Cholangiocarcinoma Occurring in a Liver With Multiple Bile Duct Hamartomas (von Meyenburg Complexes).

Ductal plate malformation results from persistence or absence of remodeling of the embryonic ductal plate during ontogenesis. This leads to different congenital bile duct disorders, such as Caroli disease and syndrome, autosomal recessive polycystic kidney disease, autosomal dominant polycystic kidney disease, congenital hepatic fibrosis, and bile duct hamartomas (BDHs, also known as von Meyenburg complexes).[1] The clinical presentation and outcome of these congenital diseases show great variation; some patients die as neonates or in early infancy (eg, perinatal, neonatal, and infantile forms of autosomal recessive polycystic kidney disease), and others (eg, BDH) present as clinically asymptomatic and usually incidental findings at laparotomy or autopsy.[1] While approximately 7% of patients with Caroli disease ultimately develop a cholangiocarcinoma, BDH has only rarely been found in association with it. We describe what we believe to be the eighth case of cholangiocarcinoma associated with multiple BDH.

REPORT OF A CASE

A 59-year-old white woman complained of epigastric pain and weight loss of 1.5 kg over a period of 4 weeks. Blood tests showed elevated levels of alkaline phosphatase (5.39 [micro]mol/L; reference interval, [is less than] 4.0 [micro]mol/L) and [Gamma]-glutamyl transferase (152 U/L; reference interval, [is less than] 32 U/L). The following tumor markers were elevated: CA 125 (52.9 U/mL; reference interval, [is less than] 35.0 U/mL), CA 15-3 (180 U/mL; reference interval, [is less than] 30.0 U/mL), and neuron-specific enolase (15.6 ng/mL; reference interval, [is less than] 12.5 ng/ mL). [Alpha]-Fetoprotein, CA 19-9, carcinoembryonic antigen, Cyfra 21-1, and [Beta]-human chorionic gonadotropin levels were within normal limits. Ultrasound and computed tomographic scans of the abdomen showed a tumor in segments 6 and 7 of the right liver lobe, measuring 8 cm in greatest diameter. Additional multiple dotlike hypodensities were found by magnetic resonance imaging. No other tumor was found in either the abdomen or the chest by further imaging studies and endoscopy, and no cystic lesions were found in the kidneys. Endoscopic retrograde cholangiopan-creatography showed patent bile ducts. A liver biopsy was performed and a right-sided hemihepatectomy was performed as a result.

PATHOLOGIC FINDINGS

The hepatic tumor measured 10 cm in greatest diameter and was located in the subcapsular region (Figure 1). The cut surface was gray-white. The surrounding parenchyma showed multiple white nodules measuring 0.2 to 0.3 cm in diameter (Figure 1).

[Figure 1 ILLUSTRATION OMITTED]

Histologically, the hepatic tumor was nonencapsulated and characterized by cells that were cuboidal to columnar in shape with round to oval nuclei (Figure 2). Occasionally a single nucleolus was present. Mitoses were commonly found. The tumor cells grew in solid sheets and bundles separated by fibrous septa. Occasionally a tubular or cribriform growth pattern was noted. Necrosis was present, but bile and mucin formation were absent. Following extensive sampling of tumor and nontumorous tissue, no dysplastic or carcinoma in situ lesions were found within the tumor or in the nearby bile ducts.

[Figure 2 ILLUSTRATION OMITTED]

The liver nodules were found to be BDHs composed of a dense stroma with a variable number of more or less dilated bile ducts. Occasionally the lumen contained inspissated bile concrements. Polypoid projections of the epithelium or dysplastic foci were not found. The BDHs were commonly located in or near portal tracts, and a mild chronic inflammation was occasionally apparent (Figure 3). The remaining liver parenchyma was normal.

[Figure 3 ILLUSTRATION OMITTED]

Immunohistochemistry with antibodies directed against pancytokeratin (AE1/AE3; BioGenex, San Ramon, Calif), cytokeratin 19 (BioGenex), and CA 19-9 (Immunotech, Marseille, France) showed immunostaining of scattered tumor cells and intense labeling of the bile duct epithelium of both portal tracts and BDHs. The hepatocytes were immunonegative. A polyclonal antibody directed against carcinoembryonic antigen (Quartett, Berlin, Germany) (which cross-reacts with biliary glycoprotein 1) stained bile canaliculi formed by hepatocytes, the surface of the biliary epithelium of portal tracts and BDH, as well as the cytoplasm and membranes of scattered tumor cells. Cytokeratin 7 (ProGen Biotechnik GmbH, Heidelberg, Germany) immunostained bile duct epithelium only. The tumor cells were immunonegative.

Immunostaining was not observed with antibodies directed against [Alpha]-fetoprotein, carcinoembryonic antigen (monoclonal antibody), chromogranin A, cytokeratin 20, and synaptophysin.

COMMENT

We found a poorly differentiated adenocarcinoma in the subcapsular region of the right liver lobe. A thorough clinical investigation was unable to find any other tumor, and this tumor was finally interpreted to be a peripheral intrahepatic cholangiocarcinoma. Scattered immunostaining of tumor cells with CA 19-9 and cytokeratin 19, antigens commonly expressed by cholangiocarcinoma (approximately 60% to 100% of cases), and negative immunostaining for cytokeratin 20 add further support to this diagnosis.[2-5]

Intrahepatic cholangiocarcinoma is a rare tumor with a prevalence ranging from 0.01% to 0.5% in autopsy series[6] and a frequency of approximately 10% among primary liver tumors.[7] Predisposing factors contributing to the development of cholangiocarcinoma are anatomic anomalies (such as congenital bile duct cysts and Caroli disease), chronic inflammatory conditions, parasites, hepatolithiasis, carcinogens (such as nitrosamines and Thorotrast), autoimmune diseases (primary sclerosing cholangitis and chronic ulcerative colitis), as well as occasionally nonbiliary cirrhosis.[6,7] Clinical investigations, including imaging studies and endoscopy, excluded all these conditions in our case. However, multiple BDHs (also known as von Meyenburg complexes) were found in the vicinity of the cholangiocarcinoma, leading to speculation that they were related to its pathogenesis.

To the best of our knowledge, 7 cases of cholangiocarcinoma associated with single or multiple BDHs have been described in the literature to date (Table).[8-14] Their features are not different from cholangiocarcinoma in general. Cholangiocarcinoma occurring in Caroli disease and congenital bile duct cysts may be due to chronic inflammation caused by chemical or mechanical irritation, cholestasis, or hepatolithiasis.[6,7] It has been suggested that cholangiocarcinomas may arise in these cases via hyperplasia/metaplasia and dysplasia, the latter being regarded as a precancerous lesion.[6,7] Bile duct hamartomas do contain inspissated bile and a more or less chronic inflammatory infiltrate. Indeed, 6 of the 7 case reports describe transition from benign to malignant epithelium or ducts, as well as a dysplastic bile duct epithelium and carcinoma in situ occurring in BDH or bile ducts close to the tumor (Table).[8,10-14] We were unable to identify any atypical or dysplastic epithelium in the BDHs, nor did we find architectural transitions from apparently benign BDH into obvious carcinoma. This observation may be interpreted in 2 ways: (1) the tumor has destroyed all evidence or (2) the cholangiocarcinoma may have developed de novo without any precancerous lesions. A gradual architectural change was not described specifically in every case,[8-11,13] and at present there is not enough evidence to suggest that cholangiocarcinoma occurring in association with BDH develops either via an architectural transition of benign to malignant glands, or a dysplasia/carcinoma in situ sequence of the biliary epithelium.

Cholangiocarcinoma Associated With Bile Duct Hamartomas: Review of the Literature(*)

Source, y                Age, y/Sex   Location     No. of Lesions

Homer et al,[8] 1968        75/M      Not stated         2
Bornfors[9] 1984            90/M      Both lobes      Multiple
Honda et al,[10] 1986       61/F      Not stated         1
Dekker et al,[11] 1989      61/F      Left lobe          1
Burns et al,[12] 1990       35/M      Right lobe         1
Hasebe et al,[13] 1995      59/M      Left lobe          1
Yaziji et al,[14] 1997      68/M      Right lobe         1
Present case                59/F      Right lobe         1

Source, y                Size, cm     Histology

Homer et al,[8] 1968     0.8             AC
Bornfors[9] 1984         Largest, 4      AC
Honda et al,[10] 1986    0.2-0.3         AC
Dekker et al,[11] 1989   4               AC
Burns et al,[12] 1990    18.5            AC
Hasebe et al,[13] 1995   5.5             AC
Yaziji et al,[14] 1997   10              AC
Present case             10              AC

                         Dysplasia and/or CIS in
                         Surrounding Biliary
Source, y                Epithelium of BDHs

Homer et al,[8] 1968     "Transition from benign to
                         malignant ducts"

Bornfors[9] 1984         Presence of dysplasia or
                         CIS not described

Honda et al,[10] 1986    "Transition between seemingly
                         benign and clearly
                         malignant epithelium";
                         presence of dysplasia or
                         CIS not described

Dekker et al,[11] 1989   "Clear transition from benign
                         to neoplastic tissue";
                         however, dysplasia
                         and CIS not found

Burns et al,[12] 1990    Evidence of nuclear atypia;
                         no CIS found

Hasebe et al,[13] 1995   Dysplasia with nuclear
                         atypia and occasional
                         mitoses

Yaziji et al,[14] 1997   Dysplasia with nuclear
                         atypia and atypical
                         mitoses

Present case             Not found

                                            No. of
Source, y                  BDH              Cases

Homer et al,[8] 1968     Multiple             1
Bornfors[9] 1984         Multiple             1
Honda et al,[10] 1986    Multiple             1
Dekker et al,[11] 1989   Multiple             1
Burns et al,[12] 1990    Multiple             1
Hasebe et al,[13] 1995   Single([dagger])     1
Yaziji et al,[14] 1997   Multiple             1
Present case             Multiple             1

(*) AC indicates adenocarcinoma; CIS, carcinoma in situ; in situ; and BDH, bile duct hamartoma.

([dagger]) Single bile duct adenoma and BDH.

The clinical consequence arising from the diagnosis is life-long follow-up of the patient, since 2 cases were reported in the literature with multiple cholangiocarcinomas[8,9] occurring in association with BDH, and our patient may be at risk for developing further cholangiocarcinomas. However, as yet there is no evidence to suggest that treatment of cholangiocarcinoma occurring in association with BDH should be different from treatment of peripheral cholangiocarcinoma in general, that is, attempting complete resection of the tumor.

References

[1.] Desmet VJ. Congenital diseases of intrahepatic bile ducts: variations on the theme "ductal plate malformation." Hepatology. 1992;16:1069-1083.

[2.] Haglund C, Lindgren J, Roberts PJ, Nordling S. Difference in tissue expression of tumour markers CA 19-9 and CA 50 in hepatocellular carcinoma and cholangiocarcinoma. Br J Cancer. 1991;63:386-389.

[3.] Balaton AJ, Nehama-Sibony M, Gotheil C, Callard P, Baviera EE. Distinction between hepatocellular carcinoma, cholangiocarcinoma, and metastatic carcinoma based on immunohistochemical staining for carcinoembryonic antigen and for cytokeratin 19 on paraffin sections. J Pathol. 1988;15:6305-6310.

[4.] Maeda T, Kajiyama K, Adachi E, Takenaka K, Sugimachi K, Tsuneyoshi M. The expression of cytokeratins 7, 19, and 20 in primary and metastatic carcinomas of the liver. Mod Pathol. 1996;9:901-909.

[5.] Tsuji M, Kashihara T, Terada N, Mori H. An immunohistochemical study of hepatic atypical adenomatous hyperplasia, hepatocellular carcinoma, and cholangiocarcinoma with alpha-fetoprotein, carcinoembryonic antigen, CA19-9, epithelial membrane antigen, and cytokeratins 18 and 19. Pathol Int. 1999;49:310-317.

[6.] Holzinger F, Z'graggen K, Buchler MW. Mechanisms of biliary carcinogenesis: a pathogenetic multi-stage cascade towards cholangiocarcinoma. Ann Oncol. 1999;10:S122-S126.

[7.] Nakanuma Y, Hoso M, Terada T. Clinical and pathological features of cholangiocarcinoma. In: Okuda K, Tabor eds. Liver Cancer. New York, NY: Churchill Livingstone; 1997:279-290.

[8.] Homer LW, White HJ, Read RC. Neoplastic transformation of v. Meyenburg complexes of the liver. J Pathol Bacteriol. 1968;96:499-502.

[9.] Bornfors M. The development of cholangiocarcinoma from multiple bile-duct adenomas. Acta Pathol Microbiol Immunol Scand A. 1984;92:285-289.

[10.] Honda N, Cobb C, Lechago J. Bile duct carcinoma associated with multiple von Meyenburg complexes in the liver. Hum Pathol. 1986;17:1287-1290.

[11.] Dekker A, Ten Kate FJW, Terpstra OT. Cholangiocarcinoma associated with multiple bile-duct hamartomas of the liver. Dig Dis Sci. 1989;34:952-958.

[12.] Burns CD, Kuhns JG, Wieman TJ. Cholangiocarcinoma in association with multiple biliary microhamartomas. Arch Pathol Lab Med. 1990;114:1287-1289.

[13.] Hasebe T, Sakamoto M, Mukai K, et al. Cholangiocarcinoma arising in bile duct adenoma with focal area of bile duct hamartoma. Virchows Arch. 1995;426: 209-213.

[14.] Yaziji N, Martin L, Hillon P, Favre JP, Henninger JF, Piard F. Cholangiocarcinome developpe sur micro-hamartomes biliaires chez un malade atteint d'hemochromatose. Ann Pathol. 1997;17:346-349.

Accepted for publication March 28, 2000.

From the Institute of Pathology (Drs Rocken and Roessner), Department of Surgery (Drs Pross and Ridwelski), and Department of Gastroenterology, Hepatology and Infectious Diseases (Dr Brucks), Otto-von-Guericke-University, Magdeburg, Germany.

Reprints: Christoph Rocken, MD, PhD, Institute of Pathology, Ottovon-Guericke-University, Leipziger Str 44, D-39120 Magdeburg, Germany.