Caroli disease

* Biliary papillomatosis is a rare entity characterized by multiple papillary adenomas involving extensive areas of the biliary tract with a great potential for recurrence and malignant transformation. It has been reported in association with Caroli disease and a choledochal cyst. We report herein a case of malignant intrahepatic biliary papillomatosis associated with cirrhosis secondary to hepatitis C. To the best of our knowledge, this is the first report of this association.

(Arch Pathol Lab Med. 2002;126:369-371)

Biliary papillomatosis is a rare pathologic condition characterized by multiple papillary lesions of the intrahepatic or extrahepatic biliary tree. Only approximately 50 cases have been described in the literature, mainly as single case reports.1

An association with congenital abnormalities of the biliary tree, such as a choledochal cyst or Caroli disease, and with polyposis coli and ulcerative colitis has previously been reported.1 However, coexistence of biliary papillomatosis and cirrhosis secondary to hepatitis C has not been described before. We report herein a case of such an association with malignant transformation.

REPORT OF A CASE

A 66-year-old man presented in April 1998 with a history of abdominal pain, malaise, and weight loss during the previous few weeks. Laboratory test results demonstrated liver dysfunction, positive hepatitis C antigen, and a markedly raised serum CA19-9 (5049). Ultrasound suggested the presence of a spaceoccupying lesion in the right lobe of the liver. A computed tomographic scan showed a heterogenous tumor with central hyperdensity and patchy calcification. The umbilical vein was dilated, and there was a moderate amount of ascites.

At laparotomy, the liver was found to be hard and sclerotic with mixed macronodular and micronodular cirrhosis. There was a small right lobe mostly occupied by a white, multinodular tumor, extending to segment IV and the left hepatic vein. In addition, there was a 1-cm lesion on the surface of the left lobe and moderate portal hypertension. However, complete removal of the tumor was deemed impossible based on the extension to the left hepatic vein. A right hepatectomy was performed to avoid recurrent bouts of cholangitis. The common bile duct was dilated and filled with mucus and tumor debris.

The patient refused any further therapy. He was later found to have lung metastases and died 15 months after hepatectomy.

MATERIALS AND METHODS

The surgical specimens, including right hepatectomy, cholecystectomy, and the lesion of the left lobe, were fixed in 4% formalin solution. Multiple tissue blocks were taken from all parts of the tumor that showed a different appearance macroscopically, the surrounding liver parenchyma, the resection margins, gallbladder, and the lesion of the left hepatic lobe. This material was embedded in paraffin and processed for routine histologic analysis.

All sections were stained with hematoxylin-eosin. A total of 5 cm3 of yellow ascitic fluid was centrifuged and stained with Papanicolaou and Diff-Quick.

PATHOLOGIC FINDINGS

On gross examination, the right hepatic lobe was micronodular, with a spherical, multicystic, 8-cm tumor. The cut surface showed a 5-cm, soft, friable, pale brown mass, with a necrotic center filling the larger cyst, surrounded by fibrous tissue and many mucinous locules (Figure 1).

On microscopic examination, the main cyst was packed with papillary tumor, which was composed of fibrovascular cores of various sizes and lined by columnar, pseudostratified, biliary-type cells with frequent cytoplasmic mucinous vacuoles (Figure 2). In some areas, the tumor had a more solid architecture with cribriform structures, nuclear crowding, and significant cytologic atypia. These atypical zones merged into a pattern of frankly well-differentiated tubular adenocarcinoma, with invasion of the surrounding liver parenchyma (Figure 3) and along the lymphatics.

In the nontumoral liver, the cirrhosis was micronodularly and macronodularly mixed with moderate activity. There was no hepatocellular dysplasia. Small bile ducts were widely dilated and demonstrated various degrees of papillary epithelial proliferation with areas of dysplasia (Figure 4). Dysplasia was also noted in the small bile ducts at the resection margin. Numerous clusters of tumor cells were seen in the ascitic fluid. The lesion of left lobe corresponded to biliary papillomatous areas without dysplasia. It is noteworthy that the gallbladder showed chronic inflammatory changes only.

COMMENT

Biliary papillomatosis is an unusual lesion characterized by multiple papillary adenomas that involve extensive areas of the biliary tree.2 It is seen in middle-aged and old adults with a male-female ratio of 2:1.(1,3) Patients present with colicky abdominal pain, repeated cholangitis, and jaundice due to partial or intermittent obstruction of the bile duct by mucus or tumor fragments.3,4 Hemobilia is sometimes sufficient to cause severe anemia.3 Abundant mucin production has been reported, even leading to fluid and electrolyte imbalance.5

Preoperative diagnosis is usually difficult. No specific radiologic features have been described.2 Endoscopic retrograde cholangiography shows multiple cystic dilatations and narrowings of the biliary tree and constant filling defects.6 The endoscopic finding of excessive mucus or blood in the duodenal lumen is in keeping with biliary papillomatosis although not diagnostic.2,4,7 Brushings are seldom diagnostic, demonstrating clumps of papillary cells.5,6

Biliary papillomatosis can arise from any site in the biliary tree, including the gallbladder, ampullary region, extrahepatic or intrahepatic ducts, and the pancreatic duct4,6 Grossly, the inner surface of the ducts is replaced by velvety papillary growths with masses filling dilated ducts. These masses are soft, friable, and white to red or pale brown.2 Microscopically, the dilated ducts contain multiple papillary adenomas composed of fibrovascular cores lined by pseudostratified, columnar, biliary-type cells, which often have cytoplasmic mucin vacuoles.6 Paneth cells and endocrine cells may be found.1 The papillae in some areas are crowded together to give an adenomatous appearance. Moderate-to-severe nuclear atypia, mitoses, and multilayering of epithelial cells are recognized.7 Occasionally, in situ or frankly invasive carcinoma may be present. In such patients, there is well-documented progression of benign-- to-malignant lesions, as in the case herein presented.1

Immunohistochemistry for laminin reveals numerous discontinuities in the basement membranes of epithelial-- lined papillae in contradiction with the bland histologic appearance.7 A point mutation of the K-ras oncogene has been described without histologic evidence of malignancy in biliary papillomatosis arising in a congenital choledochal cyst.8 Based on these findings, some authors consider these tumors to be a low-grade malignancy.1,7

Malignant transformation occurs in 25% of the cases,6 but most patients die within 3 years of the diagnosis as a result of cholangitis and hepatic failure.3 Metastasis is very rare and mainly localized to the lungs as seen in our patient.4

Although the origin of biliary papillomatosis has yet to be determined, chronic irritation by a stone, Clonorchis infestation, reactive hyperplasia in Caroli disease, ectopic pancreatic tissue, and an anomalous arrangement of the biliary tree leading to chronic biliary injury by regurgitated pancreatic juice are among the factors that are considered to be possible causes.2,3,8,9 There is one previous report of biliary papillomatosis in association with cirrhosis secondary to hepatitis B,4 but as far as we are aware, this is the first association with cirrhosis secondary to hepatitis C. Cirrhosis secondary to hepatitis C is known to be a predisposing factor for hepatocellular carcinoma and cholangiocarcinoma. However, there is no obvious causal relationship between its association with biliary papillomatosis, and their coexistence is probably coincidental.

Management of biliary papillomatosis is difficult because of its diffuse nature and propensity to grow and spread along the entire biliary tree. Curettage and local excision have been associated with a high rate of recurrence.2 Radical resection is advocated for localized lesions, although this does not guarantee freedom from recurrences.2,4,5 For disseminated lesions, liver transplantation represents the only potential curative treatment.4,10

In summary, we report herein the first association between cirrhosis secondary to hepatitis C and biliary papillomatosis with malignant transformation. Although biliary papillomatosis is a well-recognized lesion, it remains rare and presents many clinicopathologic problems. Sampling from multiple sites is necessary to eliminate malignant transformation, and careful assessment of the biliary tree is essential to determine the extent of surgical resection. However, because of its multicentric nature, high frequency of relapse, and rarity of metastasis, liver transplantation may represent the optimal therapy.

We thank Dr S. Caplin for reviewing the text.

References

1. Colombari R, Tsui WMS. Biliary tumors of the liver. Semin Liver Dis. 1995; 15:402-405.

2. Lam CM, Yuen ST, Yeun WK, Fan ST. Biliary papillomatosis. BrI.Surg. 1996; 83:1712-1715.

3. Taguchi J, Yasunaga M, Kojiro M, Arita T, Nakayama T, Simokobe T. Intrahepatic and extrahepatic biliary papillomatosis. Arch Pathol Lab Med. 1993;117:

4. Cheng MS, Ahchong AK, Mak KL, Chun Yip AW. Hepatobiliary diseases: case report: two cases of biliary papillomatosis with unusual associations. J Gas-- troentrol Hepatol. 1999;14:464-467.

5. Hell ing TS, Strobach RS. The surgical challenge of papillary neoplasia of the biliary tract. Liver Transplant Surg. 1996;2:290-298.

6. Gunven P, Gorestman J, Ohlsen H, Ruden BI, Lundell G, Skoog L. Six-year recurrence free survival after intraluminal iridium-192 therapy of human bilobar biliary papillomatosis. Cancer. 2000;89:69-73.

7. Padfield CJH, Ansell ID, Furness PN. Mucinous biliary papillomatosis: a tumor in need of wider recognition. Histopathology. 1988;13:687-694.

8. Ohta H, Yamaguchi Y, Yamakawa 0, et al. Biliary papillomatosis with the point mutation of K-ras gene arising in congenital choledochal cyst. Gastroenterology. 1993;105:1209-1212.

9. Payan MJ, Choux R, Sahel J, et al. Carol i's disease associated with pancreatic heterotopia and papillary papillomatosis. Histopathology. 1985;9:1001-1006.

10. Beavers KL, Fried MW, Johnson MW, et al. Orthotopic liver transplantation for biliary papillomatosis. Liver Transplant. 2001;7:264-265.

Najat Mourra, MD; Laurent Hannoun, MD; Geraldine Rousvoal, MD; Rolland Parc, MD; Jean-Francois Flejou, MD

Accepted for publication August 2, 2001.

From the Departments of Pathology (Drs Mourra and Flejou) and Surgery (Dr Parc), Hopital St-Antoine, and Department of Surgery (Drs Hannoun and Rousvoal), Hopital Pitie-Salpetriere, Paris, France.

Reprints: Najat Mourra, MD, Service d'Anatomie Pathologique, Hopital St-Antoine, 184 rue du faubourg St-Antoine, 75012 Paris, France.

Copyright College of American Pathologists Mar 2002
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