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Well-differentiated neuroendocrine (carcinoid) tumors of the extrahepatic biliary ducts.

Well-differentiated neuroendocrine tumors (carcinoid tumors) were first characterized in 1907 by Siegfried Oberndorfer, (1) a German pathologist who coined the term karzinoide, or "carcinoma-like." The recognition of their endocrine-related properties was later described by Gosset and Masson (2) in 1914. Neuroendocrine tumors arise from various neuroendocrine cell types, which are widely distributed in the body and are found in greatest amounts in the small intestine, with decreasing frequency in the appendix, rectum, lung, pancreas and, rarely, in the ovaries, testes, liver, bile ducts, and other locations. In the gastrointestinal tract and pancreas, 15 cell types producing different hormones can be distinguished. (3) Well-differentiated neuroendocrine tumors (NETs) of the biliary system account for approximately 0.3% of all gastrointestinal NETs. (4) Less than 60 cases of primary, well-differentiated neuroendocrine tumors arising in the biliary ducts have been described in the literature. (5-20)


Biliary duct NETs appear to be more common in females and usually present in middle age (in contrast to cholangiocarcinoma, which tends to present in older patients and does not show sexual predilection). (12) The commonest presenting symptom is jaundice. Other symptoms include right upper quadrant pain, itching, weakness, and lethargy. Less commonly, they may be an incidental finding. Although biliary duct NETs can be hormonally active, as demonstrated by positive immunohistochemical staining for gastrin, somatostatin, and serotonin, (5,6,11,13) clinical symptoms due to hormone production are extremely rare. Hormone production leading to recurrent duodenal and gastric ulcers, in addition to obstructive jaundice, has been reported (10) in a 53-year-old woman with well-differentiated neuroendocrine tumor of the common bile duct. Two cases of bile duct NET, reported in patients with von Hippel-Lindau disease, may be related to the propensity for patients with von Hippel-Lindau syndrome to develop neuroendocrine tumors. (7,20)


The classification of neuroendocrine tumors varies by site. The World Health Organization (WHO) classification for neuroendocrine tumors of the gastroenteropancreatic tract (21) broadly categorizes these tumors into 3 groups:

1. Well-differentiated neuroendocrine tumors (synonymous with carcinoid tumors) are composed of monomorphous endocrine cells with mild or no atypia, in a nested, trabecular, or pseudoglandular pattern, restricted to mucosa or submucosa. As a rule, nonangioinvasive tumors not larger than 1 cm and with 2 or less mitoses per 10 HPFs (high-power fields) are benign. Those not meeting these criteria are classified as uncertain malignant potential.

2. Well-differentiated neuroendocrine carcinomas-low-grade malignant (synonymous with malignant carcinoid tumors) are composed of endocrine cells showing moderate atypia and growing in the form of solid nests, trabeculae or larger, less well-defined aggregates, which deeply invade the gut wall (muscularis propria or beyond) or show metastases to regional lymph nodes or liver. These, as a rule, are larger than 1 cm, with a moderately elevated mitotic index (>2 mitoses/10 HPFs) or proliferation index (>2% Ki-67-positive cells). 3. Poorly differentiated neuroendocrine carcinomashigh--grade malignant are composed of highly atypical, small to intermediate-sized tumor cells growing in the form of large, ill-defined aggregates, often with necrosis and prominent angioinvasion and/or perineural invasion. The tumor usually shows a very high mitotic rate ([greater than or equal to] 10 mitoses/10 HPFs) and a high proliferation index (>15% Ki-67-positive cells), p53 immunostaining, and both local and distant metastases.

The WHO classification further specifies that clinically functioning tumors should be designated by hormone production (eg, gastrin-producing tumor, somatostatin-producing carcinoma). A site-specific subdivision based on the above classification is also included in the WHO classification, but none is provided for the biliary tract.

Interestingly, although there have been reports of cases of large cell neuroendocrine carcinoma in both the gastrointestinal (22) and biliary tract23 (similar to those described in the pulmonary system), these have not yet been included in the WHO histologic classification of high-grade neuroendocrine carcinomas of the gastroenteropancreatic tract.

More recently, the European Neuroendocrine Tumor Society (ENETS) organized a consensus conference in Frascati (a city near Rome, Italy) to discuss the ENETS guidelines on diagnosis and treatment of digestive neuroendocrine tumors. (24) As a working suggestion, it proposed applying to foregut NETs a grading system modified from that adopted by the WHO and exclusively referring to the proliferation status. Three tumor categories were proposed: G1, less than 2 mitoses per 2 [mm.sup.2] (10 HPFs, X40 magnification) and/or Ki-67 index 2% or less; G2,2 to 20 mitoses per 2 [mm.sup.2] and/or Ki-67 index between 3% and 20%; G3, 21 or more mitoses per 2 [mm.sup.2] and Ki-67 index greater than 20%. It remains to be seen whether this proposal will be universally accepted and validated.


The biliary tract has very small numbers of Kulchitsky (enterochromaffin) cells, which explains the rarity of neuroendocrine tumors at this site. Chronic inflammation of the bile ducts can lead to intestinal metaplasia of the epithelium. The resulting increase in the number of endocrine cells may act as a predisposing factor to the development of neuroendocrine tumors. (8) The most common anatomic site for the occurrence of neuroendocrine tumors within the biliary tract is the common bile duct, followed by the cystic and common hepatic ducts.

Grossly, as with well-differentiated neuroendocrine tumors from any other site, there may be circumscribed or poorly demarcated intramural or submucosal masses that appear as nodular or polypoidal elevations. The overlying mucosa may be intact or ulcerated. The cut surface is homogenous yellow-tan to gray-tan. The mass may be very firm because of striking desmoplasia.

Microscopically, the neoplastic cells have a monotonous appearance with scant to moderate amounts of pink, granular cytoplasm and a round to oval nucleus with the characteristic "salt and pepper" chromatin (Figure 1, A and B). The cells may show the characteristic nesting (insular) pattern or may be arranged as trabeculae, strands, rosettes, acini, or undifferentiated sheets.

In cytologic preparations, the cells are small to medium-sized, usually arranged in loosely cohesive groups or as single cells. Sometimes they may form acinar or rosettelike structures, which may lead to a mistaken diagnosis of adenocarcinoma. The cells may be round, columnar, or plasmacytoid with uniform, moderately granular nuclei (salt and pepper chromatin) and moderate amounts of eosinophilic cytoplasm (Figure 1, C and D). Rare mitoses may be seen. However, large numbers of mitoses, extensive necrosis, nuclear molding, significant nuclear pleomorphism, and crush artifact are not a feature of well-differentiated neuroendocrine tumors.


As with neuroendocrine tumors from other sites, the cells are positive for argentaffin and argyrophilic stains and show dense-core neurosecretory granules on ultrastructural examination. Immunohistochemically, the traditional neuroendocrine markers used in the workup of neuroendocrine tumors are chromogranin (acidic glycoproteins located in the neurosecretory granules) and synaptophysin (a glycoprotein isolated from neuronal presynaptic vesicles) (Figure 2, A and B). Other neuroendocrine markers include neuron-specific enolase and CD56. The latter also stains a wide variety of tumors including lymphoma and plasma cell myeloma, which may occasionally be part of the differential diagnosis. Most NETs also express cytokeratin. Rare cases of biliary NETs have been shown to express gastrin, serotonin, somatostatin, and pancreatic polypeptide. A Ki-67 index is also an important aspect of the baseline workup of neuroendocrine tumors (Figure 2, C). Benign, well-differentiated NETs will show a Ki-67 of 2% or less, while those of uncertain malignant potential will show a Ki-67 index greater than 2%. Extremely high Ki-67 indices, correlating with large numbers of mitoses and extensive necrosis, are a feature of high-grade neuroendocrine carcinomas.


Because of their rarity, the molecular pathways involved in the development of biliary duct NETs have not been well studied. In their study of 7 cases of well-differentiated NETs of the extrahepatic bile ducts, Maitra et al14 found that all 7 cases showed no immunoreactivity for p53 and assays for p53 loss-of-heterozygosity analysis were negative in the 2 cases studied, a fact suggesting that p53 mutations do not play a role in the pathogenesis of extrahepatic bile duct NETs.

In the same series, a mutation in codon 12 of the K-ras oncogene (which is the most common mutation seen in biliary adenocarcinomas) was found in 1 well-differentiated NET, whereas 2 of 2 cases showed immunoreactivity for Dpc4 protein (which is involved in the signaling pathway for transforming growth factor [beta]). (14) In view of the small number of NETs studied, the importance of these findings in the pathogenesis of these tumors is unclear. The presence of the the K-ras mutation did not appear to influence the clinical course because the patient in whom the mutation was detected was disease-free 24 months after surgery. (14)

Maitra et al (14) also showed loss of expression of wild-type p16 in 1 of the well-differentiated NETs. However, no concurrent loss of heterozygosity at the p16 locus (D9S171) could be demonstrated in this neoplasm. Epigenetic mechanisms, such as the CpG island methylator phenotype pathway (which appears to be involved in gastrointestinal tract neuroendocrine tumors (25)), could be responsible for the decreased expression of this gene.

Neuroendocrine tumors in general may be associated with various syndromes that have characteristic genetic abnormalities. These include multiple endocrine neoplasia type 1 (MEN1 gene), von Hippel-Lindau (VHL gene), neurofibromatosis type 1 (NF1 gene) and tuberous sclerosis (TSC1 and TSC2 genes). (25) Two cases of bile duct NET have been reported in patients with von Hippel-Lindau disease. (7,20)



1. Cholangiocarcinoma accounts for approximately 80% to 90% of bile duct malignancies and may be almost impossible to differentiate from neuroendocrine tumors clinically, before histologic review. Neuroendocrine tumors tend to occur in younger patients and have a female predilection and are less likely to show aggressive local invasion and metastases than cholangiocarcinoma. In their review of 30 cases of extrahepatic biliary NETs, Chamberlain and Blumgart (12) found that metastases were seen in only one-third of biliary NETs, compared with two-thirds of all cholangiocarcinomas.

Poorly differentiated adenocarcinomas with endocrine features may show focal positivity with neuro endocrine markers like chromogranin or synaptophysin, and this should not lead to an erroneous diagnosis. The presence of appropriate morphologic features, along with diffuse positivity for chromogranin or synaptophysin, favors a diagnosis of NET.

Other variants of cholangiocarcinoma include those with squamous metaplasia, clear cell changes, and sclerosing carcinoma (Altemeier-Klatskin tumor).

2. High-grade neuroendocrine carcinomas show high mitotic activity and extensive necrosis in addition to characteristic morphology.

3. Malignant melanoma can present primarily in the extrahepatic bile ducts, but most cases are metastatic. (26,27)

4. Lymphoma can involve the bile ducts as part of a systemic disease; their initial presentation at this site is extremely rare. (28)

5. Botryoid rhabdomyosarcoma is the most common malignant tumor of the extrahepatic bile ducts in children, (28) but rare cases have also been reported in adults. (29)

6. Benign epithelial tumors include adenomas, cystadenomas, and papillomas. Multiple papillomas (papillomatosis) have a tendency to recur and undergo malignant transformation.


7. Granular cell tumor is the most common benign, nonepithelial tumor occurring in the extrahepatic biliary ducts. (26,28) These tumors usually occur in young to middle-aged females and are composed of large polygonal cells with abundant, eosinophilic, granular cytoplasm and central, small, dark, uniform nuclei. They are S100 and inhibin positive. As in other sites, they may be associated with pseudocarcinomatous changes in the overlying epithelium.

8. Rare cases of paragangliomas arising in the extrahepatic biliary ducts have been reported. (26,28) These are composed of chief cells and sustentacular cells in a nesting or zellballen pattern. The chief cells are immunoreactive for neuroendocrine markers and the sustentacular cells are S100 positive.

9. Traumatic neuromas may occur in the stump of the cystic duct after a cholecystectomy. (30)


Biliary NETs tend to be slow growing with a limited propensity for local spread and metastasis (which is seen in about one-third of all cases). The best predictor of malignant behavior seems to be the size of the primary tumor, with tumors larger than 2 cm often extending into the liver or metastasizing. (26) Surgical resection is the mainstay of treatment and affords the best chance of long-term, disease-free survival, even in the setting of metastatic disease. (12,15) An aggressive surgical approach aimed at complete excision with negative histologic margins and restoration of bilioenteric continuity affords the best chance of cure. In most cases, surgery involves extrahepatic bile duct excision with portal lymphadenectomy, Roux-en-Y biliary reconstruction with or without partial hepatectomy. (12) The role of adjuvant therapy is controversial, with most studies failing to demonstrate a survival advantage.


Primary neuroendocrine tumors of the extrahepatic biliary ducts are rare. As compared to cholangiocarcinoma, neuroendocrine tumors tend to occur in middle-aged patients, are more common in females, behave less aggressively, and only one-third metastasize. Accurate preoperative diagnosis can be made by examining brush cytology specimens obtained during endoscopic retrograde cholangiopancreatography and/or endoscopic ultrasound-guided fine-needle aspiration and by using appropriate immunohistochemical stains. Tumor size (>2 cm) appears to be the best predictor of aggressive behavior. Complete surgical resection is curative and affords the best chance of long-term, disease-free survival, even in metastatic disease.

The authors would like to thank Craig Zuppan, MD, and Zera Tan, MD, for their help.


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Yvonne Saldanha Noronha, MD; Anwar Sultana Raza, MD

Accepted for publication June 1, 2009.

From the Department of Pathology and Laboratory Medicine, Loma Linda University Medical Center, Loma Linda, California.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Yvonne Saldanha Noronha, MD, Department of Pathology and Laboratory Medicine, Loma Linda University Medical Center, 11234 Anderson St, Room 2516, Loma Linda, CA, 92354 (e-mail:
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Author:Noronha, Yvonne Saldanha; Raza, Anwar Sultana
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Disease/Disorder overview
Date:Jul 1, 2010
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