|Ahead of print
Isolated Richter's transformation in central nervous system in a patient with refractory chronic lymphocytic leukemia
Tugba Cetintepe1, Fusun Gedız Kobak1, Sadi Bener2
1 Department of Hematology, Izmir Bozyaka Training and Research Hospital, University of Health Science, Izmir, Turkey
2 Department of Pathology, Ataturk Training and Research Hospital, Izmir Katip Celebi University, Izmir, Turkey
|Date of Submission||08-Jan-2019|
|Date of Decision||15-Jul-2019|
|Date of Acceptance||27-Jul-2019|
|Date of Web Publication||21-Jun-2021|
Department of Hematology, Izmir Bozyaka Training and Research Hospital, University of Health Science
Source of Support: None, Conflict of Interest: None
A 67-year-old woman was diagnosed with Chronic Lymphocytic Leukemia (CLL) and chemotherapy was started. Due to epileptic seizure and left hemiplegia that developed on the twenty first day of the treatment, cranial magnetic resonance imaging was performed and a markedly increased mass of a diameter of 5 cm in the right frontal lobe was seen. Diffuse large B-cell non-Hodgkin lymphoma was concluded at diagnostic brain biopsy. Repeated bone marrow biopsy implemented simultaneously, was reported as CLL. Based on the diagnosis of isolated Richter transformation in the CNS secondary to CLL, R-IDARAM (Rituximab, idarubicin, dexamethasone,cytrabine, methotrexate) treatment was initiated. The patient died on the eighteenth day of treatment due to neutropenic fever and septicemia caused by pulmonary infection.
Keywords: Central nervous system, chronic lymphocytic leukemia, Richter
|How to cite this URL:|
Cetintepe T, Kobak FG, Bener S. Isolated Richter's transformation in central nervous system in a patient with refractory chronic lymphocytic leukemia. Indian J Cancer [Epub ahead of print] [cited 2021 Jul 27]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=318899
| » Introduction|| |
Chronic Lymphocytic Leukemia (CLL) is the most common type of leukemia in adults and is characterized by increased monoclonal B-cell growth. Its prevalence is 3-4.5/100,000 and it is generally diagnosed between 65 and 74 years of age. It has a variable clinical course and many cases are asymptomatic. New onset fever, rapidly growing lymph nodes, weight loss, hypercalcemia, lactate dehydrogenase (LDH) elevation should imply the possibility of Richter's transformation. In such cases, positron emission tomography should be performed if possible, in order to determine histologically involved lymph nodes and to perform subsequent excisional biopsy. In this report, a case with isolated Richter's syndrome in nervous system (CNS) developed in a patient with refractory CLL is presented.
| » Case|| |
A 67-year-old woman patient presented to a health center with fatigue and abdominal distention. In the physical examination, splenomegaly and bilateral cervical pathological lymphadenopathy were determined and consequently she was referred to our hospital on September 2013. The following results were found at admission: white blood cell: 125 x 109/L (4-10 x109/L) , Lymphocyte: 85 x109/L (0.8-4 x109/L), Hemoglobin: 13.7 g/dL (12-16 g/dL), Platelet: 156 x 109/L (150-400 x109/L), LDH: 237 IU/L (125-220 IU/L). The mature lymphocytes comprised of 82% of the peripheral smear's total cell count and 70% of the bone marrow's total cell count. Immunohistochemical examination of lymphocytes revealed CD5, CD19, CD20, CD22, CD 25, CD38, CD45, HLA-DR, IgM, and Kappa chain and ZAP-70 positivity and CD5 and CD20 co-expression. The conventional cytogenetic analysis was performed from bone marrow sample and it revealed normal woman karyotype. The fluorescent in situ hybridization (FISH) was positive for 17p13 (TP53). Human immunodeficiency virus (HIV) serological test was negative. The patient was diagnosed with Binet Stage B and Rai stage II CLL, and a protocol of vincristine (2 mg/day, total, 1st day), Cyclophosphamide (1250 mg/day, total, 1st day) and Prednisolone (72 mg/day, 5 days) was initiated. Stability was achieved after 2 cycles of this treatment, then Fludarabine-Cyclophosphamide (F 25 mg/m2 for 3 days and C 250 mg/m2 for 3 days) combination was started. The patient was admitted to the hospital again due to epileptic seizure and left hemiplegia that developed on the 21st day of the treatment. Cranial magnetic resonance imaging was performed and a markedly increased mass of vasogenic edema at a diameter of 5 cm in the right frontal lobe was determined in T1 hypo- and T2 hyper-intense postcontrast examination [Figure 1]. Diffuse large B-cell non-Hodgkin lymphoma was concluded at diagnostic CNS biopsy. The lymphoma cells show large, round or oval nuclei [Figure 2] and [Figure 3], the Kİ-67 stain shows a proliferative rate of approximately 95% [Figure 4]. Repeated bone marrow biopsy implemented simultaneously was reported as CLL. Repeated TP53 mutation was negative, controlled LDH level was 257 IU/L, and the calcium level was normal. Based on the diagnosis of isolated Richter's transformation in the CNS secondary to CLL, R-IDARAM treatment was performed. The patient died on the 18th day of treatment due to neutropenic fever and septicemia caused by pulmonary infection.
|Figure 1: 5 cm vasogenic edematous mass located in right frontal lobe that was significant in T1 hypointense, T2 hyperintense, T2 hyperintense postcontrast images|
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|Figure 2: The lymphoma cells show large, round or oval nuclei, 1-3 small nucleoli|
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|Figure 4: The Ki-67 stain shows a proliferative rate of approximately 95%|
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| » Discussion|| |
Although extramedullary involvement of CLL is rare, it is most commonly seen in the skin and central nervous system. The number of cases with CLL-related CNS involvement identified in the literature is less than 100 and all belong to small case series. In case neurological symptoms develop in CLL patients under follow-up, neuroimaging and CSF analysis are requried to determine the cause while a comprehensive neurological examination is required for infectious and inflammatory conditions. Neurological symptoms that emerged in 172 of 4174 CLL patients, were evaluated in a study carried out between 1999 and 2014, and CNS involvement due to CLL was determined in 18 patients, while isolated Richter's syndrome in 15 patients, infection in 40 patients, autoimmune and inflammatory events in 28 patients, and other brain malignancies in 8 patients, and neurological diseases unrelated to CLL in 63 patients.
Richter's syndrome (RS) was first described by Maurice Richter in 1928 as a transformation of CLL patients into aggressive course large cell lymphoma. It was reported that diffuse large cell lymphoma (DLBCL) develops most frequently and Hodgkin Lymphoma rarely as a result of Richter's transformation. Activated B-cell having a more aggressive course is a subtype of DLBCL with highest transformation according to the Hans Choi algorithm. The incidence of Richter development in the course of CLL is known to be approximately 2-9%; however, isolated CNS Richter's syndrome reported in the literature are very few and its incidence is 0.3%. Parenchymal or leptomeningeal localization of isolated CNS Richter's syndrome may be observed at equal frequency in the brain.
In the patients followed-up with CLL, risk factors determined in terms of RS development are presence of advanced and bulky disease, CDKN2A deletion, TP53 mutation, C-myc activation, trisomy 12, NOTCH1 mutation, CD38 and ZAP-70 expressions, and non-mutated IGVH. In addition, combination of purine analogs and alkylating agents used in the treatment of CLL can increase RS development. In the literature however, it was observed that, in the early stage CLL patients having no risk factors, the transformation could also develop at considerable levels.,,,, In our case, CD38, ZAP-70 positivity, and 17p13 deletion were present, and she had a refractory disease.
There is no standard starting regime for RS developing in CNS, since there is limited literature on the subject. The agents to be selected in the treatment should be aimed to overcome CNS blood-brain barrier. The most important prognostic factor for RS is the clonal relationship between CLL and aggressive lymphoma clones, and in this regard, those unrelated to RS exhibit a better prognosis. Lymphoma clone shows a relation with the original CLL clone only in two-third of the patients with Richter's syndrome.
Institutional Review Board approval
This case report has received an approval from the institutional review board (IRB: 1108).
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]