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A 76-year-old man underwent abdominal ultrasonography for evaluation of abdominal pain, which revealed a large mass involving the body of the pancreas. Subsequent resection showed a delicately encapsulated 17.0 cm mass with cystic and necrotic-appearing areas and fleshy, tan-to-white cut surface.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2009, case 22, and is acinar cell carcinoma.
Criteria for Diagnosis and Comments:
On low-power examination, the tumor is highly cellular with a paucity of fibrous stroma. There are areas of solid growth and tightly packed, trabecular and acinar elements without much intervening stroma. There is considerable mitotic activity and an overall basophilia of the tumor. Acidophilic granules in the cytoplasm, intraluminal crystals and pale, acidophilic secretory concretions are notable.
Pancreatic tumors exhibiting acinar differentiation are rare, comprising less than 2% of pancreatic neoplasms in adults. The adult patients average 58 years of age, and males are more commonly affected. Most such neoplasms are highly aggressive acinar cell carcinomas (ACC). Presenting symptoms include abdominal pain, nausea, vomiting, and weight loss. Some patients develop massive serum lipase elevations accompanied by subcutaneous fat necrosis, which is indicative of hepatic metastasis. Serum alpha-fetoprotein elevations have been reported, especially in younger patients. Fifty percent of patients have metastases in regional lymph nodes and/or the liver at presentation, and more than half of the remaining patients subsequently develop metastatic disease. The 5-year survival of patients with ACC is very poor (6%), with a median survival of 16 – 20 months. Patients with distant metastases may survive for 2 – 3 years. ACC represents 15% of pancreatic tumors in children, and pediatric patients have a better prognosis than adults.
ACC may arise in any portion of the pancreas. Most are large, averaging 10 cm in diameter, and the periphery of the carcinoma may appear circumscribed, although invasion by tumor through the capsule is common. They are usually tan to red, soft and fleshy. ACC are cellular, stroma-poor tumors characterized by sheets of relatively uniform cells with various architectural arrangements. The acinar pattern shows minute lumina with basally located nuclei and a moderate amount of eosinophilic granular apical cytoplasm. The solid pattern lacks lumen formation but may show basal palisading of the nuclei at the interface of the solid nests with the stroma. A glandular pattern with dilated acinar structures and a trabecular pattern are less common, and a mixture of architectural patterns is often found within an individual tumor. Occasionally, cystic change, a nodular growth pattern, and intraductal growth has been documented. The nuclei in ACC are relatively uniform, often with a central, single nucleolus and easily detectable mitoses. The cytoplasm in ACC, with abundant zymogen granules, is eosinophilic and finely granular. However, special stains are needed to demonstrate the presence of enzyme production in many cases. Zymogen granules are positive on PAS stain, and are usually resistant to diastase digestion. Immunohistochemical staining for the enzymes trypsin and chymotrypsin is highly sensitive in detecting acinar differentiation. ACC often shows focal endocrine differentiation with scattered cells that stain for chromogranin or synaptophysin. ACC generally lacks mutations in the k-ras oncogene or abnormalities in p53 and p16, but often shows losses in chromosome 11p and may have abnormalities in the APC/beta-catenin pathway.
Other lesions may mimic ACC, and typical differential diagnostic considerations may include pancreatic endocrine tumor, pancreatoblastoma, solid-pseudopapillary neoplasm and well-differentiated adenocarcinoma. Some pancreatic neoplasms have significant elements of more than one line of differentiation. Most of these mixed neoplasms have a predominant acinar component and are clinically aggressive. In most cases, only immunohistochemistry can determine the presence and extent of the mixed cell types, and each component should comprise at least 25% of the neoplasm. Examples include mixed acinar-ductal, mixed acinar-endocrine, and mixed acinar-endocrine-ductal carcinomas.
Pancreatic endocrine tumor is commonly confused with ACC. Strong reactivity for chromogranin and synaptophysin is characteristic of endocrine tumors. Scattered endocrine cells or a focal endocrine component may be seen in ACC and is not sufficient for the diagnosis of a pancreatic endocrine tumor. A lesion is designated as mixed when a second component constitutes >25% of the tumor. Pancreatic endocrine tumor may show papillary growth similar to ACC, with a cellular, stroma-poor arrangement of relatively uniform cells. However, endocrine tumor cells tend to have a more nested pattern and “salt-and-pepper” chromatin, while ACC cells tend to show prominent nucleoli.
Pancreatoblastoma are fundamentally acinar neoplasms with similar histologic features, as well as prominent acinar differentiation based on immunohistochemistry. However, pancreatoblastoma usually affect children under 10 years of age. Characteristic squamoid nests distinguish pancreatoblastoma from ACC microscopically.
In the past, solid-pseudopapillary neoplasm has been referred to as “cystic ACC,” since it can show solid areas of small, monotonous cells that may mimic endocrine neoplasia or acinar neoplasia. Solid-pseudopapillary neoplasm is currently classified as of undetermined origin and occurs predominantly in girls and young women. In contrast to ACC, there is never true lumen formation or immunohistochemical expression of trypsin or chymotrypsin. Solid-pseudopapillary neoplasm shows characteristic degenerative features, including cysts, pseudopapillary or rosette-like formations, and usually expresses alpha-1-antitrypsin, vimentin, CD56, progesterone receptor, and CD10. Some neuroendocrine markers may be positive, but chromogranin is typically negative.
Well-differentiated pancreatic adenocarcinoma may sometimes resemble ACC histologically, but there is usually more desmoplasia and less circumscription compared to ACC. Immunohistochemical stains for pancreatic proteases are helpful in highlighting acinar differentiation, while ductal differentiation can be documented through B72.3, CA19-9, or CEA staining. Ductal cancers often show k-ras mutations, which are not seen in acinar tumors.