Chronic Lymphocytic Leukaemia/small Lymphocytic Lymphoma Research Articles

Rare cutaneous manifestation of B‐cell chronic lymphocytic leukaemia involving the toes

AbstractB cell chronic lymphocytic leukaemia (B‐CLL) presenting with cutaneous infiltration is rare, and when it occurs, it presents most commonly on the head and neck. We present the case of an 80‐year‐old woman with a 2‐month history of erythema, swelling and pain affecting all her toes. She had a history of B‐CLL diagnosed 20 years previously that had remained stable under observation without treatment. A toe skin biopsy showed a diffuse infiltrate of lymphoid cells occupying the dermis composed of small mature lymphoid cells with a monotonous appearance. On immunohistochemistry, the neoplastic lymphoid cells stained positive for the B‐cell marker CD20. Overall, the morphology and immunophenotype were consistent with cutaneous involvement by chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). We concluded that her symptoms were directly caused by skin infiltration of B‐CLL.

MYD88-Mutated Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma as a Distinctive Molecular Subgroup Is Associated with Atypical Immunophenotypes in Chinese Patients

Chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) is a heterogeneous disease in Western and Chinese populations, and it is still not well characterized in Chinese patients. Based on a large cohort of newly diagnosed CLL/SLL patients from China, we investigated immunophenotypes, genetic abnormalities, and their correlations. Eighty-four percent of the CLL/SLL patients showed typical immunophenotypes with scores of 4 or 5 points in the Royal Marsden Hospital (RMH) scoring system (classic group), and the remaining 16% of patients were atypical with scores lower than 4 points (atypical group). Trisomy 12 and variants of TP53, NOTCH1, SF3B1, ATM, and MYD88 were the most recurrent genetic aberrations. Additionally, unsupervised genomic analysis based on molecular genetics revealed distinctive characteristics of MYD88 variants in CLL/SLL. By overlapping different correlation grouping analysis from genetics to immunophenotypes, the results showed MYD88 variants to be highly related to atypical CLL/SLL immunophenotypes. Furthermore, compared with mantle cell lymphoma (MCL), the genetic landscape showed potential value in clinical differential diagnosis of atypical CLL/SLL and MCL patients. These results reveal immunophenotypic and genetic features, and may provide insights into the tumorigenesis and clinical management of Chinese CLL/SLL patients.

Chronic lymphocytic leukaemia/small lymphocytic lymphoma treatment with rituximab and high-dose methylprednisolone, revisited.

High‐dose methylprednisolone plus rituximab (R‐HDMP) is a useful treatment in chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) patients unfit for chemo‐immunotherapy and has proven its utility on the treatment of CLL/SLL complicated by auto‐immune cytopenias. We performed a retrospective, single‐centre study, of CLL/SLL patients treated with R‐HDMP for 9 years. Thirty‐nine patients were included, median age at time of treatment was 77 years. Most patients had stage Rai III/IV and Binet C disease. Twenty‐eight patients had relapsed/refractory disease at time of treatment with a median of 1 previous line of therapy; 53.8% had prior exposure to fludarabine and 25% to rituximab. Grade 3–4 neutropenia and thrombocytopenia were recorded in 10.2% and 17.9% patients, respectively. While on treatment, 51.3% had documented infectious complications, but no other non‐haematological toxicities grades 3–4 were identified. Overall response rate was 64%. Median overall survival and progression‐free survival were 24 and 13 months, respectively. Twenty four patients relapsed and 16 received another line of treatment after R‐HDMP, with median time to next treatment of 13.5 months. Thirteen out of the 24 patients improved performance status and were subsequently considered fit for chemo‐immunotherapy. R‐HDMP is a valuable option for elderly and frail patients, with low risk of severe myelotoxicity and other severe adverse events. It was shown to work as a bridge to other lines of treatment, including chemo‐immunotherapy.

Epidemiology, treatment patterns and survival of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) in Taiwan, 2006-2015.

Chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) is one of the most frequent types of leukaemia/lymphoma in adults in Western countries. However, there are few studies regarding its epidemiology and treatment patterns in Asian countries. To investigate CLL/SLL in Asian populations, we identified CLL/SLL patients diagnosed during 2006 to 2015 from the Taiwan Cancer Registry Database and estimated the incidence. Further, patients diagnosed during 2008 to 2015 were included for the analysis of treatment patterns and survivals. Treatments for CLL/SLL were retrieved from the Taiwan's National Health Insurance Research Database and survival data from the National Death Registry. In total, 1497 patients who were older than 20years and had newly diagnosed CLL/SLL during 2006-2015 were identified. The age-standardized incidence rates of CLL/SLL (0.36 per 100000 persons in 2006, and 0.54 in 2015) increased during the 10-year period. The sex ratio was ranged from 1.21 to 2.63 with male predominant during 2006 and 2015. For the analysis of treatment patterns (n=1236), 72.8% patients received chemotherapies. The median duration between the diagnosis and start of treatments was 27days, and monotherapy of chlorambucil, bendamustine or cyclophosphamide was the most common regimen in initial treatments. The median follow-up duration for the patients receiving therapies was 29.6months, and 45.0% patients experienced relapse or refractory. In patients with relapse/refractory CLL/SLL, 34.1% received rituximab-containing chemotherapies. Three hundred and ninety-nine (32.3%) patients received intensive treatments, and 175 (43.9%) of them received rituximab-containing chemotherapies. The 5-year overall survival (OS) rate was 61%, and age was an important prognostic factor for CLL/SLL patients. This study is the first population-based study in Asia and provides comprehensive evidence of epidemiology, treatment patterns and survivals of CLL/SLL in an Asian population.

A comprehensive retrospective cohort study of the journey of B-cell lymphoma in Taiwan

Complete disease journey and risk factors for poor outcomes are needed to facilitate effectiveness evaluations of new therapies and clinical decision-making in B-cell Non-Hodgkin lymphoma (B-NHL), particularly in Asia where such data are lacking. This retrospective cohort study used electronic medical records from a regional medical centre in southern Taiwan to follow-up 441 patients newly diagnosed with common B-NHL subtypes: Diffuse Large B-cell Lymphoma (DLBCL), Follicular Lymphoma (FL), Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma (CLL/SLL), Marginal Zone Lymphoma (MZL), Mantle Cell Lymphoma (MCL), and Waldenström macroglobulinemia (WM), between 01-Jan-2008 and 31-Dec-2013, until 31-Dec-2017. Treatment pathways were modelled using a Markov approach. Stage III/IV disease at diagnosis was frequent for patients with DLBCL, FL, MCL and WM. Hepatitis B surface antigen/hepatitis C virus seropositivity was 18.6%/12.3%. Clinical responses to 1st-line treatment were observed in 76.0% (DLBCL), 87.3% (FL), 86.0% (MZL), 60.0% (MCL), and 42.9% (WM) of patients. For DLBCL, disease control was achieved by ~ 50% after 1st-line, ~ 24% after 2nd-line, ~ 17% after 3rd-line. Patients with Stage III/IV DLBCL or age > 65 years at diagnosis had lower rates of active treatment, poorer disease control and higher mortality than patients with early stage disease or age ≤ 65 years. Disease flare < 6 months after 1st-line treatment was significantly associated with mortality. Despite good clinical response rates for some sub-types, survival remains poor. New treatments are needed to improve the outcome of B-NHL.

Clinicopathological features of splenic tumours of lymphoid tissue

BackgroundTo study the effects of splenectomy on treatment and diagnosis of tumours of lymphoid tissue of the spleen. MethodsFifty-three cases were reviewed from Peking University People’s Hospital from 2002 to 2017. According to WHO classification of tumours of haematopoietic and lymphoid tissues (2008) and classification updated (2016), the cases were studied by microscopy, immunohistochemistry and in situ hybridization, combined with the bone marrow biopsy and clinical examination. ResultsIn 53 cases, the male to female ratio was 3.4:1, the mean age was 55.4 years old, the median survival time was 17.0 months, and all patients present with variable degree of splenomegaly. The elevated percentage of lymphocyte in peripheral blood can be seen in 22 cases, and elevated LDH level in 24 cases. Abnormal blood counts can be seen in 26 cases before operation, and 22 cases remission to normal level partly or completely after operation. The clinical symptoms included abdominal pain or distension, fatigue, fever, and weight loss, etc. Seventeen cases present with lymphoadenopathy of abdomen or other sites. Fourteen cases were stage I or II, whereas 6 were stage III, 28 were stage IV. Forty-three cases were splenic B-cell marginal zone lymphoma (SMZL)(48.8%,21/43), DLBCL(23.3%,10/43), splenic diffuse red pulp small B-cell lymphoma (SDRPSBL)(11.6%,5/43), mantle cell lymphoma (MCL)(9.3%,4/43), follicular lymphoma (FL)(4.7%,2/43), composite lymphoma (CL, DLBCL and classical Hodgkin lymphoma)(2.3%,1/43) in turn, and the remaining 10 cases were chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) (n = 4), hairy cell leukaemia (HCL) (n = 1), hepatosplenic T-cell lymphoma (HSTL) (n = 5). The survival period of SMZL and DLBCL was 25.7, 18.6 months, respectively. Thirteen cases were dead (27.1%, 13/48). The chemotherapy protocol included Hyper-CVAD A/B with/without R (Rituximab), COP, CHOP with/without R etc. The prognosis of those with elevated LDH level, high clinical staging, B symptom, and older than 60 year old was obviously worse, and the prognosis of DLBCL was worse than that of SMZL. ConclusionsMost splenic lymphoid tumors present with splenomegaly and abnormal blood counts, and complete or part remission of blood counts can be seen after splenectomy, and splenectomy is also helpful for pathological diagnosis. The most common pathological types are SMZL and DLBCL. The definite diagnosis can be made by combining with clinical features, histopathology, immunophenotype, genetics, bone marrow biopsy and laboratory examination.

EZH2 is upregulated in the proliferation centers of CLL/SLL lymph nodes

Lymph node involvement of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) is characterised by the diffuse infiltration of small neoplastic lymphocytes, which is accompanied by the presence of proliferation centres (PCs) comprising prolymphocytes and paraimmunoblasts. There is increasing evidence of accumulation of various molecular alterations in the tumour cells of PCs, which may explain why extended PCs are related to a less favourable prognosis.To further characterize PCs, we compared the expression level of EZH2 protein, the overexpression of which has recently been recognized as poor prognostic factor in CLL/SLL, in the PCs and the intervening small cell areas in lymph nodes of 15 patients with CLL/SLL. We also investigated the mutational profile of EZH2 and the expression of its upstream regulators c-Myc, E2F1, pRB and miR-26a.Our results showed a significantly increased expression of EZH2 in the PCs. No EZH2 mutations were detected, however, overexpression of c-Myc, E2F1 and pRb proteins as well as reduced expression of the tumor suppressor miR-26a were demonstrated in the PCs.In summary our findings indicate that EZH2 pathway is significantly upregulated in the PCs of CLL/SLL lymph nodes, providing further evidence for the distinguished biological features of the PCs.

Analysis of proliferative lesions of haematopoietic and lymphoid tissue in the female productive tract

Objective: To study the clinicopathologic features, diagnosis and differential diagnosis of tumors of haematopoietic and lymphoid tissue in the female productive tract. Methods: Eleven cases of myeloid sarcoma and leukemia, 9 of non Hodgkin lymphoma (NHL) , 13 of cervical lymphoma-like lesions were selected from Peking University People's Hospital from January 2006 to August 2017. According to WHO classification of tumors of haematopoietic and lymphoid tissues (2008) and updated classification(2016), the cases were studied by microscopy, immunohistochemistry and in situ hybridization. Results: In 20 cases of tumors of haematopoietic and lymphoid tissue, the mean and median age was 48.5 and 56 years old (range: 16-77 years old) . In cases of lymphoma-like lesion of uterine cervix, the mean and median age was 45.9 and 48 years old (range: 23-62 years old) . The patients with neoplasm present as fever, fatigue, hypogastralgia, colporrhagia and mass etc. Eight cases had history of acute myeloid leukemia, and 3 had myeloid leukemia while pregnancy. One case of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) had history of ovary small cell carcinoma and high grade serous carcinoma resected with chemotherapy. One case of diffuse large B cell lymphoma (DLBCL) had history of renal transplantation. Lactic dehydrogenase (LDH) was elevated in 9 cases (9/18) . The cases of lymphoma-like lesion present as contact bleeding in most cases and all located in cervix. Four cases of neoplasm located in vulva, 1 in vagina, 4 in cervix, 4 in uterine corpus, 8 in ovary and 2 in placenta. Clinical staging of NHL: 4 case was stageⅠ, 1 case of stageⅢ, and 4 cases of stage Ⅳ. Pathological morphology: 9 cases were myeloid sarcoma, 2 cases were placenta invaded by myeloid leukemia. Six cases were DLBCL, and 1 case was CLL/SLL, 1 case was mucosa associated lymphoid tissuse lymphoma (MALToma) , and 1 case was anaplastic large cell lymphoma. Resected mass, chemotherapy was performed in tumors of haematopoietic and lymphoid tissue. Five cases of myeloid sarcoma and 2 of NHL died. In 13 cases of lymphoma-like lesion of uterine cervix, the general condition was good as following up. Conclusions: The clinical history, pathological morphology and immunohistochemistry are very important for diagnosing tumors of haematopoietic and lymphoid tissue in the female productive tract. Resection with chemotherapy is recommended in treatment. The prognosis of lymphoma-like lesion of uterine cervix is good, and should be differentiated from lymphoma.

Hepatitis B virus and risk of non‐Hodgkin lymphoma: An updated meta‐analysis of 58 studies

Previous studies have focused on the relationship between hepatitis B virus (HBV) infection and non-Hodgkin lymphoma (NHL). However, the results remain inconsistent and somehow conflicting in different subgroups. The aim of this study was to combine the findings of independent studies to comprehensively assess the association between HBV and NHL using a meta-analysis. Relevant studies were identified through structured keyword searches in PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) database, and 58 studies with a total of 53714 NHL cases and 1778591 controls were finally included. Pooled estimates indicated a significantly increased NHL risk in HBV-infected individuals (summary odds ratio [sOR]: 2.50; 95% confidence interval [CI]: 2.20-2.83) regardless of the study design (case-control studies: sOR: 2.47; 95% CI: 2.16-2.82; cohort studies: sOR: 2.64; 95% CI: 1.78-3.91). Considerable heterogeneity was observed across studies that was primarily attributed to the NHL subtypes (meta-regression: P<.05). Overall, B-cell NHL (sOR: 2.46; 95% CI: 1.97-3.07) presented a stronger association with HBV infection than T-cell NHL (sOR: 1.67; 95% CI: 1.34-2.10). Within the B-cell NHL subtypes, HBV infection was significantly associated with diffuse large B-cell lymphoma (DLBCL, sOR: 2.06; 95% CI: 1.48-2.88) and follicular lymphoma (FL, sOR: 1.54; 95% CI: 1.11-2.12), but not with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) and Burkitt lymphoma. The results of this meta-analysis support a positive link between HBV infection and NHL development. Further investigations for the mechanisms underlying HBV-induced NHL are warranted.

Cyclin D1 expression by histiocytes may mimic cyclin D1-positive proliferation centres of chronic lymphocytic leukaemia/small lymphocytic lymphoma

AimsCyclin D1, generally considered to be absent in chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL), has been reported in the proliferation centres (PCs) of recent CLL/SLL cases. Cyclin D1 immunostaining in CLL/SLL may lead to diagnostic confusion. The objective of this study was to identify the types of stained cells and the impact on diagnosis. MethodsCyclin D1 expression was assessed by immunostaining samples from 46 cases of CLL/SLL. CD68 and double immunostaining with CD20/CyclinD1, CD68/CyclinD1, and CD163/CyclinD1 were then performed in cases of CLL/SLL positive for cyclinD1 in the PCs. ResultsDim-positive cyclin D1 staining in randomly scattered cells in the CLL/SLLs were observed in 38/46 cases (82.6%). In five (10.9%) cases, more than 50 cyclin D1-positive cells per high-power field were detected within the PCs in CLL/SLL with weak to moderate intensity. Double immunochemical staining in these cases showed that cyclin D1 in these positive cells was mostly co-expressed with CD68 and CD163 and the cells were negative for CD20. ConclusionsThe cyclin D1-positive CLL/SLL cells in this study were mostly histiocytes. The expression of cyclin D1 by histiocytes may mimic cyclin D1+ CLL/SLL; thus, the recognition of cyclin D1 expression by non-lymphoid cells in lymphoma is important.

Targeting Bruton Tyrosine Kinase: A novel strategy in the treatment of B-cell lymphomas

AbstractIn normal B-cells, Bruton tyrosine kinase (Btk), a non-receptor tyrosine kinase involved in B-cell receptor (BCR) signalling, is essential for cell survival and maturation. Not surprisingly, Btk is also implicated in the pathogenesis of B-cell lymphomas, like Chronic Lymphocytic Leukaemia/Small Lymphocytic Lymphoma (CLL/SLL), Mantle Cell Lymphoma (MCL) and Waldenström’s Macroglobulinemia (WM), which are driven by aberrant BCR signalling. Thus, targeting Btk represents a promising therapeutic strategy in the treatment of B-cell lymphoma patients. Ibrutinib, a selective Btk inhibitor, has already been approved as second-line treatment of CLL/SLL, MCL and WM patients, while more clinical studies of ibrutinib and novel Btk inhibitors are currently under way. In light of results of the RESONATE-2 trial, the approval of ibrutinib as a first-line treatment of CLL/SLL may well be approaching. Herein, we review Btk’s role in normal and malignant BCR signalling, as well as ibrutinib’s performance in B-cell lymphoma treatment and prognosis.

Quantitative miR analysis in chronic lymphocytic leukaemia/small lymphocytic lymphoma – proliferation centres are characterized by high miR-92a and miR-155 and low miR-150 expression

Proliferation centres (PCs) are histological hallmarks of lymph nodes in chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). Chromosomal abnormalities have already been described to accumulate preferably in the PCs as opposed to the intervening small cell areas.To further characterize the pathogenic role of PCs, the expression levels of 17 selected miRs known to be involved in the development of CLL/SLL were compared in the PCs and the intervening small cell areas in lymph nodes of 15 patients with CLL/SLL. The miR expression levels were also compared to the cytogenetic alterations defined by FISH analysis.Our results show that two known oncomiRs, miR-155 and −92a were upregulated and the tumour suppressor miR-150 was downregulated in the PCs. Low expression of miR-150 was also associated with loss of 11q.In summary we found significantly higher expression of oncomiRs and lower expression of a tumour suppressor miR in PCs of CLL/SLL lymph nodes, which support the hypothesis that the PCs may drive the disease and play a role in progression.

B-cells behaving badly I: A better basis to behold belligerence in small b-cell lymphomas

Small B-cell lymphomas and leukaemias (SBCLs) are a clinically, morphologically, immunophenotypically and genetically heterogeneous group of neoplasms that include chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), lymphoplasmacytic lymphoma (LPL), marginal zone lymphoma (MZL) and hairy cell leukaemia (HCL). The pathogenesis of some of these lymphoid malignancies is characterised by distinct translocations, for example t(11;14) and t(14;18), respectively, in most cases of MCL and FL. By contrast, other entities are associated with a variety of non-specific and non-diagnostic but nevertheless recurrent and prognostically pertinent numeric abnormalities, such as del(17p), del(13q14), del(11q22) and +12 in CLL. Yet others like LPL and HCL lack specific cytogenetic aberrations. The recent surge in next generation sequencing technology has shed abundant light on the genetic landscape of SBCLs through characterisation of numerous driver mutations including BRAF (V600E) in HCL and MYD88 (L265P) in LPL, amongst others. These significant advances and panoply of available tests notwithstanding, it is important to appreciate that not all SBCLs need genetic testing for diagnosis, not all harbour their characteristic genetic features and not all are diagnostically specific. This lecture will attempt to review the role of genetic studies in SBCLs, highlighting their advantages and limitations. Small B-cell lymphomas and leukaemias (SBCLs) are a clinically, morphologically, immunophenotypically and genetically heterogeneous group of neoplasms that include chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), lymphoplasmacytic lymphoma (LPL), marginal zone lymphoma (MZL) and hairy cell leukaemia (HCL). The pathogenesis of some of these lymphoid malignancies is characterised by distinct translocations, for example t(11;14) and t(14;18), respectively, in most cases of MCL and FL. By contrast, other entities are associated with a variety of non-specific and non-diagnostic but nevertheless recurrent and prognostically pertinent numeric abnormalities, such as del(17p), del(13q14), del(11q22) and +12 in CLL. Yet others like LPL and HCL lack specific cytogenetic aberrations. The recent surge in next generation sequencing technology has shed abundant light on the genetic landscape of SBCLs through characterisation of numerous driver mutations including BRAF (V600E) in HCL and MYD88 (L265P) in LPL, amongst others. These significant advances and panoply of available tests notwithstanding, it is important to appreciate that not all SBCLs need genetic testing for diagnosis, not all harbour their characteristic genetic features and not all are diagnostically specific. This lecture will attempt to review the role of genetic studies in SBCLs, highlighting their advantages and limitations.

Diagnostic Pitfalls in “Low-Grade Lymphoma” of the Orbit and Lacrimal Gland

Aims: To investigate potential diagnostic pitfalls associated with the identification of low grade lymphoma in the orbit and lacrimal gland region.Methods: To systemically review all cases diagnosed as low grade lymphoma of orbit and lacrimal gland within a 2 year period at a specialist ophthalmic centre. To ascertain the frequency of diagnostic errors in this group of cases, in particular to look for known pitfalls associated with follicular colonisation by marginal zone lymphoma and the recently identified atypical variant of follicular lymphoma (FL). A series of 21 cases were reviewed.Results: We identified two diagnostic errors; one case of extra nodal marginal zone lymphoma (ENMZL) which showed follicular colonisation and was misinterpreted as a FL and a case of missed mantle cell lymphoma (MCL). We identified no cases of atypical FL.Conclusion: Within the orbit and lacrimal gland the term “low grade lymphoma” encompasses the following types of lymphoma: ENMZL, FL, MCL and chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). The typical and atypical immunophenotype of these entities is discussed. The diagnosis of ENMZL, by far the most common low grade lymphoma to occur in these areas, is to some extent a difficult diagnosis and is often one of exclusion. The pitfalls of follicular colonisation and the concept of atypical follicular lymphoma are discussed.

Hodgkin lymphoma transformation of chronic lymphocytic leukaemia

Transformation to high grade lymphoma occurs in approximately 5% of patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) and most cases are classified as diffuse large B-cell lymphoma (DLBCL). We describe an elderly male patient with the rare Hodgkin lymphoma (HL) type transformation of CLL/SLL. The patient had a 13 year history of CLL and in the months prior to node biopsy experienced B symptoms. The excised lymph node showed effacement of the normal architecture with a monotonous population of small lymphocytes featuring round nuclear contours, granular chromatin, small nucleoli and immunopositivity to CD20, CD79a, CD5 and CD23. These areas appeared typical for CLL and were admixed with scattered clusters containing histiocytes, eosinophils and occasional CD30, MUM-1 positive Reed-Sternberg cells. HL transformation in CLL/SLL is most commonly seen in elderly men and the median time to transformation is 4.6 years. The prognosis is inferior to that in patients with de novo HL. Discordant findings exist regarding the prognosis compared to non-Hodgkin type transformation in CLL/SLL. This case highlights the importance of recognition of this rare variant to accurately predict prognosis and guide chemotherapy.

Chronic lymphocytic leukaemia – the role of the microenvironment pathogenesis and therapy

Chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL) is one of the more common forms of B cell malignancy. Although the condition has a variable clinical course, the trend is towards eventual relapse and the disease is considered incurable. Whilst the majority of the circulating CD5-positive neoplastic B cells are arrested in the G0 phase of the cell cycle, those in the bone marrow and lymphoid tissues proliferate at a rate of 0·1-1% of the entire clone per day. This proliferation is supported by the tissue microenvironment, which has been shown to induce upregulation of anti-apoptotic proteins and enhance the survival of the neoplastic cells. Microenvironmental factors are also thought to be important in tumour relapse and resistance to therapy. This review outlines the main signalling pathways involved in these tumour cell-stromal interactions, and includes potential therapeutic strategies based on the manipulation of key components within the CLL microenvironment.

Chronic lymphocytic leukaemia/Small lymphocytic lymphoma (CLL/SLL) associated with translocation t(1;6)(p35;p25) as part of complex karyotype

Case report of a translocation : Chronic lymphocytic leukaemia/Small lymphocytic lymphoma (CLL/SLL) associated with translocation t(1;6)(p35;p25) as part of complex karyotype.

The expression of Bcl‐2 by proliferating cells varies in different categories of B‐cell lymphoma

To investigate the relationship between Bcl-2 protein expression and cell proliferation at single-cell level in B-cell lymphomas using double-labelling techniques. The relationship between Bcl-2 protein expression and cell proliferation was explored in 124 cases of B-cell lymphoma using double immunofluorescence labelling for Bcl-2 and Ki67. In follicular lymphoma, marginal zone lymphoma and a subset of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL), neoplastic cells tended to lose Bcl-2 when they are in cell cycle. This pattern is usually maintained in both follicular lymphoma and CLL/SLL when they undergo high-grade transformation. In mantle cell lymphoma, diffuse large B-cell lymphoma and a subset of CLL/SLL, the inverse relationship (between Bcl-2 and Ki67) was not observed, i.e. the proliferating cells tended to show co-expression of Bcl-2. In low-grade lymphomas, including those that are transformed, Bcl-2 expression is lost when cell proliferate. However, in more aggressive tumours (i.e. mantle cell and de novo diffuse large B-cell lymphomas) the inverse Bcl-2/Ki67 relationship was not observed. It would be of interest to explore the clinical implications in lymphoma of the presence and absence of the inverse Bcl-2/Ki67 pattern.

UK Myeloma Forum (UKMF) and Nordic Myeloma Study Group (NMSG): guidelines for the investigation of newly detected M‐proteins and the management of monoclonal gammopathy of undetermined significance (MGUS)

Avon Haematology Unit, Bristol Haematology and Oncology Centre, Bristol, Department of Haematology, St Helier Hospital, Carshalton, Surrey, UK, Department of Haematology, Sahlgrenska University Hospital, Gothenburg, Sweden, Department of Medicine, Malmo University Hospital, Malmo, Sweden, Division of Immunity and Infection, University of Birmingham, Birmingham, Department of Clinical Biochemistry, Frenchay Hospital, Bristol, Department Haematology, University College, London, Glasgow Western Infirmary, Glasgow, UK, Department of Haematology, NTNU/St Olavs Hospital, Trondheim, Department of Haematology, Ulleval University Hospital, Oslo, Norway, Department of Haematology Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark, and Myeloma UK.

B cell chronic lymphocytic leukaemia/small lymphocytic lymphoma: role of ZAP70 determination on bone marrow biopsy specimens

Background: The course of chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) partly depends on the mutational status of the variable region of immunoglobulin heavy chain genes (IgVH), which defines two subgroups...