Case 8 -

Intraductal Cholangiocarcinoma (Biliary Papillomatosis) Linda D. Ferrell, M.D. Wendy L. Frankel, M.D.

Clinical history: 54 year old woman with cirrhosis and a history of ulcerative colitis. She presented for pre-liver transplant evaluation and abdominal CT demonstrated marked hepatomegaly and severe dilation of biliary tree, suggestive of obstruction of the common hepatic duct. At gross examination, multiple ducts were found to contain papillary excrescences. Case 8 - Figure 1 - Intraductal paillary proliferation of columnar epithelium and adjacent fibrotic liver, low power Case 8 - Figure 2 - Intraductal papillary proliferation (arrow), medium power Case 8 - Figure 3 - Severely dysplastic columnar epithelium (carcinoma in-situ) with mitotic figures (arrow), high power Pathologic findings: Intraductular papillary proliferation of columnar epithelium within the liver, low power.Severely dysplastic columnar epithelium (carcinoma in-situ), high power. Diagnosis- Intraductal Cholangiocarcinoma (Biliary Papillomatosis) Comment Cholangiocarcinoma Clinical features. Cholangiocarcinoma typically occurs in the elderly, with both sexes affected equally. There is no association with cirrhosis in general, although patients with primary sclerosing cholangitis do have a significantly increased risk for developing this tumor. The tumor is most prevalent in Southeast Asia, where liver fluke infestation with Clonorchis and Opisthorchis is high. Other possible risk factors include congenital anomalies of the biliary tree such as von Meyenberg complexes, choledochol cyst, Caroli's disease, and anomalous arrangements of the pancreatic and common bile ducts; hepatolithiasis, and thorotrast. The presenting systems depend on the location of the tumor, with four locations often designated separately as peripheral (intrahepatic), hilar, extrahepatic, or intraductal. The peripheral type usually remains asymptomatic until the tumor is in a late stage; the hilar, extrahepatic, and intraductal types present with signs of obstruction. Prognosis for the peripheral, hilar, and extrahepatic types is dismal, usually because the disease has reached an advanced stage by the time it is diagnosed rendering surgical removal difficult if not impossible; however, the length of survival may be increased when tumor-free surgical margins can be attained. The intraductal papillary type, also known as intraductal papillomatosis, biliary papillomatosis, or intraductal papillary tumor generally involves extensive areas of the intrahepatic and/or the extrahepatic bile ducts, with preference for the latter. Men are more affected than woman at about a 2.4 to 1 ratio, and patients are usually middle to older age (mean age 60). Although histologically benign in most cases, the lesion is generally considered in the clinical setting as a borderline or low grade malignant tumor due to its tendency to recur, its multicentricity, its ability to undergo malignant transformation and metastasize (although only rarely), and its significant morbidity and mortality due to its intraductal growth pattern and subsequent complications such as recurrent bouts of cholangitis and obstructive jaundice, as well as episodes of sepsis and hemobilia. Even with invasion present, the incidence of metastases is still much less than the other forms of cholangiocarcinoma. In spite of the fact that most of these intraductal papillary tumors may not become invasive or metastasize, due to the multicentric nature of the lesions, the possibility of a cure is unlikely without liver transplantation. Even then, the lesion may possibly recur in the extrahepatic ducts. Gross features. The peripheral, hilar, and extrahepatic variants of cholangiocarcinoma are usually firm, white-tan lesions due to dense fibrous stroma within the lesions. In contrast, the intraductal papillomatous variants are soft, polypoid or cauliflower-like lesions that protrude into the large ducts and cause ductal dilatation; these lesions are typically multifocal. Microscropic features. The peripheral, hilar, and extrahepatic variants are adenocarcinomas that typically have a significant component of dense fibrous stroma. The tumors often are well-differentiated, with tubular gland formation and minimal cytologic changes; however, foci of atypia with increased nuclear:cytoplasmic ratios, prominent nucleoli, variation in nuclear size, and loss of polarity will often be seen. Features that have been noted to support the diagnosis of carcinoma over a benign hyperplastic or reactive process include the formation of intracytoplasmic lumina or a focal cribriform pattern. In addition, multilayering of nuclei and intraluminal cellular debris can also be helpful features to suggest the possibility of malignancy. Intraductal papillomatosis, or biliary papillomatosis (and its invasive form, papillary adenocarcinoma) grows into the duct lumina as a multifocal, papillary lesion. The architecture consists of papillae lined by columnar epithelial cells supported by a delicate fibrovascular stroma. The nuclei are round to oval, and basally located, without significant multilayering. The cytoplasm is generally abundant and mucinous, but clear, or oncocytic differentiation as well as intestinal metaplasia with goblet cell change can also be present. Mitotic figures are infrequent. Frank invasion of the stalk and underlying periductular tissues must be seen for a diagnosis of adenocarcinoma. Special studies. Immunoperoxidase and mucin staining can be used to differentiate cholangiocarcinoma from HCC as described previously (see above). However, differentiation from metastatic adenocarcinoma can be very problematic if there is no known primary at another site. An adenocarcinoma composed of tall columnar cells with an adenomatous pattern, focal cribriform pattern, lack of intraepithelial mucin, and luminal necrotic debris is more suggestive of metastatic colonic carcinoma than primary cholangiocarcinoma. The latter usually shows more intraepithelial mucinous differentiation or is composed of glands lined by low-columnar to cuboidal cells. Cytokeratin profiles for types 7, 19, and 20 have also shown to be helpful in differentiating primary from metastatic leisons. The cholangiocarcinoma is generally CK7 and 19 positive, 20 negative, while metastatic colorectal adenocarcinoma is CK7 negative in about 90% of cases, but usually positive for either 19 or 20 30,31. Another marker that could be helpful is Lex, which often shows cytoplasmic and membranous reactivity in cholangiocarcinoma but only cytoplasmic reactivity in metastatic carcinoma. In contrast, Leu-M1 and B72.3 are more likely to show the opposite pattern with cytoplasmic staining in cholangiocarcinoma and cytoplasmic and membranous staining in metastatic adenocarcinoma. References Allaire G, Rabin L, Ishak K, et al: Bile duct adenoma: A study of 152 cases. American Journal of Surgical Pathology 12:708-715, 1988. Bhathal P, Hughes N, Goodman Z: The so-called bile duct adenoma is a peribiliary gland hamartoma. American Journal of Surgical Pathology 20:858-864, 1996. Chalasani N, Baluyut A, Ismail A, et al: Cholangiocarcinoma in patients with primary sclerosing cholangitis: A multicenter case-control study. Hepatology 31:7-11, 2000. Chauduri P, Chauduri B, Schuler J, et al: Carcinoma associated with congenital cystic dilatation of bile ducts. Archives of Surgery 117:1349-1351, 1982. Devaney K, Goodman Z, Ishak K: Hepatobiliary cystadenoma and cystadenocarcinoma: A light microscopic and immunohistochemical study of 70 patients. American Journal of Surgical Pathology 18:1078-1091, 1994. Honda N, Cobb C, Lechago J: Bile duct carcinoma associated with multiple von Meyenberg complexes in the liver. Human Pathology 17:1287-1290, 1986. Klatskin G: Adenocarcinoma of the hepatic duct at its bifurcation within the porta hepatis: An unusual tumor with distinctive clinical and pathological features. American Journal of Medicine 38:241-256, 1965. Koga A, Ichimiya H, Yamaguchi K, et al: Hepatolithiasis associated with cholangiocarcinoma. Cancer 55:2826-2829, 1985. Rubel L, Ishak K: Thorotrast-associated cholangiocarcinoma. Cancer 50:1408-1415, 1982. Sameshima Y, Uchimura M, Muto Y, et al: Coexistent carcinoma in congenital dilatation of the bile duct and anomalous arrangement of the pancreatico-bile duct: Carcinogenesis of coexistent gall bladder carcinoma. Cancer 60:1883-1890, 1987. Todani T, Watanabe Y, Toki A, et al: Carcinomas related to choledochal cysts with internal drainage operations. Surgery, Gynecology & Obstetrics 164:61-64, 1987. Tsui W, Loo K, Chow L, et al: Biliary adenofibroma. American Journal of Surgical Pathology 17:186-192, 1993. Wee A, Ludwig J, Coffey R, et al: Hepatobiliary carcinoma associated with primary sclerosing cholangitis and chronic ulcerative colitis. Human Pathology 16:719-726, 1985. TABLE 5: Bile Duct Lesions   BDA VMC BDP Cystadenoma Cholangiocarcinoma Metastatic adeno Incidental yes yes no no no no Location subcap subcap Multiple no yes yes no no yes Size <0.5 cm <0.5 cm Border regular regular irregular irregular irregular Cytoplasm mucin bile mucin mucin Mitosis no no rare no yes yes Atypia no no rare no yes yes Shape round ectatic round multicystic Lymphs yes no no,neuts no no no BDA=bile duct adenoma, VMC=von Meyenberg's complex, BDP=bile duct proliferation