Immunohistochemistry showed that the tumor cells were positive for epithelial markers (OSCAR, CK8/18, CK7), with faint and patchy positivity for neuroendocrine markers (synaptophysin and chromogranin) and significant positivity (~30%) for acinar markers (trypsin and chymotrypsin) (Fig. 3). Based on the histomorphological and immunohistochemical profile, a diagnosis of MAcNEC of pancreatic type was rendered. Lymphovascular invasion was identified with 3 of 10 lymph nodes positive for metastatic carcinoma, with the metastases composed of the solid and more proliferative component.
A break-apart fluorescence in situ hybridization assay for BRAF fusions was negative for BRAF gene rearrangement. Loss of 1 copy of BRAF was seen in 50% of the cells analyzed.
The exocrine and neuroendocrine components of pancreas have a common embryological origin, which forms the basis of development of MAcNECs.2 The term “mixed acinar endocrine carcinoma” was first proposed by Klimstra et al2 in 1994 when they presented 5 cases of acinar cell carcinoma with at least 25% neuroendocrine elements. According to the World Health Organization (WHO), the diagnosis of MAcNEC is reserved for acinar neoplasms that have greater than 30% neuroendocrine cell type.3 The mean age of occurrence of these carcinomas is 60 years with a male-to-female ratio of 2:3.2 It is interesting to note that even though these neoplasms have significant numbers of neuroendocrine cells, they rarely express pancreatic or gastrointestinal hormones.8
The current case is of particular interest because of its unique location. Acinar cell neoplasia most often arises in the pancreas, but there are rare examples arising in extrapancreatic locations, particularly along the gastrointestinal tract (including at the ampulla of Vater,9 jejunum,10 and colon11 and most notably in the stomach12–15). These are thought to originate from heterotopic pancreatic tissue because their distribution correlates to locations where pancreatic heterotopia or metaplasia is frequently seen. Heterotopic pancreas has been reported in 0.5% to 13.7% of all autopsies16 and is most often found in the duodenum, stomach, jejunum, Meckel diverticulum, and ileum.5 However, this theory remains a speculation because residual nonneoplastic pancreatic heterotopic tissue is rarely actually identified. Interestingly, the liver is another common location for extrapancreatic acinar cell neoplasms.16–19 The histogenesis is also uncertain as ectopic pancreatic tissue is uncommon in the liver. Heterotopic pancreatic tissue is occasionally found adjacent to larger intrahepatic bile ducts, perhaps accounting for the rare cases of primary hepatic acinar cell carcinoma. Moreover, embryologic and immunomorphologic studies have provided evidence that pancreatic, hepatic, and biliary tract epithelium originates from the same progenitor cells.20–23 Furthermore, pancreatic acinar cell carcinomas have been reported to produce α-fetoprotein, similar to hepatocellular carcinomas. Therefore, these noncommitted progenitor cells may follow a pure acinar cell differentiation and be the origin of hepatic acinar cell neoplasms. Finally, extrapancreatic acinar cell neoplasms have also been reported originating from the somatic transformation of a teratomatous germ cell tumor.24,25
Mixed acinar neuroendocrine carcinomas arising in extrapancreatic locations are even rarer, with variants having been described only in isolated reports in the stomach and ampulla. Fukunaga et al26 described a well-differentiated adenocarcinoma with admixed acinar and endocrine components as demonstrated by immunohistochemistry. Three cases of composite glandular and endocrine tumors with pancreatic acinar differentiation arising in the stomach were reported by Jain et al.12 Kusafuka et al5 also reported a case of a MAcNEC arising in the stomach that was, interestingly, associated with an elevated α-fetoprotein level. Similar to other acinar cell neoplasms, MAcNECs arising in the stomach are assumed to arise from pancreatic heterotopia or acinar metaplasia, which is commonly seen in gastric mucosa.27 Two cases of MAcNECs were also described at the ampulla,6,7 with the case by Moncur et al6 described as originating in the duodenum.
Our current case is the first MAcNEC to be described arising in the common bile duct, away from the pancreas, stomach, and ampulla. The possible etiologies essentially reiterate the possible origins of any extrapancreatic acinar cell neoplasm as described above. Rare cases of pancreatic heterotopia have also been reported in the common bile duct.28 Also, origin in uncommitted progenitor cells remains a reasonable hypothesis. Reid22 and Carpino et al23 showed that multipotent biliary tree stem/progenitor cells are found at the bottom of peribiliary glands near the fibromuscular layer. These cells are phenotypically heterogeneous and express transcription factors as well as surface and cytoplasmic markers for progenitors of liver, pancreas, and endoderm. Since they have been shown to give rise, in vitro and in vivo, to hepatocytes, cholangiocytes, and the endocrine cells of pancreatic islets, they could be involved in the histogenesis of the MAcNEC in our case.22,23 Of course, a more distinct possibility is that of metastasis. The pancreas was not resected in this patient. However, no additional lesions in the pancreas or elsewhere have been identified in multiple imaging studies at the time of diagnosis and in follow-up.
Histologically, 3 patterns of MAcNECs have been described.2,4 The first pattern is composed of 2 distinct and separate populations of neoplastic cells that can be recognized by light microscopy (so-called “collision” pattern). The second pattern is composed of an intimate mixture of acinar and neuroendocrine cells that are morphologically difficult to distinguish. They often form a uniform and solid architecture and require the use of immunohistochemistry to identify the 2 cell populations. The third pattern is composed of a population of amphicrine cells that express both acinar and neuroendocrine features. This pattern is difficult to distinguish from the second pattern without performing dual-labeling immunohistochemistry to prove the amphicrine nature of the cells. The second pattern comprises the vast majority of MAcNECs.2 In comparison with pure acinic cell carcinomas, which may contain scattered neuroendocrine cells in 42% of cases, a major (albeit arbitrary) distinguishing feature of MAcNECs is the percentage of tumor cells positive for neuroendocrine markers.1,8 Tumors with a predominantly acinar cell morphology containing at least 25% to 30% neuroendocrine cells should be diagnosed as a MAcNEC.2–4 On cytological specimens, these tumors are particularly challenging to distinguish from pure acinar cell carcinoma, requiring careful use of immunohistochemistry for neuroendocrine and acinar markers for diagnosis.29 A minimum of 20% cells on cytological specimens expressing at least 1 neuroendocrine marker (synaptophysin or chromogranin) would suggest the diagnosis of a MAcNEC for a neoplasm with predominantly acinar differentiation.30
Most reported MAcNECs consist predominantly of acinar elements, and these neoplasms are believed to be biologically closely related to pure acinar cell carcinomas. Clinical and genetic features of these neoplasms overlap, to the extent that some authorities regard MAcNECs as simply variants of acinar cell carcinomas.4 Occasionally, however, the neuroendocrine component can predominate, but nonetheless, the behavior is more aggressive than that of a well-differentiated neuroendocrine tumor.4 Therefore, the distinction between MAcNECs and neuroendocrine tumors is important. Chemotherapy and radiotherapy may be transiently effective, if at all, for MAcNECs, and most patients die of disease, with a survival rate similar to that of pure acinar cell carcinomas (5-year survival, 35%).31,32 On the other hand, well-differentiated neuroendocrine tumors may be cured by surgical resection alone, and long-term survival occurs even in patients with incurable metastases. Morphologically, well-differentiated neuroendocrine tumors are composed of sheets, trabeculae, and cords of cells arranged in clusters or small nests separated by hyalinized or fibrotic stroma. Tumor cells have mild to moderate cytologic atypia with round nuclei, stippled chromatin, and inconspicuous nucleoli. They generally have a low mitotic rate (<20 mitoses per 10 high-power fields, and often <3). Unlike MAcNEC, well-differentiated neuroendocrine tumors do not have morphologically identifiable areas of acinar differentiation, but they may contain individual cells expressing acinar differentiation by immunohistochemistry, again arguing that a significant proportion of cells (25%–30%) expressing acinar differentiation must be present for the diagnosis of MAcNEC to be made.33,34
The identification of MAcNECs is not always obvious. This is particularly true for tumors with the second or third patterns of MAcNECs as described above because of the homogenous appearance of the cell population. In the current case, prior to immunohistochemical staining, the morphologic diagnosis was favored to be a WHO grade 2 well-differentiated neuroendocrine tumor, with the more proliferative solid nodule representing transformation to a high-grade (WHO G3) component, a phenomenon now well described in primary pancreatic neuroendocrine neoplasms and also in a few extrapancreatic primaries.35 Acinar differentiation was not initially suspected, particularly because of the origin of the tumor in the common bile duct, where neuroendocrine but not acinar neoplasms are recognized to arise. Clues to acinar differentiation that were present included an elevated mitotic rate (and Ki-67 index), focally prominent nucleoli, and mild granularity to the cytoplasm. The difficulty of distinguishing pancreatic acinar neoplasms from neuroendocrine tumors has been repeatedly acknowledged, arguing for immunolabeling for both neuroendocrine (synaptophysin and chromogranin) and acinar (trypsin, chymotrypsin, and bcl10) markers in all but the most histologically classic cases.36
Recently, genomic profiling of pancreatic acinar cell carcinoma, including mixed variants, has led to the discovery of recurrent fusions in BRAF and RAF1 (seen in 23% of cases).37,38 Chmielecki et al38 found that acinar cell carcinomas with a specific recurrent BRAF fusion, SND1-BRAF, had activation of the MAPK pathway, potentially conferring sensitivity to treatment with MEK inhibitors such as trametinib. They also found that “fusion-negative” tumors showed genomic alterations that led to inactivation of DNA repair genes (45% of cases). These tumors may be more sensitive to platinum-based chemotherapy and PARP inhibitors.38 The identification of actionable genomic alterations is a step toward the personalized targeted therapy in pure and mixed acinar cell carcinomas. In the current case, BRAF fusions were not identified using a recently developed break-apart fluorescence in situ hybridization assay.39 While the significance of the BRAF copy number loss detected in the current case is unknown, it would not be predicted to cause activation of the MAPK pathway, and therefore MEK inhibition would not be a rational therapeutic strategy.
MAcNECs are rare carcinomas that are mostly found arising from the pancreas and have rarely been reported in the stomach and ampulla. We have described the first reported case of a MAcNEC arising in the common bile duct.
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Keywords:© 2018 Lippincott Williams & Wilkins, Inc.
common bile duct cancer; mixed acinar neuroendocrine carcinoma; pancreatic cancer; pancreatic heterotopia