillary-like (pseudopapillary) features due to their growth around vessels and loosely cohesive nature. Also, the tumor cells are uniform with indistinct nucleoli. The cytoplasm of SPN cells contains PASD-positive globules, unlike the granules of ACC, and these globules react positively for alpha-1 antitrypsin. Some immunohistochemical overlap also exists between SPN and ACC, but with different patterns. Synaptophysin and chromogranin A can be positive focally in both, but nuclear beta-catenin is positive in almost all cases of SPN, while this is seen only occasionally with ACC. This is because an activating point mutation in the CTNNB1 gene (which codes for beta catenin) is present in almost all cases of SPN. The presence of a pseudopapillary neoplasm with positive CD10, alpha-1 antitrypsin, androgen receptor and/or nuclear beta-catenin staining in a young woman should favor SPN. 

Lastly, ACC can sometimes have hepatoid features and, because of its expression of AFP, be mistaken for hepatocellular carcinoma (HCC) or some other hepatoid carcinoma. Also, because the liver is a common site for ACC metastases, lesions in the liver may inadvertently be miscalled HCC, especially when a history of a pancreatic lesion is not available. Further compounding this is the fact that ACC can express albumin, demonstrable by in situ hybridization methods. However, a history of a pancreatic lesion and positive trypsin and/or chymotrypsin staining, in addition to negative HepPar1 or arginase1 staining, should help in identifying a lesion as ACC rather than HCC. 

1. Which of the following is true regarding acinar cell carcinoma (ACC) of the pancreas?
   
   
   1. It is a common neoplasm of the pancreas, presenting with duct obstruction.
   2. It is characterized by the presence of trypsin-positive and usually CK7-negative cells.
   3. It is not possible to distinguish it from ductal adenocarcinoma of the pancreas.
   4. Most cases contain a point mutation in the CTNNB1 (beta-catenin) gene.
   5. Positive albumin by in situ hybridization excludes this diagnosis.
2. Which of the following is a helpful histopathological differentiation between ACC and pancreatoblastoma (PBM)?
   
   
   1. ACC demonstrates squamoid foci not seen with PBM.
   2. ACC demonstrates synaptophysin, unlike PBM.
   3. ACC expresses PASD-positive granules, while PBM does not.
   4. CK19 is typically negative in ACC, but positive in PBM.
   5. Unlike PBM, ACC has a mean age of incidence under 10 years.
3. Which of the following pancreatic neoplasms is likely to have the worst outcome?
   
   
   1. ACC
   2. Acinar cystadenocarcinoma
   3. Pancreatic ductal adenocarcinoma
   4. Pancreatic neuroendocrine tumor
   5. Solid pseudopapillary neoplasm

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1. It is characterized by the presence of trypsin-positive and usually CK7-negative cells. (b)
2. CK19 is typically negative in ACC, but positive in PBM. (d)
3. Pancreatic ductal adenocarcinoma (c)