Ultrastructural examination of three of the neoplasms revealed numerous cytoplasmic, membrane-bound, dense-core neurosecretory granules measuring approximately 200 to 600 [mgr]m in diameter.
In the two tumors analyzed (patient nos. 6 and 7), no LOH was detected at D18S64, D9S171, PYGM, or TP53. Both tumors were noninformative at the p53-Alu marker, and no MI was detected in either case by BAT26 assay. The tumor from patient no. 6 demonstrated wild-type K-ras, whereas patient no. 7 had a codon 12 mutation (GGT[rarr]GAT transition) in exon 1 of the K-ras oncogene.
Approximately 98[percnt] of all malignant neoplasms arising in the EHBDs are carcinomas, predominantly well-to moderately differentiated adenocarcinomas. 1,2 Carcinoids of the EHBDs are exceedingly rare, representing only 0.2[percnt] to 0.3[percnt] of tumors at this site. 2 Because so few cases of EHBD carcinoids have been reported, little is known about the clinical features and natural history of these neoplasms. Nevertheless, certain distinguishing clinicopathologic characteristics of EHBD carcinoids have been identified.
Both adenocarcinomas and carcinoids may have similar presenting clinical features, including painless jaundice with or without pruritus. However, whereas adenocarcinomas of the EHBDs have a slight male predilection and typically present in the seventh or eighth decades of life, 1 carcinoid tumors in this location are nearly twice as common in women, and present at a younger age. In addition, although adenocarcinomas occur with increased frequency in patients with inflammatory bowel disease and primary sclerosing cholangitis, carcinoids have rarely been reported to occur in association with multiple endocrine neoplasia type 1 (MEN-1) and the von Hippel[ndash]Lindau syndromes. 16 Unlike carcinoid tumors in some other locations, carcinoid tumors of the EHBDs do not give rise to systemic manifestations. Lastly, the prognosis for these tumors is markedly different[colon] Although adenocarcinomas are aggressive tumors and are almost always fatal, carcinoid tumors are far more indolent. Indeed, patients with carcinoid tumors of the EHBDs have long-term life expectancy, even in the face of hepatic metastases. 15
Our series of seven patients supports the clinicopathologic features described earlier[colon] All of the patients were women, and the average age at presentation (49.8 yrs) was nearly a decade younger than that typical for adenocarcinomas of the EHBDs. The most common presenting complaint was painless jaundice with or without pruritus. Although one of the seven patients had persistent peptic ulcer disease in association with her gastrin-secreting carcinoid, there was no evidence of Zollinger[ndash]Ellison syndrome. None of the patients had inflammatory bowel disease, primary sclerosing cholangitis, the MEN-1 syndrome, or von Hippel[ndash]Lindau syndrome.
The carcinoid tumors in our patients were most often located in the CBD (57[percnt]), with the remaining tumors arising in the CHD. None of the neoplasms in this series occurred in the cystic duct, although this site accounts for seven cases reported in the literature. 13,17,21,24,33,43,46 At the time of surgery, the neoplasms were locally invasive but did not involve the liver or the pancreas. Although two patients showed lymph node metastases, none had distant metastatic disease. Tumor size did not correlate with the development of lymph node metastasis. A 5-mm carcinoid tumor of the cystic duct that metastasized has been reported. 24 All seven patients are alive and disease free after curative surgical resections, with an average follow-up period of 6.6 years (range, 2[ndash]11 yrs).
Histologic features of EHBD carcinoids are similar to those of intestinal carcinoids. They tend to grow in cords, nests, or trabeculae, and usually, as seen in our patients, invade the ductal wall (100[percnt]). Moreover, perineural (57[percnt]) and lymphovascular (29[percnt]) invasion is common.
In view that most carcinoid tumors of the EHBDs often secrete more than one hormone 23 or are immunoreactive only for chromogranin, functional classification of carcinoid tumors by immunohistochemistry is of little value.
The differential diagnosis for EHBD carcinoids principally includes poorly differentiated adenocarcinomas with numerous endocrine cells and small cell carcinomas. Because as many as one third of adenocarcinomas in this location demonstrate increased numbers of endocrine cells, immunohistochemical reactivity for chromogranin and synaptophysin in an EHBD lesion should not cause an erroneous diagnosis of carcinoid[colon] Such mistakes have been made in the past with adenocarcinomas of the gallbladder, 55 which show extensive gland formation and greater cytologic atypia. In addition, diffuse and strong positivity for chromogranin and synaptophysin in all of the tumor cells favors a diagnosis of carcinoid. Conversely, focal, scattered positivity is seen with adenocarcinoma. By the same token, small cell carcinomas may occasionally demonstrate a trabecular growth pattern with rosette formation, leading to diagnostic confusion with carcinoid tumors. However, a diffuse chromatin pattern, a high mitotic rate, extensive tumor necrosis, and only focal positivity for chromogranin and synaptophysin favor a diagnosis of small cell carcinoma.
As manifested by their clinicopathologic characteristics, carcinoid tumors of the EHBDs appear to have fundamentally different biologic features from adenocarcinomas in this location. Not only do the EHBD carcinoids demonstrate limited propensity for growth and metastatic spread, but patient survival is also far greater for these neoplasms than for biliary adenocarcinomas. We would suspect, therefore, that carcinoids would have different molecular changes than adenocarcinomas. Contrary to our expectations, however, one of the two carcinoid tumors examined molecularly contained an activating G-A mutation in codon 12 of the K-ras oncogene, which is the most common mutation seen in biliary adenocarcinomas (50[percnt][ndash]75[percnt] of tumors, depending on the series). 27,39,52 In contrast to our findings in this series, K-ras mutations have not been detected in typical carcinoids arising in the duodenum, appendix, lung, and cervix. 34,35,51,53,58 It is worth noting that, as is noted in adenocarcinomas of the EHBDs, 39 the presence of the K-ras mutation in carcinoids does not appear to influence the clinical course, because the patient in whom the mutation was detected remains alive and disease free 24 months after surgery. Although we were limited by the paucity of archival material available for mutational analysis, these findings suggest that critical genetic alterations contributing to the aggressive clinical course in adenocarcinomas (compared with carcinoid tumors) do not lie in the K-ras oncogene. Additional studies are warranted, however, before definitive conclusions may be drawn.
Loss of expression of wild-type p16 was present in one of the carcinoid tumors. p16 functions at the G1 cell cycle checkpoint, and the P16 gene has been found to be inactivated by mutations, methylation, or deletion in a large number of epithelial malignancies, 41 including bile duct adenocarcinomas. 56 Loss of p16 expression in an EHBD carcinoid suggests that alterations in this gene may be involved in the genesis of some carcinoid tumors at this site. Interestingly, no concurrent LOH at the P16 locus (D9S171) could be demonstrated in this neoplasm, raising the possibility that epigenetic mechanisms, such as promoter hypermethylation, may be causing the decreased expression of this gene. 7
Dpc4 is a newly described protein that is important in the signaling pathway for transforming growth factor beta. 22 Mutations of this DPC4 gene have been identified in a majority of pancreatic adenocarcinomas. 42 We found persistent immunoreactivity for Dpc4 in both of the carcinoid tumors examined, and LOH at chromosome 18q21.1 was not seen. The importance of this finding is unclear in the absence of a larger series of patients, but it suggests that DPC4 alterations may not be critical in the pathogenesis of biliary tract carcinoids.
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