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Journal of Clinical Oncology, Vol 26, No 27 (September 20), 2008: pp. 4509-4511 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.6172
Splenic Marginal Zone Lymphoma: Transformation to Diffuse Large B-Cell Lymhoma With Isolated Cerebral ManifestationDepartments of Medicine, Hematology and Oncology, University Hospital of Muenster, Muenster, Germany
Institute of Neuropathology, University Hospital of Muenster, Muenster, Germany
Department of Pathology, University of Wuerzburg, Wuerzburg, Germany
Department of Nuclear Medicine, University Hospital of Muenster, Muenster, Germany
Departments of Medicine, Hematology, and Oncology, University Hospital of Muenster, Muenster, Germany
Department of Pathology, University of Wuerzburg, Wuerzburg, Germany
Departments of Medicine, Hematology, and Oncology, University Hospital of Muenster, Muenster, Germany We report on a 51-year-old male patient with the diagnosis of splenic marginal zone lymphoma (SMZL) stage IV A (Ann Arbor classification), complaining about increasing weakness, early satiety, and dry cough in the middle of 2003. The diagnosis involved typical characteristic features of SMZL with moderate splenomegaly (length: 19 cm), enlarged hilar lymph nodes, and bone marrow infiltration. Peripheral blood was also involved with mild anemia National Cancer Institute Common Toxicity Criteria grade 1 (Hb 11.2 g/dL), thrombocytopenia National Cancer Institute Common Toxicity Criteria grade 1 (92.000/µL), and normal values for leukocytes with relative lymphocytosis (52%) partly consisting of atypical lymphocytes characterized by villous pattern with irregular cytoplasmatic outline and prominent nucleous with clumped chromatin. Immunophenotyping or cytogenetic analysis of the peripheral lymphocytes was not available. Beta-2-microglobulin was slightly increased with 2487 ng/mL (normal range, 800-2400 ng/mL), whereas lactic dehydrogenase and serum albumin showed normal values with no paraproteinemia. A serological screen for hepatitis was negative. Furthermore, whole-body positron emission tomography/computed tomography (PET/CT) showed one enlarged right axillary lymph node (2.5 cm, specific uptake value [SUV] 11) and an additional tumor in the left lung (dorsobasal, 8 x 10 cm, SUV 13), both highly suspective for lymphoma. Gastroduodenoscopy and coloscopy revealed no further tumor manifestations. Histological analysis of right axillary lymph node showed typical marginal zone lymphoma pattern with inter- as well as perifollicular infiltration of atypical B lymphocytes, which were strongly positive for CD20 with coexpression of CD5. Additionally, these cells coexpressed immunoglobin D, whereas the Mib1/Ki67 index was below 10%, and Cyclin D1, as well as CD3, CD10, CD23, CD30, and LMP1, was negative. Molecular genetics of the rearrangement of the immunoglobulin heavy chain (IgH) –receptor showed monoclonal amplification. Bone marrow aspirate was performed and showed characteristic intrasinusoidal pattern of a SMZL involvement, and immunohistochemical staining revealed 40% lymphoid infiltration consisting of small cells with prominent nucleolus (Fig 1A), positive for CD20 and bcl-2 and a lambda light chain restriction. Due to the advanced stage of SMZL, chemoimmunotherapy was initiated with rituximab in combination with the cyclophosphamide, doxorubicin, vincristine, and prednisone regimen given every 3 weeks. Complete clinical and radiological remission was achieved after the application of seven cycles. Staging by whole-body PET/CT scan showed no remaining tumor manifestations and a normalized spleen size, accompanied by a persistent good physical state of the patient with blood values in normal ranges and no more evidence for infiltration in bone marrow histology. The treatment was followed by 12 additional applications of rituximab given monthly as maintenance. Follow-ups every 3 months by whole body PET/CT and blood samples showed no signs of relapse. In early 2007—3.5 years after the diagnosis of SMZL—the patient complained of increasing forgetfulness, intermittent disorientation, and weakness of the left arm. B symptoms were denied. The patient presented with a spastic left-sided hemiparesis and a right-sided ptosis on physical examination. Magnetic resonance image (MRI) scan of the head showed four intracerebral tumorous lesions with maximum lesion measuring 3.5 cm in the right basal ganglia, 1.6 cm in the left basal ganglia, and two lesions with 1 cm each in the right parietal lobe. Whole-body PET/CT revealed no further tumor beside the cerebral manifestation which had a strong [18F]fluorodeoxyglucose uptake with SUV 47.0 (liver reference, SUV 2.9) suggesting a high-malignant process (Fig 2). Spleen size was normal, and an evaluation of a bone marrow biopsy specimen including cytology and immunohistology was without signs of a neoplastic involvement. Furthermore, the blood, its differentiation as well as lactic dehydrogenase were normal. Histological investigation of the tumorous lesions after a stereotactic operation showed a lymphoid tumor consisting of medium- to large-sized blastic tumor cells with small, basophilic cytoplasm, and a light nucleus with small nucleoli (Fig 1B). Immunohistologically, CD20, CD45, CD 79a, and bcl-6 were expressed with a MIB1/Ki67 index of more than 80%. Further testing of tumor cells for CD3, CD5, CD10, CD21, CD30, CyclinD1, bcl-2, and LMP1 was negative, yielding to the diagnosis of monomorphic-centroblastic diffuse large B-cell lymphoma (DLBCL). To investigate the clonal relationship between the initial SMZL and the newly diagnosed DLBCL, the FR2A and FR3A region of the IgH gene were analyzed by polymerase chain reaction. The amplifications showed the same rearrangements in both tumors, confirming that they were clonally related (Fig 1). Consequently, the diagnosis of a transformation to DLBCL was made. Treatment was promptly initiated with high-dose methotrexate (4 mg/m2) and dexamethasone intravenously every two weeks. Unfortunately, progress of the central lesions was diagnosed after the fifth cycle. Radiation of the neurocranium followed with a total dose of 38 Gy and an 8 Gy boost accompanied by dexamethasone. Radiation was well tolerated by the patient with improving general condition and neurological symptoms during treatment. Subsequent MRI of the cranium showed a partial remission. Whole body [18F]fluorodeoxyglucose PET/CT showed no remaining vital reuptake of the cerebral lesions, indicating good metabolic response to radiation (Fig 2). The patient entered a rehabilitation program and follow-up visits including cerebral MRI every 6 to 8 weeks.
SMZL is a rare but distinctive and well-defined low-grade B-cell non-Hodgkin's lymphoma that has been recognized as a discrete entity by WHO classification.1,2 The positivity for CD5 in SMZL, as in our case, is documented in up to 20% of SMZL cases in the literature.3,4,5 Furthermore, peripheral lymph node or other organ involvement, as presented here, is rare but can occur in advanced stages of SMZL.4,6 In such cases, the pathologic characteristics are identical to those seen in splenic hilar nodes, though the degree of architectural effacement seems to be greater in peripheral nodes.7 Despite its low aggressiveness, histological transformation to high-grade lymphoma has been described in sporadic reports of SMZL.8,9 The frequency, characteristics, and underlying molecular abnormalities of this phenomenon have not been fully elucidated. We report the unique case of a patient with an isolated cerebral manifestation of a DLBCL due to blastic transformation of a low-grade SMZL diagnosed 3.5 years earlier. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. Harris NL, Jaffe ES, Diebold J, et al: The World Health Organization classification of hematological malignancies report of Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997. Mod Pathol 13:193-207, 2000[CrossRef][Medline] 2. Jaffe ES, Harris NL, Stein H, et al: Pathology and Genetics: Tumours of Haematopoietic and Lymphoid Tissue (World Health Organization Classification of Tumours). Lyon, France, IARC Press, pp 352, 2001 3. Berger F, Felman P, Thieblemont C, et al: Non-MALT marginal zone B-cell lymphomas: A description of clinical presentation and outcome in 124 patients. Blood 95:1950-1956, 2000 4. Thieblemont C, Felman P, Callet-Bauchu E, et al: Splenic marginal-zone lymphoma: A distinct clinical and pathological entity. Lancet Oncol 4:95-103, 2003[CrossRef][Medline] 5. Baseggio M, Petinataud F, Callet-Bauchu E, et al: CD5 positive splenic marginal zone lymphoma: Clinical, cytological, immunological, molecular, and cytogenetical features of a series of 35 cases. Haematologica 92:104, 2007 (abstr 0288) 6. Chacón JI, Mollejo M, Munoz E, et al: Splenic marginal zone lymphoma: Clinical characzteristics and prognostic factors in a series of 60 patients. Blood 100:1648-1654, 2002 7. Oscier D, Owen R, Johnson S: Splenic marginal zone lymphoma. Blood Rev 19:39-51, 2005[CrossRef][Medline] 8. Camacho FL, Mollejo M, Mateo MS, et al: Progression to large B-cell lymphoma in splenic marginal zone lymphoma: A description of a series of 12 cases. Am J Surg Pathol 25:1268-1276, 2001[CrossRef][Medline] 9. Parry-Jones N, Matutes E, Gruszka-Westwood AM, et al: Prognostic features of splenic lymphoma with villous lymphocytes: A report on 129 patients. Br J Haematol 120:759-764, 2003[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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