Journal of Medical Virology 80:1350–1353 (2008)

Concomitant Diffuse Large B-Cell Lymphomaand Hepatocellular Carcinoma in ChronicHepatitis C Virus Liver Disease:A Study of Two Cases

Amy Lin,1 Jaydeep S. Kadam,1 Henry C. Bodenheimer,2 John Leonard,1

Maureen A. Joyce,1 and Gerond Lake-Bakaar1*1Department of Medicine, Weill Cornell Medical College, New York, New York2Department of Medicine, Beth Israel Medical Center, New York, New York

Chronic hepatitis C virus HCV infection pro-gresses through liver fibrosis and cirrhosis tohepatocellular carcinoma HCC. It appears tobe causally related to B-cell non-Hodgkin’slymphoma since regression after antiviral ther-apy has been described. Two cases are describedof non-Hodgkin’s lymphoma and HCC arisingsimultaneously in two patients. The first patientdid not have cirrhosis on liver biopsy. HCVhad been undetectable in plasma followingsuccessful therapy with interferon and ribavirintreatment 7 years earlier. The second patientdeveloped an aggressive form of hepatocellularcarcinoma HCC within weeks of stopping treat-ment with interferon and ribavirin. Therapy hadinduced complete viral suppression for over40 weeks. The two cases suggest that non-Hodgkin’s lymphoma and HCC can develop inthe absence of detectable hepatitis C viremiaand argues for continued surveillance evenafter sustained virological response to treatment.J. Med. Virol. 80:1350–1353, 2008.� 2008 Wiley-Liss, Inc.

KEY WORDS: chronic hepatitis C; non-Hodgkinslymphoma; hepatocellular carci-nima

INTRODUCTION

Chronic hepatitis C virus HCV infection isassociated with the development of hepatocellularcarcinoma HCC [Herr et al., 1993; Kato et al.,1994; el-Refaie et al., 1996; Niederau et al., 1998; Costaand Schiff, 1999; Silva et al., 2004] and B-cell non-

Hodgkin’s lymphoma [Pozzato et al., 1994, 1996;Zuckerman et al., 1997; Mazzaro et al., 1998;Cucuianu et al., 1999; Hermine et al., 2002]. Re-gression of non-Hodgkin’s lymphoma after antiviraltherapy with interferon suggests a link betweenactive viral replication and lymphoproliferation[Hermine et al., 2002; Weng and Levy, 2003; Gisbertet al., 2005; Saadoun et al., 2005; Svoboda et al., 2005].The orderly progression from liver fibrosis throughcirrhosis to hepatocellular cancer has strongly favorednecroinflammation associated with persisting viralinfection as the causative link between HCV and HCC[Chen and Morgan, 2006; Hijikata, 2006]. The syn-chronous development of HCC and non-Hodgkin’slymphoma in two patients - the first 7 years aftersustained virological response and the other, afterseveral weeks of complete viral suppression withinterferon, raises doubts as to the validity of theassumption that active viral replication is a prereq-uisite for the development of non-Hodgkin’s lymphomaand HCC.

CASE REPORT #1

A 70-year-old male contracted HCV infection afterblood transfusions in 1967. At initial presentationin 1992, a liver biopsy showed portal inflammationand stage F1 fibrosis. He was treated unsuccessfully

*Correspondence to: Gerond Lake-Bakaar, MD, Liver Center,Suite 7-A055, Beth Israel Deaconess Medical Center, 110 FrancisStreet, Boston, MA 02215. E-mail: glakebak@bidmc.harvard.edu

Accepted 27 November 2007

DOI 10.1002/jmv.21109

Published online in Wiley InterScience(www.interscience.wiley.com)

� 2008 WILEY-LISS, INC.

with interferon monotherapy in 1995. A repeatbiopsy in 1998 showed less inflammation, butwith F2 fibrosis. Re-treatment with interferon andribavirin in 1998 led to SVR. Thereafter, biennialHCV RNA remained consistently negative. In theabsence of biopsy evidence of cirrhosis, alpha-fetopro-tein levels were not monitored. HIV testing wasnegative.

In July 2005, he presented with generalized abdomi-nal pain, lymphadenopathy and increasing fatigue. Hewas diagnosed with a de novo diffuse large B-celllymphoma. However, an occult preceding marginal zonelymphoma that had transformed and presented as adiffuse large B-cell lymphoma could not be ruled out.R-CHOP (rituximab, cyclophosphamide, doxorubicin,vincristine and prednisone) with Velcade was started inNovember 2005. A month later, PET imaging demon-strated interval resolution of hypermetabolic activitywithin the lymph nodes. However, abdominal CTrevealed new heterogeneous masses in both hepaticlobes.

Laboratory tests were as follows: Total protein 4.7 gm/dl; albumin 2.7 gm/dl; total bilirubin 1.3 mg/dl; AST 70iu/l, ALT 44 iu/l; and AlkP 254 iu/l. Hemoglobin 13.4 g/dl;WBC 13.1; Platelets 152,000. Blood chemistry was nor-mal except for Na 128 mEq/l. HCV RNA and serologicalmarkers of HBV were negative. Alpha-fetoprotein was235,151 units/ml.

A liver biopsy demonstrated mostly necrotictissue with few malignant cells immuno-reactive forHepatocyte-1. Immuno-histochemical stains for lym-phocyte markers CD79a, CD20, CD3, and CD45 werenegative.

CASE REPORT #2

A 65-year-old female with a history of hypertension,hypothyroidism, idiopathic thrombocytopenic purpuratreated with splenectomy was diagnosed with HCV in1992, presumably as a result of multiple IVIg andplatelet transfusions. She was later diagnosed with non-Hodgkin’s lymphoma (marginal zone B-cell) in 1997 andreceived CHOP and irradiation therapy to her left neckand axilla. In 2005, she received Rituximab for recur-rence of her lymphoma.

An initial attempt to treat her chronic HCVinfection in December 2005 with interferon andribavirin failed, because of the severe thrombo-cytopenia. In January 2006, serum alpha-fetoproteinwas 8.4 iu/ml. With the support of IVIg and platelettransfusions, she restarted therapy with pegylatedinterferon and ribavirin in March 2006. Viral loadfell sharply and by September 2006, serum HCV RNAwas undetectable by Transcription Mediated Amplifi-cation TMA. CT scan showed a normal sized liverwithout surface nodularity. Lymph nodes had alsodecreased in size. Serum alpha-fetoprotein was

12.2 iu/ml in September 2006 and HCV RNA remainedundetectable until December 2006. She finished48 weeks of therapy in January 2007.

Five days after stopping treatment, she started tocomplain of pain in the right lower quadrant of herabdomen. Ultrasound of the liver 2 days later showed amarkedly enlarged liver to 22 cm, with obvious nod-ularity. Over the next 4 weeks she continued to haveright lower quadrant abdominal pain with fever,fatigue, and decreased appetite. She was noted to havea markedly enlarged liver extending to her right lowerquadrant.

Laboratory tests drawn at the end of Februarywere as follows: HCV viral load 37,700 IU/ml;AST 191, ALT 42, Alk Phos 178; Total protein7.2; Albumin 2.9; total bilirubin 1.1. Her alpha-fetoprotein had risen slowly from 8.4 iu/ml inJanuary 2006 to 54.2 iu/ml in February 2007.Medical resonance imaging of the abdomen de-monstrated multiple liver masses. Computed Tomo-graphy guided biopsy showed evidence of HCC.Two months later, she developed metastatic diseaseto her femur and was admitted to hospital. Shedeveloped a significant central nervous system catas-trophe within 1 week and died.

DISCUSSION

HCC as a complication of chronic HCV liverdisease is rarely observed in the absence of cir-rhosis [Herr et al., 1993]. Liver biopsy 7 years earlier,in patient 1 had shown stage 2 fibrosis. Since then,he had received treatment with interferon and ribavirinand had developed a sustained virological response.This is commonly associated with histological improve-ment [Poynard et al., 2002]. In the rare cases of HCCthat have been described after sustained virologicalresponse, late stage fibrosis and increased alcoholconsumption have been incriminating variables [Tokitaet al., 2005]. Neither seemed pertinent to this case.Markers of HBV have also been demonstrated toincrease the risk of HCC development in patientswith chronic HCV infection [Momosaki et al., 2005;Ikeda et al., 2007]. These markers were absent in thefirst patient.

By contrast, the second patient was positive foranti-HBc alone and although she had not had aliver biopsy because of her low platelet count, thereversed AST/ALT ratio was presumed evidence ofcirrhosis. The slowly increasing alpha-fetoprotein,8.4 iu/ml at the start of therapy, rising to 12.2 iu/mlafter 8 months and then to 54.2 iu/ml within 1 yearsuggests that the tumor may have ante-dated the start oftreatment. Therefore, an occult HCC in patient 2,suppressed by interferon treatment is a likely pos-sibility. The remarkable increase in liver size and theaggressive course of the disease, as soon as interferon

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Chronic Hepatitis C Virus Liver Disease 1351

was stopped, is consistent with this view. Interferonis known to have antiproliferative effects. Interferontreatment reduces the incidence of HCC in patients withHCV related cirrhosis [Camma et al., 2001; Hino andOkita, 2004; Ikeda et al., 2007].

Although the simultaneous development of HCCand NHL in a patient with chronic HCV infectionhas been previously described [Ohtsubo et al., 2006],the observation is rare. Indeed, recent data suggestdifferences in HLA profile between CHC patients thatdevelop HCC and those that develop lymphoma [De Reet al., 2004].

Only indolent lymphomas are generally consider-ed antigen-driven. Although the lymphoma inpatient 1 had been diagnosed as a de novo diffuselarge B-cell lymphoma, an occult preceding marginalzone lymphoma that had transformed, presentingas a diffuse large B-cell lymphoma could not be ruledout.

The role of active viral replication in the etiology ofHCV related lymphoma is unclear. Regression afterantiviral therapy with interferon suggests a linkbetween viral persistence and lymphoproliferation[Hermine et al., 2002; Weng and Levy, 2003; Gisbertet al., 2005; Saadoun et al., 2005; Svoboda et al., 2005].Virus was undetectable in plasma from patient 1 for atleast 7 years. Low levels of virus that can only bedetected by ultrasensitive detection methods in peri-pheral blood mononuclear cells has been described[Radkowski et al., 2005], but the observation is stillcontroversial. Re-emergence of HCV following immunesuppression, 8 years after SVR [Lee et al., 2005] lendssupport to low levels of replicating virus in patients withapparent aviremia.

These observations suggest that elimination ofHCV from serum in patients with SVR may not pre-clude later development of HCC or NHL. Careful,continued long-term surveillance of patients for devel-opment of HCC and lymphoma appears indicated inthese patients.

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