Chronic lymphocytic leukaemia presenting with central nervous system involvement

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1HediealOneology(1999) 16, 65--68 9 1999 StocktonPress All rights reserved 0736-0118/99 $12.00


Chronic lymphocytic leukaemia presenting with central nervous system involvement Lidia Poplawska-Szczyglowska 1, Jan Walewski 1, Barbara Pienkowska-Grela 2, Grzegorz Rymkiewicz3 and Olga Mioduszewska 3 1Department of Lymphoproliferative Diseases, 2Cytogenetic Laboratory, 3Department of Pathology, Centre of Oncology, Maria Sklodowska-Curie Memorial Institute, Warsaw, Poland

A 68-year-old man presented with hemiparesis, lymphocytosis, and cerebral lesions on MRI. Flow cytometry of blood, bone marrow and cerebrospinal fluid showed B-CLL lymphocytes with bright CD20 expression, slg, and absence of CD23 antigen. Fluorescence in situ hybridisation showed trisomy 12 in 50% of analysed peripheral mononuclear cells. The patient died 6 months after the diagnosis. Rapidly progressive and fatal course of the disease was consistent with known bad prognostic significance of CD20 bright expression and trisomy 12. Keywords: B-cell chronic lymphocytic leukaemia; central nervous system involvement; immunophenotype; trisomy 12; FISH

Introduction Chronic lymphocytic leukaemia (CLL) is the most common type of adult leukaemia with a characteristic indolent natural course. Central nervous system involvement in CLL is extremely rare. One of the most common cytogenetic abnormalities in B-cell CLL is trisomy 12.1-4 This aberration was found in about 13% of all CLL patients studied, and in about one third of those with clonal chromosomal abnormalities. 3 These abnormalities had been related to progressive course of leukaemia5-7 and poor survival. 6"8

Case report A 68-year-old man was admitted to neurological department in August 1997 with hemiparesis and motor aphasia. Generalised lymphadenopathy was found on Correspondence: Jan A Walewski, Head, Department of Lymphoproliferative Diseases-Section A, Centre of Oncology-Maria Sklodowska-Curie Memorial Institute, ul. W.K. Roentgena 5, 02-781 Warsaw, Poland. Fax: 48226440121 Received 9 December 1998; accepted 19 December 1998

physical examination. Histopathology of a peripheral lymph node was consistent with small lymphocytic lymphoma. A routine blood count showed Hb 130 g/1, WBC 26.2 • 109/1 and platelets 136 • 109/1, and 70% of lymphocytes on differential. Chest X-ray and abdominal ultrasound were normal. Bone marrow aspirate showed depressed haematopoiesis with small lymphocytes accounting for 90% of cells. Magnetic resonance imaging (MRI) of the brain (Figure la and b) showed multiple infiltrates in cerebral and cerebellar hemispheres as well as pons infiltration that could be leukaemic. In November 1997 the patient was admitted to our department. The major clinical abnormality was hemiparesis and motor aphasia. Cerebrospinal fluid (CSF) cytology was remarkable for high pleocytosis. The cells were CD20 positive on immunohistochemical examination. Flow cytometry of blood, marrow, and cerebrospinal fluid showed B-CLL lymphocytes with bright expression of CD20 molecule, surface immunoglobulin (sIg) expression, and lack of CD23 antigen. FMC7 was not tested for. Cytogenetic analysis of dividing ceils revealed trisomy of the chromosome 12. Fluorescence in situ hybridisation (FISH) showed

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Figure 3

Figure l a and b M R / o f the brain before chemotherapy'

multiplication of chromosome 12 (3-6 copies per cell) in 50% of analysed cells (Figure 2a and b). The patient was given individual chemotherapy tailored to his particular clinical condition with CCNU 60 mg p.o.d. 1, procarbazine 100mg p.o.d. 1-7, and dexamethasone 40mg i.v. every other day, dd. 1-20d., followed by dexamethasone 20mg i.v. every other day, dd. 21-45. Intrathecal methotrexate 15 mg was given on days 1, 5, 10, and 15. This therapy resulted in a substantial clinical improvement with almost complete resolution of hemiparesis and aphasia. At the time of the planned second chemotherapy cycle the patient presented with fever and lung infiltrations that were initially interpreted as pneumonia (Figure3). Despite i.v. antibiotics, lung lesions had been progressing. Repeat MRI scan of the brain showed no specific abnormalities, and a control Tc 91m SPECT (single photon emission computed tomography) scan was normal. Leukaemic cells were, however, detected in cerebrospinal fluid with flow

ChestX-ray showing hmg infiltrations

cytometry. The patient died of progressive lung infiltration 6 months after the first signs of disease.

Discussion Chronic lymphocytic leukemia is the most common type of adult leukemia. Its characteristic feature is indolent natural course and involvement of blood, bone marrow, peripheral lymph nodes and eventually, liver and spleen. Central nervous system involvement, as in the case described, is extremely rare. Only few cases of Richter's syndrome with cerebral involvement have been reported in patients with CLL. In all of them transformations into high grade non-Hodgkin's lymphoma was established. 9-11 A single case of nontransformed CLL was reported, in which cerebral infiltration was diagnosed by stereoscopic biopsy, whilst CSF was normal. 12 The incidence of meningeal CLL involvement has been reported in 1% of CLL patients. However, specific CSF abnormalities were not identified. 13"14 In the case reported here, we demonstrated B-CLL cells in the bone marrow, blood, and CSE We

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Figure 2 Fluorescence in situ hybridization with a-satellite probe for chromosome 12 to interphase nuclei: a cells with two and three copies of chromosome 12 (2 and 3 hybridisation signals respectively); b cell with two and four copies of chromosome 12 (2 and 4 hybridisation signals respectively)

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68 documented also atypical immunophenotype of leukaemic cells, bright expression of CD20, sIg, and lack of CD23 antigen; a pattern frequently related to the trisomy 12.15'16 Cytogenetic analysis by use of FISH confirmed this aberration. The disease course was progressive and fatal, as anticipated with coexistence of the bright CD20 expression 17 and trisomy of chromosome 12. 5-8

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8 Ju!iusson G, Immunological and cytogenetic studies improve prognosis prediction in chronic B-lymphocytic leukemia: A multivariate analysis of 24 variables. Cancer 1986; 58: 688-692. 9 Lane E Townsend R, Beckstead J, Corash L. Central nervous system involvement in a patient with chronic lymphocytic leukemia and non-Hodgkin's lymphoma (Richter's syndrom), with concordant cell surface immunoglobulin isotypic and immunophenotypic markers. A m J Clin Pathol 1988; 89: 254-259. 10 O'Neill B, Habermann T, Banks E O'Fallon J, Earle J. Primary central nervous system lymphoma as a variant of Richter's syndrome in two patients with chronic lymphocytic leukemia. Cancer 1989; 64: 1296-1300. 11 Bayliss K, Kueck B, Hanson C, Matthaeus W, Almagro U. Richter's syndrome presenting as primary central nervous system lymphoma. Transformation of an identical clone. A m J Clin Pathol 1990; 93: 117-123. 12 Majumdar G. Chronic lymphocytic leukaemia with cerebral infiltration. Leuk Lymphoma 1998; 28: 603-605. 13 Weizsaecker M, Kelmel H. Meningeal involvement in leukemias and malignant lymphomas of adults: incidence, course of disease, and treatment for prevention. Acta Neurol Scand 1979; 60: 363-370. 14 Cash J, Fehir K, Pollack M. Meningeal involvement in early stage chronic lymphocytic leukemia. Cancer 1987; 59: 656-659. 15 Finn Wet al. Karyotypes correlates with peripheral blood morphology and immunophenotype in chronic lymphocytic leukemia. A m J Clin Pathol 1996; 105: 458-467. 16 Matutes E et al. Trisomy 12 defines a group of CLL with atypical morphology: Correlation between cytogenetic, clinical and laboratory features in 544patients. Br J Haematol 1996; 92: 382-388. 17 Molica S, Dattil A, Levato D. Clinical relevance of the intensity of CD20 antigen in B-cell chronic lymphocytic leukemia. Blood 1996; 88(suppl): 239a.

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