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.
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.
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.
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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