Mini-symposium: pancreatic pathology
Acinar cell carcinoma of the pancreas and related neoplasms: a review

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Abstract

Acinar cell carcinomas (ACCs) are rare tumours of the exocrine pancreas, accounting for up to 2% of all pancreatic neoplasms in adults and 15% of those in children. They are typically solid, cellular, stroma-poor tumours composed of sheets of relatively uniform cells. This sheet-like arrangement is usually punctuated by variable numbers of acinar structures. Variable amounts of neuroendocrine elements in the form of scattered individual cells are quite common, and some cases have more significant neuroendocrine or ductal elements (mixed acinar neuroendocrine carcinoma and mixed acinar ductal carcinoma).

Demonstration of acinar differentiation, usually by immunohistochemistry, is necessary for the diagnosis. Among the antibodies recognizing various pancreatic enzymes, trypsin and chymotrypsin are the most useful. Molecular alterations characteristic of ductal adenocarcinomas such as mutation in the KRAS oncogene are absent in ACCs. However, allelic loss on chromosomes 11p and mutations in the APC/β-catenin pathway have been identified in about 50% and 25% of cases, respectively.

ACCs are fairly aggressive tumours, although they are not as dismal prognostically as ductal adenocarcinomas. Those patients who present with localized disease have a much better prognosis than those who present with metastases (5-year survival rate of 25% vs. 50%). Unfortunately, metastases, usually involving the liver, are present in 50% of patients at the time of diagnosis.

Section snippets

General features

Despite the fact that the majority of the normal pancreas is composed of acinar cells, acinar cell carcinomas (ACCs) are extremely uncommon and represent only 2% of all pancreatic neoplasms. They can occur at any age but are much more common in adults (mean age = 58 years), and paediatric cases comprise only 6% of all ACCs. Males are affected more frequently (M:F = 3.6:1).1, 2

Clinical presentation

Most patients have non-specific symptoms including abdominal pain, bloating, nausea, vomiting, diarrhoea and weight loss. Since ACCs usually do not obstruct the common bile duct, jaundice is not common. Ten to 15% of the patients, almost invariably those with liver metastases, develop the lipase hypersecretion syndrome, a manifestation of excessive lipase secreted by the tumour into the serum.3 The syndrome is characterized by diffuse subcutaneous fat necrosis and polyarthralgia with or without

Gross features

ACCs may arise in any portion of the pancreas. Most are large, with a mean size of 11 cm, and they are generally more circumscribed than ductal adenocarcinomas. They are usually tan to red, soft and fleshy (Figure 1). Areas of haemorrhage, necrosis and cystic degeneration can be present. A few cases have a diffuse multicystic gross appearance; these acinar cell cystadenocarcinomas are discussed below. Rare ACCs involve the ductal system and, in addition to the solid areas, reveal intraductal

Microscopic features

At low magnification, ACCs are markedly cellular and are devoid of the intervening desmoplastic stroma characteristic of ductal adenocarcinomas (Figure 2). The periphery of the carcinoma may appear circumscribed, often surrounded by a thin fibrous capsule, although capsular invasion and extension into adjacent parenchyma is common. In most cases, necrosis is not prominent. Occasional tumours, however, have abundant coagulative necrosis.

Of the several different architectural patterns described,

Histochemistry

PAS staining after diastase digestion reveals small PAS-positive granules (Figure 7) corresponding to zymogen granules, particularly in the apical aspect of the cells.9 However, the amount varies greatly from case to case and even within different areas of the same tumour. If present, intraluminal secretory concretions and crystals are also PAS-positive.6 Unlike in ductal adenocarcinomas, no intracellular mucin is detected by mucicarmine or alcian blue stains, although occasional focal staining

Immunohistochemistry

The diagnosis depends on the demonstration of acinar differentiation, obtained using antibodies recognizing various pancreatic enzymes that, although specific, show different sensitivity for the diagnosis. Both trypsin (Figure 8) and chymotrypsin are detectable in over 95% of cases and are most diagnostically useful markers; however, some studies have shown less sensitivity for chymotrypsin. Lipase is less commonly identified, in approximately 70–85% of cases. Other markers that are reportedly

Electron microscopy

Zymogen granules are the ultrastructural hallmark of acinar differentiation and occur as electron-dense granules that may vary in number, shape, size and distribution. Typical granules are round, range from 125 to 1000 nm in size and are usually concentrated in the apical cytoplasm, adjacent to the luminal border. A second population of granules has bizarre shapes with a fibrillary internal structure, ranging up to 3500 nm in size. Some of these appear to be membrane bound, but others are free

Molecular findings

By molecular genetic analysis, ACCs very rarely if ever show KRAS, TP53, SMAD4 (DPC4), or CDKN2A(p16) gene mutations, in contrast to pancreatic ductal adenocarcinomas. As a result, immunohistochemically, only rare cases exhibit abnormal nuclear accumulation of the p53 protein, and DPC4 is retained. However, a high frequency of allelic loss on chromosomes 11p, 4q and 16q has been identified. In addition, 25% of ACCs have mutations in APC/β-catenin pathway, either activating mutations of the

Acinar cell cystadenocarcinoma

A cystic variant of ACC is well documented but is extremely uncommon; only a handful of cases have been reported.15, 16, 17, 18, 19 Grossly, the lesions are large (mean, 24 cm), circumscribed and diffusely cystic with individual locules ranging from a few millimetres to several centimetres. Microscopically, the cysts are separated by delicate fibrous septa and lined by single or several layers of neoplastic acinar cells, sometimes forming minute lumina within the epithelial lining (Figure 10).

Mixed acinar carcinomas

Mixed acinar carcinomas exhibit more than one line of differentiation (acinar and neuroendocrine; acinar and ductal; or acinar, neuroendocrine, and ductal), usually with the acinar component predominating. By arbitrary definition, each component must comprise at least 25% of neoplasm for a diagnosis of mixed acinar carcinoma. Although some mixed carcinomas have distinctive histologic features suggesting that more than one line of differentiation exists, in many cases, mixed differentiation is

Differential diagnosis

The main differential diagnosis of ACC is with other pancreatic neoplasms that are characterized by a solid, cellular pattern, namely pancreatic neuroendocrine tumours, pancreatoblastoma, solid–pseudopapillary neoplasm and intraductal tubulopapillary neoplasm (Table 1).

Staging

Pure and mixed ACCs are staged using the TNM staging system for carcinomas of the exocrine pancreas, based on the size and extent of the primary neoplasm, and the presence of regional lymph node and distant metastases.30

Prognosis

The clinical course of ACC is aggressive, although it is usually not as dismal as that of stage-matched ductal adenocarcinomas. The five-year survival rate ranges from 6%1 (based on cases recruited before 1999) to 50%31, 32, 33 in different studies. Patients who present with localized disease have much better prognosis than those who present with metastases, which are most often found in regional lymph nodes and the liver3 although occasionally in lung, cervical lymph nodes and ovary.34 Longer

Research directions

At the molecular level, ACC is very different from other types of pancreatic neoplasms, ductal adenocarcinoma in particular. These observations along with anecdotal demonstration of significant responses to treatment1 suggest there may be promise to identify therapeutic targets for this variant of pancreatic cancer. Because ACCs harbour abnormalities in the APC/β-catenin pathway, chemotherapy directed more towards intestinal-type carcinomas has been tested with some success. Future research

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