A 55-year-old woman was hospitalized with a palpable and painful mass in her upper abdomen. Abdominal computed tomography revealed a 10 × 7-cm tumor extending into the abdominal cavity from the left hepatic lobe and multiple metastatic lesions in the right hepatic lobe. A left hepatic lobectomy was performed for debulking and palliative resection. Histopathological examination of the resected specimen diagnosed the large hepatic tumor in the left hepatic lobe as a malignant melanoma. Physical and radiological examinations were performed on dermatological, ophthalmic, gynecological, and central nervous system areas, and endoscopic examinations were performed on the upper digestive tract and colon. No other lesions were disclosed as possible primary tumors for the disease. This result suggested that the tumor might arise from the left hepatic lobe.

Neuroendocrine differentiation is known to be one of the prognostic factors in many carcinomas. However, the characteristics of neuroendocrine differentiation are not well elucidated in extrahepatic bile duct (EBD) carcinomas. One hundred ninety-four cases of EBD carcinomas were analyzed using immunohistochemistry with synaptophysin and chromogranin. The tumors were graded as degree 0, 1, and 2 when the positive tumor cells were 5% or less, 6% to 25%, and 26% or more, respectively. Immunohistochemical results were compared with clinicopathologic variables and survival rate. Synaptophysin and chromogranin were positive in 54 (27.8%) and 74 (38.1%) cases, respectively. Thirty-four cases (17.5%) were positive for both synaptophysin and chromogranin, 20 (10.3%) and 40 cases (20.6%) were positive only for synaptophysin and for chromogranin, respectively, and 100 cases (51.6%) were negative for both markers. There was a significant survival difference between overall synaptophysin-positive (median, 27 months) and synaptophysin-negative (38 months) groups (P < .05). However, there was no survival difference between chromogranin-positive and chromogranin-negative groups. There was a significant survival difference between the dual-positive expression to synaptophysin and chromogranin group (median, 21 months) and the dual-negative expression group (median, 35 months; P < .05). In summary, synaptophysin expression was an important prognostic factor because synaptophysin-positive cases showed a worse prognosis than synaptophysin-negative cases. The more tumor cells expressed chromogranin, the poorer the survival. Therefore, immunohistochemical studies for neuroendocrine differentiation may be helpful in routine pathological examinations for evaluating the survival and the prognosis of patients with EBD carcinomas.

A small cell carcinoma of the extrahepatic bile duct in a 75-year-old Japanese man is reported. The patient suffered from obstructive jaundice, and percutaneous transhepatic cholangiography-drainage (PTCD) revealed a massive lesion in the lower common bile duct. Because it was diagnosed as a malignant tumor, pancreaticoduodenectomy was performed. A nodular infiltrating tumor measuring 4.5 x 3.0 x 2.0 cm was located in the intrapancreatic portion of the extrahepatic bile duct. Histologically, the tumor was composed of a dense proliferation of small atypical cells with a little region of high-grade dysplasia in the adjacent epithelium of the common bile duct. Tumor cells were immunoreactive to neuroendocrine markers such as chromogranin A, synaptophysin, CD56, and Leu7. Although carcinoma cells invaded into pancreas and duodenum, there were no histological findings that indicated the carcinoma arose from the mucosa of either the pancreatic duct or duodenum. These results indicated that the tumor was a small cell carcinoma derived from the epithelium of the extrahepatic bile duct; a rare neoplasm with only a few cases reported. A few neuroendocrine cells were recognized in the adjacent epithelium of the extrahepatic bile duct, suggesting that the tumor cells might be derived from them. Using immunohistochemical examination, no p53 abnormality was found. Tumor cells showed positive nuclear staining for p16, while negative for cyclin D1, suggesting that functional retinoblastoma protein (pRB) might be lost in the p16/pRB pathway, as in small cell lung cancer.

Although metaplastic changes can occur in the extrahepatic bile ducts, a detailed morphologic study of these lesions has not been done. We examined the bile duct mucosa in 42 pancreaticoduodenectomy specimens, 32 with neoplastic lesions and ten with inflammatory lesions of the extrahepatic bile ducts, to assess the prevalence and type of metaplastic lesions. For comparison, the common bile ducts from 10 autopsy cases were reviewed. Twenty of the 42 total cases (48%), 13 of the 32 neoplastic cases (40%), and 7 of the 10 inflammatory cases (70%) had metaplastic changes. Pyloric gland metaplasia was the most common type (16/20 cases; 80%), whereas intestinal metaplasia was seen in 1/20 cases (5%). A combination of pyloric gland and intestinal metaplasia occurred in 2/20 cases (10%), and squamous metaplasia plus the above-mentioned two types of metaplasia was seen in 1/20 cases (5%). None of the normal common bile ducts obtained from ten autopsies had metaplastic changes. Endocrine cells were identified in nine (56%) of 17 metaplastic lesions. In contrast, endocrine cells within the intramural glands were seen in only 2 of the 10 normal common bile ducts. Although a significant proportion of carcinomas (6/13 cases) was in close proximity to areas of metaplasia, we were unable to find dysplastic foci within the metaplastic glands or the metaplastic surface epithelium. Reactive atypical cells involved the surface biliary epithelium and intramural glands and were associated with inflammation and metaplastic changes. The presence of goblet, mucinous, squamous, and reactive atypical cells in association with hyperplasia of intramural glands in frozen sections or small biopsy specimens may be mistaken for malignancy; hence, recognition of these lesions is of diagnostic importance.

A rare case of composite glandular-endocrine cell carcinoma of the common bile duct is presented. Histologically, this tumor consisted of adenocarcinoma and small-cell neuroendocrine carcinoma, with a transition between the two components. The two distinct areas of the tumor were immunohistochemically different, whereas the transitional zone exhibited characteristics of both areas. These features suggest that the tumor arose from a multipotential stem cell. Although it has been reported that the presence of neuroendocrine differentiation in carcinomas indicates a poor prognosis, the patient in the present case was well at the time of writing this report. This may be due to the fact that adenocarcinoma, which characteristically has a low proliferative activity, constituted the majority of the tumor.

A composite glandular-endocrine cell carcinoma of the extrahepatic bile duct in a 64 yr old Japanese man is reported. A nodular polyp measuring 1.9 x 1.1 cm was located in the confluence of the extrahepatic bile duct. Histologically, the tumor was composed of well differentiated tubular adenocarcinoma and small cell neuroendocrine carcinoma with a transition between the 2 components. The 2 areas of the tumor immunohistochemically revealed a clear-cut difference in functional differentiation. Tumor cells in the glandular component were immunoreactive to both carcinoembryonic antigen (CEA) and CAM 5.2, while those in the small cell area were immunoreactive to neuroendocrine markers such as neuron specific enolase (NSE), chromogranin A and serotonin. These results suggest that the tumor arose from a multipotential stem cell capable of differentiation in 2 directions.

The second edition of the WHO Histological Classification of Tumors of the Gallbladder and Extrahepatic Bile Ducts is more comprehensive and detailed than the previous one. Advances in our understanding of dysplasia, carcinoma in situ, various lines of differentiation among the carcinomas, and the recognition of a variety of tumor-like lesions have resulted in more than three times as many entities in the current classification as in the previous one. The new edition should facilitate pathologic, epidemiologic, and therapeutic comparisons.

A total of 66 cases of well differentiated adenocarcinomas of the gallbladder comprising 12 mucosal carcinomas and 54 advanced carcinomas were examined histologically and immunohistochemically for metaplastic changes in the tumor tissue and non-neoplastic mucosa adjacent to the tumor tissue in order to elucidate the histogenesis of gallbladder carcinoma. Among the various kinds of metaplastic changes in the gallbladder mucosa, the occurrence of endocrine cells and lysozyme immunoreactivity were used as markers. The 66 cases of adenocarcinoma were divided into 12 cases showing no metaplastic changes (non-metaplastic type) and 54 cases containing at least one marker of metaplastic changes (metaplastic type). The frequency of metaplastic changes was compared between mucosal carcinoma and advanced carcinoma to determine whether these metaplastic changes could be a phenotypic expression of the original tissue from which the tumor was derived or a secondary phenomenon associated with the progression of the tumor. No difference could be observed between the two. Moreover, the carcinoma of the non-metaplastic type was often surrounded by an ordinary mucosa without metaplastic changes, whereas the carcinoma of the metaplastic type was frequently surrounded by a metaplastic mucosa. Some cases among the non-metaplastic type carcinomas showed a morphological transition between the ordinary mucosa and the carcinoma or contained the residue of ordinary type adenoma within the tumor. On the other hand, 5 cases of the metaplastic type carcinoma contained adenomatous residue of the metaplastic type. These results suggest that there might be two types of adenocarcinoma, one being derived from the ordinary epithelium of the gallbladder and the other from the metaplastic epithelium.

Among 284 cases of carcinoma of the gallbladder, 21 were identified as undifferentiated carcinoma (UC), with little glandular or other specific epithelial differentiation. These tumors were classified into three histologic types according to the components: (1) small cell type (eight cases); (2) pleomorphic cell type (eight cases); and (3) spindle cell or pseudosarcomatous type (five cases). Histochemical and immunohistochemical study by the immunoperoxidase technique revealed that most of the tumors (13/21) contained mucosubstances, and that all examples of the UC were immunoreactive for epithelial membrane antigen (EMA), keratin, and carcinoembryonic antigen (CEA), thereby indicating the epithelial nature of the neoplastic cells. Vimentin immunoreactivity was found in nine tumors. In 19, the tumor contained various neoplastic endocrine cells, including somatostatin-immunoreactive (14/19), gastrin-immunoreactive (14/19), human chorionic gonadotropin (HCG)-immunoreactive (9/19), pancreatic polypeptide-immunoreactive (4/19), and serotonin-immunoreactive cells (4/19). The prognosis of patients with UC of the gallbladder was poorer than that of patients with differentiated adenocarcinoma.

Forty two carcinomas of the gallbladder and 25 mucinous cystadenocarcinomas of the pancreas were analyzed using silver stains and immunohistochemical techniques. Fourteen (33.3%) gallbladder carcinomas had argyrophil and argentaffin cells and 17 (40%) contained endocrine cells as shown by immunoperoxidase stains. The gallbladder tumors that had the largest number of endocrine cells were the well differentiated adenocarcinomas with colonic features. The most common endocrine cell in these tumors was the serotonin-containing (EC) cell followed by somatostatin-containing cells and cells that reacted to pancreatic polypeptide and gastrin. Intestinal metaplasia with pseudopyloric gland hyperplasia was present in the gallbladder mucosa adjacent to 11 carcinomas and had an endocrine cell population similar to that of the tumors. Endocrine cells were demonstrated in 18 (70%) of the 25 mucinous cystadenocarcinomas of the pancreas by the immunoperoxidase method although only 9 had argyrophil and argentaffin cells. The population of endocrine cells in these mucinous pancreatic tumors was similar to that found in gallbladder carcinomas. Endocrine cells were more numerous in areas with colonic-type glands, goblet cells and Paneth cells. The secretory products of the endocrine cells in these gallbladder and pancreatic tumors did not give rise to systemic endocrine manifestations. The presence of endocrine cells in these tumors can be explained on the basis of intestinal differentiation.