A 67-Year-Old Man with Hepatitis C Virus Infection and a Liver Tumor

• CASE REPORT
• DIFFERENTIAL DIAGNOSIS
• PATHOLOGIC FINDINGS
• Gross Pathology
• Histopathologic Findings
• CLINICAL COURSE
• DISCUSSION
• SUMMARY
• DIAGNOSES
• ABBREVIATIONS
• REFERENCES

CASE REPORT

A 67-year-old Caucasian man was found to have an incidental mass in the right lobe of the liver. He had a history of diabetes mellitus, hypertension, three operations for herniated lumbar discs, and coronary artery disease, for which he underwent three-vessel coronary artery bypass grafts 6 months prior. There was no history of liver disease, ethanol use, or occupational exposure. He had been treated with furosemide, carvedilol, transdermal nitroglycerin, and insulin.

On physical examination, the patient's blood pressure was 160/90 mmHg. Other vital signs were within normal limits. Chest auscultation was remarkable for scattered ronchi and wheezes. There were no signs of liver failure or any features of chronic liver disease.

Laboratory work-up included complete blood count, which showed mild anemia (Hgb 11.3 g/dL), a normal coagulation screen, normal chemistry and a normal liver function profile. The patient had a positive hepatitis C virus antibody (anti-HCV) by RIBA. Anti-HBs (hepatitis B surface), HBsAg (hepatitis B surface antigen) and anti-HBc (hepatitis B core) were negative. CA 19-9 was 36.2 U/mL (normal < 37.0), alpha-fetoprotein (AFP) was 2.2 ng/ml (normal < 20.0) and carcinoembryonic antigen (CEA) was 0.9 ng/mL (normal < 5.0).

Chest x-ray showed mild congestion without infiltrates or pleural effusion. Echocardiography demonstrated global hypokinesia with an ejection fraction of 45%. A sonogram of the upper abdomen demonstrated a 6-cm solid lesion in the right lobe of the liver. A CT scan showed the mass in the posterior right lobe, which was enhanced during the arterial phase (Fig. [1]). A MRI confirmed a well-circumscribed lesion in the right inferior segment, which was bright on T2-weighted images. Intraoperatively, there was a 8 × 5 cm firm, white-gray mass involving segments VI, VII, and VIII. The remaining liver parenchyma was unremarkable. The patient underwent a right hepatic lobectomy, which he tolerated well.

DIFFERENTIAL DIAGNOSIS

A 67-year-old man was found to have a 8 cm incidental tumor in the right lobe of the liver. The only other finding relevant to this condition was a positive anti-HCV. He had no known liver diseases. Serological markers for hepatitis A and B infections were all negative. His serum liver enzyme levels, AFP, CA19-9, and CEA were within normal limits.

The possibility that the mass was a malignant tumor was more than likely given the patient's age and sex, and the tumor appearance and size on imaging studies. Most common malignant tumors in the liver are metastatic tumors, with gastrointestinal tumors being one of the more common sources.[1] However, this tumor was solitary and the serum CEA level was not elevated.

Primary malignant tumor is roughly divided into hepatocellular carcinoma (HCC) arising from hepatocytes and intrahepatic cholangiocarcinoma (ICC) arising from bile duct epithelium.[2] Rarely, combined HCC and cholangiocarcinoma (CC) may develop from the bipotential precursor cells in the liver.[3] [4] [5] Nevertheless, HCC remains the more frequently encountered primary malignant tumor in patients with chronic hepatitis C virus infection.[6] [7] [8] [9] [10] HCV-positive HCCs generally develop on a background of cirrhosis with a male sex predominance.[11] [12] Rarely, they may arise in noncirrhotic livers with chronic hepatitis C. Serum AFP level was not elevated in this patient. Normal AFP levels can be found in about 60% of patients with HCC.[13] [14]

Intrahepatic cholangiocarcinoma, which is the second most common primary liver tumor, affects persons over 65 years of age, and both sexes almost equally. The degree of male predominance is much less than HCC, ranging from 1 to 2.2.[15] [16] [17] [18] It is associated with liver fluke infestation, intrahepatic gallstones, intravenous contrast agents (Thorotrast), cystic liver diseases, primary sclerosing cholangitis, and inflammatory bowel disease.[19] [20] [21] [22] [23] [24] Recently, it has been suggested that hepatitis C virus infection is involved in the pathogenesis of intrahepatic cholangiocarcinoma.[25] ICC is usually not associated with cirrhosis.[26] The tumor is often solitary, solid, firm, poorly demarcated, and gray-white in color. The levels of serum CEA and CA19-9 may be elevated in patients with ICC.[21] [24] [27]

More recently, several investigators have also reported an association between HCV infection and nonHodgkin lymphoma.[28] [29] Chronic antigenic stimulation in patients with chronic HCV infection was believed to play a role in the pathogenesis of lymphoma.[30] Lymphoma can also present as a solid solitary intrahepatic or hilar tumor not associated with cirrhosis.[28] [31]

In our noncirrhotic patient with chronic hepatitis C, all three of these entities (i.e., HCC, ICC, lymphoma) needed be considered in the differential diagnoses. Aside from the characteristic elevated serum markers, a definitive diagnosis can be difficult to make preoperatively, because all present as solid tumors and have similar appearance on imaging studies. Biopsy of the lesion can provide a definitive diagnosis that would be important in deciding the extent of surgical resection to be carried out.

PATHOLOGIC FINDINGS

Gross Pathology

The right hepatic lobectomy specimen measured 26x17x9 cm in greatest dimension and weighed 1597 grams. The external capsule was red-brown and smooth. On sectioning, there was a well-circumscribed, firm, white-gray, nonencapsulated tumor that measured 8 × 5 × 4.5 cm (Fig. [2]). The tumor had an irregular boundary and bulged through the capsule on the posterior surface. The resection margins were not involved by the tumor. Serial sectioning through the remainder of the parenchyma revealed unremarkable red-brown parenchyma. The bile ducts, hepatic arteries and hepatic veins at the resection margins were patent and unremarkable.

Histopathologic Findings

Representative sections were taken from the tumor and the nontumorous liver parenchyma. The tumor consisted of well-formed, angulated glands that varied in size and were separated by dense fibrous stroma. The cells were columnar with pleomorphic nuclei and high cytoplasmic and nuclear ratio (Fig. [3]). Surgical resection margins were negative for tumor. No angiolymphatic or perineural invasion was identified. The remainder of the liver parenchyma showed mild lymphocytic portal infiltration. There was mild portal fibrosis and short fibrous septum formation (Fig. [4]). Rare foci of lobular inflammation were observed. There was no evidence of piecemeal necrosis or cirrhosis. The findings were consistent with chronic hepatitis C.

CLINICAL COURSE

The only postoperative complication was a small wound seroma, which was drained. Six months post surgery, the patient was doing well and his abdominal imaging studies did not show any recurrence.

DISCUSSION

Hepatitis C virus represents one of the major causes of acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma around the world. The nature of the association between infection with HCV and hepatocarcinogenesis remains uncertain. It is not clear whether the virus acts as initiator, promoter, or both in the multistep events that result in HCC. However, most cases of HCV-associated HCC occur on the background of cirrhosis.

Recently, it been suggested that HCV infection plays a role in the pathogenesis of intrahepatic cholangiocarcinoma.[25] Yamamoto et al. found anti-HCV antibodies in 32% of patients with ICC.[32] In contrast to HCC, the development of ICC is generally unrelated to cirrhosis and has been associated with other etiologies, but not with viral hepatitis. The mechanisms of cholangiocarcinogenesis are not known. HCV has been shown to cause injury to bile duct epithelial cells.[33] [34] [35] Moreover, the presence of HCV antigens and sequences have been demonstrated in bile duct epithelium.[36] [37] [38] [39] It has been speculated that ICC might develop in cholangioles infected with HCV or in hepatocytes, that have undergone ductal metaplasia in the areas of piecemeal necrosis.[32]

The association between HCV and ICC, in addition to the recent reports of HCV-related B cell lymphoma, reiterates the possible strong oncogenic potential of HCV not only in hepatocytes, but bile duct and lymphoid cells as well, the three cell lineages targeted by the virus.[36] [37] [38] [39]

SUMMARY

A 67-year-old man with no known liver disease was found to have an incidental tumor in the right liver lobe. His serum liver enzyme and alphafetoprotein were within normal limits, but he was found to be reactive for anti-HCV. The tumor was an intrahepatic cholangiocarcinoma. Since the only risk factor in this patient was hepatitis C infection, this case appears to support the recently suggested role of hepatitis C virus in the development of intrahepatic cholangiocarcinoma.

DIAGNOSES

Chronic hepatitis C virus infection

Cholangiocarcinoma

ABBREVIATIONS

AFP alpha-fetoprotein

CEA carcinoembryonic antigen

HBs hepatitis B surface

HBsAg hepatitis B surface antigen

HBc hepatitis B core

HCC hepatocellular carcinoma

HCV hepatitis C virus

ICC intrahepatic cholangiocarcinoma

REFERENCES

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REFERENCES

• 1 Anthony P P. Tumours and tumour-like lesions of the liver and biliary tract. In: MacSween RNW, Anthony PP, Scheuer PJ, eds. Pathology of the Liver London: Churchill Livingstone 1994: 635-711
  Search in Google Scholar
• 2 Higginson J, Steiner P E. Definition and classification of malignant epithelial neoplasms of the liver.  Acta Union Internat Cancerum. 1961;  17 593-603
  PubMedSearch in Google Scholar
• 3 Theise N D, Nalesnik M, Cubukcu O, Thung S N. A stem cell tumor of the liver with differentiation to hepatocellular carcinoma and cholangiocarcinoma.  Hepatology. 1994;  20 406A
  PubMedSearch in Google Scholar
• 4 Goodman Z D, Ishak K G, Langloss J M. Combined hepatocellular-cholangiocarcinoma: a histologic and immunohistochemical study.  Cancer. 1985;  55 124-135
  CrossrefPubMedSearch in Google Scholar
• 5 Tanaka T, Imamura A, Hayashi S. Minute mixed hepatoma with two components: hepatocellular and cholangiocarcinoma, which developed in liver cirrhosis with HCV.  Hepatogastroenterology . 1998;  45 220-223
  PubMedSearch in Google Scholar
• 6 Colombo M. Hepatocellular carcinoma.  J Hepatol. 1992;  15 225-236
  CrossrefPubMedSearch in Google Scholar
• 7 Nishioka K, Watanabe J, Furuta S. A high prevalence of antibody to the hepatitis C virus in patients with hepatocellular carcinoma in Japan.  Cancer. 1991;  67 429-433
  PubMedSearch in Google Scholar
• 8 Liang T J, Jeffers L J, Reddy K R. Viral pathogenesis of hepatocellular carcinoma in the United States.  Hepatology. 1993;  18 1326-1333
  CrossrefPubMedSearch in Google Scholar
• 9 Bruix J, Barrera J M, Calvet X. Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis.  Lancet. 1989;  2 1004-1006
  PubMedSearch in Google Scholar
• 10 Kew M C, Houghton M, Choo Q L. Hepatitis C virus antibodies in southern African blacks with hepatocellular carcinoma.  Lancet. 1990;  335 873-874
  CrossrefPubMedSearch in Google Scholar
• 11 Farinati F, Fagiuoli S, De Maria N. Anti-HCV positive hepatocellular carcinoma in cirrhosis. Prevalence, risk-factors and clinical features.  J Hepatol. 1992;  14 183-187
  PubMedSearch in Google Scholar
• 12 Simonetti R G, Camma C, Fiorello F. Hepatitis C virus infection as a risk factor for hepatocellular carcinoma in patients with cirrhosis. A case-control study.  Ann Intern Med. 1992;  116 97-102
  PubMedSearch in Google Scholar
• 13 Thung S N, Gerber M A, Sarno E, Popper H. Distribution of five antigens in hepatocellular carcinoma.  Lab Invest. 1979;  41 101-105
  PubMedSearch in Google Scholar
• 14 Taketa K. Alpha-fetoprotein: reevaluation in hepatology.  Hepatology. 1990;  12 1420-1432
  PubMedSearch in Google Scholar
• 15 Edmondson H A, Steiner P E. Primary carcinoma of the liver. A study of 100 cases among 48,900 necropsies.  Cancer. 1954;  7 462-503
  CrossrefPubMedSearch in Google Scholar
• 16 Okuda K, Kubo Y, Okazaki N. Clinical aspects of intrahepatic bile duct carcinoma including hilar carcinoma.  A study of 57 autopsy-proven cases.  Cancer. 1977;  232-246
  PubMedSearch in Google Scholar
• 17 MacSween RNW. A clinicopathological review of 100 cases of primary malignant tumours of the liver.  J Clin Pathol. 1974;  27 669-682
  CrossrefPubMedSearch in Google Scholar
• 18 Patton R B, Horn R C. Primary liver carcinoma. Autopsy study of 60 cases.  Cancer. 1961;  17 757-768
  PubMedSearch in Google Scholar
• 19 Flavel D J. Liver-fluke infection as an aetiological feature in bile duct carcinoma of man.  Trans R Soc Trop Med Hyg. 1981;  75 814-824
  CrossrefPubMedSearch in Google Scholar
• 20 Belamaric J. Intrahepatic bile duct carcinoma and C. sinensis infection in Hong Kong.  Cancer. 1973;  31 468-473
  PubMedSearch in Google Scholar
• 21 Nakanuma Y, Terada T, Tanaka Y. Are hepatolithiasis and cholangiocarcinoma aetiologically related? A morphological study of 12 cases of hepatolithiasis associated with cholangiocarcinoma.  Virchows Arch A Pathol Anat Histopathol. 1988;  406 45-58
  PubMedSearch in Google Scholar
• 22 Nakajima T, Kondo Y, Miyazaki M. A histopathologic study of 102 cases of intrahepatic cholangiocarcinoma: histologic classification and modes of spreading.  Hum Pathol. 1988;  19 1228-1234
  PubMedSearch in Google Scholar
• 23 Wee A, Ludwig J, Doffey R J. Hepatobiliary carcinoma associated with primary sclerosing cholangitis and chronic ulcerative colitis.  Hum Pathol. 1985;  16 719-726
  PubMedSearch in Google Scholar
• 24 Sugihara S, Kojiro M. Pathology of cholangiocarcinoma. In: Okuda K, Ishak KG, eds. Neoplasms of the Liver Tokyo: Springer-Verlag 1987: 143-158
  Search in Google Scholar
• 25 Tomimatsu M, Ishiguro N, Taniai M. Hepatitis C virus antibody in patients with primary liver cancer (hepatocellular carcinoma, cholangiocarcinoma, and combined hepatocellular-cholangiocarcinoma) in Japan.  Cancer. 1993;  72 683-688
  CrossrefPubMedSearch in Google Scholar
• 26 Craig J R, Peters R L, Edmondson H A. Tumors of the Liver and Intrahepatic Bile Ducts.  Washington, DC: Armed Forces Institute of Pathology 1989
  Search in Google Scholar
• 27 Nakajima T, Kondo Y. Well-differentiated cholangiocarcinoma: diagnostic significance of morphologic and immunohistochemical parameters.  Am J Surg Pathol . 1989;  13 569-573
  CrossrefPubMedSearch in Google Scholar
• 28 Ascoli V, Coco F, Artini M. Extranodal lymphomas associated with hepatitis C virus infection.  Am J Clin Pathol. 1998;  109 600-609
  PubMedSearch in Google Scholar
• 29 Silvestri F, Barillari G, Fanin R. Hepatitis C virus infection among cryoglobulinemic and non-cryoglobulinemic B-cell non-Hodgkin's lymphomas.  Haematol. 1997;  82 314-317
  PubMedSearch in Google Scholar
• 30 Lai R, Weiss L M. Hepatitis C virus and non-Hodgkin's lymphoma.  Am J Clin Pathol. 1998;  109 508-10
  PubMedSearch in Google Scholar
• 31 Suriawinata A, Ye M Q, Emre S, Strauchen J, Thung S N. Hepatocellular carcinoma and non-hodgkin lymphoma in a patient with chronic hepatitis C and cirrhosis.  Arch Pathol Lab Med. (In press),.
  PubMed
• 32 Yamamoto M, Takasaki K, Nakano M, Saito A. Minute nodular intrahepatic cholangiocarcinoma.  Cancer. 1998;  82 2145-2149
  CrossrefPubMedSearch in Google Scholar
• 33 Scheuer P J, Ashrafzadeh P, Sherlock S. The pathology of hepatitis C.  Hepatology . 1992;  15 567-571
  PubMedSearch in Google Scholar
• 34 Bach N, Thung S N, Schaffner F. The histological features of chronic hepatitis C and autoimmune chronic hepatitis: a comparative analysis.  Hepatology. 1992;  15 572-577
  CrossrefPubMedSearch in Google Scholar
• 35 Gerber M A, Krawczynski K, Alter M J. Histopathology of community acquired chronic hepatitis C.  Mod Pathol. 1992;  5 483-486
  PubMedSearch in Google Scholar
• 36 Gerber M A. Pathobiologic effects of hepatitis C.  J Hepatol. 1995;  22(Suppl 1) 83-86
  PubMedSearch in Google Scholar
• 37 Krawczynski K, Beach M J, Bradley D W. Hepatitis C virus antigen in hepatocytes: immunomorphologic detection and identification.  Gastroenterology. 1992;  103 622-629
  PubMedSearch in Google Scholar
• 38 Nouri-Aria K T, Sallie R, Mizokami M. Intrahepatic expression of hepatitis C virus antigens in chronic liver disease.  J Pathol. 1995;  175 77-83
  PubMedSearch in Google Scholar
• 39 Nouri-Aria K T, Sallie R, Sangar D. Detection of genomic and intermediate replicative strands of hepatitis C virus in liver tissue by in situ hybridization.  J Clin Invest. 1993;  91 2226-2234
  PubMedSearch in Google Scholar