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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.

Key Points Comparison of the mutation frequencies and numbers of 122 genes in 3096 cases enables identification of “mutation-driven” entities.Differences in mutation patterns in cases with or without CHIP-associated mutations across entities suggest differences in pathophysiology., Visual Abstract, Acquired somatic mutations are crucial for the development of most cancers. We performed a comprehensive comparative analysis of the mutational landscapes and their correlation with CHIP-related (clonal hematopoiesis of indeterminate potential) mutations and patient age of 122 genes in 3096 cases of 28 different hematological malignancies. Differences were observed regarding (1) the median number of mutations (highest, median n = 4; lowest, n = 0); (2) specificity of certain mutations (high frequencies in atypical chronic myeloid leukemia [aCML; ASXL1, 86%], follicular lymphoma [FL; KMT2D, 87%; CREBBP, 73%], hairy cell lymphoma [BRAF, 100%], lymphoplasmacytic lymphoma [MYD88, 98%; CXCR4, 51%], myeloproliferative neoplasm [MPN; AK2, 68%]); (3) distribution of mutations (broad distribution within/across the myeloid/lymphoid lineage for TET2, ASXL1, DNMT3A, TP53, BCOR, and ETV6); (4) correlation of mutations with patient’s age (correlated with older age across entities: TET2, DNMT3A, ASXL1, TP53, EZH2, BCOR, GATA2, and IDH2; younger age: KIT, POT1, RAD21, U2AF2, and WT1); (5) correlation of mutation number per patient with age. Moreover, we observed high frequencies of mutations in RUNX1, SRSF2, IDH2, NRAS, and EZH2 in cases comprising at least 1 DTA (DNMT3A, TET2, ASXL1) mutation, whereas in cases without DTA mutations, TP53, KRAS, WT1, and SF3B1 were more frequent across entities, suggesting differences in pathophysiology. These results give further insight into the complex genetic landscape and the role of DTA mutations in hematological neoplasms and define mutation-driven entities (myelodysplastic syndrome/MPN overlap; secondary acute myeloid) in comparison with entities defined by chromosomal fusions (chronic myeloid leukemia; myeloid/lymphoid neoplasm with eosinophilia).

Primary splenic lymphoma (PSL) is a rare malignancy representing about 1% of all lymphoproliferative disorders, when using a strict definition that allows only involvement of spleen and hilar lymph nodes. In contrast, secondary low-grade B-cell lymphomas in the spleen, such as follicular lymphomas (FL), lymphoplasmacytic lymphoma and chronic lymphocytic leukemia/ small lymphocytic lymphoma, particularly as part of advanced stage disease, are more common. Indolent B cell lymphomas expressing CD10 almost always represent FL, which in its primary splenic form is the focus of this review. Primary splenic follicular lymphoma (PSFL) is exceedingly infrequent. This type of lymphoproliferative disorder is understudied and, in most cases, clinically characterized by splenomegaly or cytopenias related to hypersplenism. The diagnosis requires correlation of histopathology of spleen, blood and/or bone marrow with the correct immunophenotype (determined by flow cytometry and/or immunohistochemistry) and if necessary, additional molecular profiling. Management of this incurable disease is evolving, and splenectomy remains the mainstream treatment for stage I PSFL.

A 53-year-old woman was diagnosed with lymphoplasmacytic lymphoma (LPL)/Waldenström's macroglobulinemia (WM) in 2008. Six courses of R-COP (rituximab, cyclophosphamide, vincristine, and prednisolone) resulted in complete remission, but LPL/WM relapsed in 2015. After six courses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone), the M-peak disappeared, but the patient presented with muscle weakness and sensory disturbance in the lower extremities. No lesions were apparent in the brain parenchyma, but T2-weighted magnetic resonance imaging (MRI) showed a signal-hyperintense area with contrast enhancement in the spinal cord at the C2-4 and Th2-3 levels, and cerebrospinal fluid (CSF) examination showed only a few mononuclear cells. In 2020, the patient started to require walking assistance, and MRI findings worsened. Neurologically, lower limb muscle strength was reduced (manual muscle test score 3), and sensations of touch and pain were about 30% of normal. Vibratory sensation was absent at the knees and medial malleoli, accompanied by dysuria due to neurogenic bladder. CSF cell count was 15/μl (all mononuclear cells). Bing-Neel syndrome (BNS) was diagnosed and tirabrutinib was started. Within 2 months of treatment, lower extremity muscle strength had normalized and MRI findings had improved. Tirabrutinib may offer a promising therapeutic option for BNS.

Cutaneous reactive angiomatosis, a group of disorders defined by benign vascular proliferation, is associated with a number of systemic processes, including intravascular occlusion by cryoproteins. We report a case of a 64-year-old female patient who presented with a one-year history of non-tender petechiae of the bilateral arms and lower legs. Dermoscopic evaluation showed increased vascularity with a globular pattern. Over a period of months, her findings progressed to erythematous to violaceous plaques with admixed hypopigmented stellate scarring of the bilateral lower extremities, forearms, and lateral neck. Biopsy showed increased thin-walled, small dermal blood vessels with focal inter-anastamosis. Some vessels were occluded by eosinophilic globules suspicious for cryoprotein. Subsequent laboratory studies confirmed a diagnosis of type 1 cryoglobulinemia, prompting a bone marrow biopsy that revealed lymphoplasmacytic lymphoma. Herein we report the fourth case of angiomatosis secondary to intravascular cryoproteins as the initial presentation of an underlying hematologic malignancy. We also present a review of the literature and emphasize the need for thorough initial work-up and close and prolonged clinical monitoring for underlying systemic disease in these patients. This article is protected by copyright. All rights reserved.

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder caused by a reduced concentration and/or function of von Willebrand factor (VWF) with no prior or family history of congenital vo...

Purpose 68Ga-pentixafor PET/CT was reported to have a high sensitivity in detecting tumor involvement of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) in our previous study. We aimed to further investigate the semi-quantitative measurements of 68Ga-pentixafor PET/CT in response assessment in WM/LPL. Methods Fifteen patients with WM/LPL were recruited in a prospective cohort study and underwent both 68Ga-pentixafor and 18F-FDG PET/CT at baseline and post-treatment. PET/CT-based responses were analyzed with semi-quantitative assessments of metabolic tumor volume (MTV) and total lesions glycolysis/uptake (TLGFDG and TLUCXCR4), and the correlation between PET/CT-based response and clinical response, monoclonal protein and IgM response was analyzed. Results After chemotherapy, 5 patients had complete response or very good partial response, 8 had partial response or minimal response and 2 had progressive disease. In quantitative analysis, 68Ga-pentixafor PET/CT-based response (measured in ∆TLUCXCR4%, ∆MTVCXCR4%, ∆SUVpeak%) showed a significant direct correlation with clinical response, monoclonal protein and IgM response (p 18F-FDG PET/CT-based response was independent from clinical response (p > 0.05). Conclusions The semi-quantitative measurements of 68Ga-pentixafor PET/CT outperformed 18F-FDG PET/CT in response assessment of WM/LPL.

Background Primary malignant tumours of the retropharyngeal space are rare with only a few case reports in the literature. Lymphoplasmacytic lymphoma is a rare subtype of non-Hodgkin lymphoma and is very rarely found as a primary tumour of the retropharyngeal space. Case presentation We report the case of progressive upper airway obstruction in a 49-year-old male caused by a primary malignant tumour of the retropharyngeal space lymph nodes. He had an emergency tracheostomy to relieve the upper airway obstruction followed a week later by an elective surgical excision of the tumour via the trans-cervical route. A mixed population of lymphocytes, with a marked presence of Dutcher bodies, was noted on histopathology and positive CD20 on immunohistochemistry, confirming the lymphoplasmacytic lymphoma of the retropharyngeal space. The watchful waiting treatment method for the lymphoma was employed for him since he had no symptoms relating to lymphoma and no serum Waldenström’s macroglobulinemia. He has remained symptom-free 3 years post-surgery. Conclusion Primary malignant tumours involving the retropharyngeal space lymph nodes are very rare. They can rarely grow to a size huge enough to cause obstructive upper aerodigestive symptoms. Primary lymphoma of the retropharyngeal space should be considered in the diagnosis of the tumours involving the retropharyngeal space lymph nodes. Excisional biopsy is important to obtain tissue for histopathological diagnosis and the relief of upper aerodigestive tract obstruction when present.

Background Acquired factor X deficiency is an uncommon condition, and affected individuals have severe and spontaneous bleeding. The associated conditions include malignancy, infection, burn, and inflammatory bowel disease. Many previous studies reported association between lymphoproliferative disease and factor X disappearance. Amyloid deposition causing factor X absorption was the most common mechanism. Here, we report a case of stage IV lymphoplasmacytic lymphoma (LPL) with factor X deficiency who was successfully treated with bendamustine plus rituximab (BR) regimen. Case presentation A 52-year-old Thai woman presented with heavy menorrhea, hoarseness, and widespread ecchymosis at her extremities. On physical examination, the patient had bilateral periorbital purpura and vocal cord hematoma. Coagulation testing showed prolonged prothrombin time (PT) and prolonged activated thromboplastin time (aPTT); however, after mixing with 1:1 normal pooled plasma, PT and aPTT were both corrected to normal levels. Factor assays demonstrated markedly decreased factor X levels, but no presence of factor X inhibitor. Bone marrow examination revealed numerous abnormal lymphoplasmacytoid lymphocytes with kappa light chain expression. Serum free light chain assay also showed kappa light chain restriction [kappa 716.16 mg/L, lambda 16.96 mg/L, ratio 42.23 (0.26-1.65)]. The patient was diagnosed as lymphoplasmacytic lymphoma with factor X deficiency. She received chemotherapy with 6 cycles of bendamustine plus rituximab (BR) regimen. The patient responded favorably to treatment, she remains in lymphoma remission at one year after diagnosis, and her factor X level was more than 20%. Conclusion We performed a literature review to identify previous case reports about lymphoma-associated factor X deficiency or inhibitor to determine a possible explanation in our patient. It is important to emphasize that when patients present with acquired factor deficiency, including factor X, lymphoproliferative disease is commonly one of the underlying conditions. Furthermore, the recovery of coagulation factor deficiency is possible if successful remission of lymphoma can be achieved.

Objective/background B-cell neoplasms are clonal tumors of B cells at various stages of maturation, including diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic lymphoma (CLL), Burkitt lymphoma (BL), lymphoplasmacytic lymphoma (LPL)/Waldenstrom’s macroglobulinemia (WM), splenic marginal zone lymphoma (SMZL), nodal marginal zone lymphoma (NMZL), mantle cell lymphoma (MCL), follicular lymphoma (FL), and hairy cell leukemia (HCL). In this study, we analyzed the frequency of MYD88 L265P mutation and its correlation with clinico-hematological profile in mature B-cell neoplasms. Methods A total of 110 consecutive cases of B-cell neoplasms showing peripheral blood and/or bone marrow infiltration were included. MYD88 L265P mutation was detected by polymerase chain reaction amplification of exon 5 of MYD88 gene, followed by restriction fragment length polymorphism analysis. Results Among the 110 cases, the major group was of CLL (54.5%, n = 60), followed by HCL. Other cases included MCL, LPL, DLBCL, SMZL, NMZL, FL, and BL. MYD88 L265P mutation was seen in 21 (19.1%) cases of B-cell neoplasm, whereas 89 (80.9%) cases were negative for MYD88 L265P mutation. It was most commonly seen in LPL/WM cases followed by HCL, SMZL, CLL, and MCL cases. No case of DLBCL, FL, and BL showed MYD88 L265P mutation. Statistically significant difference was seen for hemoglobin level in CLL cases, with MYD88 L265P mutated cases showing higher mean hemoglobin levels than MYD88 wild-type cases (p = .001). For other parameters, no statistically significant difference was noted between mutated and unmutated cases. Conclusion MYD88 L265P mutation is seen in various B-cell neoplasms; it is most commonly seen in LPL/WM cases but not specific for it.

Background: Kidney damage in lymphomas/leukemia’s presents with either acute kidney injury (AKI), chronic kidney disease (CKD), or both; and whilst AKI leads to evaluation often based on the clinical data, in some AKI and in almost all CKD cases kidney biopsy gives a clue to the diagnosis. Methods: A single center non-interventional retrospective study identified 36 patients with biopsy-proven kidney damage: 6 with Hodgkin’s lymphoma (HL), 18 with non-Hodgkin’s lymphoma/leukemia (NHL/CLL), and 12 with lymphoplasmacytic lymphoma (LPL). Results: Fifty-eight percent males and 42% females mean age 56.2 ± 17.4 years, presented with nephrotic syndrome in 47.2%, and with AKI in 11.1% of cases; 75% of patients diagnosed with CKD; in 13.9% AKI was superimposed on CKD. Patients with NHL/CLL presented with AKI significantly more often compared to HL and LPL—44% versus 16.6% versus 0 respectively. Monoclonal immunoglobulin (MIg) related glomerulopathies (GP) were found in 83.3% versus 16.6% cases in the LPL and NHL/CLL sub-groups, respectively ( p = 0.013). Patterns of damage included intracapillary monoclonal deposition disease, light and heavy chain amyloidosis, monotypic membranous nephropathy (MN), cryoglobulinemic glomerulonephritis (GN) and C3-GN in the LPL; and monotypic MN and proliferative GN with MIg deposits in the NHL/CLL sub-groups respectively. Paraneoplastic GPs were found in 83.3%, 38.8%, and 16.6% of patients with HL, NHL/CLL, LPL, respectively (HL vs LPL, p < 0.001), and included minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and IgA-nephropathy in the HL; membranoproliferative GN, MN, and MCD in NHL/CLL; and FSGS in the LPL sub-groups. Tubulointerstitial damage revealed in NHL/CLL sub-group only, and found in every other case with 80% of lymphoid infiltration. Conclusions: Pattern glomerular damage depends on lymphoma type: paraneoplastic GPs are typical for HL, MIg-related GPs dominate in LPL, NHL/CLL presents mainly as paraneoplastic with single MIg-related patterns. Tubulointerstitial damage due to specific kidney infiltration attributable to NHL/CLL.

Cutaneous macroglobulinosis is a rare manifestation of Waldenstrom macroglobulinemia when there is deposition of IgM in the dermis. The clinical presentation varies from skin colored to pink papules and ulcerative nodules on trunk, extensor surfaces of upper and lower limbs to hyperkeratotic lesions on the soles. We herein report a 78-year-old-male with Waldenstrom macroglobulinemia who presented with serpiginous purpura. The differential diagnoses included occlusion of vessel lumen by the lymphoplasmacytoid cells, high level of IgM or cryoglobulin, as well as small to medium vasculitis secondary to Waldenstrom macroglobulinemia. The histopathology revealed vasculopathy and vasculitis, while further immunohistochemistry highlighted deposition in the vessel lumen and vessel wall with IgM, suggesting the diagnosis of cutaneous macroglobulinosis. In this case report, we discuss this rare presentation and reviewed previous cases of cutaneous macroglobulinosis.

Background Primary central nervous system (CNS) lymphoma is an uncommon non-Hodgkin disease limited to the CNS, and most cases are diffuse large B-cell lymphomas. Other pathologies, including lymphoplasmacytic lymphoma (LPL), are exceedingly rare and poorly understood. The clinical presentation of primary CNS LPL is diverse. It depends on the original site and the tumor's extension. There is currently no consensus on a treatment strategy for this uncommon manifestation. To our knowledge, no previously published case was successfully treated with radiation therapy alone. Case presentation We present here a case of primary CNS LPL. A 46-year-old, previously healthy woman was presented with a worsening headache and lower extremity numbness. Multifocal enhanced masses were detected in an MRI with biopsy results consistent with LPL. A complete staging workup was performed with no evidence of systemic disease. The patient received external-beam radiotherapy alone and had a complete remission. After 2 years of follow-up, she remains disease-free. Conclusion Radiation alone is a promising treatment option for primary CNS lymphoplasmacytic lymphoma.

There is a paucity of data regarding racial disparities in the survival of patients with indolent non-Hodgkin lymphomas (iNHL) in the contemporary time-period. Hence, we sought to determine whether racial disparities exist in the survival of patients with iNHLs in the US. We included 68,059 adult patients with follicular lymphoma (FL, n=41,943), marginal zone lymphoma (MZL, n=22,485), and lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (LPL/WM, n=3,631) who were diagnosed in the US between 2000-2017. Race was categorized as White, Black, Asian/Pacific Islander, or American Indian/Alaska Native (API/AI). The primary outcome was relative survival (RS), which was estimated using flexible parametric survival models. RS estimates varied according to race and disease histology but were consistently lower for racial minorities, including those diagnosed during the most recent 5-year time-period of 2012-2017. On multivariable analysis for RS, Black patients with FL had a 32% higher excess mortality rate compared to White patients [adjusted excess hazard ratio (aEHR), 1.32; 95% CI, 1.15-1.51; P

Purpose The aim of this work was to study the clinical presentation, management and outcomes of orbital and adnexal amyloidosis. Methods This retrospective analysis included all the patients diagnosed with orbital and adnexal amyloidosis between January 1990 and December 2019. Positive staining with Congo Red and apple-green birefringence on polarized light microscopy established the diagnosis. Data analyzed included demographic profile, varied presentations, management, and outcome. Results Thirty-three eyes of 26 patients were included. The male:female ratio was 1:1. The mean age of the study population was 42.6 ± 16 years. The median duration of symptoms was two years. Unilateral involvement was seen in 19 eyes (right = 11, left = 8). The most common presenting feature was acquired ptosis. Eyelid was the most commonly affected site followed by orbit and conjunctiva. Two patients had systemic involvement in the form of multiple myeloma and lymphoplasmacytic lymphoma. Complete excision was done in seven (26.9%) cases while 19 (73.1%) cases underwent debulking. Three patients underwent ptosis surgery. The median duration of follow-up was 1.5 years. Three cases had recurrence and underwent repeat surgery. Conclusion Orbit and adnexa is a rare site for amyloidosis. It is usually localized; however it can occur as a part of systemic amyloidosis. Eyelid is the most common site of involvement and patients usually present as eyelid mass or ptosis. Complete excision is difficult and most of the patients usually undergo debulking surgery. All patients should undergo screening for systemic amyloidosis.

Clinical Practice Points • The Bing-Neel syndrome is a rare clinicopathological entity which refers to central nervous system localization by lymphoplasmacytic lymphoma. • The treatment of Bing-Neel syndrome remains non‐standardized and further data about patient long‐term outcome is needed. • This case-report supports the evidence of effectiveness and safety of MaTrix regimen as induction therapy in Bing-Neel syndrome patients.

Disease overview Waldenstrom macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. Diagnosis Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in the majority of IgM MGUS patients. Risk stratification Age, hemoglobin level, platelet count, β2 microglobulin, LDH and monoclonal IgM concentrations are characteristics that are predictive of outcomes. Risk-adapted therapy Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or ibrutinib. Purine nucleoside analogues are active but usage is declining in favor of less toxic alternatives. The preferred Mayo Clinic induction is rituximab and bendamustine. Management of refractory disease Bortezomib, fludarabine, thalidomide, everolimus, Bruton Tyrosine Kinase inhibitors, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in relapsed WM. Given WM's natural history, reduction of therapy toxicity is an important part of treatment selection. This article is protected by copyright. All rights reserved.

Introduction The categorization of mature B cell neoplasms (MBN) infiltrating blood and bone marrow are met with difficulties. The inclusion of CD148 and CD180 in the routine flow cytometry/FCM panels has been suggested to refine the diagnosis. We studied the discriminatory ability of CD148 and CD180 median fluorescence intensity(MFI), CD148/CD180 ratio and their expression relative to T cells (CD148ab/T , CD180ab/T ), neutrophils (CD148ab/gr , CD180ab/gr ) and normal B cells (CD148ab/n , CD180ab/n ) in the differentiation of mature B cell neoplasms (MBN) especially non-chronic lymphocytic leukaemia (CLL). Methodology The flow cytometric (FCM) expression of CD148 and CD180 was studied prospectively in 102 patients (non-CLL; n = 72); diagnosed by a comprehensive panel of immunophenotypic and cytogenetic studies. The MFI and ratios were statistically compared across MBNs by Mann-Whitney U test. Cut-off values, sensitivity and specificity were calculated for significant parameters by receiver operator characteristic curve. Results CD180MFI > 4.35 showed 100% sensitivity and 90.9% specificity for a diagnosis of marginal zone lymphoma (MZL) while, CD148/180 > 5.15 was 100% specific and 81.8% sensitive for lymphoplasmacytic lymphoma. CD148ab/T (>4.3; 100% specificity, 83.4% sensitivity) and CD148ab/gr (>1.1; 100% sensitivity, 90% sensitivity) were useful for differentiating blastoid-mantle cell lymphoma/MCL from diffuse large B cell lymphoma; while CD148MFI (≥20.25), CD148ab/T (>3.35) and CD148ab/gr (>0.95) showed >90% specificity and sensitivity for distinguishing MCL from CLL. Pairwise analysis also showed a good discriminant function of various parameters for distinguishing SMZL from other MBNs like FL, MCL as well as CLL. Conclusions The current study shows an excellent utility of CD148MFI, CD180MFI, their ratio and relative expression levels in the subcategorization of immunophenotypically related MBNs.

Lymphoplasmacytic lymphoma (LPL) is a B cell neoplasm composed of small lymphocytes, plasmacytoid lymphocytes, and plasma cells, which typically involves the bone marrow. Most cases of LPL present with Waldenstrom macroglobulinemia (WM) defined as the presence of monoclonal immunoglobulins of IgM type and LPL in the bone marrow. Herein, we present a case of LPL/WM presenting with intractable refractory seizures. A 71-year-old man with a 5-month history of seizures was brought to the emergency room after being found unresponsive. Automated hematology analysis revealed imprecise counts, wide variation, and multiple error flags. Peripheral smear review showed extracellular pale blue clumps of amorphous material. A marked cryoprecipitate of 7% was detected on a cryoglobulin screen. Serum protein electrophoresis (SPEP) detected a M-protein (1.58 g/dL) in the gamma region. Serum immunofixation revealed an IgM lambda monoclonal protein. A bone marrow biopsy showed hypercellularity with increased lymphocytes forming interstitial aggregates, admixed with plasmacytoid lymphocytes and plasma cells. Immunohistochemically, the lymphoma cells were positive for CD20 and negative for CD3, CD5, CD10, CD23, Cyclin D1 (Bcl-1), and Bcl-6. CD138 highlighted increased plasma cells. Flow cytometric analysis revealed 2.7% B cells with a predominance of lambda light chains, suggestive of a monoclonal B cell population. MYD88 mutational analysis revealed c.794T>C(p.L265P) mutation. A diagnosis of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia was established. The patient underwent plasmapheresis leading to significant improvement in his symptoms. This case highlights a rare, unusual presentation of LPL/WM where the interference in automated testing led to identification of cryoglobulinemia and subsequent diagnosis of LPL/WM.

Correct subclassification of B cell lymphoma requires integration of histologic and immunohistochemical findings in addition to results of flow cytometric immunophenotyping, cytogenetic analysis, and molecular studies. Evaluation for the MYD88 L265P mutation and immunohistochemical staining for LEF1 can be helpful in the workup of small B cell lymphomas. In this case report of two diagnostically difficult cases, we present two patients with lymphoplasmacytic lymphoma (LPL) and a CD5+ lymphoproliferative process presenting as composite disease within the bone marrow. In both cases, integration of ancillary studies and results of biopsy at other sites of disease in addition to a careful histologic review and an expanded immunohistochemistry panel were important for the correct final classification.

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disease characterized by benign skin hamartomas, pulmonary cysts leading to spontaneous pneumothorax, and an increased risk of renal cancer. BHD syndrome is caused by germline mutations in the folliculin (FLCN) gene, a putative tumor suppressor, which result in loss of function of the folliculin protein and may cause cancer predisposition. In a 45-year-old woman with anemia, lymphadenopathy, and a history of recurrent spontaneous pneumothorax,F-18-FDG PET/CT detected diffuse and slight (18)F-FDG accumulation in the bone marrow, enlarged spleen, and systemic multiple enlarged lymph nodes. Genetic examination identified a germline nonsense mutation [c.998C > G (p.Ser333*)] on exon 9 of FLCN. Pathological examination of the lymph node revealed a diffuse neoplastic proliferation of plasmacytoid lymphocytes. The neoplastic lymphoid cells were positive for CD20, CD138, and light chain kappa as per immunohistochemistry and mRNA in situ hybridization, and a MYD88g ene mutation [c.755T > C (p.L252P)] was identified. Accordingly, she was diagnosed with lymphoplasmacytic lymphoma concomitant with BHD syndrome. To the best of our knowledge, this is the first report describing the development of hematological malignancy in a patient with BHD syndrome. The FLCN mutation might contribute lymphomagenesis as an additional mutation cooperating with the MYD88 mutation.

Pulmonary amyloidosis, whether isolated or seen as part of systemic amyloidosis, has a variety of radiographic manifestations. Known parenchymal lung findings include reticulonodular opacities, diffuse interstitial infiltrates, or cystic lesions. Here, we present a case of systemic amyloid light-chain (AL) amyloidosis presenting with severe exertional dyspnea and emphysematous lung lesions on chest CT, a finding described only once before. Although factors that influence the pattern of pulmonary amyloid deposition remain unclear, CT image findings typically reflect the histopathologic patterns of deposition. In this case, we hypothesize that the emphysematous changes in the lower lung zones are likely a manifestation of severe alveolar-septal involvement. This case suggests that radiographic findings of pulmonary amyloidosis are not limited to the more common findings of reticular opacities or interstitial infiltrates. Emphysematous changes are possible, and clinicians should maintain a broad differential when seen in the setting of dyspnea.

Waldenstorms Macroglobulinemia (WM) is a rare mature B cell neoplasm characterized by a lymphoplasmacytic lymphoma and an IgM monoclonal protein. It is managed by Rituximab based chemotherapy. A single-centre retrospective study was carried out to analyse the clinical presentation, laboratory features, and treatment outcomes of all consecutive patients of WM, diagnosed over a period of 86 months. First-line treatment regimens included RCD (Rituximab/Cyclophosphamide/Dexamethasone), BDR (Bortezomib /Dexamethasone/ Rituximab) and (Lenalidomide/Dexamethasone). A total of 26 patients of WM were diagnosed during this period, with a median age of 65 years. Majority (89%) of these patients were of intermediate (47%) to high risk (42%). An overall response rate of 76.4% was achieved. RCD was found superior to BDR in terms of treatment response. For those who required 2nd line chemotherapy, the median time to next treatment was 22 months. To conclude, a late presentation and higher risk categories were common in our cohort of patients. Treatment outcome was comparable to those reported in western literature. RCD regimen was found to be a better treatment option in terms of overall survival.

Detailed information regarding follow-up of ocular adnexal lymphoma and of the frequency of large cell transformation of low-grade ocular adnexal lymphoma is limited. We studied 174 patients with ocular adnexal lymphoma (OAL) to evaluate long-term clinical outcome and patterns of failure. All lymphomas presenting with involvement of the ocular adnexa diagnosed at the Massachusetts General Hospital (MGH) between 1974 and 2007, in which at least 6 months of follow-up was available, were included in this study. There were 106 extranodal marginal zone lymphomas (MALT lymphomas, MZL), 40 follicular lymphomas (FL), 16 diffuse large B cell lymphomas (DLBCL), 5 mantle cell lymphomas (MCL), 3 small lymphocytic lymphomas/chronic lymphocytic leukemias, 1 lymphoplasmacytic lymphoma, 2 B lymphoblastic lymphomas, and 1 extranodal NK/T cell lymphoma. Relapses occurred in 42 of 106 MZL patients (40%) and in 14 of 40 FL patients (35%). Two MZL and one FL progressed to DLBCL. Five and 10-year relapse-free survival (RFS) and five and 10-year overall survival (OS) respectively were: MZL 67%, 36%, 93%, 88%; FL: 54%, 32%, 90%, 82%; DLBCL: 79%, 79% 88%, 88% MCL: 20%, 0%, 100%, 25%. MZL and FL patients often developed relapses but had long survival; progression to DLBCL was uncommon. DLBCL had a favorable prognosis. MCL had a poor prognosis.

BACKGROUND: Social determinants and demographics exert an overwhelming influence on the health of the individual and overall population health (J Am Geriatr Soc. PMID: 28369694).The Hispanic paradox has been well characterized, demonstrating that although Hispanic patients (HisP) have higher disability, depressive, metabolic, and inflammatory risk when compared to non-Hispanic (nHisP), they continue to live long lives (J Health Soc Behav. PMID: 31771347). The characterization of these differences in hematology has not been well documented. This study seeks to characterize Lymphoplasmacytic lymphoma (LPL). LPL is a rare lymphoma of B-cell origin demonstrating an incidence of 1000 to 1500 new cases per year in the United States (Hematol Oncol Clin North Am, PMID: 31229160). Epidemiological research is not well documented in this lymphoma subtype, especially regarding the HisP. Given that Texas has the second highest state with HisP in the country (US Census Bureau), we studied the demographics of this disease and specifically researched the demographics, treatment patterns and survival between HisP and nHisP in Texas. METHODS: This is a retrospective study of a cohort of patients diagnosed with lymphoma (Hodgkin and Non-Hodgkin) from the Texas Cancer Registry (TCR) database. Patient's included were those >18 years of age during 2006-2016 and this study focused on the LPL subset. Standard demographic variables collected include gender, race, ethnicity, birthplace, occupation, dates at diagnosis and death, primary payer at diagnosis, subtype of lymphoma, stage, type of treatment, poverty index, and vitality status among others. The significance of variation in the distribution of categorical outcomes with ethnicity (HisP, nHisP) was assessed with Fisher's Exact tests or Pearson's Chi-square tests as appropriate; age was assessed with T-tests or Wilcoxon tests as appropriate. Survival time was measured in years from date of primary diagnosis to date of death. Survival distributions were described with Kaplan-Meier curves and significance of variation in median survival with ethnicity was assessed with log rank testing. All statistical testing was two-sided with a significance level of 5%. RESULTS AND DISCUSSION: Out of 490 patients diagnosed with LPL, 64 were HisP and 426 nHisP. Of this population, the HisP had a higher percentage of patients at the higher end of the poverty index (42.4% to 20% with p value CONCLUSION: In this study we show that in Texas, for those diagnosed with LPL, there is a statistically significant difference in the rates of poverty and insurance when comparing Hisp to nHisP. While this is true, there is no clear statistically significant difference in overall treatment or survival probability, which is consistent with the Hispanic paradox. Due to the rarity of this disease, the population size is limited which may skew the data. More research is needed in order to further characterize the differences between these two populations and determine what can be done to narrow these differences. Disclosures Diaz Duque: ADCT Therapeutics: Research Funding; Molecular Templates: Research Funding; AstraZeneca: Research Funding; Hutchinson Pharmaceuticals: Research Funding; Seattle Genetics: Speakers Bureau; Verastem: Speakers Bureau; AbbVie: Speakers Bureau.

Waldenstrom macroglobulinemia (WM) has an annual incidence of 3-3.2 cases per million-person/year. National Cancer Data Base was used to identify newly diagnosed WM cases requiring initiation of therapy and their annual facility volume was used to divide the treatment facilities into four quartiles (Qs). Cox regression was used to analyze the association between facility volume and survival, adjusted by demographics, socioeconomic, geographic, comorbidity factors and year of diagnosis. A total of 3064 patients treated in 795 facilities were included. The unadjusted median overall survival (OS) by facility volume was: Q1:6.5 years (5-year OS 55%), Q2:7 years (5-year OS 60%), Q3:8 years (5-year OS 64%), and Q4: NR (5-year OS 71%)

Purpose of review Neurologists commonly evaluate patients with a monoclonal gammopathy and peripheral neuropathy. As both monoclonal gammopathy and peripheral neuropathy are common in the general population, their coexistence may, in some instances, be purely coincidental. However, monoclonal gammopathies or underlying lymphoplasmacytic disorders can affect the peripheral nervous system by various mechanisms. This article discusses how to approach patients with monoclonal gammopathy and peripheral neuropathy, highlighting clinical and laboratory clues that may aid in establishing a diagnosis in a timely manner. Recent findings From a hematologic standpoint, a monoclonal gammopathy may be of undetermined significance or can be associated with an underlying myeloma, lymphoplasmacytic lymphoma, or amyloidosis. Each of these conditions can cause peripheral neuropathy, with varying clinical and electrodiagnostic profiles. Treatment usually consists of treating the underlying hematologic disorder. IgM-associated peripheral neuropathy may not require treatment from a hematologic standpoint, and only anecdotal evidence exists for the use of immunotherapy in such patients. Therefore, treatment should be determined on a case-by-case basis. Summary Evaluating for an association between a monoclonal gammopathy and a peripheral neuropathy in a patient depends on the monoclonal gammopathy subtype and the clinical and electrodiagnostic characteristics of the peripheral neuropathy.

Background In order to study the CXCR4 expression with [68Ga]pentixafor PET in different types of non-Hodgkin lymphoma, we performed a retrospective study to describe the [68Ga]pentixafor PET/CT imaging in a spectrum of lymphomas and to compare it with [18F]FDG PET/CT. Results Twenty-seven patients with newly diagnosed non-Hodgkin lymphoma were recruited retrospectively. [68Ga]pentixafor PET showed increased radioactivity in lymphoplasmacytic lymphoma (n = 8), marginal zone lymphoma (n = 4), diffuse large B cell lymphoma (n = 3), follicular lymphoma (n = 2), mantle cell lymphoma (n = 1), unclassified indolent B cell lymphoma (n = 3), and enteropathy associated T cell lymphoma (n = 3). However, peripheral T cell lymphoma, not otherwise specified (n = 1), and NK/T cell lymphoma (n = 2) were not avid for [68Ga]pentixafor. In comparison to [18F]FDG PET, [68Ga]pentixafor PET demonstrated more extensive disease and higher radioactivity in lymphoplasmacytic lymphoma and marginal zone lymphoma. Conclusion CXCR4 expression varies in different types of non-Hodgkin lymphoma. Overexpression of CXCR4 was detected with [68Ga]pentixafor PET/CT in lymphoplasmacytic lymphoma, marginal zone lymphoma, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, unclassified indolent B cell lymphoma, and enteropathy associated T cell lymphoma. The uptake of [68Ga]pentixafor was higher than [18F]FDG in lymphoplasmacytic lymphoma and marginal zone lymphoma.

Waldenstrom macroglobulinemia is a lymphoplasmacytic lymphoma with bone marrow involvement and a monoclonal IgM gammopathy. Infiltration of the skin by neoplastic cells is very rare, and it can be difficult to distinguish from marginal zone lymphoma. The MYD88 L265P mutation is strongly associated with Waldenstrom macroglobulinemia, and it may be helpful in differentiating the two disorders, although the presence of this mutation is not specific, and other factors must be considered when making the final diagnosis. We present a diagnostically challenging case of cutaneous Waldenstrom macroglobulinemia in which the MYD88 L265P mutation was identified in the skin but not in the bone marrow, due to a low tumor burden.

The aim is to evaluate the efficacy of the first-line rituximab-containing therapy of B-cell lymphoproliferative diseases in Russian clinical practice between 2014 and 2017. Materials and methods. In the post-authorisation multicenter study EQUILIBRIUM were included 1 thousand patients aged from 21 to 91 with B-cell non-Hodgkins lymphoma or chronic lymphatic leukemia who had received at least 4 cycles of rituximab-containing therapy using the drug Acellbia. This article was devoted to the group of indolent non-Hodgkins lymphomas and included 253 patients: follicular lymphoma 51% of cases, marginal zone lymphoma 44% of patients, extremely rare were registered lymphoplasmacytic lymphoma and Waldenstrom macroglobulinemia in 3% and in 2% of cases, respectively. The median age in patients with indolent non-Hodgkins lymphomas was 62 years (2191 years). The vast majority of patients were diagnosed with stage IIIIV 190 (75%) of patients. More than 1/2 (53.4%) of patients in routine practice received R-CHOP therapy as a first-line. BR regimen was applied in 15.4% of cases, 14.2% of patients were treated with R-CVP/R-COP. We indicated rare use of rituximab as monotherapy in induction mode only 4.4% of patients. And 2.4% of patients were treated with fludarabine-containing therapy. Results. The final assessment of the effect was carried out after 68 cycles of treatment and as a result the overall effect was more than 90%: the frequency of complete remission was 61%, partial responses 32.9%. The progression admitted only in 17 (6.7%) patients among 253 observed. With a median of 15 months, the median of overall survival and event-free survival was not achieved. Conclusion. The use of the available and appropriate treatment according to the domestic clinical guidelines with the inclusion of the Russian biosimilar anti-CD20 monoclonal antibody Acellbia, demonstrates high direct efficacy and satisfactory long-term treatment results comparable to the retrospective analysis of the previous clinical studies of the original drug rituximab.

BACKGROUND Lymphoplasmacytic lymphoma is a rare non-Hodgkin’s lymphoma, occurring mostly in the elderly. It develops slowly and leads to malignant proliferation of lymphoid line cells in the bone marrow, lymph nodes and spleen. It may also affect nerve roots and meninges; some patients develop sensorimotor polyneuropathy which may precede general symptoms of lymphoma. CASE SUMMARY We present a case of a 36-year-old man diagnosed in 2012 with chronic inflammatory demyelinating polyneuropathy (CIDP), then he was hospitalized in 2019 due to progressive symptoms of heart failure and significant weight loss over the previous four months. Based on clinical and laboratory findings a diagnosis of lymphoplasmacytic lymphoma was suspected and confirmed by bone marrow flow cytometry. There was no improvement in the results of laboratory tests and the patient's condition after immediate implementation of chemotherapy. Patient died on the fifth day of treatment. CONCLUSION While CIDP and malignant disease co-occurrence is rare, it should be suspected and investigated in patients with atypical neuropathy symptoms.

Tirabrutinib (Velexbru®) is an orally administered, small molecule, Bruton's tyrosine kinase (BTK) inhibitor being developed by Ono Pharmaceutical and its licensee Gilead Sciences for the treatment of autoimmune disorders and haematological malignancies. Tirabrutinib irreversibly and covalently binds to BTK in B cells and inhibits aberrant B cell receptor signalling in B cell-related cancers and autoimmune diseases. In March 2020, oral tirabrutinib was approved in Japan for the treatment of recurrent or refractory primary central nervous system lymphoma. Tirabrutinib is also under regulatory review in Japan for the treatment of Waldenstrom's macroglobulinemia and lymphoplasmacytic lymphoma. Clinical development is underway in the USA, Europe and Japan for autoimmune disorders, chronic lymphocytic leukaemia, B cell lymphoma, Sjogren's syndrome, pemphigus and rheumatoid arthritis. This article summarizes the milestones in the development of tirabrutinib leading to the first approval of tirabrutinib for the treatment of recurrent or refractory primary central nervous system lymphoma in Japan.

Background Waldenström macroglobulinemia (WM) is a subset of lymphoplasmacytic lymphoma (LPL) with bone marrow (BM) involvement and an IgM monoclonal gammopathy of any level. We aimed to identify the clinical, laboratory, and BM findings of patients with WM and to evaluate the usefulness of CD154 for the diagnosis and prognosis of WM. Methods We reviewed the medical records and BM studies and/or flow cytometric immunotyping of 31 patients with untreated WM. Semiquantitative immunohistochemistry (CD20, CD138, tryptase, and CD154) of BM was performed. Results Only six patients presented with symptoms of hyperviscosity syndrome. Eleven patients had solid cancer and/or another hematologic malignancy. Mast cells (MC) increased in all samples, with some in close contact with tumor cells. Tryptase-positive MC (17.1/ high-power fields [HPF], 1.2–72.0/HPF) and CD154-positive MC (8.6/HPF, 0.1–31.1/HPF) were observed. The high CD154-positive MC (≥8.6/HPF) group showed a lower overall five-year survival rate than the low CD154-positive MC (

Purpose The epidemiology of B-cell non-Hodgkin lymphoma (BNHL) in Asia is not well described, and rates of second primary malignancies (SPM) in these patients are not known. We aimed to describe temporal changes in BNHL epidemiology and SPM incidence in Korea. Materials and methods A retrospective cohort study used claims data from the National Health Insurance Service that provides universal healthcare coverage in Korea. Newly diagnosed patients aged at least 19 years with a confirmed diagnosis of one of six BNHL subtypes (diffuse large cell B-cell lymphoma [DLBCL], small lymphocytic and chronic lymphocytic [CLL/SLL], follicular lymphoma [FL], mantle cell lymphoma [MCL], marginal zone lymphoma [MZL], and lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia [WM]) during the period 2006-2015 were enrolled and followed up until death, dis-enrolment, or study end, whichever occurred first. Patients with pre-existing primary cancers prior to the diagnosis of BNHL were excluded. Results A total of 19,500 patients with newly diagnosed BNHL were identified out of 27,866 with non-Hodgkin lymphoma (NHL). DLBCL was the most frequently diagnosed subtype (41.9%-48.4% of NHL patients annually, 2011-2015). Standardized incidence of the six subtypes studied per 100,000 population increased from 5.74 in 2011 to 6.96 in 2015, with most increases in DLBCL, FL, and MZL. The incidence (95% confidence interval) of SPM per 100 person-years was 2.74 (2.26-3.29) for CLL/SLL, 2.43 (1.57-3.58) for MCL, 2.41 (2.10-2.76) for MZL, 2.23 (2.07-2.40) for DLBCL, 1.97 (1.61-2.38) for FL, and 1.41 (0.69-2.59) for WM. Conclusion BNHL has been increasingly diagnosed in Korea. High rates of SPM highlight the need for continued close monitoring to ensure early diagnosis and treatment.

Waldenström macroglobulinemia is a rare hematologic malignancy characterized by an IgM-associated lymphoplasmacytic lymphoma. Often, it is associated with an indolent disease course, and many patients are candidates for careful monitoring. As many patients present with advanced age and nonspecific constitutional symptoms, careful consideration should be given to treatment decisions, including when and how to treat for maximized clinical benefit with minimal toxicity. This article provides an evidence-based practical approach to appropriate monitoring of the asymptomatic patient and management of symptomatic patients who require treatment for this rare malignancy.

Monoclonal B-cell lymphocytosis (MBL) is an early or precursor asymptomatic proliferation of chronic lymphocytic lymphoma (CLL)-like B-cells. Lymphoplasmacytic lymphoma (LPL), often clinically associated with Waldenstrom macroglobulinemia, is a B-cell neoplasm characterized by frequent MYD88 L265P mutation. Here, we report a rare composite MBL and LPL in a patient with IgM light chain (AL) amyloidosis. A 74-year-old male with a known IgM monoclonal protein developed proteinuria. No lymphocytosis was detected. Renal biopsy showed deposition of AL λ amyloid in the glomeruli and vessels. Subsequent bone marrow biopsy revealed nodular atypical CLL-like small B-cell proliferation and scattered peripheral LPL. Immunohistochemistry and/or flow cytometry revealed that the atypical CLL-like population expressed CD19, CD20, CD5, weak CD23, LEF-1 and diminished surface Igκ. The LPL was positive for CD19, CD20 and surface Igλ. Using laser-capture microdissection and allele-specific polymerase chain reaction, we confirmed that MYD88 L265P was detectable in the LPL but not in the atypical CLL-like population. Thus, we demonstrated that these two populations were clonally independent, and made the diagnosis of composite MBL and LPL. An integrated clinical, pathological, immunophenotypic and genetic assessment is essential in such complicated cases, and especially 'clone-specific' MYD88 genotyping may facilitate the differential diagnoses of low-grade B-cell lymphomas.