Merkel cell polyomavirus (MCPyV) in chronic lymphocytic leukemia/small lymphocytic lymphoma

Merkel cell polyomavirus (MCPyV) is a novel polyomavirus that shows a strong association with Merkel cell carcinoma (MCC). Recent studies have demonstrated MCPyV in some cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), a malignancy with a similar demographic as MCC. We tested for the presence of MCPyV by PCR and immunohistochemistry in 18 cases of CLL/SLL. Very low-level MCPyV DNA was detected in 33% of CLL/SLL cases by real-time PCR, but only one case demonstrated immunohistochemical positivity for MCPyV. MCPyV was not identified in 17 cases of follicular lymphoma, suggesting either that MCPyV is involved in CLL/SLL pathogenesis or that the immunodeficiency state of CLL/SLL induces low-level MCPyV reactivation.     

An unusual case of indolent B-cell lymphoma with distinct chronic lymphocytic leukemia and marginal zone differentiation according to the site of involvement

The immunological profile of lymphoproliferative disorders is usually conserved whatever the involved site, thus allowing a reliable diagnosis from peripheral blood analysis, especially in small lymphocytic lymphoma/chronic lymphocytic lymphoma (SLL/CLL). Here we present a case wherein the cytology and immunophenotype of blood specimen and bone marrow argue in favor of SLL/CLL with a typical Matutes score (5/5), whereas the cyto-histology and immunophenotype of spleen specimen led to the diagnosis of splenic marginal zone B-cell lymphoma (SMZL). Moreover genomic analysis showed that the splenic cells displayed a SMZL signature. Whereas these data suggested the presence of 2 B-cell clones, the study of the mutational status of IgV_H gene in blood and spleen demonstrated the presence of a single clone, which likely developed simultaneously along two distinct ways of differentiation according to the anatomic site suggesting here the predominant role of a micro-environmental factor in cell differentiation. Although rare, this kind of event must be kept in mind as a cause of discrepancies between diagnoses from different sites.     

CD5+ true SLL/CLL with plasmacytic differentiation and an unusual 1p36 translocation: case report and review of the literature

Lymphoplasmacytic lymphoma (LPL) and small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL)are distinct clinicopathologic entities. Although some cases of SLL/CLL may show plasmacytic differentiation and be associated with monoclonal immunoglobulin in serum, such cases appear to be very rare, and if plasma cell differentiation were marked, differentiation of SLL/CLL from LPL could be difficult. We report a rare case of true CD5-positive small lymphocytic lymphoma/chronic lymphocytic leukemia with unequivocal plasmacytic differentiation. This case also showed an abnormality of chromosome 1p36 not previously described in small lymphocytic lymphoma/chronic lymphocytic leukemia.     

How to Diagnose and Treat CD5-Positive Lymphomas Involving the Spleen

Patients with CD5-expressing lymphomas presenting with splenomegaly are frequently diagnosed with chronic lymphocytic leukemia. The most important differential diagnosis is mantle cell lymphoma, both in its classical and leukemic, non-nodal forms, given its prognostic and therapeutic implications. Other small B-cell neoplasms that frequently involve the spleen and occasionally express CD5 include the splenic marginal zone lymphoma, hairy cell leukemia and, rarely, lymphoplasmacytic lymphoma. The frequency of CD5 positivity depends in part on the sensitivity of the detection methods employed. Usually, a combination of morphological, immunophenotypic and molecular findings allows for a precise sub-classification of CD5-positive, low-grade B-cell lymphomas of the spleen. Some of these tumors may display a mixture of small and larger B cells, raising the possibility of more aggressive lymphomas, such as diffuse large B-cell lymphomas (DLBCL). Approximately 5–10% of DLBCL are CD5-positive and some may manifest as primary splenic lesions. When available, the morphology of DLBCL in the splenic tissue is distinctive and a leukemic picture is very rare. In conclusion, the appropriate morphological and clinical context assisted by flow cytometry panels and/or immunohistochemistry allows the differential diagnosis of CD5-positive, non-Hodgkin, B-cell lymphomas involving the spleen.     

Magnitude of stromal hemangiogenesis correlates with histologic subtype of non-Hodgkin's lymphoma.

PURPOSE: Tumor stromal microenvironment promotes neoplastic growth and angiogenesis. We have previously shown that recruitment of marrow-derived vascular endothelial growth factor receptor-1(+) (VEGFR-1(+)) proangiogenic hematopoietic progenitors contributes instructively and structurally to neoangiogenesis in mouse models. Here, we investigated whether stromal incorporation of CD68(+) hemangiogenic cells and alpha-smooth muscle actin(+) (alpha-SMA(+)) stromal cells correlates with neoangiogenesis and progression in human non-Hodgkin's lymphoma subtypes. EXPERIMENTAL DESIGN: Spatial localizations of vascular and stromal cells expressing CD34, VEGFR-1, alpha-SMA, and CD68 were examined by immunohistochemistry in 42 cases of non-Hodgkin's lymphoma, including diffuse large B-cell lymphoma, Burkitt lymphoma, follicular lymphoma, and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and compared with benign follicular hyperplasia. RESULTS: Compared with indolent lymphomas, there was a profound increase in recruitment of CD68(+) cells and VEGFR-1(+) neovessels in aggressive subtypes (including those transformed from indolent subtypes), where CD68(+) cells were localized to the perivascular region of neovessels as well as the stromal compartment. The perivascular CD68(+) cells expressed VEGFR-1 and VEGF-A. In contrast, there was a diffuse increase in alpha-SMA incorporation throughout the stromal compartment of indolent subtype of CLL/SLL compared with the scant perivascular pattern in aggressive subtypes. Overall, there was no correlation between CD34(+) microvessel density and lymphoma histologic subtype. CONCLUSIONS: Heightened stromal hemangiogenesis as marked by infiltration of proangiogenic VEGFR-1(+)CD68(+)VEGF-A(+) cells and their paracrine cross-talk with neovasculature appears to be a distinct feature of aggressive lymphoma, providing novel targets for antiangiogenic therapy, whereas alpha-SMA(+) stromal vascular network may be differentially targeted in CLL/SLL.     

Clinical outcome of incidental pelvic node malignant B-cell lymphomas discovered at the time of radical prostatectomy

Incidental pelvic node malignant B-cell lymphomas diagnosed at the time of radical prostatectomy are rare. Their clinical outcome has not been studied. We studied thirteen such cases with long-term clinical follow-up. Patients were followed between 9 and 94 months after surgery. Of 13 cases, 9 were chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 3 marginal zone B-cell lymphoma (MZL) and 1 mantle cell lymphoma (MCL). All 13 patients did not receive radiation or chemotherapy; and five of 13 cases showed hematologic evidence of lymphoma progression between 1 and 5 months after radical prostatectomy. After progression, the mantle cell lymphoma patient received aggressive chemotherapy and had systemic dissemination. Two of 13 cases had recurrent prostate carcinoma. None of 13 patients had died from lymphoma or prostate carcinoma at the last follow-up. In conclusion, most incidental pelvic node lymphomas (8/13) showed no evidence of systemic dissemination to peripheral blood or bone marrow after a mean 42.8 weeks of follow-up despite the fact that no additional treatment was given. Strong consideration should be given to withholding further treatment in patients diagnosed with pelvic low-grade B-cell lymphoma at the time of radical prostatectomy until disease progression occurs.     

Simultaneous diagnosis of hairy cell leukemia and chronic lymphocytic leukemia/small lymphocytic lymphoma: a frequent association?

The association of hairy cell leukemia (HCL) with other neoplasms, mainly non-Hodgkin's lymphomas, is well known. However, the simultaneous diagnosis of HCL and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is rare, with only few cases of such an association having been reported. We describe three patients with a well-characterized HCL in whom a CLL/SLL population was detected. Of note, these cases represent a significant proportion (11.5%; 95% CI: 0% to 24%) of the total number of HCL cases diagnosed in our institution during the same period of time. All three patients were treated with deoxycoformycin. They achieved a complete response of the HCL, whereas the CLL/SLL population persisted in all cases. The immunoglobulin gene rearrangement analysis, in two informative cases, suggested that the HCL and CLL/SLL populations arose from different B cell clones. This study indicates that the association of HCL and CLL/SLL might be much more frequent than previously recognized. Therefore, a large panel of monoclonal antibodies, including those necessary to detect CLL/SLL, should be employed when studying patients with HCL.     

Incidence of phenotypic aberrations in a series of 467 patients with B chronic lymphoproliferative disorders: basis for the design of specific four-color stainings to be used for minimal residual disease investigation.

Multiparameter immunophenotypic analysis of neoplastic cells has proven to be of great help for the investigation of minimal residual disease in acute leukemias; however, its utility has not been systematically explored in B cell chronic lymphoproliferative disorders. The aim of the present study was to investigate the incidence of phenotypic aberrations in a series of 467 consecutive leukemic B cell chronic lymphoproliferative disorders through the comparison of the phenotypic characteristics of tumor vs normal peripheral blood (n = 10) and bone marrow (n = 10) B cells, in order to explore the applicability of this strategy for minimal residual disease monitoring. An additional goal of our study was to evaluate the sensitivity of multiparameter flow cytometry for the detection of minimal residual disease in leukemic B cell chronic lymphoproliferative disorders through dilutional experiments (n = 19). From the patients analyzed 382 corresponded to B cell chronic lymphocytic leukemia/small lymphocytic lymphoma (353 typical and 29 atypical); five to prolymphocytic leukemia; 13 to hairy cell leukemias; 12 to lymphoplasmacytic lymphomas; 14 to splenic marginal zone lymphomas; 22 were follicular lymphomas; and 19 mantle cell lymphomas. The following triple stainings were systematically applied to both normal and leukemic samples: FMC7/CD5/CD19, CD22/CD23/CD19, CD103/CD25/CD19, CD10/CD11c/CD19 and sIg/sIg(lambda)/CD19. Overall, 98% of the leukemic B cell chronic lymphoproliferative disorders cases displayed aberrant phenotypes at diagnosis with no significant differences being found between cases analyzed in peripheral blood vs bone marrow samples. The most common types of aberrant criteria detected included asynchronous antigen expression (92%) and antigen over-expression (54%); abnormally light scatter characteristics were found in 17% of the cases. Most of the cases studied (90%) displayed four or more phenotypic aberrations. Once patients were divided according to the different diagnostic subgroups, the overall incidence of aberrant phenotypes ranged from 79 to 80% among atypical B cell chronic lymphocytic leukemia/small lymphocytic lymphoma and prolymphocytic leukemia to 97% of follicular lymphoma and 100% of typical B cell chronic lymphocytic leukemia/small lymphocytic lymphoma, hairy cell leukemia, lymphoplasmacytic lymphomas, splenic marginal zone lymphomas and mantle cell lymphomas. Based on the aberrant phenotypes detected unique four-color stainings could be built for the specific identification of aberrant phenotypes. These include CD22/CD23/CD19/CD5 and sIg(kappa)/sIg(lambda)/CD19/CD5 for lymphocytic leukemia/small lymphocytic lymphoma and prolymphocytic leukemia, CD103/CD25 or CD22/CD19/CD11c for hairy cell leukemia, FMC7/CD22/CD19/CD103 and sIg(kappa)/sIg(lambda)/CD22/CD19 for splenic marginal zone lymphomas, CD22/CD23/CD19/CD10 for follicular lymphomas and CD10/CD22/CD19/CD5 for mantle cell lymphomas. Serial dilutional experiments showed that the sensitivity level of immunophenotyping ranges between 10(-4) and 10(-5). In summary, the present study shows that immunophenotypic analysis allows the identification of aberrant phenotypes in 98% of leukemic B cell chronic lymphoproliferative disorders and these phenotypes can be used for minimal residual disease monitoring with a sensitivity limit of 10(-4)-10(-5).     

Role of fluorine-18 fluoro-deoxyglucose positron emission tomography scan in the evaluation and follow-up of patients with low-grade lymphomas

BACKGROUND: Fluorine-18 fluoro-deoxyglucose positron emission tomography (FDG-PET) scanning has excellent sensitivity and specificity for staging non-Hodgkin lymphomas, but to the authors' knowledge few studies to date have evaluated FDG-PET in low-grade lymphomas only. METHODS: A retrospective study was performed on patients with biopsy-proven nontransformed and transformed follicular lymphoma (FL), B-cell small-cell lymphocytic lymphoma (SLL/CLL), or marginal zone lymphoma (MZL) who underwent PET and computed tomography (CT) scans within 3 weeks. Standard uptake values (SUV) of all abnormal foci were measured. RESULTS: In FL, PET demonstrated 94% sensitivity and 100% specificity for staging. PET was more specific than CT for detecting recurrence or assessing therapeutic responses (91% vs. 50%). FDG avidity among patients with WHO Grades 1, 2, and 3 disease was not significantly different (analysis of variance [ANOVA]). For MZL staging, PET had moderate sensitivity (71%) and outperformed CT alone in the depiction of extranodal sites (85% vs. 57% sensitivity). In SLL/CLL, PET sensitivity was 53% and underestimated disease extent in 5 of 19 patients (26%) compared with CT. PET did not affect initial management but confirmed suspected recurrences in 75% of patients. Nontransformed FL had a higher SUV (ANOVA, P < .05) compared with MZL and SLL/CLL. SUV was higher in transformed than in nontransformed tumors (P < .001, Student t test). CONCLUSIONS: PET usefulness in staging low-grade lymphomas varies depending on histology. PET sensitivity is excellent in FL and moderate in MZL. PET is more specific than CT for follow-up in all types. PET has limited usefulness for SLL/CLL staging. However, a suggestive pattern of hazy and mild uptake was often noted in positive scans. In all low-grade lymphomas, the emergence of foci of intense uptake should raise suspicion of conversion to high-grade disease.     

Hodgkin lymphoma transformation of chronic lymphocytic leukemia—A real life data from the Polish Lymphoma Research Group

Richter transformation (RT) of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) to Hodgkin lymphoma (HL) is a rare and unexpected event in the course of the disease and data on this phenomenon is still limited. To better understand the clinical and histological characteristics and the outcomes of HL variant of RT (HvRS) the Polish Lymphoma Research Group performed a nationwide survey which identified 22 patients with histologically proven HvRS diagnosed between 2002 and 2016. There were 16 (73%) males. The median age at CLL/SLL and HvRS diagnosis was 59 (39‐77) and 64 (40‐77) years, respectively. The median interval between CLL/SLL and HvRS diagnosis was 38 months (range: 0‐187). All patients had an advanced stage HL, and majority, 17 (77%), presented with B symptoms. The predominant subtypes of HL were nodular sclerosis (12; 55%) and mixed cellularity (9; 41%). Eighteen patients received non‐palliative treatment, including 13 who received driamycin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen first line. Objective response was: 50%, with 33% complete remissions (61% and 46% for ABVD, respectively). Median overall survival reached 13.3 months (95% CI, 3.7‐NA). The only adverse prognostic factor for survival was a higher number (≤1 versus ≥2) of prior lines of treatment given for CLL/SLL with HR 3.57 (95% CI, 1.16‐10.92). We conclude, HvRS harbors a poor prognosis, especially in patients heavily pretreated for CLL/SLL. Response to standard first‐line anti‐HL chemotherapy is unsatisfactory, and new agents should be tested to improve the outcome.     

Histological and immunophenotypic changes in 59 cases of B-cell non-Hodgkin's lymphoma after rituximab therapy

Rituximab is a chimeric monoclonal antibody that recognizes the CD20 antigen. It has been used to treat B-cell non-Hodgkin lymphoma (B-NHL), but recently rituximab resistance has been a cause for concern. We examined histological and immunohistochemical changes in 59 patients with B-NHL after rituximab therapy. The patients comprised 32 men and 27 women with a median age of 59 years. Pre-rituximab specimens comprised 34 follicular lymphomas (FL), 11 diffuse large B-cell lymphomas (DLBCL), 10 mantle cell lymphomas, two marginal zone B-cell lymphomas (MZBCL), and two chronic lymphocytic leukemias (CLL). CD20 expression in lymphoma cells was evaluated by immunohistochemistry or flow cytometry. Post-rituximab materials were taken a median of 6 months (4 days to 59 months) after rituximab therapy. Sixteen cases (27%) showed loss of CD20 expression with four histological patterns: pattern 1, no remarkable histological change (FL, 5; DLBCL, 3; and CLL, 2); pattern 2, proliferation of plasmacytoid cells (FL, 2; DLBCL, 1; and MZBCL, 1); pattern 3, transformation to classical Hodgkin's lymphoma (FL, 1); and pattern 4, transformation to anaplastic large cell lymphoma-like undifferentiated lymphoma (FL, 1). Loss of CD20 was unrelated to the interval of biopsies, treatment regimen, clinical response, and frequency of rituximab administration. Loss of CD20 within 1 month of rituximab therapy (3/14, 21%) and regain of CD20 (2/7, 29%) were not frequent. CD20-positive relapse with transformation occurred most frequently in cases of early relapse. In conclusion, B-NHL showed various histological and immunophenotypic changes after rituximab therapy, including not only CD20 loss but also proliferation of plasmacytoid cells or transformation to special subtypes of lymphoma. ( Cancer Sci 2009; 100: 54–61)     

CD148 and CD27 are expressed in B cell lymphomas derived from both memory and naïve B cells

CD148 and CD27 are activation antigens involved in B cell and T cell activation and development. They have been recently proposed as markers of normal human memory B cells corresponding to the presence of somatically hypermutated IgV genes. We undertook an immunohistochemical study of CD148 and CD27 expression on neoplastic B cells in 116 cases of B cell non-Hodgkin's lymphoma. All cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma, Burkitt's lymphoma, and the vast majority of cases of marginal zone B cell lymphoma and most cases of plasmacytoma/myeloma expressed CD148 and CD27. Follicular lymphoma and diffuse large B cell lymphoma were also immunoreactive for CD148 and CD27 with some variation and discordance in expression. Cases of precursor B-lymphoblastic lymphoma/leukemia did not express CD148 or CD27. Our findings demonstrate that CD148 and CD27 are expressed in a wide range of B cell non-Hodgkin's lymphomas, and, therefore, do not serve to distinguish between neoplastic cells of na?ve and memory B cell derivation.     

Veterans with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have a markedly increased rate of second malignancy, which is the most common cause of death

Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) have an increased incidence of high-grade lymphoid malignancy. The risk of non-lymphoid second malignancy in this population is not well-defined to date. To test the hypothesis that patients with CLL/SLL have an increased risk of second malignancy, we studied the rate of second malignancy in 132 CLL/SLL patients and compared it to the rate of malignancy (excluding non-melanomatous skin cancer) in the Central Arkansas Veterans Healthcare System population of approximately 38,000 veterans over a period of 11.5 years. The rate of second malignancy, diagnosed concomitantly or after CLL/SLL, and the age-adjusted rate of malignancy calculated from tumor registry reports and demographic data, were used to calculate a Standardized Morbidity Ratio (SMR) with 95% confidence interval (CI). Twenty-one (16%) of the CLL/SLL patients had second malignancies (19 non-lymphoid, 1 Richter's transformation and 1 Hodgkin's disease), which were fatal in 15 (71%) patients. The SMR for the CLL/SLL population was 2.97 (95% CI 1.84 - 4.55) for second malignancy and 2.69 (95% CI 1.62 - 4.21) for non-lymphoid second malignancy. This study of a well-defined CLL/SLL population shows a significantly increased risk of second malignancy, which was the primary cause of death for 9% of all CLL/SLL patients (34% of all patient deaths).     

Periodontal disease and risk of non‐Hodgkin lymphoma in the Health Professionals Follow‐Up Study

Periodontal disease is a chronic inflammatory condition that has been associated with chronic diseases, including cancer. In an earlier prospective cohort analysis within the Health Professionals Follow‐Up Study (HPFS), we observed a 31% higher risk of non‐Hodgkin lymphoma (NHL) among participants with severe periodontal disease at baseline. Here, we extend the study with an additional 8 years of follow‐up, and conduct analyses with updated periodontal disease status and NHL subtypes. The HPFS is an ongoing prospective cohort study of 51,529 men in the USA Between baseline in 1986 and 2012, 875 cases of NHL were diagnosed, including 290 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 85 diffuse large B‐cell lymphomas and 91 follicular lymphomas. We performed multivariable Cox proportional hazards regression to evaluate associations of interest. History of periodontal disease at baseline was positively associated with risk of NHL overall (hazard ratio (HR) = 1.26, 95% confidence interval (CI): 1.06–1.49) and CLL/SLL (HR = 1.41, 95% CI: 1.04–1.90). With updated periodontal status, HRs were 1.30 (95% CI: 1.11–1.51) for NHL overall and 1.41 (95% CI: 1.08–1.84) for CLL/SLL. In contrast, after adjusting for periodontal disease, tooth loss was inversely associated with NHL, suggesting that other causes or consequences of tooth loss may have different implications for NHL etiology. Our findings suggest that periodontal disease is a risk factor for NHL. Whether periodontal disease is a direct or indirect cause of NHL, or is a marker of underlying systemic inflammation and/or immune dysregulation, warrants further investigation.     

CD45 expression in low-grade B-cell non-Hodgkin's lymphomas

CD45 is a glycoprotein expressed in all lymphohemopoietic cells. Its expression increases during B-lymphocyte ontogeny. Few data are available about CD45 expression in the various types of low-grade B-cell non-Hodgkin's lymphomas (NHL). Low levels of CD45 have been reported in pathologic lymphocytes from typical chronic lymphocytic leukemia (CLL) and higher levels of this antigen have been observed in some cases of atypical CLL and in some cases of other types of NHL. One hundred and seven bone marrow samples of NHL with bone marrow infiltration were investigated: 45 typical CLL, 15 atypical CLL, 9 mantle cell lymphomas (MCL), 1 MCL with CD23 expression, 18 marginal zone lymphomas (MZL), 6 lymphoplasmacytic lymphomas (LPL), 6 follicular lymphomas (FL), and 7 hairy cell leukemias (HCL). CD45 expression was evaluated by flow cytometry: pathologic lymphocytes were identified on the basis of specific immunophenotypic profile, CD19/K or CD19/lambda co-expression. Results were expressed as median fluorescence intensity (MFI) along a 1024 linear scale. CD45 expression was measured also on autologous T-lymphocytes and a "CD45 index" was calculated as the ratio MFI of pathologic B-lymphocytes/MFI of T-lymphocytes, to normalize the results obtained. We found four CD45 expression patterns: very low in typical CLL; relatively low in MCL; intermediate intensity in MZL, LPL, and FL; very high expression in HCL. Among the atypical cases, very high CD45 expression was found in one case of CD23-negative CLL, in CD23-positive MCL, and CLL with atypical morphology. The results indicate different levels of maturation in low-grade NHL and may help to characterize such neoplasias.     

PI3K signaling pathway in normal B cells and indolent B-cell malignancies

In chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphomas (NHLs), B-cell receptor signaling leads to activation of the phosphatidylinositol 3-kinase (PI3K) pathway. Idelalisib, a PI3Kδ inhibitor was approved in 2014 by the US Food and Drug Administration (FDA) in combination with rituximab for the treatment of patients with CLL for whom single-agent rituximab would be considered appropriate and as a single agent for patients with relapsed small lymphocytic lymphoma (SLL) and relapsed follicular lymphoma (FL). Following its approval, several trials investigating various PI3Kδ inhibitors as single agents or in combination with chemoimmunotherapy or other molecular targeted agents in CLL and indolent NHL (iNHL) have uncovered some severe autoimmune related toxicities. This review discusses and summarizes the biologic basis and the clinical experience of the PI3Kδ inhibitors in indolent B-cell malignancies.     

The cut-off levels of CD23 expression in the differential diagnosis of MCL and CLL

Flow cytometric analysis of CD23 expression in CD5-positive B-cells is a widely applied method in the differential diagnosis of chronic lymphocytic leukaemia (CLL) and mantle cell lymphoma (MCL). According to the most accepted criteria, the leukaemic cell population is CD19/CD5/CD23 triple positive in CLL but CD23-negative in MCL. Recently, several groups have reported CD23-positive MCL cases; however, these studies mostly analysed only CD23 positivity but not intensity. To determine the role and the cut-off levels of CD23 positivity and intensity in the differential diagnosis of CLL and MCL, 26 cases of MCL and 84 cases of CLL were compared using flow cytometric analysis. Our results suggest that high values of CD23 positivity (>92.5%) and/or high fluorescence intensity (>44.5 mean fluorescence intensity (MFI)) of CD23 are related to CLL, whereas low CD23 positivity (<30%) is related to MCL. However, cases with intermediate CD23 positivity (between 30 and 92.5%) and lower intensity (<44.5 MFI) can either belong to CLL or MCL. In these cases, additional tests such as FISH analysis of the translocation t(11;14) or immunohistochemical detection of cyclin D1 overexpression are required to differentiate CLL from MCL.     

A prospective analysis of circulating saturated and monounsaturated fatty acids and risk of non‐Hodgkin lymphoma

Circulating saturated (SFA) and monounsaturated fatty acids (MUFA), which are predominantly derived from endogenous metabolism, may influence non‐Hodgkin lymphoma (NHL) risk by modulating inflammation or lymphocyte membrane stability. However, few biomarker studies have evaluated NHL risk associated with these fats. We conducted a prospective study of 583 incident NHL cases and 583 individually matched controls with archived pre‐diagnosis red blood cell (RBC) specimens in the Nurses’ Health Study (NHS) and Health Professionals Follow‐Up Study (HPFS). RBC membrane fatty acid levels were measured using gas chromatography. Using multivariable logistic regression, we estimated odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL and major NHL subtypes including T cell NHL (T‐NHL), B cell NHL (B‐NHL) and three individual B‐NHLs: chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B‐cell lymphoma (DLBCL) and follicular lymphoma. RBC SFA and MUFA levels were not associated with NHL risk overall. However, RBC very long chain SFA levels (VLCSFA; 20:0, 22:0, 23:0) were inversely associated with B‐NHLs other than CLL/SLL; ORs (95% CIs) per standard deviation (SD) increase in level were 0.81 (0.70, 0.95) for 20:0, 0.82 (0.70, 0.95) for 22:0 and 0.82 (0.70, 0.96) for 23:0 VLCSFA. Also, both VLCSFA and MUFA levels were inversely associated with T‐NHL [ORs (95% CIs) per SD: VLCSFA, 0.63 (0.40, 0.99); MUFA, 0.63 (0.40, 0.99)]. The findings of inverse associations for VLCSFAs with B‐NHLs other than CLL/SLL and for VLCSFA and MUFA with T‐NHL suggest an influence of fatty acid metabolism on lymphomagenesis.     

脾边缘区淋巴瘤的诊断

目的:探讨脾边缘区淋巴瘤的临床特征、诊断及鉴别诊断。方法:回顾性分析华中科技大学同济医学院附属同济医院2019年收治的3例表现为脾大、血细胞减少的CD5 - CD10 - B细胞非霍奇金淋巴瘤患者的临床诊断及鉴别诊断过程,并复习相关文献。 结果:3例均为老年患者,均出现不同程度的脾大和血细胞减少,均在骨髓或淋巴结中发现CD5 - CD10 -单克隆B淋巴细胞。综合患者的临床特征、外周血及骨髓形态、免疫表型和遗传学特征,2例患者诊断为脾边缘区淋巴瘤,1例患者诊断为弥漫大B细胞淋巴瘤。 结论:脾边缘区淋巴瘤的诊断需综合临床特征、外周血及骨髓形态、免疫表型和遗传学特征,与其他CD5 - CD10 -小B细胞淋巴瘤进行仔细鉴别。新一代基因突变高通量检测和表达谱分析有助于不典型疑难病例的精准诊断。     

Expression of DNA mismatch repair proteins in transformed non-Hodgkin's lymphoma: relationship to smoking

It has been hypothesized that defects in DNA-mismatch repair are associated with smoking in certain types of transformed non-Hodgkin lymphoma (NHL). We have analyzed biopsy samples from two indolent B-cell lymphomas, follicular lymphoma (FL) and chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL), that have transformed to diffuse-large B-cell lymphoma (DLBCL). We correlated the presence or absence of DNA-mismatch repair enzymes by immunostaining as well as the p53 status to smoking history. Of all patients (n = 30), 37% showed negative immunostaining of MLH1, 16% showed negative immunostaining of MSH2 and 63% had p53 mutations and/or protein expression. Eighteen out of 20 transformed follicular lymphomas and seven out of 10 CLL/SLL that have transformed to DLBCL (Richter's syndrome) were informative for smoking histories. We found that the relative risk of negative immunostaining for either MLH1 or MSH2 was 2.2 times higher in smokers than non-smokers (relative risk = 2.2041, 95% confidence interval: 0.89714, 5.41491). No direct correlation was found between smoking and the mutations in the p53 gene. These results suggest that cigarette smoking may play a role in the development of transformed lymphomas through defective mismatch repair.