Case 3 -

Pigmented Carcinoid Tumor of the Bile Duct David N. Lewin Medical University of South Carolina Charleston, SC

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Clinical History: A 47 year old white male was seen for evaluation of a transient episode of abdominal pain, fever/chills, and mild jaundice with abnormal LFTs. He was seen by his local doctor and underwent an abdominal ultrasound which revealed a mild common and intrahepatic bile duct dilatation of unknown cause. The gallbladder itself was normal with no gallstones or signs of cholecystitis. This was followed by an abdominal CT scan which again showed biliary duct dilatation, but essentially no other abnormalities. At presentation to our institution one week later he was actually quite well with only minimal abdominal discomfort. He was no longer jaundiced, and had no further fever or chills. His appetite had returned and his weight remained stable. There was no alteration to his bowel habits. The review of systems was negative. His only significant history was of hypertension. Physical exam was unremarkable. Endoscopic retrograde cholangiopancreatography (ERCP) revealed a filling defect proximal to the low cystic duct takeoff in the mid common bile duct. Intraductal ultrasound revealed a 6 x 14 mm lesion penetrating all three layers of the bile duct. 10% of the lesion was exophytic into the lumen of the bile duct. Bile duct brushings and biopsy were obtained which revealed atypical cells. Two weeks later the patient was taken to the operating room for a bile duct resection. The specimen was received in the frozen section room. Grossly there was diffuse thickening of the bile duct. The lesion was nodular, tan grey with focal brown-black pigmentation. A cross section of the bile duct lesion is provided for evaluation. Pertinent Laboratory Data: His bilirubin reached a peak of 4.0, and one week later returned to normal (0.9). The AST and ALT were abnormal, at 82 and 210 respectively, however also returned to normal 8 days later. The amylase and lipase were initially abnormal and similarly returned to normal 8 days later. His complete blood count and electrolytes are all completely normal. CEA was 1.5 (normal) and a CA19-9 was 51 (upper limit of normal 37). Case 3 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 3 - Figure 1 Low power H&E with a nested proliferation of neoplastic cells in the submucosa and muscularis of the bile duct wall. Case 3 - Figure 2 Medium power H&E examination of the nested proliferation of neoplastic cells with bland nuclear morphology. Case 3 - Figure 3 High power H&E revealing eccentric nuclei with "salt and pepper" nuclear chromatin. Case 3 - Figure 4 High power H&E with brown black pigment granules in the neoplastic cells (upper portion of the image) and neural invasion (lower portion of image). Case 3 - Figure 5 High power H&E with prominent brown cytoplasmic pigment. Case 3 - Figure 6 Low power synaptophysin immunohistochemical stain with brown positive staining of all the neoplastic cells. Case 3 - Figure 7 Low power HMB-45 immunohistochemical stain with no brown staining of the neoplastic cells (negative). Case 3 - Figure 8 Medium power Fontana-Masson stain positive within the pigment in the lesion. Introduction: This case represents a 47 year old male with transient episode of abdominal pain, fever/chills, and mild jaundice with abnormal LFTs. A distal common bile duct lesion was identified and surgically resected. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: Sections of bile duct reveal expansion of the bile duct wall with an infiltrative tumor. The surface epithelium of the bile duct is focally eroded and has some reactive change, however the tumor mass is not arising from the epithelium. The tumor is comprised of an infiltrating, nested collection of cells. There is no desmoplastic reaction to the tumor. The tumor cells are epithelioid. There is nuclear size variation. The nuclei are round to oval with a stippled (salt and pepper) type chromatin. Focal tumor apoptosis is present. Significant mitotic activity is not appreciated. In multiple areas both intracellular and extracellular black pigment is identified within the tumor. There is prominent perineural invasion identified. Immunohistochemical stain results are as follows: Synaptophysin and Chromogranin are strongly positive. Neuron specific enolase, MART-1, HMB-45, S-100, Cytokeratin 7 and Cytokeratin 20 are all negative. A Fontana masson stain is positive on the brown pigment. Alcian-blue/ periodic acid Schiff with diastase stain is negative for mucin. Differential Diagnoses: Invasive adenocarcinoma Melanoma Pigmented Carcinoid Tumor of the Bile Duct Granular cell tumor Final Diagnosis: Pigmented Carcinoid Tumor of the Bile Duct Case Discussion: This case represents a difficult differential diagnosis. The majority of bile duct mass lesions will be epithelial in origin (papilloma or more commonly invasive adenocarcinoma). Invasive adenocarcinoma has a very poor prognosis and is often unresectable. Pre-operative diagnosis by bile duct brushing and bile duct biopsy is difficult in adenocarcinoma (most series have a specificity of approximately 50%) and may be impossible in submucosal lesions such as carcinoid tumors. The surface epithelium (sampled by cytology brushing) is focally eroded and reactive secondary to the submucosal lesion and obstruction. Often times these samples will be called atypical which the clinician will take to imply an adenocarcinoma (the majority of the time they will be correct). Sampling the tumor cells by brush cytology may impossible. Fine needle aspiration of these lesions may provide a pre-operative diagnosis, however often they are small and no amenable to FNA. Most of these diagnoses will be made intraoperatively. Distinguishing between a carcinoid tumor and an invasive adenocarcinoma at frozen section should be relatively easy. Adenocarcinoma will have a desmoplastic response, irregular and infiltrative gland formation and possible mucin production. An in-situ lesion may also be identified. Carcinoid tumor should have a nested pattern with relatively small cells with round to oval nuclei and little nuclear contour irregularity. This cases adds an additional complication to the differential diagnosis. The pigmentation of the lesion and the histologic finding of a brown pigment in the neoplastic cells brings melanoma into the potential differential diagnosis. At the time of frozen section, this differential diagnosis will be next to impossible. Metastatic melanoma to the bile duct may occur. Immunohistochemical studies (MART-1, HMB-45, and Melan-A) are necessary to exclude melanoma. Review of the Literature/Treatment Options: Carcinoid tumors of the extrahepatic biliary tree are a relatively rare entity. Carcinoid tumors of the extrahepatic biliary tree are stated to represent between 0.2 and 2% of all gastrointestinal carcinoid tumors, with most reported in the gallbladder. A little more than 50 cases of the extrahepatic bile duct tumor have been reported in the literature, none with associated pigmentation. The average age at diagnosis is approximately 50 years old and most common presentation is painless jaundice (similar to this case). The lesion is more common in women. Most individuals do not have systemic effects from the lesion. Approximately 1/3 of individuals will have lymph node metastasis, however even with metastatic disease the prognosis is very favorable with resection. Most individuals are still alive at 10 years. Resection (pancreato-duodenectomy, bile duct resection, and even liver transplantation depending on the site of disease) is the treatment of choice. Post operative chemotherapy and radiation do not appear to be indicated. Octreotide may be used for those with liver metastasis. Melanin pigment has not been described in carcinoid tumors of the bile duct, however has been described rarely in carcinoid tumors of other sites (lung and thymus). In these cases Fontana-Masson stains were positive for melanin pigment. A few cases were subjected to electron microscopic exam and revealed cells with melanosomes and neurosecretory granules. These cases all behaved similar to carcinoid tumors and in a more indolent fashion than melanoma, thus were considered carcinoid tumor with melanin production or pigmented carcinoid tumor. Conclusion(s): Carcinoid tumor should be in the differential diagnosis of bile duct mass lesions. 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