Hepatic B-cell non-Hodgkin's lymphoma of MALT type in the liver explant of a patient with chronic hepatitis C infection

Authors


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Abstract

B-cell non-Hodgkin's lymphoma (B-NHL) is a well-documented complication of hepatitis C virus (HCV) infection. Marginal zone (mucosa-associated lymphoid tissue; MALT) lymphomas constitute a less common type of B-NHL. In this article, we report a case of liver MALT in a cirrhotic patient, incidentally discovered after liver transplantation (LT). We discuss pertinent diagnostic and management strategies in this clinical setting. (Liver Transpl 2005;11:796–799.)

We present a case of a marginal zone (mucosa-associated lymphoid tissue; MALT) type B-cell non-Hodgkin's lymphoma (B-NHL) found in the liver explant of a patient who underwent orthotopic liver transplantation (LT) for end-stage liver disease secondary to HCV.

Abbreviations

B-NHL, B-cell non-Hodgkin's lymphoma; MALT, mucosa-associated lymphoid tissue; HCV, hepatitis C virus; LT, liver transplantation.

The patient was a 53-year-old Italian-American man with end-stage liver disease due to hepatitis C virus (HCV)-related cirrhosis. His past medical history was remarkable for cryoglobulin-negative vasculitis manifesting as lower extremity rash and microscopic hematuria, presumed to be due to immune complex glomerulonephritis. He had an elevated alpha-fetoprotein with negative abdominal magnetic resonance imaging and computed tomography for hypervascular lesions. On physical examination, the patient was jaundiced. The spleen was a palpable 3.5 cm below the left costal margin. No ascites was noted. A maculopapular purpuric rash was present in both legs with underlying bilateral pitting edema. No lymphadenopathy was palpated anywhere. His remarkable laboratory work-up is shown in Table 1. The patient underwent LT from a related living donor. His immunosuppression consisted of tacrolimus and prednisone. The pathologic evaluation of the liver explant showed micronodular cirrhosis, consistent with advanced hepatitis C infection and a diffuse lymphoproliferative process, involving fibrous septa, portal areas, and hepatic hilar lymph nodes consistent with low-grade B-NHL (Fig. 1). The lymphocytes were small, with condensed chromatin and scant cytoplasm and infiltrated intranodular areas, sometimes forming nodular aggregates. A few residual follicles were present in lymph nodes. The lymphoma formed several lymphoepithelial lesions in the bile ducts, as typical of MALT lymphoma (Fig. 2). The immunohistochemical stains demonstrated that the majority of the cells were positive for CD20, CD43, and CD 79 and negative for cyclin D1, CD3, CD5, and CD10 antibodies (Fig. 3).

Table 1. Laboratory Data
 Pre-OLTPost-rituximabNormal values
  1. Abbreviations: WBC, white blood cell; Hb, hemoglobin; Ht, hematocrit; PLT, platelet; AST, aspartate aminotransferase; ALT, alanine aminotransferase; HCV Ab, hepatitis C virus antibody; HIV; human immunodeficiency virus.

Hematology   
 WBC480025004.2-10.2 ×109/L
 Hb10.19.913.2-17.5 g/dL
 Ht29.328.838.7%-48.3%
 PLT6600028000151-355 ×109/L
Blood chemistry   
 Total bilirubin1.60.50.1-1.1 mg/dL
 AST1256512-31 U/L
 ALT965410-45 U/L
Serum protein electrophoresis   
 Total protein5.86.06.3-7.9 g/dL
 Albumin3.4340.2-0.4 g/dL
 Alpha 2-globulin0.60.80.5-1.1 g/dL
 Beta globulin0.70.90.7-1.3 g/dL
 Gamma globulin1.20.70.8-1.7g/dL
Serology/immunology   
 Rheumatoid factor83 0-39 IU/mL
 Antinuclear antibody<0.9 0.0-0.9 Units
 Anti–smooth muscle actin antibodyNeg Neg
 Antimitochondrial antibody<0.1 <0.1 Units
 c-Anticentromere antibody(−) Neg
 Cryoglobulin(−) Neg %PPT
 HCV Ab(+) Neg
 HCV viral titer122.496625447<615 IU/mL
 HCV Genotyping1a  
 Alpha fetoprotein124.9 0.0-7.9 ng/mL
 Helicobacter pylori(−)  
 Complement, total<105730-75 U/mL
 C3 complement functional<33121-50 U/mL
 C4 complement<33014-40 mg/dL
Figure 1.

Low-grade B-NHL, consistent with MALT/marginal zone lymphoma involving the liver and hepatic hilar lymph nodes (hematoxylin and eosin stain, 4× magnification).

Figure 2.

Note the lymphoepithelial lesions in the bile ducts, typical of MALT lymphoma noted in the explanted liver (hematoxylin and eosin stain, 20× magnification).

Figure 3.

Immunohistochemical stains demonstrating diffuse staining for CD20 in the lymphocytes (20× magnification).

A computed tomography scan of the abdomen, pelvis, and thorax was performed for staging, which revealed no other sites of active disease. Bone marrow aspirate and biopsy were hyperplastic, with 5% involvement by lymphoma. Immunophenotyping of the bone marrow showed lymphocytic aggregates which were predominantly CD20+. An upper endoscopy was performed to evaluate for gastric lesions. The stomach biopsy was negative for lymphoma and the serology for Helicobacter pylori was negative. At this point the decision was made to use rituximab instead of pegylated interferon and ribavirin to treat his HCV infection, given the risk of rejection in the early post-LT period. Immunosuppression was maintained unchanged. After the second dose of rituximab, the patient developed cytomegalovirus infection that needed treatment with valganciclovir. The patient went on to complete a 4-dose course of rituximab (375 mg/m2) without any further complications. At that time, a computed tomography scan of the thorax/abdomen/pelvis after the monoclonal antibody treatment showed no enlarged lymph nodes and a stable spleen size.

The association of HCV infection and B-NHL has been addressed by several authors.1–4 A recent meta-analysis reviewing case-control studies showed that the HCV prevalence in patients with B-NHL was 15%, compared to the general population (1.5%) and patients with other hematologic malignancies (2.9%), suggesting a role of HCV in the etiology of B-NHL.5 Various mechanisms have been proposed for HCV-induced lymphoproliferation and lymphomagenesis, such as lymphocyte infection and transformation, interaction with CD81, and chronic antigenic stimulation.6–8

The most common form of B-cell lymphoproliferative disorder in the setting of HCV is essential mixed cryoglobulinemia. However, B-NHL has also been associated with HCV, but to a lesser degree.8 Most studies report the predominance of specific histological types among HCV-associated B-NHL: marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma/immunocytoma, and diffuse large B-cell lymphoma.6 Extranodal MALT-type lymphomas develop in organs normally devoid of lymphoid tissue, and they are though to be triggered by chronic antigenic stimulation associated with inflammation or autoimmune disease, such as H. pylori infection in the stomach, Hashimoto's thyroiditis in the thyroid, and Sjogren's syndrome in the salivary glands. Primary MALT-type lymphoma of the liver is uncommon, and there are few cases reported in the literature and only one association of a hepatic MALT-type lymphoma and HCV infection.9

According to the Revised European-American Lymphoma/World Health Organization classification there are 3 types of marginal zone lymphomas: splenic marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma of MALT-type, and nodal marginal zone B-cell lymphoma.10 MALT-type lymphoma has been described as a primary liver tumor in patients with primary biliary cirrhosis.11, 12 There is just one description of hepatic MALT lymphoma associated with HCV in the literature, a patient with a 1.5-cm round and heterogeneous liver nodule in segment 6, detected on a computed tomography.9 Abdominal angiography demonstrated a hypervascular area in the same segment. The patient underwent resection of the tumor, which was positive for CD20 and CD79a, but negative for CD3e, CD5, and CD45Ro.9

Disappearance of gastric MALT-type lymphoma in patients infected with HCV has been reported after treatment with interferon-alpha-2b and ribavirin.13 In patients with splenic lymphoma with villous lymphocytes who are infected with HCV, treatment with interferon can lead to regression of the lymphoma.14 Rituximab is a monoclonal antibody targeting the CD20 epitope expressed on mature B cells. Most lymphomas of the B-cell lineage, including MALT-type lymphomas, express CD20. The efficacy of rituximab in B-cell lymphomas has been attributed to a combination of immune-mediated effects, including complement-mediated lysis, antibody-dependent cell-mediated cytotoxicity, and direct effects induced by CD20 ligation leading to apoptosis.15 Rituximab is active in patients with advanced MALT-type lymphoma, leading to objective responses in about 50%.15 Rituximab has been demonstrated as an effective option for the induction of remission in refractory HCV associated cryoglobulinemic vasculitis and the underlying lymphoproliferative disease.16, 17 Rituximab may be used safely for patients infected with HCV without leading to its reactivation.18 The next step in the treatment of this patient may be antiviral treatment to control the trigger factor for the development of lymphoma.14, 19

This is the first case report of a MALT-type B-NHL in the liver explant, regional node, and bone marrow of a patient with end-stage liver disease due to chronic HCV after LT. We treated his disease with rituximab without changing his immunosuppression regimen. Despite aggressive preoperative imaging to rule out neoplasia, unexpected lymphomas are possible, such as the one presented herein. The transplant physician should be prepared to respond, sometimes with innovative approaches. Care should be taken to monitor for infectious complications of in the post-LT setting during therapy, as outlined above.

Ancillary

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