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The mature splenic B‐cell lymphomas are an enigmatic group of lymphoid neoplasms that have long caused significant difficulty for the practicing pathologist due to overlapping diagnostic features among entities and the decreasing availability of splenic tissue for assessment. While some entities have highly characteristic and specific clinicopathological features (e.g. hairy cell leukaemia), others are substantially more difficult to recognise (e.g. splenic diffuse red pulp lymphoma). At the same time, classification systems have been evolving, resulting in multiple changes to the boundaries among these entities and even the existence of some entities in their own right. Moreover, unbiased multi‐omic interrogation (whole genome/transcriptome sequencing, methylome) of the splenic B‐cell lymphomas over the past decade has given us significant insights into the underling biology of these neoplasms. We present a clinicopathological perspective on the historical, current and future state of the diagnosis and classification of splenic B‐cell lymphomas integrating multi‐omic data and highlighting areas of focus for the field in order to continue to strive to improve patient outcomes through accurate diagnosis. [ABSTRACT FROM AUTHOR]

The article in the British Journal of Haematology discusses the treatment of refractory severe idiopathic immune thrombocytopenia (ITP) with daratumumab, an anti-CD38 antibody. The study reports on a case series of seven patients who received daratumumab treatment, with four patients achieving sustained complete remission. The findings suggest that daratumumab may be a valid treatment option for refractory ITP patients, leading to durable responses in some cases. Additional data from prospective clinical trials are needed to further evaluate the efficacy of daratumumab in treating ITP. [Extracted from the article]

This letter to the editor discusses a study that identified a new genetic variant in the TNFRSF13B gene in a family with lymphoid neoplasms. The TNFRSF13B gene is linked to immunodeficiency and an increased risk of certain cancers. The study provides clinical details of two patients with lymphoid malignancies and identifies other genetic variants related to hematologic malignancies. The findings suggest a possible genetic predisposition to tumors in this family. The authors recommend genetic screening for patients with a family history of tumors to aid in treatment planning and counseling. [Extracted from the article]

BRAF is one of multiple RAF proteins responsible for the activation of the MAPK cell signalling cascade involved in cell growth, differentiation, and survival. A hotspot BRAFV600E mutation, in exon 15, was determined to be a driver in 100% hairy cell leukaemias, 50%–60% of human melanomas, 30%–50% of human thyroid carcinomas and 10%–20% of human colorectal carcinomas. The orthologous BRAFV595E mutation was seen in 67% and 80% of canine bladder transitional cell carcinomas and prostatic adenocarcinomas, respectively. Since veterinary and human cancers exploit similar pathways and BRAF is highly conserved across species, BRAF can be expected to be a driver in a feline cancer. Primers were developed to amplify exon 15 of feline BRAF. One hundred ninety‐six feline tumours were analysed. Sanger sequencing of the 211 bp PCR amplicon was done. A BRAF mutation was found in one tumour, a cutaneous melanoma. The mutation was a BRAFV597E mutation, orthologous to the canine and human hotspot mutations. A common synonymous variant, BRAFT586T, was seen in 23% (47/196) of tumours. This variant was suspected to be a single nucleotide polymorphism. BRAF was not frequently mutated in common feline tumours or in tumour types that frequently harbour BRAF mutations in human and canine cancers. As is seen in canine cancer genomics, the mutational profile in feline tumours may not parallel the histologic equivalent in human oncology. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) and HCL‐like disorders have to be distinguished because of their different biology and treatment response. Thus, we conducted a retrospective study on patients with HCL and hairy cell leukemia variant (HCLv) to assess diagnostic algorithms and treatment outcomes in a real‐world setting. We analyzed 225 HCL and 26 HCLv patients with median follow‐up of 67.9 months (HCL) and 20.1 months (HCLv). Median age at diagnosis was 56.2 (HCL) and 69.5 years (HCLv), male predominance was observed in both groups (76.0% vs. 73.1%). Diagnostics was mostly based on morphological evidence of hairy cells in the peripheral blood and bone marrow. At diagnosis, BRAFV600E mutation was detected in 94.7% of examined HCL patients and in no HCLv patient. Front‐line treatment was indicated in 205 (91.1%) HCL and 18 (69.2%) HCLv patients. The majority of HCL patients were administered a cladribine‐based regimen (91.2%). Overall response rate (ORR) was higher in cladribine‐treated patients compared to those given other treatments (97.7% vs. 81.3%), the same applied with achieving Complete remission (CR) (91.2% vs. 62.5%). HCLv treatment was heterogeneous, but cladribine remained the most frequent option (44.4%) with ORR 81.3% and CR rates 43.8%. Second‐line treatment was indicated in 52 HCL and 8 HCLv patients, 25.4% and 44.4% of those treated in first‐line. In the whole HCL group, median time to next treatment (TTNT) was not reached and 10‐year TTNT was estimated at 74.1%. HCLv patients who underwent first‐line treatment had a median TTNT of 56 months. The median overall survival (OS) in HCL patients was not reached compared to HCLv with a median OS of 9.5 years. These data confirm an excellent prognosis for HCL patients treated with cladribine‐based therapy. On the contrary, HCLv with its aggressive behavior represents a group of patients in whom novel treatment approaches are needed. [ABSTRACT FROM AUTHOR]

Summary: First‐line purine nucleoside analogues (PNAs) in hairy cell leukaemia (HCL) allow deep and long‐lasting responses. We retrospectively analysed 53 HCL patients treated frontline with cladribine and assessed for response at 2 and 6 months after treatment to evaluate the kinetics of response. The estimated median progression‐free survival was significantly different according to the degree of residual HCL infiltrate detected by immunohistochemistry at the bone marrow biopsy at 2 months (≤5% vs. >5%, 247 vs. 132 months, respectively, p = 0.033), but not at 6 months (p = 0.79). Our data suggest a favourable prognostic impact of early marrow HCL clearance in patients treated with cladribine. [ABSTRACT FROM AUTHOR]

The fifth edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO‐HAEM5) is the product of an evidence‐based evolution of the revised fourth edition with wide multidisciplinary consultation. Nonetheless, while every classification incorporates scientific advances and aims to improve upon the prior version, medical knowledge remains incomplete and individual neoplasms may not be easily subclassified in a given scheme. Thus, optimal classification requires ongoing study, and there are certain aspects of some entities and subtypes that require further refinements. In this review, we highlight a selection of these challenging areas to prompt more research investigations. These include (1) a 'placeholder term' of splenic B‐cell lymphoma/leukaemia with prominent nucleoli (SBLPN) to accommodate many of the splenic lymphomas previously classified as hairy cell leukaemia variant and B‐prolymphocytic leukaemia, a clear new start to define their pathobiology; (2) how best to classify BCL2 rearrangement negative follicular lymphoma including those with BCL6 rearrangement, integrating the emerging new knowledge on various germinal centre B‐cell subsets; (3) what is the spectrum of non‐IG gene partners of MYC translocation in diffuse large B‐cell lymphoma/high‐grade B‐cell lymphoma and how they impact MYC expression and clinical outcome; how best to investigate this in a routine clinical setting; and (4) how best to define high‐grade B‐cell lymphoma not otherwise specified and high‐grade B‐cell lymphoma with 11q aberrations to distinguish them from their mimics and characterise their molecular pathogenetic mechanism. Addressing these questions would provide more robust evidence to better define these entities/subtypes, improve their diagnosis and/or prognostic stratification, leading to better patient care. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) is an infrequent and persistent B-cell inert lymphoid leukemia. In this study, we present the case of a 71-year-old female patient with a previous diagnosis of variant HCL who experienced a severe herpes zoster infection leading to an extensive skin eruption. The patient's initial diagnosis of HCL occurred 7 years ago, and she underwent treatment with cladribine, interferon, COP (cyclophosphamide, vincristine, and prednisone), benztropine tablets + clarithromycin dispersible, and ibrutinib. Immune disorders resulting from repeated prior chemotherapy and targeted therapy may potentially precipitate herpes zoster infection. Despite an initial two-week period of unresponsiveness to antivirals and nerve nutrition treatments, the introduction of topical Coptis liquid to the treatment regimen yielded significant efficacy. This case report underscores the potential of Chinese medicine as an adjunct to conventional antiviral therapy in the management of herpes zoster infection in immunocompromised patients. This treatment protocol has the potential to enhance efficacy, enhance quality of life, and serve as a more robust foundation for clinical diagnosis and improved treatments. [ABSTRACT FROM AUTHOR]

The variant form of hairy cell leukaemia (HCL‐V) is a rare disease very different from hairy cell leukaemia (HCL), which is a very well‐defined entity. The 5th WHO edition (Leukemia, 36, 2022 and 1720) classification (WHO‐HAEM5) introduced splenic lymphomas/leukaemias including four different entities: (1) HCL, (2) splenic marginal zone lymphoma (SMZL) with circulating villous cells in the peripheral blood, (3) splenic lymphoma with prominent nucleolus (SLPN), which replaced HCL‐V and CD5 negative B‐prolymphocytic leukaemia (B‐PLL), and (4) splenic diffuse red pulp lymphoma (SDRPL). All these entities have to be distinguished because of a different clinical course and the need for a different treatment. The diagnosis can be challenging because of complex cases and overlap and/or grey zones between all the entities and needs integrating clinical, histologic, immunophenotypic, cytogenetic and molecular data. We review the diagnostic criteria including clinical, immunophenotypic and molecular characteristics of patients with HCL‐V and other HCL‐like disorders including HCL, SDRPL, SMZL, B‐PLL and the Japanese form of HCL. We also discuss the different criteria allowing us to separate these different entities and we will update the recent therapeutic options that have emerged, in particular the advances with chemoimmunotherapy and/or targeted therapies. [ABSTRACT FROM AUTHOR]

This article discusses the development of a lentiviral vector-based gene therapy platform for the treatment of liver metastases (LMS). Liver metastases commonly arise from gastrointestinal tumors and are difficult to treat due to the immunosuppressive environment of the liver. The lentiviral vector delivers interferon-alpha (IFNα) to liver macrophages, which activates the immune system and reduces the growth of LMS. The study also found that combining gene-based IFNα delivery with monoclonal antibodies blocking CTLA-4 resulted in a strong therapeutic response. The use of lentiviral vectors in gene therapy has shown promise in various clinical applications and has the potential to be used in the treatment of LMS. [Extracted from the article]

Flow cytometry (FCM) has become a method of choice for immunologic characterization of chronic lymphoproliferative disease (CLPD). To reduce the potential subjectivities of FCM data interpretation, we developed a machine learning random forest algorithm (RF) allowing unsupervised analysis. This assay relies on 16 parameters obtained from our FCM screening panel, routinely used in the exploration of peripheral blood (PB) samples (mean fluorescence intensity values (MFI) of CD19, CD45, CD5, CD20, CD200, CD23, HLA‐DR, CD10 in CD19‐gated B cells, ratio of kappa/Lambda, and different ratios of MFI B‐cells/T‐cells [CD20, CD200, CD23]). The RF algorithm was trained and validated on a large cohort of more than 300 annotated different CLPD cases (chronic B‐cell leukemia, mantle cell lymphoma, marginal zone lymphoma, follicular lymphoma, splenic red pulp lymphoma, hairy cell leukemia) and non‐tumoral selected from PB samples. The RF algorithm was able to differentiate tumoral from non‐tumoral B‐cells in all cases and to propose a correct CLPD classification in more than 90% of cases. In conclusion the RF algorithm could be proposed as an interesting help to FCM data interpretation allowing a first B‐cells CLPD diagnostic hypothesis and/or to guide the management of complementary analysis (additional immunologic markers and genetic). [ABSTRACT FROM AUTHOR]

Key Clinical Message: This case of non‐nodal mantle cell lymphoma (MCL) showcases atypical hairy cell‐like features, distinguishing it via next‐generation sequencing. Despite a TP53 mutation indicating poor prognosis, our case followed an indolent course, highlighting the importance of genetic testing and phenotypical examination in MCL. [ABSTRACT FROM AUTHOR]

In this study, we aim to explore the outcomes of Covid‐19 infection in patients with Hairy cell leukemia (HCL). The cohort is based on data obtained from electronic medical records. It includes 218 consecutive patients diagnosed with HCL between 16 June 1998, and 20 September 2022, out of which the coronavirus has infected 85 patients during the Omicron surge. Out of 85 patients with HCL who were infected by Covid‐19; 7 patients (8.2%) have been hospitalized, and the mortality rate was 2.3% (two patients). Thirteen of the 85 patients had been infected by Covid‐19 in previous waves, including 9/13 after vaccination, and none of them developed a severe disease. Humoral immune response after three doses of the BNT162b2 mRNA vaccination regimen was evaluated in 40 patients and was attained in 67.5%. Based on multivariate analysis: unfavorable outcome was significantly more common in patients with HCL above 65 years old, who had at least one cytopenia, and with comorbidity of cardiovascular disease or asplenia. Our results indicates that the course of COVID‐19 in patients with HCL during the Omicron wave has been improved relatively favorable. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a 54-year-old patient with hairy-cell leukemia who survived severe COVID-19 without specific humoral immunity. The patient had undergone treatment with rituximab, which depleted both malignant and normal B cells. The study found that the patient had an increase in GM-CSF co-producing cells and a unique subset of CD4+ T cells with similarities to T-memory-stem cells (TSCM). These TSCM-like cells expressed a variety of chemokine receptors and were highly polyfunctional. The findings suggest that B cells may play a role in the terminal differentiation of T cells and that TSCM-like cells may have a diverse homing potential. [Extracted from the article]

Key Clinical Message: 18F‐FDG PET/CT has clinical relevance in HCL at diagnosis and for the follow‐up of patients treated, especially in case of atypical presentations such as bone involvements (which are probably underestimated) and poor bone marrow infiltration. Bone lesions are rarely reported in Hairy Cell Leukemia (HCL). We report two BRAFV600E mutated HCL patients presented bone lesions at foreground, poor bone marrow involvement, and the important role 18F‐FDG PET/CT played in their management. We discuss the crucial role that 18F‐FDG PET/CT could play in HCL routine practice. [ABSTRACT FROM AUTHOR]

The article discusses a case of relapsed hairy cell leukemia with atypical large cells in a 90-year-old man. The patient presented with fatigue, dyspnea, and bruising, with no lymph node or splenic enlargement. The diagnosis was confirmed through bone marrow aspirate, flow cytometry, karyotype, and next-generation sequencing. Despite previous treatments, the patient declined further treatment and passed away from progressive disease. This rare case sheds light on the challenges of managing relapsed hairy cell leukemia with atypical features. [Extracted from the article]

Introduction: Frontline treatment of hairy cell leukemia (HCL) with a single course of the purine nucleoside analog (PNA) produces a high rate of complete remission (CR) with prolonged durations. At the time of relapse, although treatment guidelines recommend re‐treatment with a PNA alone or in combination with rituximab (R), practice patterns vary and data supporting each approach are limited. Methods: We conducted a multisite outcomes analysis of patients treated for HCL between 1995 and 2018 at six US medical centers. All patients were treated with frontline PNA and subsequently required treatment with a PNA alone (PNA) or with R (+R). Results: Of the 88 patients analyzed, 56 (63.6%) received second‐line PNA and 22 (36.4%) received a PNA + R. Baseline characteristics of both groups were similar. There was no difference in median PFS [67 months (95% CI 43.8 non‐reached (NR)) vs. 65 months (95% CI 60‐NR)] or 5‐year OS [98% (95% CI 0.94–1) vs. 94% (95% CI 0.83–1), p =.104] in the PNA versus PNA + R cohorts, respectively. Conclusion: To our knowledge, this is the largest study evaluating the role of R in treatment of relapsed HCL and suggests that there is no advantage to the addition of R to PNA therapy at the time of first re‐treatment. [ABSTRACT FROM AUTHOR]

BRAFV600E mutation is the pathogenic driver of hairy cell leukemia (HCL) found in the vast majority of cases both at onset and during recurrences. The identification of the mutated allele in blood and marrow correlates with the presence of neoplastic cells and can be considered a marker of active disease. Likewise, the absence of the mutation after treatment may indicate a state of deep response. The BRAFV600E burden was measured by droplet digital polymerase chain reaction (ddPCR) and expressed as fractional abundance in 35 HCL patients at different stages of disease (onset, relapse, complete response [CR] after treatment, long‐term remission) in peripheral blood and/or bone marrow (when available). Mean values of fractional abundance for patients at diagnosis, relapse and response, respectively, were 12.26%, 16.52% and 0.02% in peripheral blood and 23.51%, 13.96% and 0.26% in bone marrow. Four patients out of 6 evaluated at response were molecularly negative for BRAFV600E in peripheral blood. Mean fractional abundance in peripheral blood tested in 14 patients with long lasting CR was 0.05%, and 10 patients were BRAFV600E negative. These preliminary results suggest that ddPCR permits to assess the active tumor burden in HCL at different disease phases and support the hypothesis that some patients in CR qualify for a molecular CR. [ABSTRACT FROM AUTHOR]

Skeletal involvement is a rare complication of hairy cell leukemia (HCL) with an incidence of approximately 3%. Bone lesions are commonly lytic, and the most common sites of involvement are the femoral head and neck. Skeletal involvement is typically associated with high tumor burden and bone marrow infiltration. However, isolated cases of skeletal disease without splenomegaly or bone marrow involvement are occasionally reported. This review focuses on skeletal lesions in HCL, particularly the pathogenesis, clinical symptoms, diagnostic methods, and treatment approach. A literature review of the MEDLINE database for articles in English concerning hairy cell leukemia, skeletal symptoms, bone involvement was conducted via PubMed. Publications from January 1970 to May 2020 were scrutinized. Additional relevant publications were obtained by reviewing the references from the chosen articles. [ABSTRACT FROM AUTHOR]

Mature lymphoid B‐cell proliferations with hairy cells represent heterogeneous entities where specific diagnosis is difficult but important since it impacts therapeutic management. The clinical cases of variant hairy cell leukemia reported herein illustrate the persistence of a clear interest in the use of splenectomy as a therapeutic alternative. Furthermore, ibrutinib appears to be a promising treatment in patients with relapsed/refractory disease. [ABSTRACT FROM AUTHOR]

BRAF mutation detection is worthwhile for the management of patients with some advanced cancers. The tumor samples are sometimes difficult to analyze using DNA‐based molecular methods because of poor tumor DNA quality or quantity. Anti‐BRAFV600E VE1 immunohistochemistry (IHC) has been proposed as a valuable ancillary tool to analyze some "molecularly challenging" tumor samples. In this technical study, we focused on its application in the field of decalcified tumor samples. We selected four patients with known BRAFV600E‐mutated cancer (3 metastatic melanomas and 1 hairy cell leukemia) and paired non‐decalcified/decalcified tumor samples. Molecular analyses failed in the four decalcified samples (3 bone metastases and 1 osteo‐medullar biopsy) with non‐contributive mutation status. Whereas non‐decalcified tumor samples were all positive using anti‐BRAFV600E VE1 IHC, the four decalcified samples were concluded negative. Because decalcified tumor samples are difficult to analyze from a molecular point of view, it is tempting to use IHC instead of DNA‐based methods searching for BRAFV600E mutations in these samples. Nevertheless, the decalcification process may also cause false‐negative results using VE1 IHC. Decalcified samples require specific and optimized IHC and molecular protocols and quality controls. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia (HCL) and Merkel cell carcinoma (MCC) are two rare malignancies with distinct cells of origin. HCL is a lymphoid malignancy of mature B cells, and MCC derives from neuroendocrine cell origin. HCL has a favorable prognosis with most patients achieving long-term remission and potential cure. In contrast, MCC is an aggressive malignancy affecting the skin and can metastasize quickly with a dismal prognosis. Immunocompromised patients, such as those with AIDS, posttransplant, and the elderly, have higher incidences than the general population, suggesting a possible immune mechanism. We report a case where a patient presented with HCL and metastatic MCC synchronously. This is the first reported case of these two rare malignancies occurring concurrently at initial presentation and may represent a role of immunosuppression in the pathogenesis of MCC. [ABSTRACT FROM AUTHOR]

Listeria monocytogenes infections have been described in patients with diverse types of malignancy, especially leukemia. We report the case of a 65-year-old man with previously untreated hairy cell leukemia characterized by CD5 positivity and trisomy 12 (3% of blood lymphocytes) who developed bacteremia due to L. monocytogenes serotype 1/2b. We summarize clinical features and treatment of this patient and five previously reported patients with hairy cell leukemia who also had L. monocytogenes infections. All six patients were men. Their mean age at infection diagnosis was 70 y. Three men had undergone splenectomy 4–11 y before they developed L. monocytogenes infection. The central nervous system was the primary site of infection in four men. Bacteremia alone occurred in two other men. At diagnosis of infection, one man was receiving antileukemia chemotherapy and another man was receiving treatment for Kaposi’s sarcoma. Two other patients had other comorbid conditions. All six men recovered from their infections. [ABSTRACT FROM AUTHOR]

Aims Hairy cell leukaemia ( HCL) is a rare B cell neoplasm that mainly affects bone marrow ( BM), peripheral blood ( PB) and spleen. Involvement of lymph nodes and extranodal structures is considered infrequent. Herein we describe our institutional experience of nodal ( n = 10) and extranodal ( n = 3) HCL during a 30-year period. Methods and results Ten patients had prior evidence of HCL within the BM or PB at a median 35.8 months before nodal/extranodal diagnosis (range: <1-175 months), and HCL was diagnosed concurrently within the bone marrow of one additional patient. Nodal involvement showed distinct architectural patterns, including diffuse (62% of cases), sinusoidal (25%) and nodular (13%). Extranodal involvement was characterized as diffuse infiltration through underlying structures in all cases. Morphological features ranged from classic 'fried-egg' cytology to a plasmacytoid appearance. Nodal/extranodal disease showed an overlapping immunophenotypical profile with other small B cell lymphomas, including expression of cyclin D1 (70%), CD43 (55%), CD10 (38%) and CD5 (8%). Rates of both CD43 and CD10 reactivity were higher than described previously in leukaemic HCL, suggesting that expression may be enriched in cases with extramedullary extension. Conclusions Although uncommon, HCL should be considered in the differential diagnosis of small B cell neoplasms involving nodal/extranodal sites, given the therapeutic implications. In particular, recent discoveries including detection of the BRAF V 600E mutation in nearly all cases of HCL and the availability of an antibody to CD103 for use in paraffin-embedded tissues will facilitate the distinction of HCL from other small B cell lymphomas in the nodal/extranodal setting. [ABSTRACT FROM AUTHOR]

Patients with hairy cell leukaemia ( HCL) have highly favourable outcomes after purine analogue therapy. However, most patients subsequently relapse and require re-treatment. A minority of patients develop purine analogue-refractory disease. Targeted therapies have improved outcomes for such patients. Recently, the BRAF V600E mutation was identified in most patients with classical HCL, resulting in constitutive mitogen-activated protein kinase pathway activation; impressive responses are achieved in heavily pre-treated patients with BRAF inhibition. The CD22-targeted immunoconjugate moxetumomab pasudotox and BTK inhibitor ibrutinib also achieve responses in relapsed and refractory patients. HCL variant and the IGHV4-34 molecular variant of HCL lack BRAF mutation and have inferior outcomes with standard purine analogue therapy. The addition of rituximab to purine analogues achieves very high rates of minimal residual disease-negative complete remission and improves outcomes for patients with HCL variant. Given the rarity of HCL, optimal integration of novel therapies into treatment algorithms will require well-designed, collaborative studies. [ABSTRACT FROM AUTHOR]

Nucleoside analogues are highly active in patients with hairy cell leukaemia (HCL); however, patients continue to relapse. This phase II study evaluated the efficacy and safety of cladribine followed by rituximab in patients with untreated HCL ( N = 59), relapsed HCL ( N = 14) and HCL variant (HCLv, N = 7). Cladribine 5·6 mg/m2 was given intravenously (IV) daily for 5 d and was followed approximately 1 month later with rituximab 375 mg/m2 IV weekly for 8 weeks. Complete response rate in patients with untreated HCL, relapsed HCL and HCLv was 100%, 100% and 86%, respectively. With a median follow up of 60 months, 5-year failure-free survival (FFS) in patients with untreated HCL, relapsed HCL and HCLv was 95%, 100% and 64%, respectively. Median duration of response to the cladribine followed by rituximab was significantly longer than the first-line cladribine single agent in patients who received this treatment as second-line treatment (72 months vs not reached, P = 0·004). Almost all patients (94%) achieved negative minimal residual disease (MRD) after the treatment. Positive MRD during the follow up did not necessarily result in clinically relevant relapse. Cladribine followed by rituximab is highly effective even in patients with relapsed disease and HCLv, and can achieve durable remission. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which describes the development of large B-cell lymphoma after hairy cell leukaemia-variant (HCL-v) mutation.

Key Clinical Message: The morphologic diagnosis of hairy cell leukemia coexisting with another lymphoproliferative disorder is hindered by the small size of hairy cell population. It can be simplified by presorting peripheral blood mononuclear cell using an anti‐CD antibody microarray on transparent support (including anti‐CD11c, CD25, CD103, and CD123) before their morphology analysis. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Diffuse large B‐cell lymphoma in rare instances can present initially in a leukemic phase and mimic other lymphoid diseases. In such cases, advanced diagnostic testing including immunophenotyping, FISH analysis, and karyotyping can help determine the accurate diagnosis which is key in the management of the disease. [ABSTRACT FROM AUTHOR]

We describe an unusual case of hairy cell leukemia (HCL) in a 55-year-old male presenting with isolated skeletal disease as the initial manifestation without abnormal peripheral blood counts, bone marrow involvement, or splenomegaly. To the best of our knowledge, there have been only two previous reports of a similar case. The patient presented with pain in the right femur. Anteroposterior radiographs of both femurs revealed mixed lytic-sclerotic lesions. PET scan showed multiple metastatic lesions on axial skeleton, pelvis, and both femurs. Histopathological examination of the bone biopsy revealed an infiltrate of HCL. Localized radiation therapy to both proximal femurs and subsequently 4 weeks later, a 7-day course of 0.1 mg/kg/day cladribine provided complete remission with relief of symptoms and resolution of bone lesions. We addressed the manifestations and management of HCL patients with skeletal involvement. [ABSTRACT FROM AUTHOR]

In this multicenter retrospective analysis, we aimed to present clinical, laboratory and treatment results of 94 patients with Hairy cell leukemia diagnosed in 13 centers between 1990 and 2014. Sixty-six of the patients were males and 28 were females, with a median age of 55. Splenomegaly was present in 93.5% of cases at diagnosis. The laboratory findings that came into prominence were pancytopenia with grade 3 bone marrow fibrosis. Most of the patients with an indication for treatment were treated with cladribine as first-line treatment. Total and complete response of cladribine was 97.3% and 80.7%. The relapse rate after cladribine was 16.6%, and treatment related mortality was 2.5%. Most preferred therapy (95%) was again cladribine at second-line, and third line with CR rate of 68.4% and 66.6%, respectively. The 28-month median OS was 91.7% in all patients and 25-month median OS 96% for patients who were given cladribine as first-line therapy. In conclusion, the first multicenter retrospective Turkish study where patients with HCL were followed up for a long period has revealed demographic characteristics of patients with HCL, and confirmed that cladribine treatment might be safe and effective in a relatively large series of the Turkish study population. [ABSTRACT FROM AUTHOR]

Aims Hairy cell leukaemia ( HCL) is an indolent B-cell neoplasm that primarily involves the peripheral blood, bone marrow, and spleen. Rarely, patients with HCL present with a lymphoma-like clinicopathological picture mimicking other types of low-grade B-cell lymphoma. Distinguishing HCL from other types of lymphoma is essential, given the different treatments and prognoses. We report two cases of the lymphomatous variant of HCL to draw attention to this unusual presentation. Methods and results Two cases of HCL presented initially as salivary gland and soft tissue masses. Morphologically, the neoplastic cells showed a typical fried-egg or monocytoid appearance with reniform nuclei, and were positive for CD11c, CD20, CD25, CD103, annexin A1, and cyclin D1. Both cases were positive for the BRAF V600E mutation, as shown by pyrosequencing and mutation-specific immunohistochemistry. The diagnosis was challenging in both patients, and one patient experienced 5 years of disease relapse and progression after treatment with multiple lymphoma-type regimens before the final diagnosis of HCL was established and complete remission was achieved following cladribine therapy. Conclusions HCL can very rarely present as an extranodal mass. Being aware of this unusual presentation of HCL is essential to avoid diagnostic confusion with other types of low-grade B-cell lymphoma and to facilitate appropriate therapy. [ABSTRACT FROM AUTHOR]

Few studies have examined melanoma and non-melanoma skin cancer ( NMSC) incidence rates after a diagnosis of hairy cell leukaemia ( HCL). We assessed 267 HCL patients treated at Memorial Sloan Kettering Cancer Center ( MSKCC) and Surveillance, Epidemiology and End Results ( SEER) data for melanoma and NMSC incidence rates after HCL. Incidence data from MSKCC patients demonstrated a 10-year combined melanoma and NMSC skin cancer rate of 11·3%, melanoma 4·4% and NMSC 6·9%. Molecular analysis of skin cancers from MSKCC patients revealed activating RAS mutations in 3/9 patients, including one patient with melanoma. Of 4750 SEER patients with HCL, 55 (1·2%) had a subsequent diagnosis of melanoma. Standardized incidence ratios ( SIRs) did not show that melanoma was more common in HCL patients versus the general population ( SIR 1·3, 95% CI 0·78-2·03). Analysis of SEER HCL patients diagnosed before and after 1990 (approximately before and after purine analogue therapy was introduced) showed no evidence of an increased incidence after 1990. A better understanding of any potential association between HCL and skin cancer is highly relevant given ongoing trials using BRAF inhibitors, such as vemurafenib, for relapsed HCL, as RAS-mutant skin cancers could be paradoxically activated in these patients. [ABSTRACT FROM AUTHOR]

The Kytococcus genus formerly belonged to Micrococcus. The first report of a Kytococcus schroeteri infection was in 2002 in a patient diagnosed with endocarditis. We report a case of central line associated Kytococcus schroeteri bacteremia in a patient with underlying Hairy Cell Leukemia. Kytococcus schroeteri is an emerging infection in the neutropenic population and in patients with implanted artificial tissue. It is thought to be a commensal bacterium of the skin; however, attempts to culture the bacteria remain unsuccessful. There have been a total of 5 cases (including ours) of K. schroeteri bacteremia in patients with hematologic malignancies and neutropenia and only 18 documented cases in any population. Four of the cases of bacteria in neutropenic patients have been fatal, but early detection and treatment could make a difference in clinical outcomes. [ABSTRACT FROM AUTHOR]

The article presents the Plasma cell leukemia morphologically resembling hairy cell leukemia variant. Topics discussed include the morphological characteristics of myeloma plasma cells vary from mature to plasmablastic and pleomorphic forms; and describe one rare case of PCL, presenting as hairy cell leukemia variant (HCL-v).

Frequencies of human leucocyte antigens ( HLA) were determined in 287 classic hairy cell leukaemia ( HCL) patients. With respect to both population ( n = 287) and allele (2 n = 574) frequency respectively, the most common HLA class I and II antigens expressed were HLA-A*02 (49·1% and 28·6%), HLA-B*07 (21·3% and 11·1%), HLA-C*07 (46·7 and 28·2%), HLA- DQB1*03 (62·7% and 37·3%), HLA- DRB1*11 (30·0% and 16·0%) and HLA- DRB4*01 (45·3% and 29·6%). In comparing 6-14 databases of control Caucasians to 267 Caucasian HCL patients, only HLA- DRB1*11 was consistently over-represented in HCL, 31·1% of patients vs. 17-19·9% of controls ( P = 0·0055 to <0·0001) and 16·5% of alleles vs. 6·5-12·3% of control alleles ( P = 0·022 to <0·0001). HLA- DRB1*11 is a known risk factor for acquired thrombotic microangiopathy. Anti- CD22 recombinant immunotoxin BL22 in HCL was associated with a 12% incidence of completely reversible grade 3-4 haemolytic uraemic syndrome ( HUS), mainly during the second or third retreatment cycle. Of 49 HCL patients receiving ≥2 cycles of BL22, 7 (14%) had HUS and HLA- DRB1*11 was expressed in 71% of 7 with HUS compared with only 21% of 42 without ( P = 0·015). These data suggest that DBR1*11 may be a marker for increased susceptibility to HCL and, among HCL patients, could be a risk factor for BL22-induced HUS. [ABSTRACT FROM AUTHOR]

A large, multicentre, retrospective survey of patients with hairy cell leukaemia ( HCL) was conducted in France to determine the frequency of second malignancies and to analyse the long-term effects of the established purine nucleoside analogues ( PNAs), cladribine and pentostatin. The survey retrospectively reviewed the medical history of patients and their immediate family, clinical and biological presentation at the time of HCL diagnosis, treatment choice, response to treatment, time to relapse and cause of death. Data were collected for 487 patients with HCL. Of the patients included in the survey, 18% (88/487) had a familial history of cancers, 8% (41/487) presented with malignancies before HCL diagnosis and 10% (48/487) developed second malignancies after HCL was diagnosed. An excess incidence of second malignancies was observed, with a standardized incidence ratio ( SIR) of 1·86 (95% confidence interval ( CI): 1·34-2·51), with no significant difference between PNAs. For second haematological malignancies alone, the SIR was markedly increased at 5·32 (95% CI: 2·90-8·92). This study highlights the high frequency of cancers in HCL patients and their family members. The frequency of second malignancies is notably increased, particularly for haematological malignancies. The respective role of pentostatin and cladribine in the development of second malignancies is debatable. [ABSTRACT FROM AUTHOR]

B cell receptor ( BCR) signalling plays a critical role in the progression of several B-cell malignancies, but its role in hairy cell leukaemia ( HCL) is ambiguous. Bruton tyrosine kinase ( BTK), a key player in BCR signalling, as well as B cell migration and adhesion, can be targeted with ibrutinib, a selective, irreversible BTK inhibitor. We analysed BTK expression and function in HCL and analysed the effects of ibrutinib on HCL cells. We demonstrated uniform BTK protein expression in HCL cells. Ibrutinib significantly inhibited HCL proliferation and cell cycle progression. Accordingly, ibrutinib also reduced HCL cell survival after BCR triggering with anti-immunoglobulins and abrogated the activation of kinases downstream of the BCR ( PI3 K and MAPK). Ibrutinib also inhibited BCR-dependent secretion of the chemokines CCL3 and CCL4 by HCL cells. Interestingly, ibrutinib inhibited also CXCL12-induced signalling, a key pathway for bone marrow homing. Collectively, our data support the clinical development of ibrutinib in patients with HCL. [ABSTRACT FROM AUTHOR]

Although purine analogues have significantly improved the outcome of hairy cell leukaemia ( HCL) patients, 30-40% relapse, illustrating the need for minimal residual disease ( MRD) markers that can aid personalized therapeutic management. Diagnostic samples from 34 HCL patients were used to design an 8-colour flow cytometry (8- FC) tube for blood MRD (B/ RD) analysis (188 samples) which was compared to quantitative IGH polymerase chain reaction (Q- PCR) on 83 samples and to qualitative consensus IGH PCR clonality analysis on 165 samples. Despite heterogeneous HCL phenotypes at diagnosis, discrimination from normal B lymphocytes was possible in all cases using a single 8- FC tube, with a robust sensitivity of detection of 10−4, comparable to Q- PCR at this level, but preferable in terms of informativeness, simplicity and cost. B/ RD assessment of 15 patients achieving haematological complete remission after purine analogues was predictive of a clinically significant relapse risk: with a median follow-up of 95 months; only one of the nine patients with reproducible 8- FC B/ RD levels below 10−4 (B/ RDneg) relapsed, compared to 5/6 in the B/ RDpos group ( P = 0·003). These data demonstrate the clinical interest of a robust 8- FC HCL B/ RD strategy that could become a surrogate biomarker for therapeutic stratification and new drug assessment, which should be evaluated prospectively. [ABSTRACT FROM AUTHOR]

Vasculitis is relatively uncommon in lymphoproliferative disease and may predate the diagnosis of lymphoproliferative disease. Many vasculitides have been associated with hairy cell leukemia ( HCL), including polyarteritis nodosa ( PAN) and leukocytoclastic vasculitis. We herein report a case whose initial presentation was like Behçet's disease ( BD) (arthritis, oral and genital ulcerations, papulopustular skin lesions) in addition to pancytopenia, but turned out to have HCL. Because of the overlap between their symptoms, like oral ulcerations, skin lesions, arthritis and constitutional findings, HCL and BD may mimic each other. We should keep in mind other reasons for vasculitis such as lymphoproliferative disease, especially whose who have hematological abnormalities such as pancytopenia. [ABSTRACT FROM AUTHOR]

The BRAF V600 E mutation in exon 15 is considered the disease-defining mutation in hairy cell leukaemia ( HCL), but single HCL cases lacking this mutation have been described. In 24 HCL, as well as in 194 various mature B- and T-cell neoplasms, we extended the search for BRAF mutations to exon 11. Two V600E-negative HCL contained novel, potentially functionally relevant mutations in exon 11 (F468C and D449E), while one other HCL was BRAF wild-type in exons 2-17. All non- HCL lymphomas lacked BRAF mutations. We therefore suggest screening of BRAF V600E-negative HCL for alternative exon 11 mutations in the diagnostic setting. [ABSTRACT FROM AUTHOR]

We report a 43-year-old woman, who underwent therapy with interferon-α for hairy cell leukemia. During interferon-α therapy she developed multiple subcutaneous swellings, accompanied by fever and fatigue. A skin biopsy revealed lobular, T-cell lymphocytic panniculitis. In conjunction with the clinical and immunological findings, the diagnosis of lupus panniculitis was made and interferon-α therapy stopped. Initially, she responded well to oral prednisone and hydroxychloroquine, but after several months she became resistant to it. Her condition worsened, she developed skin ulcers in the inflamed regions. Only with the leukemia-targeted therapy using cladribine and rituximab her skin condition could be controlled, suggesting hairy cell leukemia as an additional trigger of the lupus panniculitis. Our report is the first one to show induction of lupus panniculitis under interferon therapy of hairy cell leukemia and its presumable sustentation by the latter. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia ( HCL) is a very rare mature B-cell neoplasm and its simultaneous occurrence with chronic myeloid leukemia has been reported in only three cases. The pathogenesis and relationship of the two diseases are not clear. Here we report a case of HCL expressing a BCR/ ABL1 clone, which showed molecular remission of the fusion clones and achieved partial remission over nine months of cladribine therapy. After a thorough analysis of previous studies and the results of this patient, we speculate that a subclone evolved to have an additional genetic BCR/ ABL1 rearrangement. We also review all published literature on HCL with BCR/ ABL1 rearrangement and discuss the pathophysiology of these unusual cases. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia/lymphoma (HCL) is a rare B-cell neoplasm primarily involving spleen, bone marrow, and blood. However, other sites of primary involvement do occur and can present a diagnostic and therapeutic challenge. We present an unusual case of HCL involving predominantly the breast that was diagnosed as an incidental finding during an elective reduction mammoplasty in an otherwise healthy asymptomatic woman. Bone marrow performed for staging revealed limited involvement by HCL. Notably, there was no splenomegaly and/or involvement of other extramedullary sites. The peripheral blood revealed minimal involvement detected by flow cytometry. Extensive immunohistochemical studies supported by positive BRAF V600E mutational status confirmed the diagnosis of HCL. The patient remains asymptomatic without treatment one year following the diagnosis. This is the first case of a well-documented HCL presenting primarily in the breast in an asymptomatic patient. We review the literature on extramedullary, extrasplenic involvement by HCL and discuss the diagnostic challenges as well as the utility of immunohistochemistry and molecular studies in the diagnosis of atypical presentations of HCL. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia is a rare lymphoid neoplasm arising from mature B-lymphocytes. Clinically, the disease presents with splenomegaly and abdominal discomfort, frequent infections, fatigue and bleeding because of related cytopenias. Bone marrow biopsy is essential for diagnosis. Below we describe a case of a 70-year-old African-American male who presented to our hematology clinic complaining of fatigue. Clinical exam and computed tomography imaging did not reveal splenic enlargement. Blood work-up revealed pancytopenia and bone marrow was diagnostic for hairy cell leukemia. The patient was started on cladribine, with gradual improvement of his symptoms and blood count abnormalities. Therefore, it is essential to keep hairy cell leukemia in the differential of pancytopenia even in the absence of a splenomegaly. [ABSTRACT FROM AUTHOR]

Hairy cell leukemia can cause massive splenomegaly which may lead to urinary retention and constipation. Patients usually require a splenectomy for relief of symptoms. [ABSTRACT FROM AUTHOR]

The article discusses a study on sensitive diagnostic marker BRAF V600E mutation-specific antibody revealing minimal residual disease in hairy cell leukaemia (HCL). The study included Reverse transcription polymerase chain reaction and conventional staining. The study assessed the specificity and sensitivity of immunohistochemical diagnosis of HCL using BRAF V600E mutated cells specific antibody demonstrating detection of minimal residual disease (MRD).

Hairy cell leukaemia variant ( HCL-variant) and splenic marginal zone lymphoma ( SMZL) are disorders with overlapping features. We investigated the prognostic impact in these disorders of clinical and molecular features including IGH VDJ rearrangements, IGHV gene usage and TP 53 mutations. Clinical and laboratory data were collected before therapy from 35 HCL-variant and 68 SMZL cases. End-points were the need for treatment and overall survival. 97% of HCL-variant and 77% of SMZL cases required treatment ( P = 0·009). Survival at 5 years was significantly worse in HCL-variant [57% (95% confidence interval 38-73%)] compared with SMZL [84% (71-91%); Hazard Ratio 2·25 (1·20-4·25), P = 0·01]. In HCL-variant, adverse prognostic factors for survival were older age ( P = 0·04), anaemia ( P = 0·01) and TP 53 mutations ( P = 0·02). In SMZL, splenomegaly, anaemia and IGHV genes with >98% homology to the germline predicted the need for treatment; older age, anaemia and IGHV unmutated genes (100% homology) predicted shorter survival. IGHV gene usage had no impact on clinical outcome in either disease. The combination of unfavourable factors allowed patients to be stratified into risk groups with significant differences in survival. Although HCL-variant and SMZL share some features, they have different outcomes, influenced by clinical and biological factors. [ABSTRACT FROM AUTHOR]

Summary The British Committee for Standards in Haematology first produced guidelines for the diagnosis and management of hairy cell leukaemia and hairy cell leukaemia variant in 2000. This revision updates those guidelines and covers the areas of diagnosis, treatment and assessment of response to therapy. [ABSTRACT FROM AUTHOR]