Pitfalls in mononucleotide microsatellite repeats instability assessing (MSI) in the patients with B-cell lymphomas.

Analysis of microsatellite instability (MSI) is a routine study in the diagnostics of solid malignancies. The standard for determining MSI is a pentaplex PCR panel of mononucleotide repeats: NR-21, NR-24, NR-27, BAT-25, BAT-26. The presence of MSI is established based on differences in the length of markers in the tumor tissue and in the control, but due to the quasimonomorphic nature of standard mononucleotide loci the use of a control sample is not necessary in the diagnosis of MSI-positive solid tumors. The significance of the MSI phenomenon in oncohematology has not been established. This paper presents the results of a study of MSI in B-cell lymphomas: follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBL). We have shown that aberrations of mononucleotide markers occur in these diseases, but the nature of the changes does not correspond to the classical MSI in solid neoplasms. This fact requires further study of the pathogenesis of such genetic disorders. Due to the possibility of ambiguous interpretation of the results of the MSI study for previously uncharacterized diseases, strict compliance with the methodology of parallel analysis of the tumor tissue and the control sample is mandatory.

Gray-zone lymphoma. Examples of rare clinical manifestation.

Mediastinal gray-zone lymphoma (MGZL, lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma) was declared as a separate entity in WHO classification of Tumors of Haematopoetic and Lymphoid Tissues in 2008 and 2017 years. Despite of similar pathomorphological characteristics between primary mediastinal B-cell lymphoma and Hodgkin lymphoma, clinical features and optimal therapeutic approach to MGZL are not clearly defined. Usually MGZL manifests with mediastinal lymphadenopathy, although extranodal lesions often occur (grey-zone lymphoma, GZL). Patients with MGZL have unfavorable prognosis, taking into account high rate of relapse. This article describes two cases of MGZL. First case manifested by arrhythmias due to primary heart involvement. In spite of cardiac failure antracycline-containing chemotherapy (6 courses of R-DA-EPOCH) it allowed to achieve a complete remission and resolving of arrhythmias. Second case was represented by metachronous tumors: primary mediastinal B-cell lymphoma at the time of disease onset and classical Hodgkin lymphoma, NS II, diagnosed after disease progression. Thus, we demonstrated two examples of MGZL that differ by clinical manifestation, response to chemotherapy, which emphasizes an importance of pathogenesis studying, and using of new therapeutic approaches.

[CNS involvement and the feasibility of intratecal chemotherapy administration in patients with a nodal form of diffuse large B-cell lymphoma not otherwise specified. Data of prospective study].

Aim of the issue was to determine indications for intratecal chemotherapy drugs administration to prevent relapse of diffuse large B-cell lymphoma (DLBCL) with central nervous system (CNS) involvement. MATERIALS AND METHODS: Since January 2009 to December 2018 102 patients with primary nodal DLBCL over 18 years old were treated in the National Research Center for Hematology, Moscow, Russian Federation. Diagnosis were established in all cases according to histological and immunohistochemical studies which made it possible to exclude the transformation of mature B-cell lymphoma into DLBCL. RESULTS: Isolated leptomeningeal involvement of CNS in the debut of the disease was detected in 1 (0.98%) out of 102 patients with DLBCL. Focal brain tissue involvement was not detected in any patient. More than half of the patients (54%) had a high risk of disease recurrence or progression with CNS involvement: in 8 (7.8%) patients had kidney/adrenal involvement, in the same proportion - bone marrow involvement, paranasal sinuses involvement - in 5 (4.9 %), epidural space - in 7 (6.9%) and breast - in 5 (4.9%) of patients. In 82 (80%) patients, a non-GCB (postgerminal differentiation of B-cell analog) molecular subtype of DLBCL was determined. CONCLUSION: The introduction of chemotherapy drugs into the spinal canal is recommended in isolated cases of leptomeningeal involvement of CNS at the time of DLBCL onset and is carried out according to standard recommendations. Prevention of relapse with involvement of central nervous system using intratecal chemotherapy in patients with nodal form of DLBCL is not indicated due to the absence of cases with disease progression or recurrence into CNS when patients were treated with R-m-NHL-BFM-90, R-DA-EPOCH and R-CHOP protocol.

[The role of translocations involving c-MYC/8q24, BCL2/18q21 and/or BCL6/3q27 genes in patients with follicular lymphoma. Retrospective analysis of single - centre data].

Aim of the issue was to compare clinical characteristics and treatment results of patients with follicular lymphoma (FL) with translocations involving loci of c-MYC/8q24, BCL2/18q21 and/or BCL6/3q27 genes and patients with high - grade B-cell lymphoma [High - grade B-cell lymphoma (HGBL), double - hit (DH)]. Materials and methods. Since 2004 to 2017 years in National Research Center for Hematology 12 patients with high - grade B-cell lymphoma double - hit (HGBL DH) and 6 FL patients with translocations involving c-MYC and BCL2 and/or BCL6 had been treated. We performed a comparative analysis of clinical characterisctics in both groups. As primary endpoints was assessed frequency of complete remission (CR) or progressive disease (PD); as secondary endpoints - overall (OS) and event - free survival (EFS). Results. 5 patients with HGBL DH had c-MYC/BCL6, 7 - c-MYC/BCL2 rearrangements; 2 patients with FL had c-MYC/BCL2, 3 - c-MYC/BCL6, 1 - c-MYC/BCL2/BCL6 rearrangements. FL was represented by grade 3A in 2, grade 3B - in 4 cases, 3 of them had large - cell transformation. In HGBL DH and FL patients had no significant differences in clinical characteristics. The majority of patients had a widespread tumour, increased LDH activity, high frequency of extranodal and bone marrow involvement. Ki-67 expression level was lower in patients with FL (p.

[Follicular lymphoma. High-dose immunochemotherapy with autologous blood stem cell transplantation: Results of the first prospective study in Russia]. / Follikulyarnaya limfoma. Vysokodoznaya immunokhimioterapiya s transplantatsiei autologichnykh stvolovykh kletok krovi: rezul'taty pervogo prospektivnogo issledovaniya v Rossii.

AIM: to evaluate the efficiency of high-dose chemotherapy (HDCT) with further autologous blood stem cell transplantation (auto-BSCT) in the first-line therapy of patients with follicular lymphoma (FL) and poor prognostic factors. SUBJECTS AND METHODS: In 2000 to 2015, the National Research Center for Hematology, Ministry of Health of the Russian Federation, performed therapy in 39 patients with FL and poor prognostic factors (a total of 215 patients with FL). The R-CHOP treatment was done as induction therapy. Sequential HCT and further auto-BSCT were performed in 29 (74%) of the 39 patients, who had shown a partial tumor response to the induction therapy or achieved partial remission after 4-6 cycles of CT, but had poor prognostic factors. 22 of the 29 patients underwent auto-BSCT in first-line therapy after induction R-CHOP regimens. Among them, there were 17 men with a median age of 46 years (31-68 years). 21 of the 22 patients were recorded to have Stage IV by the Ann Arbor staging classification. Bulky peritoneal and retroperitoneal tumors larger than 7 cm were detectable at disease onset in 14 of the 22 cases. Two patients were noted to have phenomena of leukemization. 16 patients had bone marrow (BM) involvement. According to the Follicular Lymphoma International Prognostic Index-1 (FLIPI-1), the patients were divided into 3 groups: 1) a low risk (n=5); 2) an intermediate risk (n=3); a high risk (n=14). B-symptoms were observed in 16 cases. 16 patients were diagnosed with cytological grade I-II FL and 6 had grade IIIA. According to the tumor proliferative pattern, the distribution turned out to be as follows: nodular (n=6), nodular-diffuse (n=13), and diffuse (n=3). The proliferative activity index averaged 30% (8-90%). Serum and urine proteins were immmunochemically assayed in 18 cases, out of them 8 patients were diagnosed as having serum ß2-microglobulin concentrations above normal as a poor prognostic factor. In 14 of the 22 patients, the activity of lactate dehydrogenase was greater than normal (266-7806 U/l). RESULTS: Out of the 22 patients, 20 who have undergone auto-BSCT in first-line therapy are survivors and have remission of the underlying disease: 18 and 2 patients achieved complete and partial remission, respectively. The follow-up period was 7 to 178 months (median, 32 months). After auto-BSCT in the first remission, 2 patients developed disease recurrences: an early recurrence after 9 months in one case and a late recurrence 6 years after completion of therapy in the other. CONCLUSION: The first prospective study of intensive therapy for FL in Russia has demonstrated that HDCT with further auto-BSCT in first-line therapy allows complete remission in patients with poor prognostic factors and higher overall and progression-free survival rates.

[B-cell lymphoma, unclassifiable, intermediate between diffuse large B-cell lymphoma and Burkitt's lymphoma].

B-cell lymphoma that is unclassifiable and intermediate between diffuse large B-cell lymphoma (DLBCL) and Burkitt's lymphoma (BL)--(UBL) is an aggressive lymphoma that has simultaneously morphological, immunophenotypical, and cytogenetic signs of both DLBCL and LB. At the same time due to its biological characteristics and clinical manifestations, UBL cannot be referred to as one of the above nosological entities. UBL has been first identified as an individual nosological entity in the 2008 World Health Organization classification. The review details the epidemiology, clinical manifestations, morphological pattern, immunophenotypic and karyotypic features, as well as therapeutic approaches and prognostic factors.

[Diagnosis and treatment in patients with B-cell lymphoma unclassified that is intermediate between diffuse large B-cell lymphoma and Burkitt's lymphoma]. / Diagnostika i lechenie bol'nykh V-kletochnoi limfomoi neklassifitsiruemoi, zanimayushchei promezhutochnoe polozhenie mezhdu diffuznoi V-krupnokletochnoi limfomoi i limfomoi Berkitta.

AIM: To characterize a group of patients with B-cell lymphoma (BCLU) unclassified that is intermediate between diffuse large B-cell lymphoma and Burkitt's lymphoma, to identify poor prognostic factors, and to evaluate therapeutic efficiency in patients with BCLU. SUBJECTS AND METHODS: Twenty-five patients with BCLU were examined. Double-hit lymphoma (DHL) was diagnosed in 8 (32%) patients. According to the Ann-Arbor classification of lymphoma, its stages II, III, and IV were diagnosed in 3 (12%), 2 (8%), and 20 (80%) patients, respectively. MYC rearrangement was observed in 11 (48%) out of 23 patients: single-hit lymphoma in 3 patients and DHL in 8 (BCL2+/MYC+ in 6 cases and BCL6+/MYC+ in 2). The expression of с-MYC (cut off ≥40%) was revealed in 17 (74%) out of 23 patients; that of BCL2 (cut off ≥50%) was detected in 14 (58%) out of 24 patients; coexpression of both proteins was seen in 12 (52%) out of 23 patients. The DHL group showed a correlation between the rearrangement of the BCL2+/MYC+ genes and the expression of MYC and BCL2 proteins in 5 out of 6 patients. Taking into account the heterogeneity of the entire patient group, DHL and non-DHL subgroups were considered separately. Both subgroups were comparable by clinical characteristics. BCLU patients younger than 60 years of age received treatment according to the LB-M-04 ± rituximab; those aged 60 or older had CHOP-like regimens ± rituximab. Autologous stem cell transplantation (auto-SCT) was performed in 5 patients belonging to a high-risk group. RESULTS: The 3-year overall survival (OS) was 62% and the 3-year event-free survival (EFS) was 51%. The 3-year OS was lower for the DHL group than that for the non-DHL group (43 and 75%, respectively). CONCLUSION: In the DHL group, both OS and EFS are significantly lower (the risk of poor outcome, including death, is higher) than those in the non-DHL group. It is conceivable that intensified chemotherapy with auto-SCT increases treatment results in patients with BCLU; however, a larger number of observations are needed to obtain valid data.