Primary Hepatic Low-Grade B-Cell Lymphoma of the Mucosa-Associated Lymphoid Tissue Type: A Case Report and Review of the Literature

Primary hepatic lymphoma, mostly diffuse large B-cell lymphoma, is a rare disease. We describe an extremely rare case of low-grade B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type occurring in the liver. A 61-year-old man with a history of hepatitis A presented with early gastric cancer and a liver mass. Needle biopsy of the liver tumor suggested low-grade B-cell lymphoma by histology and polymerase chain reaction of the immunoglobulin heavy chain gene. The tumor (3.4 x 2.8 x 2.4 cm) was completely resected from the anterior segment of the right lobe of the liver. Atypical lymphoid cells of small to intermediate size proliferated in the tumor, and lymphoepithelial lesions were recognized. Immunohistochemically, lymphoma cells were positive for CD20 and negative for CD5, CD10, and cyclin D1. Staging procedures showed no lymphoma lesion other than the liver tumor. Thus, the patient was diagnosed with low-grade hepatic marginal zone B-cell lymphoma of the MALT type. The patient has been followed up for 1.5 years since surgical resection with no recurrence. The clinicopathologic characteristics and management of this rare disease are discussed.     

Transition of thyroid autoantibodies by rituximab treatment for thyroid MALT lymphoma

Thyroid MALT lymphoma is an extremely rare malignancy believed to arise against a background of Hashimoto's thyroiditis. Rituximab is a monoclonal antibody directed against B cell specific antigen CD20. Recently, there have been reports that rituximab is effective for autoimmune thyroid diseases such as Graves' disease as well as for treatment of B cell malignant lymphoma. We present the changes in thyroid autoantibodies in Hashimoto's thyroiditis after rituximab administration for 3 cases of thyroid MALT lymphoma. Case 1 had been taking levothyroxine and was diagnosed with thyroid MALT lymphoma. She was treated with rituximab monotherapy, and her thyroid enlargement improved. Anti-thyroid peroxidase antibody (TPOAb) turned negative after rituximab monotherapy, and TSH levels decreased with the same levothyroxine dosage. Case 2 was diagnosed with recurrent thyroid MALT lymphoma after chemotherapy (CHOP). He suffered from leg sensory disturbance because of vincristine sulfate. The patient was treated with rituximab. TPOAb decreased, but did not turn negative. TSH levels were within normal range during the disease course, but TSH levels were low in comparison with before rituximab therapy. Case 3 was diagnosed with thyroid MALT lymphoma after radiation therapy on the neck for laryngeal cancer. Thyroid enlargement improved after rituximab monotherapy, and thyroid autoantibody levels decreased. TSH increased transiently after radiation therapy, but TSH decreased gradually without levothyroxine after rituximab monotherapy. We report 3 cases in which thyroid autoantibody levels in Hashimoto's thyroiditis decreased after rituximab monotherapy for thyroid MALT lymphoma, but it is controversial whether thyroid dysfunction due to Hashimoto's thyroiditis is restored.     

CD20-negative DLBCL transformation after rituximab treatment in follicular lymphoma: a new case report and review of the literature

Rituximab is a monoclonal antibody against the CD20 molecule which is used to treat B-cell lymphomas. In 60% of low-grade B lymphomas in which rituximab was effective at first, there was no clinical response in a second treatment and a few cases of follicular lymphomas (FL) with transformation to diffuse large B-cell lymphoma (DLBCL) have been reported. We describe a new case and hypothesize about the mechanisms of transformation: a 52-year-old man, in follow-up during 8 years for FL, who after rituximab treatment and complete remission of FL showed progressive disease involving the liver and duodenal mucosa. Immunohistochemical and molecular studies were performed on paraffin-embedded tissue samples of lymph nodes, the small intestine, and liver tumors. After rituximab treatment, biopsies of a liver lesion and the small bowel both showed CD20-negative large B-cell lymphoma. Molecular study of the initial and relapse specimens shows a CDR2 IgH rearrangement with the same height and t14;18 (MBR). The rapid relapse with the same rearrangement of IgH seems to support the interpretation that the change of grade of lymphoma and loss of CD20 expression occurred before rituximab treatment. The existence of a varying proportion of a CD20-negative cell population in every B-cell lymphoma which does not respond to rituximab should therefore be considered. The reduction of CD20 expression could be a resistance mechanism to rituximab retreatment in DLBCL as a consequence of the progression of low-grade B-cell non-Hodgkin's lymphoma (B-NHL). It is necessary to perform new biopsies to evaluate CD20 expression in relapse or the progression of B-cell lymphoma after rituximab treatment.     

Stable remission after administration of rituximab in a patient with primary hepatic marginal zone B-cell lymphoma

We describe a case of primary hepatic marginal zone B-cell lymphoma in a 36-year-old Caucasian male with a history of chronic hepatitis B infection. Immunohistochemically, extensive infiltration by a CD20-positive, CD5- negative and CD10-negative lymphoid cell population displaying a follicular arrangement was detected. Molecular analysis of immunoglobulin heavy chain gene rearrangements confirmed the clonal expansion of lymphoma cells. Fourteen months after surgical treatment, the tumour recurred in close proximity to the liver hilus, hampering further surgery. Therefore, we implemented a therapy using the monoclonal anti-CD20-antibody rituximab in a dose of 375 mg/m(2), administered four times once a week. Six, 10, 18, and 26 months later the recurrent lymphoma could no longer be detected as shown by abdominal ultrasonography and CT. This case report demonstrates the difficulties of treating this extremely rare liver disease and shows its response to rituximab therapy.     

Mucosa-associated lymphoid tissue lymphoma of the duodenum: report of a case resistant to Helicobacter pylori eradication

We present a case of mucosa-associated lymphoid tissue (MALT) lymphoma of the duodenum treated with surgical resection. A 64-year-old woman underwent upper gastrointestinal endoscopy because of melena. Examinations revealed an ulcer-forming lesion at the second portion of the duodenum that was diagnosed histologically as low-grade MALT lymphoma. We attempted Helicobacter pylori eradication therapy, although all the tests revealed negative results for its infection. No sign of remission was observed and we performed surgical resection. The patient has shown no sign of recurrence at present, 39 months after the operation. Duodenal MALT lymphoma is a rare entity. Only 17 cases have been reported in the English literature. We summarized the characteristics of the disease and tried to figure out differences in comparison with those in the stomach, including the involvement of the Helicobacter pylori infection.     

CD5+ Epstein-Barr virus-positive intravascular large B-cell lymphoma in the uterus co-existing with huge myoma

A 42-year-old female underwent hysterectomy because of a huge uterine mass. Histologically, she was diagnosed as having intravascular lymphoma co-existing with myoma uteri. Lymphoma cells were large in size and were positive for CD5, CD20, CD45, CD79a, lambda light chain, and EBV but were negative for CD3 and cyclin D1. No other organs except for the adjoining bilateral ovaries seemed to be affected by the lymphoma cells. She received the combination chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisolone) together with rituximab and has been well without definite disease progression. So far, this is the first case of CD5+ EBV+ intravascular large B-cell lymphoma (CD5+ EBV+ IVLBL) in the uterus of a patient who was incidentally diagnosed and successfully treated.     

Disappearance of CD 20 after treatment with rituximab of mantle cell lymphoma

A 60-year-old female visited our hospital in May 2001 because of systemic lymphadenopathy. Her white blood cell count was 25,510/microliters with 93% of lymphocytes. Bone marrow aspiration revealed that 86% of nucleated cells were lymphocytes. Lymphocytes in the peripheral blood and bone marrow were positive for CD 5, 19, 20, and sIgx and negative for CD 23. FISH analysis detected the chimeric bcl 1/IgH fusion gene. Immunohistochemistry of a biopsied lymph node revealed that lymphoma cells were positive for cyclin D 1. Mantle cell lymphoma (MCL) was diagnosed at clinical stage IV A. Although a partial remission was obtained after CHOP plus rituximab therapy, the patient's disease recurred in March 2002 and she died in spite of salvage therapy including rituximab. Immunohistochemistry of the bone marrow cells after salvage rituximab therapy revealed that lymphoma cells were still positive for CD 5 and cyclin D 1, but negative for CD 20 and sIgx. We could not exactly determine how frequently CD 20 expression becomes negative in B-cell lymphomas after treatment with rituximab. We found only two reported cases that suggested rituximab down-regulated CD 20 expression in MCL. We herein describe a case of MCL with very notable clinical features.     

Lymphocytic gastritis in Helicobacter pylori-positive gastric MALT lymphoma--report of two cases.

Both lymphocytic gastritis and gastric mucosa associated lymphoid tissue (MALT) lymphoma are associated with Helicobacter pylori (H. pylori) infection. However, this association has not been fully elucidated. We report two cases of lymphocytic gastritis in 57-year-old male and 47-year-old female patients which were diagnosed after the H. pylori eradication to treat gastric MALT lymphoma. MALT lymphoma was successfully treated in case 1, but residual MALT lymphoma remained in case 2. During the follow-up endoscopic examinations, several elevated erosions in case 1 and irregular mucosal atrophy in case 2 were newly detected. Biopsy specimens showed marked infiltration of lymphocytes in the surface epithelium (56.6+/-15.9 intraepithelial lymphocytes (IELs)/100 epithelial cells in case 1 and 40.5+/-9.3 IELs/100 epithelial cells in case 2), which were exclusively CD8-positive T lymphocytes. These findings suggest that H. pylori infection may cause a monoclonal proliferation of B lymphocytes, leading to MALT lymphoma as well as polyclonal proliferation of T lymphocytes which subsequently infiltrated into the surface epithelium as a host immune reaction, resulting in lymphocytic gastritis.     

Aggressive B-cell lymphoma with dual surface immunoglobulin light-chain expression

Dual surface immunoglobulin light-chain expression in B-cell malignant neoplasm is a rare event, and has been predominantly reported in chronic lymphocytic leukemia. Herein, we report a case of aggressive B-cell lymphoma with kappa/lambda-dual surface immunoglobulin light-chain expression of a 69-year-old woman. The lymphoma cells were positive for CD5, CD19, CD20, HLA-DR, Ig kappa and Ig lambda. Southern blot analysis confirmed rearranged bands for both light chains with a monoclonal heavy chain rearrangement. She was treated with a combination of rituximab and CHOP regimen, but died of the progressive disease. To our knowledge, this is the first case of aggressive B-cell lymphoma showing dual kappa/lambda expression; the possible mechanisms of abnormal light chain expression are discussed.     

Monoclonal gammopathy after low-grade MALT lymphoma: evidence for a second neoplasm

We report the case of a patient with lymphoma of the salivary gland, at first diagnosed as lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) but later found to infiltrate the bone marrow. At diagnosis, the patient had a polyclonal increase of gamma-globulins. Five years after initial diagnosis, the patient presented with monoclonal gammopathy and infiltration of the bone marrow with neoplastic cells. Initially, the patient had received chemotherapy with different protocols (including etoposide, cyclophosphamide, fludarabin, methotrexate, and vincristine), none of which induced a lasting response. Therapy with rituximab (chimeric anti-CD20 monoclonal antibody) finally led to partial remission. Eighteen months after rituximab, progressive lymphoma in the abdomen and a monoclonal gammopathy developed. The bone marrow showed infiltration by lymphoplasmacytoid cells (monoclonal expression of the light-chain type lambda, positive for CD20, heterogeneous expression of CD45). The patient achieved another short clinical response with 4 cycles of the CHOP-protocol, but soon the lymphoma progressed again. Five years and 8 months after the initial diagnosis, the patient died from septicemia and progressive lymphoma. By polymerase chain reaction (PCR) for the IgH gene it was shown that lymphoma cells were initially oligoclonal in the salivary gland and, later, biclonal in the bone marrow. Sequencing of two bands of apparently same length showed that these manifestations of lymphoma were not identical. Taken together, our data show that the initial low-grade oligoclonal MALT lymphoma was no longer present and a more aggressive biclonal lymphoma with plasmacytoid differentiation had developed. The new lymphoma was clonally distinct and produced high amounts of monoclonal IgG lambda by immunoelectrophoresis. The relationship of the second lymphoma to the initial MALT lymphoma is discussed.     

Occurrence of lymphoplasmacytic lymphoma 6?years after amelioration of primary cold agglutinin disease by rituximab therapy

Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia, classified into primary and secondary types. Secondary CAD accompanies infection or malignant disease, most often lymphoma, whereas primary CAD frequently represents a lymphoproliferative bone marrow disorder characterized by clonal expansion of B cells. Here, I describe a case of lymphoplasmacytic lymphoma (LPL) developed 6?years after amelioration of primary CAD by rituximab monotherapy. A 54-year-old Japanese woman was diagnosed with primary CAD characterized by a small fraction of B lymphocytes and kappa laterality in the peripheral blood. M-protein was not detected by immuno-electrophoresis. The patient achieved remission following two courses of rituximab monotherapy. The level of IgM was specifically decreased, although levels of IgG and IgA were slightly increased. Six years after rituximab monotherapy, she developed LPL without CAD recurrence. Flow cytometry performed on bone marrow specimens revealed that lymphoma cells were positive for CD19 and CD20 with kappa laterality. The lymphoma may have transformed from clonal B lymphocytes at presentation of CAD. Rituximab monotherapy induced remission of CAD by specific decrease of IgM level, but did not eliminate the clonal B lymphocytes that may have progressed to LPL. This experience may provide clues toward the understanding of the pathophysiology of primary CAD with clonal lymphoproliferative disease of the bone marrow.     

Gastric mucosa-associated lymphoid tissue lymphoma and Helicobacter pylori: scratch and win

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is generally associated with Helicobacter pylori infection and, in the great majority of patients, regresses after eradication. H. pylori-negative MALT lymphoma occurs in a small minority of cases in which treatment is based on surgery or chemoradiotherapy. In the search for H. pylori based on histology and the C13 urea breath test, this report describes a case with a series of false-negative results, thus confirming the possibility of a lower detectability of H. pylori in patients with MALT gastric lymphoma and supporting the use of additional tests in evaluating such pathology, including polymerase chain reaction. Additionally, treatment with CD20 monoclonal antibody (rituximab) is suggested as an alternative to surgery or treatment with chemotherapy or radiotherapy in patients with truly H. pylori-negative gastric MALT lymphoma.     

MALT lymphoma of the small bowel with protein-losing enteropathy

Mucosa-associated lymphoid tissue (MALT) lymphoma usually arises from chronic inflammation. We herein report a case of small intestinal MALT lymphoma with protein-losing enteropathy (PLE). A 73-year-old woman presented with lower leg edema and severe hypoalbuminemia. She had a medical history of pylorus-preserving pancreaticoduodenectomy with Billroth II reconstruction. Oral and anal route double-balloon enteroscopies revealed irregular nodular mucosal lesions with erosion extending from the jejunum to terminal ileum. Histopathological evaluation of the biopsied mucosa showed proliferation of small-to-medium-sized lambda light chain-restricted B cells. Plasmacytic differentiation and lymphoepithelial lesions were present, leading to the diagnosis of MALT lymphoma. Tc-99m albumin scintigraphy indicated tracer exudation in the small bowel, suggesting the presence of PLE. Combination immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) regimen improved both MALT lymphoma and PLE, whereas rituximab monotherapy was not successful. This case is considered to be common type of MALT lymphoma at an uncommon site and is distinct from immunoproliferative small intestinal disease (IPSID). To our knowledge, this is the first case of non-IPSID-type small intestinal MALT lymphoma complicated by PLE. Gastrointestinal reconstruction may be responsible for underlying chronic inflammation via small intestinal bacterial overgrowth.     

原发性肺黏膜相关淋巴组织淋巴瘤4例临床病例分析

目的 总结原发性肺黏膜相关淋巴组织(MALT)淋巴瘤的临床表现、影像学特点、诊断手段、治疗方法及预后,提高临床诊治水平.方法 回顾性分析4例经病理确诊的原发性肺MALT淋巴瘤的临床资料并随诊分析预后.结果 4例原发性肺MALT淋巴瘤患者均为老年女性,为原发性肺非霍奇金淋巴瘤的最常见类型.其中3例为查体发现,1例因咳嗽、咳痰和痰中带血就诊.发病时间为7个月至5年.肺部体征无特异性.血炎症指标和肿瘤相关指标多为正常.影像学以肿块影和结节为主要表现.患者肺通气和弥散功能正常.经胸腔镜、CT引导下肺穿刺、开胸手术获取病变组织而确诊.病理表现为弥漫浸润生长的小淋巴细胞,可见淋巴上皮增生.治疗主要是化疗和手术.随访1～8.8年,1例随访4.5年时可疑复发,其余3例均病情稳定.结论 肺原发性MALT淋巴瘤为少见病,好发于老年女性,起病隐匿,临床表现不典型.诊断须靠有经验的病理专家作出.治疗尚无指南,无症状者可采取“观察等待”策略,待肿瘤进展或出现症状时,首选苯丁酸氮芥化疗,联合利妥昔单抗与否均可.预后良好,但复发率高.     

Primary diffuse large B-cell lymphoma of the bone marrow complicated with autoimmune hemolytic anemia and erythroid hypoplasia

A 75-year-old woman was admitted for general fatigue. Diagnostic investigations showed no lymphadenopathy or hepatosplenomegaly. Laboratory examinations revealed severe anemia and an undetectable level of haptoglobin in the peripheral blood. A direct Coombs test was positive. Bone marrow examination showed abnormal, large, CD20-positive lymphocytes and erythroid hypoplasia. Accordingly, a diagnosis of primary diffuse large B-cell lymphoma (DLBCL) of the bone marrow with autoimmune hemolytic anemia (AIHA) and erythroid hypoplasia was made. The patient was treated with prednisolone and 3 courses of rituximab, followed by 6 courses of R-CHOP. AIHA and erythroid hypoplasia subsided after prednisolone and 3 courses of rituximab. Treatment with 6 courses of R-CHOP resulted in complete remission. Isolated bone marrow disease as a presenting feature of DLBCL is very rare. Although malignant lymphomas are often associated with immunologic disorders, this is the first report of diffuse large B-cell lymphoma with isolated bone marrow disease and simultaneous autoimmune hemolytic anemia and erythroid hypoplasia. This case provides valuable information concerning the pathophysiology of an immunologic anomaly with malignant lymphoma.     

Diagnosis of a gastric mucosa-associated lymphoid tissue lymphoma by endoscopic ultrasonography-guided biopsies in a patient with a parotid gland localization

We report the case of a 32-year-old man with a low-grade mucosa-associated lymphoid tissue (MALT) lymphoma of the parotid gland associated with Sj?gren syndrome. He underwent an upper endoscopy as part of the screening of a gastric localization which showed a diffuse non-specific gastritis. However, endoscopic ultrasonography (EUS) evidenced a focal wall thickening of the vertical portion of the smaller curvature. EUS-guided biopsies of this area disclosed a MALT lymphoma, whereas biopsies under endoscopy concluded to mild chronic gastritis. The search for Helicobacter pylori infection remained negative. Four months after treatment with anti-CD20 antibodies, EUS showed a diminution of the abnormal thickening of the second layer. Regression was confirmed histologically on new EUS-guided biopsies. MALT lymphoma is usually considered a localized disease; however, dissemination is probably more frequent than initially believed. Our case reflects the importance of a systematic screening for a gastric localization in patients with MALT lymphoma of the salivary glands. In this situation, association to autoimmune disease such as Sj?gren syndrome is more likely to explain the gastric location than infection with H. pylori. Endoscopic ultrasonography has a major impact for the staging of gastric MALT lymphoma, but may also help diagnose focal infiltration by the disease.     

Hepatic mucosa-associated lymphoid tissue lymphoma and hepatocellular carcinoma in a patient with hepatitis B virus infection

Primary hepatic mucosa-associated lymphoid tissue (MALT) lymphoma is an extremely rare disease. A 65-year-old female patient with chronic hepatitis B presented with multiple solid masses in segment (S) 4, S5, and S6 of the liver. The nodule in S5 was diagnosed preoperatively as hepatocellular carcinoma by computed tomography, magnetic resonance imaging, and angiography. The nodule in S4 was initially interpreted as lymphoid follicles by needle biopsy. Segmentectomy of S5 and partial resection of S6 were performed. Microscopic examination of the S5 nodule revealed moderately differentiated hepatocellular carcinoma. The nodule from S6 showed nodular proliferation of atypical intermediate to medium-sized lymphoid cells in the portal area and lymph epithelial lesions of bile ducts. The atypical lymphoid cells were positive for LCA, L-26 and bcl-2 and negative for UCHL-1. These features were consistent with the diagnosis of MALT lymphoma. This is the first case report of synchronous hepatic MALT lymphoma and hepatocellular carcinoma associated with chronic hepatitis B.     

Acute Liver Injury Due to T-cell Infiltration into the Liver as an Initial Clinical Finding of Adult T-cell Leukemia/Lymphoma

Acute liver injury (ALI) has been rarely reported as a clinical finding of adult T-cell leukemia/lymphoma (ATLL). A 74-year-old Japanese female patient who was histologically diagnosed as having autoimmune hepatitis (AIH) one year earlier, showed elevations in her aminotransferase and total bilirubin levels, and this was considered to be an exacerbation of AIH. Liver biopsy revealed interface hepatitis. Because atypical lymphocytes and human T-cell leukemia virus 1 immunoglobulin G antibody were positive, the patient was diagnosed to have ATLL. The biopsy revealed CD4+ and CD8+, but not CD20+ lymphocytes. Thus, the ALI in the patient was due to T-cell infiltration into the liver, and not due to an exacerbation of AIH.     

Autoimmune hepatitis associated with the antiphospholipid syndrome

The antiphospholipid syndrome has rarely been described in patients with autoimmune hepatitis. Two cases with type I autoimmune hepatitis and antiphospholipid syndrome are presented. The first case is that of a 53-year-old Caucasian female with a history of arterial thrombosis and fetal loss who was submitted to clinical and laboratory testing due to persistent transaminasaemia and was found to have autoimmune hepatitis. Antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant) were positive. The second case is that of a 31-year-old Caucasian woman with a history of autoimmune hepatitis who was submitted to laboratory testing due to a second-trimester fetal death, revealing an increased activated partial thromboplastin time and positive antiphospholipid antibodies. In conclusion, secondary antiphospholipid syndrome may accompany autoimmune hepatitis.     

Clinical study of 31 patients with primary gastric mucosa-associated lymphoid tissue lymphoma

BACKGROUND: The purpose of the present paper was to investigate the clinical, endoscopic and histological features of 31 patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma to enable correct, early stage diagnosis. METHODS: A retrospective study was undertaken of 31 patients with gastric MALT lymphoma. The cases were examined immunohistologically with anti-CD(20CY) and CD(45RO) antibodies for further diagnosis. Helicobacter pylori infection was also detected with modified Giemsa staining. RESULTS: Patients with MALT lymphoma were aged between 22 and 73 years (mean, 45.0 years), and the male:female ratio was 11:20. The patients presented with non-specific symptoms, but chronic epigastric pain was the common symptom in a large proportion of the cases. The gastric smaller curvature was involved in 83.9% of cases (26/31) and in 13/31 cases (41.9%) it was confined the antrum. Under endoscopy, large and deep ulcers were similar to cancers in the majority of patients. Only 29.0% of patients were diagnosed by endoscopy on first examination. CD(20CY) were expressed in all cases and CD(45RO) expressed in only one case among 10 cases of indefinite diagnosis. Helicobacter pylori infection was found in 87.1% of patients. CONCLUSIONS: These findings suggest that primary gastric MALT lymphoma has unique clinical, endoscopic and histological features. The diagnosis for primary gastric MALT lymphoma was delayed not only due to the non-specific symptoms but also due to lack of attention to its features. Endoscopy and submucosal multiple biopsy were the principal diagnostic tools in patients with gastric MALT lymphoma. CD(20CY) and CD(45RO) immunological staining are recommended, especially for patients with indefinite diagnosis of gastric MALT lymphoma.