Mixed Large Cell Neuroendocrine Carcinoma and Adenocarcinoma with Spindle Cell and Clear Cell Features in the Extrahepatic Bile Duct

Abstract

Mixed adenoneuroendocrine carcinomas, spindle cell carcinomas, and clear cell carcinomas are all rare tumors in the biliary tract. We present the first case, to our knowledge, of an extrahepatic bile duct carcinoma composed of all three types. A 65-year-old man with prior cholecystectomy presented with painless jaundice, vomiting, and weight loss. CA19-9 and alpha-fetoprotein (AFP) were elevated. Cholangioscopy revealed a friable mass extending from the middle of the common bile duct to the common hepatic duct. A bile duct excision was performed. Gross examination revealed a 3.6 cm intraluminal polypoid tumor. Microscopically, the tumor had foci of conventional adenocarcinoma (CK7-positive and CA19-9-postive) surrounded by malignant-appearing spindle cells that were positive for cytokeratins and vimentin. Additionally, there were separate areas of large cell neuroendocrine carcinoma (LCNEC). Foci of clear cell carcinoma merged into both the LCNEC and the adenocarcinoma. Tumor invaded through the bile duct wall with extensive perineural and vascular invasion. Circumferential margins were positive. The patient's poor performance status precluded adjuvant therapy and he died with recurrent and metastatic disease 5 months after surgery. This is consistent with the reported poor survival rates of biliary mixed adenoneuroendocrine carcinomas.

Primary Biliary Mixed Adenoneuroendocrine Carcinoma (MANEC): A Short Review

“…Clinical laboratory tests can show biliary obstruction, with elevated bilirubin, alkaline phosphatase, 5 0 nucleotidase, and gamma-glutamyl transpeptidase, especially with involvement of the common bile duct. 20,26 Although one case had a significantly elevated level of hepatic enzymes without liver involvement, contiguous liver invasion and metastases should be ruled out in such a scenario, particularly with elevated alkaline phosphatase. 24,25 Carbohydrate antigen 19-9 (CA 19-9) is probably the most useful serologic tumor marker, but elevation of serum carcinoembryonic antigen and chromogranin A have also been documented.…”

“…19 Supporting this view, the occurrence of multiple different histologic components has been well documented in biliary MANECs, which have shown SCC, osteosarcoma, clear cell carcinoma, and spindle cell neoplasm. [19][20][21] Postnatal development of intrahepatic bile ducts is partly determined by Notch signaling. 22 This pathway also prevents the NE differentiation of endodermal elements via its effector Hes1, which inhibits the transcription factor Ascl1 (Achaete-scute homolog 1, an inducer of NE phenotype).…”

“…24,25 Carbohydrate antigen 19-9 (CA 19-9) is probably the most useful serologic tumor marker, but elevation of serum carcinoembryonic antigen and chromogranin A have also been documented. 17,20,24,25 MACROSCOPIC AND MICROSCOPIC FEATURES Macroscopically, biliary MANECs are solid, polypoid, nodular, or papillary tumors with a firm consistency and a homogeneous tan to gray-white cut surface (Figure 1, A). 14,19,21 Focal hemorrhage, necrosis, and mucin-filled cysts can also be evidenced on gross examination.…”

“…15,25,28 Focal areas of SCC, osteosarcoma, carcinoma with clear cell features, and spindle cell sarcomatoid elements have also been documented. 17,[19][20][21] Potential precursor lesions are frequently present in the mucosa surrounding biliary MANECs. Intestinal metaplasia with and without dysplasia has been found in tumors containing AC of both intestinal and biliary phenotypes.…”

“…1 Individual reports of biliary MANECs show posttreatment survival times ranging from 5 to 24 months. 20,25 However, information on follow-up is limited to 11 cases, many of which report follow-up intervals of 12 months or less. 19,20,24,25,27,28,30 Kim et al 31 found that prognosis of biliary MANECs is very poor and comparable with pure NET grade 3, with a disease-free survival of 5.3 months, overall survival of 12.2 months, and 0 of 7 patients alive after 2 years.…”