Carcinomatous arteriopathy as an unusual feature of pulmonary spread of cholangiocarcinoma arising in Caroli disease.

Pulmonary carcinomatous arteriopathy, also referred to as pulmonary tumor thrombotic microangiopathy, carcinomatous endarteritis, or embolic carcinomatosis, (1,2) is a rare and distinct form of pulmonary spread of solid malignant tumors. It is characterized by fibrointimal proliferation of small pulmonary arteries and arterioles initiated by tumor emboli that may be accompanied by fibrin thrombosis. Although patients with profound pulmonary vascular involvement may present clinically with progressive dyspnea, pulmonary hypertension, and even cor pulmonale, they may show clear lung fields on chest radiography. (1,2) In autopsy series, carcinomatous arteriopathy is found in 3.3% of cancer patients, (2) mostly associated with adenocarcinomas, including adenocarcinomas of the stomach, breast, colon, pancreas, and prostate, as well as choriocarcinoma and hepatocellular carcinoma. (1-3) To our knowledge, no case of carcinomatous arteriopathy associated with cholangiocarcinoma has been described in the literature to date, (2,3) even though pulmonary metastasis has been found in up to 15% of cases. (4)

Cholangiocarcinoma is a relatively uncommon tumor with an autopsy incidence ranging from 0.01% to 0.5%, which accounts for about 3% of all cancers. (4,5) In most cases, the etiology is obscure. Identifiable risk factors, such as hepatolithiasis, sclerosing cholangitis, liver flukes, and exposure to Thorotrast, account for only a small proportion of the cases. (5,6) Cholangiocarcinoma has been reported to occur as a complication of Caroli disease, an extremely rare congenital disease of the intrahepatic biliary tree characterized by segmental cystic dilatation of the larger intrahepatic bile ducts, recurrent bacterial cholangitis, and biliary lithiasis. (5-8) More than 300 cases of Caroli disease and Caroli syndrome (Caroli disease associated with congenital hepatic fibrosis) have been reported in the world literature, (9) and cholangiocarcinoma has been found in 7% to 14% of the cases. (5,7,9)

We report a case of cholangiocarcinoma that arose in Caroli disease. Postmortem examination revealed extensive pulmonary vascular spread in the form of carcinomatous arteriopathy in addition to metastasis to the regional lymph nodes.

REPORT OF A CASE

A 61-year-old African American woman with a 2-month history of jaundice was hospitalized because of abdominal pain, nausea, and vomiting. She had a 10-year history of "liver disease" and was told she had had "hepatitis" in the past, but she received no treatment. On admission, the patient was cachectic and afebrile. The liver was enlarged and slightly tender. Laboratory studies showed elevated bilirubin and liver enzyme levels and elevated white blood cell counts. Results of her hepatitis serologies were all negative. Serologic tumor marker study results were negative for [alpha]-fetoprotein but positive for CA 19-9 (37800 U/mL; normal, <40 U/mL). An abdominal computed tomographic scan revealed markedly irregular intrahepatic biliary dilatations containing high-density material involving both lobes. Multiple ill-defined hypodense areas were also identified and were compatible with tumor. An endoscopic retrograde cholangiography also showed a large number of irregular saccular areas with filling defects in the intrahepatic biliary ducts. Stones and pus were observed in the common bile duct endoscopically. Culture of the pus grew out mixed aerobic organisms and Staphylococcus aureus, but multiple blood cultures were negative. Radiographs of the chest were unremarkable, except for a small amount of bilateral pleural effusions. Based on these findings, a clinical diagnosis of Caroli disease with stone formation, bacterial cholangitis, and possible cholangiocarcinoma was suspected. The patient was treated with multiple antibiotics and underwent a partial workup for liver transplant. It was felt, however, that the patient's overall poor condition would preclude her from getting a transplant at that time. After discussions with her family, the patient decided to go home on hospice care. She died at home 2 months after initial presentation.

PATHOLOGIC FINDINGS

At autopsy, icterus and anasarca were present. The liver (2466 g) was bile stained but noncirrhotic. Cystically dilated intrahepatic bile ducts, typical of Caroli disease, were observed in both left and right lobes. They measured up to 2 cm in diameter and were filled with pigmented calculi (Figure 1, A). The intervening liver parenchyma contained many irregular, ill-defined, gray-white, and firm areas. Microscopically, the dilated ducts were lined with a single layer of columnar epithelium and showed marked fibrosis and mild chronic inflammation (Figure 1, B). Multiple sections failed to demonstrate the presence of dysplasia in the lining epithelium. Histologic examination of the gray-white intervening areas revealed well-differentiated cholangiocarcinoma characterized by infiltrating glandular structures in a fibrotic background (Figure 1, C). The neoplastic epithelial cells were cuboidal and had round or oval nuclei and inconspicuous nucleoli. Mitotic figures were sparse. No bile production was evident. Pathologic examination of the liver also identified a 10-cm abscess in the right lobe that had extended into the subphrenic space. Choledochal cyst and cystic kidney disease, 2 abnormalities that could be associated with Caroli disease, (8) were not found in this patient.

Metastases were grossly identified in the porta hepatis, pancreatic, and mesenteric lymph nodes, which were confirmed by histologic examination. No portal tumor thrombosis was present.

The lungs (left, 565 g; right, 439 g) had smooth and glistening pleural surfaces, and both were congested. Gross examination was unremarkable, except for several tiny thromboemboli and a few small areas of hemorrhagic infarction. No metastatic nodules were appreciated grossly. On histologic examination, however, numerous microscopic tumor emboli were found that extensively involved the arterioles and small arteries in both lungs. Tumor cells were present within the vascular lumens without invading the vascular walls. Three histologic patterns were recognized, in which tumor cells were either closely attached to the endothelium or replacing the endothelial lining without causing significant intimal proliferation or luminal obstruction (Figure 2, A), were associated with fibrin thrombi (Figure 2, B), or were embedded in obliterated lumens caused by marked fibrointimal proliferation (Figure 2, C). Careful examination of the lungs revealed no evidence of lymphangitic metastasis or involvement of the lung parenchyma. No tumor thromboemboli or overt metastasis was found in other organs.

[FIGURE 2 OMITTED]

Immunohistochemical staining using an antibody against factor VIII (1:100; Dako Corporation, Carpinteria, Calif) confirmed the histologic observations that in the majority of the vascular lesions in the lungs, the endothelial lining was replaced by tumor cells (Figure 3, A). More immunohistochemical studies demonstrated cytoplasmic positivity for vascular endothelial growth factor (1:100; Zymed Laboratories, South San Francisco, Calif) (Figure 3, B) and membranous positivity for cell adhesion molecules E-cadherin (1:100; Zymed) (Figure 3, C and D) and [beta]-catenin (1: 50; Transduction Laboratories, Lexington, Ky) (Figure 3, E and F) in tumor cells. Antigen retrieval was performed using microwave heating in 10mM citrate buffer, pH 6.0, for 10 minutes. Compared to primary tumor in the liver, the tumor cells that spread to the lungs did not show a significant decrease or increase in their immunostaining intensity for these 2 adhesion molecules.

[FIGURE 3 OMITTED]

COMMENT

It is generally believed that Caroli disease is a developmental abnormality of the embryonic ductal plate that leads to bile duct stricture and subsequent dilatation. (8, 9) The mode of inheritance of the disease is unclear, but both autosomal-recessive and autosomal-dominant inheritance have been suggested. The development of cholangiocarcinoma in the background of Caroli disease appears to be associated with long-standing inflammation of the biliary tree caused by bile stasis, hepatolithiasis, and recurrent bacterial infection, which induces biliary epithelial hyperplasia followed by dysplasia. (6, 7) A recent study by Parada et al (10) on a liver biopsy specimen from a patient with Caroli disease (without cholangiocarcinoma) has demonstrated several clonal chromosomal abnormalities. It is unclear, however, whether these genetic alterations are important for the subsequent development of cholangiocarcinoma.

The prognosis of Caroli disease is poor in general, even in the absence of cholangiocarcinoma. (8) Most patients die of septicemia or liver failure. The goal of treatment is to maintain sufficient biliary drainage and to control infection. Surgical resection may be the treatment of choice in patients with monolobar disease. When the disease is diffuse, liver transplantation should be considered. (8, 9)

The patient described in this report had every major complication of Caroli disease, including recurrent cholangitis, liver abscess, biliary lithiasis, and cholangiocarcinoma. Most interestingly, pulmonary carcinomatous arteriopathy was demonstrated at postmortem examination, which was not recognized before death. It is not certain, however, whether this patient had progressive dyspnea and pulmonary hypertension before death, because she was not under medical care.

The mechanisms underlying the development of carcinomatous arteriopathy are unknown. It is believed, however, that the distinct fibrointimal proliferation is related to direct attachment of tumor cells to the endothelial surface and/or local thrombosis initiated by tumor emboli. (2) Tumor cell attachment may cause damage to the endothelial cells and thus trigger the coagulation cascade. Release of growth factors during the local coagulation process and/or from tumor cells may be responsible for the subsequent fibrointimal proliferation that eventually leads to luminal stenosis and occlusion. The mechanisms that determine why some cancers are more prone to develop carcinomatous arteriopathy than others (1-3) also remain unclear. It is conceivable that a specific interaction between tumor cells and small pulmonary arteries and arterioles (particularly the endothelial cells) may be necessary. The limited immunohistochemical studies performed in this case suggest that modulation of expression of cell adhesion molecules E-cadherin and [beta]-catenin may play a role in the development of carcinomatous arteriopathy. This presumption is based on the fact that metastatic tumors in general express a decreased amount of E-cadherin and [beta]-catenin when compared with their primaries. Lack of a decrease in their expression may thus preclude tumor cells lodged in the pulmonary blood vessels from undergoing further steps in the process of metastasis. Whether the expression of vascular endothelial growth factor in tumor cells is important in the development of carcinomatous arteriopathy remains to be determined.

Carcinomatous arteriopathy and tumor embolism are not necessarily associated with the same prognosis as parenchymal or lymphangitic metastasis. (3) In fact, they may not even necessarily be regarded as true metastasis, since tumor cells within the pulmonary blood vessels may be destroyed during thrombus formation and organization without further parenchymal invasion. This concept may have important implications in therapeutic management for the patients with pulmonary carcinomatous arteriopathy if an antemortem diagnosis is made, which requires high clinical suspicion in cancer patients who present with progressive dyspnea.

References

(1.) Colby TV, Koss MN, Travis WD. Tumors of the lower Respiratory Tract. Washington, DC: Armed Forces Institute of Pathology; 1994:517-546. Atlas of Tumor Pathology, 3rd series, fascicle 13.

(2.) von Herby A, Illes A, Waldherr R, Otto H. Pulmonary tumor thrombotic microangiopathy with pulmonary hypertension. Cancer. 1990;66:587-592.

(3.) Winterbauer RH, Elfenbein IB, Ball WC Jr. Incidence and clinical significance of tumor embolization to the lungs. Am J Med. 1968;45:271-290.

(4.) Pitt HA, Dooley WC, Yeo CJ, Cameron JL. Malignancies of the biliary tree. Curr Probl Surg. 1995;32:1-90.

(5.) Chapman RW. Risk factors for biliary tract carcinogenesis. Ann Oncol. 1999; 10(suppl 4):S308-S311.

(6.) Shimonishi T, Sasaki M, Nakanuma Y. Precancerous lesions of intrahepatic cholangiocarcinoma. J Hepatobiliary Pancreat Surg. 2000;7:542-550.

(7.) Dayton MT, Longmire WP Jr, Tompkins RK. Caroli's disease: a premalignant condition? Am J Surg. 1983;145:41-48.

(8.) Taylor AC, Palmer KR. Caroli's disease. Eur J Gastroenterol Hepatol. 1998;10: 105-108.

(9.) Abdalla EK, Forsmark CE, Lauwers GY, Vauthey JN. Monolobar Caroli's disease and cholangiocarcinoma. HPB Surg. 1999;11:271-277.

(10.) Parada LA, Hallen M, Hagerstrand I, Tranberg KG, Johansson B. Clonal chromosomal abnormalities in congenital bile duct dilatation (Caroli's disease). Gut. 1999;45:780-782.

Accepted for publication October 16, 2001.

From the Department of Pathology, The University of Chicago Hospitals, Chicago, Ill.

Reprints: Hanlin L. Wang, MD, PhD, Division of Anatomic Pathology, Department of Pathology & Immunology, Washington University School of Medicine, Campus Box 8118, 660 S Euclid Ave, St Louis, MO 63110-1093 (e-mail: [e-mail]).