Acinar cell carcinoma (ACC) of the pancreas and pancreatic neuroendocrine tumor (NET) are different neoplasms; however, it is well known that 35% to 55% of ACCs have focal (neuro)endocrine differentiation.1-3 The endocrine component usually consists only of scattered cells. If it is greater than 25% to 30% of the neoplastic cells, the carcinoma is called mixed acinar-(neuro)endocrine carcinoma (MAEC).3-6 By definition, metastases show the same mixed exocrine-endocrine features as the primary tumor.3
A 51-year-old woman was admitted to the hospital because of epigastric pain and loss of appetite. Abdominal imaging revealed a growing mass in the tail of the pancreas (Figs. 1A, B) and multiple liver metastases. Laboratory data showed a markedly elevated elastase l level (40,000 ng/dL), whereas carcinoembryonic antigen and CA-19-9 levels were normal. Chemotherapy was ineffective, and the patient died 1 year after admission, with hemorrhage from the pancreatic mass. An autopsy was performed. Macroscopically, a well-circumscribed solid mass measuring 22 × 15 × 13 cm3 was found in the body/tail of the pancreas. The cut surface of the mass was white to tan, soft, and revealed lobulation with central cystic necrosis. Direct invasion into the stomach wall and liver metastases were also present. Microscopic slides revealed cellular nodules composed of densely packed neoplastic cells arranged in solid sheets and nests punctuated by occasional acinar structures. The cells had a moderate amount of mildly granular cytoplasm and relatively uniform round-to-oval nuclei (Fig. 1C). About 1 to 3 mitoses per high-power field were present. Immunohistochemically, trypsin was detected in more than 80% of the cells. In addition, approximately two-thirds of the cells expressed chromogranin A (Figs. 2A, B). A few individual cells were labeled for glucagon. The liver metastases revealed a similar immunohistochemical profile as the primary. Ultrastructurally, the neoplastic cells contained variable electron-dense granules with a mean size of 433 nm, some of which were concentrated near the apical cell membrane (Fig. 2C).
The histologic and immunohistochemical features of the tumor established the diagnosis of a MAEC of the pancreas.
Mixed (ductal-[neuro]endocrine, acinar-[neuro]endocrine, acinar-ductal, and acinar-[neuro]endocrine-ductal) carcinomas of the pancreas are being increasingly recognized, with the increasing use of immunohistochemistry. Among these, MAEC is most frequently encountered.5,6 Although some MAECs have distinctive histologic features suggesting 2 different lines of differentiation, many are histologically similar to ACCs, with the endocrine differentiation only detected by immunohistochemistry, and share many clinicopathologic features with ACC. Therefore, some authors have been referring to MAEC as a variant of ACC.3,4
Most patients with MAECs are adults, but some tumors may occur in children. The male predominance of ACCs is not seen in MAECs.3,4 Presenting symptoms are nonspecific and are usually related to the presence of an expanding mass. None of the reported patients had paraneoplastic syndromes such as a lipase hypersecretion syndrome or an endocrine hormonal hypersecretion syndrome characteristic of either line of the differentiation.6 A computed tomographic scan usually reveals a circumscribed mass without strong enhancement. Endoscopic retrograde pancreatography may reveal interruption or filling defects of the main duct due to invasion or intraductal spread of the tumor (Fig. 3).7 Somatostatin receptor scintigraphy with indium 111 (111In) octreotide (Octreoscan) is negative.8
Similar to ACCs, MAECs typically form a circumscribed, solid, and fleshy mass. They show no preferential localization. The tumor size is usually larger than 5 cm. Extensive necrosis and cystic degeneration may be present. Some tumors may extend into the main duct forming polypoid nodules (so may ACCs and NETs). Infiltration of adjacent structures, such as duodenum, spleen, stomach, or major vessels, can occur.
MAECs are predominantly composed of cellular nodules with little stroma. These nodules reveal a solid growth pattern with a substantial acinar component, identical to that of ACCs, regardless of the amount of the concomitant endocrine component. Microscopically, 2 different patterns have been described3-6: the first one is characterized by only subtle areas of histologic transition between acinar and endocrine cell types within the tumor. The histologic findings primarily suggest ACC, but the immunohistochemical labeling reveals not only acinar cells but also a substantial number of endocrine cells. The second one is characterized by the presence of 2 sharply segregated, histologically distinct acinar and endocrine components, with almost no transitional zone. The endocrine component is embedded in or adjacent to the prevailing acinar component and usually shows distinctive insular/nesting or trabecular structures (Fig. 4). The acinar cells are characterized by a granular, eosinophilic cytoplasm, and uniform round-to-oval nuclei with a single prominent nucleolus. The endocrine cells show either conventional cellular features showing moderate amounts of pale eosinophilic cytoplasm and uniform round-to-oval nuclei with coarsely clumped salt-and-pepper chromatin or transitional cellular features from acinar to endocrine cells.
Intraductal growth of neoplastic cells may be present,7,9 but high-grade PanIN lesions have not yet been reported in MAECs.
MAECs show mainly acinar differentiation including both round zymogen granules and irregular fibrillary granules. Dense core neurosecretory granules can also be detected, and rare "amphicrine" cells containing both granule types have been described.6
A thorough immunohistochemical evaluation using acinar and endocrine markers is necessary for establishing the diagnosis of MAEC. Reliable markers are trypsin1,2 for the acinar cell lineage and chromogranin A and synaptophysin for the endocrine cell lineage. Double immunohistochemical labeling for acinar and endocrine markers may show occasional amphicrine cells that express both markers. Important to note is that the labeling does not always correlate with the histologic pattern, and endocrine marker-expressing cells may outnumber acinar marker-expressing cells. It is rare for MAECs to label for peptide hormones, but glucagon-, somatostatin-, pancreatic polypeptide-, gastrin-, vasoactive intestinal polypeptide- and serotonin-expressing cells have been detected in small numbers.3,4,10 MAECs fail to show immunoreactivity for somatostatin receptors, usually detected in NETs.
Data regarding the genetics of MAECs are limited. No point mutations of the K-ras gene and no p53 immunoreactivity were detected in MAECs.3,11 There are no studies in MAECs concerning chromosome 11p losses and abnormalities in the APC/β-catenin pathway, which have been found in some ACCs.12
As a general consideration for the histogenesis of MAEC, at least 2 pathways may be postulated3,13: First, MAECs might derive from a common progenitor cell with a potential for dual acinar-endocrine differentiation. The progenitor may be a primitive multipotent (stem cell-like) or intermediate cell. Second, MAECs might develop from ACCs, with additional genetic events.
Pancreatic epithelial neoplasms, including ACC, NET, pancreatoblastoma, and poorly differentiated/undifferentiated type of adenocarcinomas, characterized with an expansively growing fleshy mass and/or solid, cellular histology, are in the differential diagnosis of MAEC.
ACCs share many clinicopathologic features with MAECs (Table 1).1-3 The endocrine component is, by definition, limited to scattered cells and constitutes only a small proportion (<25%) of the tumor in the former.
Some NETs may express acinar markers focally or contain acinar arrangement focally or widely; however, they still have the conventional histologic features (eg, trabecular or nesting growth pattern, hypervascularity, salt-and-pepper chromatin) and biologic behavior (eg, slow-growing) of the ordinary NETs, and the differential is usually not difficult (Table 1). On the other hand, NETs with abundant eosinophilic (oncocytic) cytoplasm may be challenging to distinguish from MAEC (Fig. 5).
Pancreatoblastoma, a malignant epithelial neoplasm of the pancreas showing multiple lines of differentiation, usually exhibits extensive acinar differentiation and contains endocrine cells scattered or in nests, which may mimic MAEC (Fig. 6).15 However, these are usually seen in children and, by definition, possess squamoid nests.
Although other mixed acinar carcinomas, including mixed acinar-ductal carcinoma and mixed acinar-(neuro)endocrine-ductal carcinoma, overlap with MAECs histologically, a significant proportion (>25%) of the glandular component corresponding to ordinary invasive ductal adenocarcinoma is needed to reach their respective diagnoses.
ACCs with entrapped (nonneoplastic) endocrine cells or NETs with entrapped acinar cells are also in the list of differential diagnosis. One should be aware of the benign nature of the entrapped component to reach the correct diagnosis.
Finally, collision carcinomas composed of ACC and NET should be carefully distinguished, as they may contain transitional features.
Gastric and ampullary carcinomas resembling pancreatic MAECs have been reported.16-18 They may arise from ectopic or metaplastic pancreatic tissue. Alternatively, they may originate from innate multipotent cells with a potential for pancreatic differentiation.
The prognosis of MAECs seems to be similar to that of ACCs: Patients with surgically resectable cases have a favorable prognosis with a 5-year survival of 30% to 50%,19,20 whereas most patients with nonresectable disease usually do not survive beyond 5 years. After complete resection, the patients may develop local recurrence or metachronous metastases.
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