Abstract
A primary hepatic marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT) is very rare. We found a solitary mass 27 mm in size in the left lobe of the liver of a 58-year-old Japanese man with a history of hepatitis-C infection. Based on the results of imaging studies, the tumor was diagnosed as a hepatocellular carcinoma (HCC). The left lobe of the liver was lobectomized and microscopic findings showed that the tumor was a hepatic MALT lymphoma, while immunohistochemistry showed it to be positive for CD20 and CD79a. In a fluorodeoxyglucose-positron emission tomography examination integrated with computed tomography scanning (FDG-PET CT) before surgery, the tumor was revealed to have a high standardized uptake value (SUV) for FDG. The patient received chemotherapy after surgery. To the best of our knowledge, 45 cases had been reported with a mean age for all patients of 61.4 years. The pathogenesis remains unclear, although half of the patients had a past history of chronic inflammatory liver disease. Surgical resection was performed in most cases and some patients received postoperative chemotherapy or radiotherapy. The clinicopathologic characteristics and management of this extremely rare disease are also discussed.
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1 Introduction
Primary hepatic malignant lymphomas are rare, with the most common histological type reported to be a diffuse large B cell lymphoma [1]. We treated an extremely rare case of mucosa-associated lymphoid tissue (MALT) type that originated in the liver [2]. To the best of our knowledge, this is the only report of primary hepatic MALT lymphoma that was examined with fluorodeoxyglucose-positron emission tomography integrated with CT scanning (FDG-PET CT). Herein, we compare our findings to those of previously reported cases with respect to clinical presentation, pathologic features, therapy, and clinical outcome.
2 Case report
A 58-year-old Japanese male was referred by his physician for an abdominal ultrasonography (US) examination in June 2007. The patient had a history of hepatitis C virus (HCV) infection discovered 15 years ago and was curatively treated with polyethylene glycol interferon (PEG-IFN)-α-2b and ribavirin in August 2005. Thereafter, HCV-RNA was negative in follow-up examinations and there was no evidence of hepatocellular carcinoma (HCC) in imaging studies. He also showed no abnormal physical findings, including lymphadenopathy and hepatosplenomegaly. Blood cell counts and serochemical findings including liver enzymes, concentrations of serum α-fetoprotein (AFP), fucosylated AFP (L3-AFP), protein induced by vitamin K absence or antagonist II (PIVKA-II), and soluble Interleukin 2 (s-IL2) receptor were within normal limits and anti-Helicobacter pyloric antibody was positive (Table 1). Our abdominal US examination showed a solitary and hypoechoic homogeneous mass with a maximum size of 27 mm in the second segment (S2) of the left lobe of the liver. There were no masses in the spleen, splenomegaly, lymphoadenopathy, ascites, or other abnormal findings.
The liver tumor was enhanced peripherally in the early phase and detected in the delayed phase by dynamic CT scanning (Fig. 1). Using FDG-PET CT imaging, the tumor was revealed by a high standardized uptake value (SUV) for FDG, while there was no other areas with high levels of SUV (Fig. 2). CT angiography (CTA) and CTA portography (CTAP) findings were similar to those of dynamic CT. Due to the results of the imaging studies and his past history of infection with HCV, we diagnosed the tumor as an HCC and performed a hepatic resection in July 2007.
Macroscopic findings of the resected specimen revealed that the tumor measured 25 × 20 mm and had no capsular formation. Microphotography showed heterogeneous lymphocytes forming reactive follicles. Plasma cells and giant cells proliferating in a medullary manner and clearly nodular pattern were observed in the tumor. Immunohistochemistry findings were positive for CD20 and CD79a, while they were negative for CD3, CD5, and CD10 (Fig. 3). As a result, we diagnosed the tumor as a primary hepatic marginal zone B cell lymphoma of MALT type. t(11;18)(q21;q21) that is most popular fusion signal in MALT lymphoma could not be proven by a two-color fluorescence in situ hybridization (FISH) assay after resection.
FDG-PET CT, and upper endoscope and colonscope examinations found no other MALT lymphoma in any other organ. The patient received three courses of chemotherapy (R-CHOP consisting of rituximab at 375 mg/m2 on day 1, cyclophosphamide at 750 mg/m2 on day 2, doxorubicin at 50 mg/m2 on day 2, vincristine at 1.4 mg/m2 on day 2, and prednisolone at 100 mg/kg of body weight on days 2–6) after resection and has not shown relapse up to the time of writing.
3 Discussion
Jaffe et al. [3] reported that hepatic malignant lymphomas comprised less than 1% of all malignant lymphomas, while hepatic MALT lymphomas are reported to occur in only 3% of cases of hepatic malignant lymphoma [1]. In the present patient, the levels of s-IL2 receptor were not high, and he had a past history of hepatitis with HCV and HCV-RNA that was eliminated by IFN therapy (PEG-IFN-α-2b), therefore, we treated the tumor as an HCC, based on the results of imaging studies. A retrospective analysis of the ultrasonographic findings at admission showed that the tumor appeared as a cystic lesion. Although there were no findings to indicate a malignant lymphoma in systemic screening, it is important to distinguish not only HCC but also hepatic malignant lymphoma by considering the criteria for each [1].
The etiology of hepatic malignant lymphomas, especially MALT lymphomas, has not been elucidated. Although a past report [4] noted a relationship between HCV and hepatic malignant lymphoma, there are no reports that concluded a relationship between HCV and MALT lymphoma. In an interesting study of gastric MALT lymphomas in patients infected with HCV, Tursi [5] reported the disappearance of a gastric MALT lymphoma after successful treatment with IFN-α-2b and ribavirin. However, although a relationship between HCV-infection and MALT lymphoma is speculated, the MALT lymphoma in the present patient occurred following successful treatment with IFN. Although, infection of Helicobacter pylori (H. pylori) have influence for gastric MALT lymphoma, we cannot deny the relationship between infection of H. pylori and the pathogenesis of primary hepatic MALT lymphoma. Iida [6] described that there was a strong association between the presence of H. pylori in the stomach and in the bile juice. More accumulation of cases will be needed for certain conclusion.
The molecular genetics underlying the pathogenesis of MALT lymphomas are only recently beginning to be understood. At least three recurrent chromosomal translocations, t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21) have been implicated in the pathogenesis and t(11;18)(q21;q21) is the most frequent translocation depending on the site of tumor origin; lung (38%), stomach (24%), conjunctiva (19%), and orbit (14%) [7]. In the present case, we have examined the t(11;18)(q21;q21) by FISH analysis and no fusion signal has been detected.
In regard to imaging studies, Perry et al. [8] reported that FDG-PET CT was useful for initial staging in patients with an extranodal MALT lymphoma, although the intensity of FDG uptake seemed to be lower in indolent non-Hodgkin’s lymphoma when compared with aggressive non-Hodgkin’s lymphoma. Since the sensitivity of FDG-PET CT depends on disease location and stage at initial diagnosis, the present primary hepatic MALT lymphoma was revealed with a high uptake of FDG. To the best of our knowledge, there are no other reports of patients with a hepatic MALT lymphoma that underwent an FDG-PET CT examination. Since the present case did not show high levels of tumor markers (AFP, L3-AFP, PIVKA-II), we considered other types of liver tumors beside an HCC. In these cases, FDG-PET CT may reveal the liver tumor as a primary hepatic MALT lymphoma, although a greater accumulation of case reports is needed.
A primary hepatic MALT lymphoma is an extremely rare disorder, with only 45 cases reported [6, 9–38] (Table 2), mainly elderly patients (mean age, 61.4 years old). In most patients, the liver tumor was identified incidentally by surgical resection or imaging studies during examinations for liver or other diseases. In 16 cases, pre-existing liver disease, including primary biliary cirrhosis and infectious liver diseases (e.g. hepatitis B virus, HCV, ascariasis), was present and chronic liver inflammation is assumed to be a factor in the development of MALT lymphomas. The present case had a past history of hepatitis with HCV and HCV-RNA that was eliminated by IFN therapy (PEG-IFN-α-2b), and we consider that the participation of HCV in the development of a hepatic MALT lymphoma was not denied by our findings.
Because of the small number of patients with a primary hepatic MALT lymphoma, therapeutic methods have not been established. Surgical resection was performed in most of the reported patients with good liver function. Recently, one case underwent radiofrequency ablation therapy (RFA) [26] and another radiotherapy alone [27], while other patients received chemotherapy or postoperative radiotherapy. Nasr [39] reported that therapeutic methods for primary hepatic non-Hodgkin lymphoma have not been established (e.g. surgery, radiation, chemotherapy, or combinations). Further, Raderer [40] found that rituximab was effective for 50% of cases with an advanced MALT lymphoma and could be used safety without a reactivation of HCV. We selected chemotherapy after surgical resection, because an extra-gastric MALT lymphoma, not only hepatic but also extra-hepatic, is reported to be relapse more frequently than a gastric MALT lymphoma (gastric MALT lymphoma vs. extra-gastric MALT lymphoma: 22.2 vs. 48.0%) [38]. To date, no recurrence of the MALT lymphoma has occurred after the surgical resection and chemotherapy treatments. Establishment of therapeutic methods for MALT lymphoma is expected, although additional accumulation of cases is needed to establish effective diagnostic methods (e.g. FDG-PET CT) and treatments.
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Doi, H., Horiike, N., Hiraoka, A. et al. Primary hepatic marginal zone B cell lymphoma of mucosa-associated lymphoid tissue type: case report and review of the literature. Int J Hematol 88, 418–423 (2008). https://doi.org/10.1007/s12185-008-0153-9
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DOI: https://doi.org/10.1007/s12185-008-0153-9