Cell Lymphoproliferative Disorders Research Articles

A-257 Small Medium Pleomorphic T cell lymphoproliferative disorder - 20 years of experience from a specialist centre

A-257 Small Medium Pleomorphic T cell lymphoproliferative disorder - 20 years of experience from a specialist centre

Mixed cryoglobulinemia as a potential indicator of clinically silent Hepatitis C infection

Hepatitis C virus (HCV) is one of the major causes of chronic liver disease and its prevalence is increasing worldwide. There are many extra hepatic manifestations of Hepatitis C infection including B –cell lymphoproliferative disorders. Mixed cryoglobulinemia (MC) is the most common prototype of B-cell lymphoproliferative disorders. Cryoglobulinemia is an immune complex mediated disease causing multi organ damage with vasculitis being the primary manifestation. We report a case of 50 years old Asian lady having clinically silent chronic liver disease secondary to hepatitis C who presented to us with a purpuric skin rash, joint pains and fatigue. She was confirmed to be a case of mixed cryoglobulinemia. Patient was prescribed direct antiviral agents and prednisolone which improved her condition to a great extent. Heightened awareness of cutaneous manifestations of MC associated with HCV might improve the detection rate of clinically silent HCV infection.

Clinical and genetic profile of Chinese patients with indolent natural killer-cell lymphoproliferative disorder of the gastrointestinal tract

Indolent natural killer cell lymphoproliferative disorder of the gastrointestinal tract (iNKLPD-GI) is an uncommon, recently recognized lymphoid proliferation of mature NK cells primarily manifesting in the GI tract. Unlike NK/T lymphoma, iNKLPD-GI exhibits a rather indolent clinical course, underscoring the need for cautious management to prevent unnecessary interventions. However, clinical and molecular features of this entity have not been thoroughly understood. This study aimed to add more information to the current knowledge of this disease. Seven patients with iNKLPD-GI were included in our study. Clinical data included initial symptoms, endoscopic manifestations, pathological features, and therapies. Besides, next-generation sequencing was arranged to explore the underlying genetic mechanism of this disease. In our study, iNKLPD-GI in the urinary bladder was first identified. Edema of extremities (3, 42.8 %) was the most prevalent onset symptom which was reported for the first time. Pathological and immunohistological features were found to display the phenotype of NK cells. Unlike extranodal NK/T cell lymphoma, Epstein-Barr virus-encoded small RNA (EBER) were negative in all patients. Moreover, we found that two patients harbored JAK3 mutation. Apart from JAK3 K563_C565del previously reported in the literature, we discovered new JAK3 mutation sites. Other mutations including BRAF, KRAS, and SH2B3 were also identified. In conclusion, iNKLPD-GI was an indolent atypical NK-cell proliferation with diverse clinical characteristics. “Watch and wait” therapy was preferable to intense chemotherapy. Recurrent JAK3 mutation may be the underlying mechanism responsible for the neoplastic nature of the disease and may serve as a potential target for patients with severe symptoms.

Fcm in characterizing mature B cell lymphoproliferative disorders

Fcm in characterizing mature B cell lymphoproliferative disorders

Hydroa vacciniforme lymphoproliferative disorder: a retrospective study of 42 paediatric cases.

Hydroa vacciniforme lymphoproliferative disorder (HVLPD) is a rare disease related to Epstein-Barr virus (EBV), mainly in children, and is an EBV-associated cutaneous T and natural killer (NK) cell lymphoproliferative disorder. The disorder in some patients may progress to EBV-associated systemic T or NK-cell lymphoma. To summarize the characteristics of HVLPD in Chinese paediatric patients and to examine the risk factors indicating poor prognosis. We performed a retrospective analysis of patients with HVLPD from the Department of Dermatology, Beijing Children's Hospital. Based on diagnosis, medical history, examination results, and immunophenotype, we analysed HVLPD in 42 paediatric cases in order to examine the clinical features, prognoses, and risk factors. Forty-two paediatric patients were enrolled, with a median onset age of five years. All patients presented with papulovesicular lesions, and 32 systemic HVLPD (sHVLPD) patients had systemic symptoms, including fever, lymphadenopathy, hepatomegaly, splenomegaly, and liver dysfunction. Of the sHVLPD cases, 13 also had severe mosquito bite allergy (SMBA). Twenty-five cases were T-type, and nine were CD56+-dominant type. Follow-up data showed that 12 patients had complete remission, and three patients died. SMBA is a risk factor for disease progression in patients with HVLPD, and the pathological CD56+-dominant phenotype is associated with poor prognosis.

Cutaneous lymphoproliferative disorders: Back to the future.

In the 1980s, immunohistochemistry and clonality analyses became instrumental in the recognition and definition of new types of cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma (CBCL) and the development of new classifications. By accepting loss of pan-T-cell antigens and clonal T-cell receptor gene rearrangements as important criteria to differentiate between benign and malignant T-cell proliferations, and monotypic immunoglobulin light-chain expression and clonal immunoglobulin gene rearrangements as crucial criteria to distinguish between benign and malignant B-cell proliferations, many cases, until then diagnosed as cutaneous lymphoid hyperplasia or pseudolymphoma, were reclassified as primary cutaneous CD4+ small/medium T-cell lymphoma (PCSM-TCL) or primary cutaneous marginal zone lymphoma (PCMZL), respectively. However, in recent years there is growing awareness that neither these immunohistochemical criteria nor demonstration of T-cell or B-cell clonality is specific for malignant lymphomas. In addition, many studies have reported that these low-grade malignant CTCL and CBCL have an indolent clinical behavior and an excellent prognosis with disease-specific survival rates of or close to 100%. As a result, recent classifications have downgraded several low-grade malignant cutaneous lymphomas to lymphoproliferative disorder (LPD). Both the 5th edition of the WHO classification (2022) and the 2022 International Consensus Classification (ICC) of mature lymphoid neoplasms reclassified PCSM-TCL as primary cutaneous CD4+ small/medium T-cell LPD and primary cutaneous acral CD8+ T-cell lymphoma as primary cutaneous acral CD8+ T cell LPD. While the 2022 ICC introduced the term "primary cutaneous marginal zone LPD," in the 5th edition of the WHO classification PCMZL is maintained. In this review we describe the background and rationale of the continually changing terminology of these conditions and discuss the clinical consequences of downgrading malignant lymphomas to LPDs.

Clinical Characteristics and Treatment Outcome of Waldenstrom Macroglobulinemia: Experience from a Tertiary Cancer Centre

Background: Waldenstroms macroglobulinemia (WM) or Lymphoplasmacytic lymphoma is a rare B cell lymphoproliferative malignancy characterized by serum monoclonal immunoglobulin M (IgM) protein and lymphoplasmacytic infiltration in the bone marrow. Patients usually present in their seventh decade with symptoms related to the infiltration of the marrow or the effects of monoclonal IgM in the blood. Objective: Was to study the clinical characteristics and treatment outcome of patients diagnosed with WM. Materials and Methods: This is a retrospective analysis of 26 cases of WM treated at a tertiary cancer centre. Results: WM constituted 0.68% of our nonHodgkin’s lymphoma. The median age at presentation was 67 years with a male to female ratio of 2:1. Four patients had lymphadenopathy, six had splenomegaly and four patients had evidence of hyper viscosity. All patients had IgM paraproteinemia, the M band was IgM-kappa in 19 patients and IgM-lambda in seven patients. All patients had a histopathological confirmation. According to IPSS-WM, 12 patients each were in the intermediate and high risk group and 2 in the low risk group. Among the 26 patients, 20 patients received upfront treatment and four patients were kept under observation. The indications for treatment were cytopenia in ten patients, constitutional symptoms in five, hyper viscosity in four and symptomatic lymphadenopathy in one patient. Sixteen patients received rituximab-based chemotherapy. Four patients with features with hyper viscosity underwent plasmapheresis. The three year progression free survival and overall survival were 69.4% and 78 % respectivel. Conclusions: WM is a low grade B cell lymphoproliferative disorder having an indolent course and do not require treatment for prolonged period. Diagnosis is challenging due to lack of distinct diagnostic features. Rituximab containing regimens are the standard of care. Newer targeted treatment options may improve the outcome of this incurable disease.

Clinical features and prognosis of chronic natural killer cell lymphoproliferative disorders

ABSTRACT Objective To analyze the current treatment status and prognostic regression of the chronic NK cell lymphoproliferative disorder (CLPD-NK). Methods We retrospectively analyzed the clinical features, treatment and prognosis of 18 patients with CLPD-NK who were treated at our Hospital between September 2016 and September 2022. Results Eighteen patients were included: three patients were treated with chemotherapy, five patients underwent immune-related therapy, one patient was treated with glucocorticoids alone, five patients were administered granulocyte colony-stimulating factor, blood transfusion therapy, or anti-infection therapy, followed by observation and follow-up, and four patients were observed without treatment. Fifteen patients survived, including two patients who achieved complete remission (CR) and seven patients who achieved partial remission (PR), of whom one patient progressed to Aggressive NK-cell leukemia (ANKL) and sustained remission after multiple lines of treatment; three patients were not reviewed, of which one patient was still in active disease, three patients developed hemophagocytic syndrome during treatment and eventually died, one of them had positive Epstein–Barr virus (EBV) expression. The 5-years overall survival rate was 83%. Conclusion Most patients with CLPD-NK have inert progression and a good prognosis, whereas some patients have a poor prognosis after progressing to ANKL and combined with hemophagocytic syndrome. Abnormal NK cells invading the center suggest a high possibility of ANKL development, and immunosuppressants and hormones are effective treatments for this disease.

What is new in the classification of peripheral Tcell lymphomas?

In this review focus article, we highlight the main modifications introduced in the latest 2022 International Consensus Classification and World Health Organization classification (ICC and WHO-HAEM5) of matureT (and NK) cell neoplasms (PTCLs) and consequent implications for diagnostic practice. The changes result from recent advances in the genomic and molecular characterization of PTCLs and enhanced understanding of their pathobiology. Specifically, consideration is given to the following groups of diseases: Epstein-Barr virus (EBV)-associated neoplasms; follicular helper Tcell lymphoma; anaplastic large cell lymphomas; primary intestinalT and NK cell lymphomas and lymphoproliferative disorders; and PTCL, not otherwise specified.

T-Cell Lgll of the Γδ Subtype: Clinically Relevant Fact or Academically Interesting Finding?

Large granular lymphocyte leukemia (LGLL) is a rare group of mature T and NK cell lymphoproliferative disorders, with an annual incidence of 0.2 - 0.72 cases per 1 million individuals. Median age of onset is 65, with case prevalence roughly equivalent between sexes. T-Cell LGLL (T-LGLL) makes up 85-91% of cases. The majority of T-LGLL clones express Tαβ, with only 5% of cases expressing Tγδ. Outcomes and treatment data on this subtype is limited. Recent observational data suggest reduced overall survival (OS), increased incidence of cytopenias and associated autoimmune diseases, and favorable response to first line therapy with cyclosporine, in comparison to the Tαβ subtype. Here, we summarize disease biology and clinical presentation and provide review of recent literature describing clinical course and treatment options in the context of a patient case. A woman in her early 70's with osteoporosis, asthma and hypertension presented to hematology after she was found to have leukocytosis of 12.1* 103/µL during routine lab work. CBC w/differential showed lymphocytosis of 11.0* 103/µL with absolute neutrophil count of 496 *103/µL and thrombocytopenia (121* 103/µL). She was asymptomatic without history of malignancy or autoimmune disease, prior available labwork was normal and physical exam was unremarkable. Peripheral smear showed atypical lymphocytes, with flow cytometry demonstrating 50.45% clonality with CD2+, CD3+, CD4-, CD7+, CD8 +/- , CD16+, CD 56-, CD57+/-, Tγδ + phenotype. Bone marrow biopsy demonstrated hypercellular (70%) marrow with scattered lymphoid aggregates with clonal infiltration of 20% core cellularity by CD3 immunohistochemistry. Bone marrow flow demonstrated the T-Cell phenotype seen in peripheral blood. T-Cell clonality study demonstrated TCR gamma chain rearrangement. PET/CT showed mildly increased FDG uptake throughout bone marrow. Next-Generation Sequencing confirmed mutations of STAT3 (D661Y), ASXL1, and TET2. There is conflicting data on whether Tγδ positivity portends reduced OS compared to Tαβ. Observational studies show that Tγδ is more frequently symptomatic and conveys higher risk of cytopenias. Not all cases require treatment. Treatment is usually prompted by single-lineage cytopenias. First line single agent therapy with methotrexate (MTX), cyclosporine, and cyclophosphamide have shown similar overall response rates of 40-50%, though STAT3 mutated disease is associated with better response to MTX. STAT3 mutations are associated with more severe cytopenias, more frequent autoimmune/inflammatory disorders, and more frequently required therapy, however neither STAT mutations nor cytopenias convey decreased OS in Tγδ disease. STAT3 and STAT5b mutations occur in 40% of all LGLL cases, with STAT3 mutations associated with neutropenia and rheumatoid arthritis. Nearly two thirds of STAT3 genetic mutations are Y640F and D661Y. Our patient was initiated on prednisone, though due to poor tolerance was transitioned to MTX titrated to 12.5 mg weekly. She has remained on this dose with good tolerability for 18 months with resolution of lymphocytosis and improvement in neutropenia. T-LGLL has an OS of 9 years. Rarity of Tγδ disease has limited the ability to generate subtype specific survival data. The largest retrospective study to date included 137 Tγδ patients across 8 centers and provided a signal that Tγδ disease may predict reduced OS compared to the Tαβ subtype, however data was limited by disparate median follow-up time amongst cohorts due to high rates of censorship in the Tγδ cohort. Median OS was not reached at median follow up time of 48 months. This trend would be clinically expected given that Tγδ subtype has been consistently associated with severe cytopenias and autoimmune diseases, but should not be accepted until higher quality evidence is generated over longer median follow-up times. The same study found better responses to cyclosporine as first line therapy, an interesting observation as MTX has been generally accepted as first line therapy based on predominantly retrospective studies, though these studies did not stratify treatment responses by TCR phenotype. These findings underscore the need for prospective studies characterizing Tγδ specific disease course, survival analyses and treatment response.

A 9-year-old patient with indolent NK cell lymphoproliferative disorder: What role does an inherited SESN3 mutation play?

A 9-year-old patient with indolent NK cell lymphoproliferative disorder: What role does an inherited SESN3 mutation play?

Blood-Based Diagnostic Assay for λ Light Chain Amyloidosis through Quantification of an Amyloidogenicity-Indicating Neo-Epitope

Light chain amyloidosis (AL) is a rare, progressive, and often fatal protein misfolding disease. AL is caused by aberrant clonal plasma cell proliferation, where excess amounts of amyloidogenic monoclonal Free Light Chain (FLC) are produced, secreted into the circulation, misfolded and deposted as amyloid fibrils in various vital organs, such as the heart, kidney, liver, and nerves. The involed lambda (λ) FLC accounts for ~75% of all AL cases. Amyloidogenic FLCs (aFLCs) are believed to be the toxic species contributing to AL disease pathology. Specific quantification of aFLCs can provide critical guidance in clinical practice but has been hampered by the LCs sequence diversity as well as the lack of tests that are able to differentiate between circulating normal polyclonal FLCs and aFLCs. Contrary to non-amyloidogenic, aFLCs are kinetically and oftentimes thermodynamically unstable. aFLCs are prone to misfolding and formation of pathogenic conformations such as non-native structures, proteolytic fragments, soluble aggregates, and amyloid fibrils. We exploited such characteristics of aFLCs by applying limited proteolysis using Proteinase K, where less stable λ aFLC proteins readily yield a 23KDa fragment composed of the homodimeric LC constant domain (dLCCD) linked by a disulfide bond. Formation of the dLCCD fragment reveals a highly conserved, novel, cryptic epitope at the N-terminus of the fragment. We have generated monoclonal antibodies (mAbs) that explicitly bind to such novel epitope and developed immunoassays for the specific detection and sensitive quantification of λ aFLCs in biological samples. Western blot or Meso Scale Discovery (MSD) analyses were employed to detect and quantify dLCCD signal using the dLCCD mAbs on plasma samples from randomly selected, treatment naïve and λ-restricted cases with biopsy-proven AL amyloidosis before and after exposure to optimized proteolytic conditions. Tissue amyloid deposits of λ-type were confirmed in most AL cases. Informed consent for data and plasma sample collections were obtained from the Institutional Review Boards and in accordance with the Declaration of Helsinki. Multiple myeloma (MM) plasma samples of unknown LC restriction type, treatment or amyloid deposits status and normal volunteer control samples were purchased from BioIVT (USA). A set of representative results based on three runs are shown in Fig. 1. As little as 2 µL of biofluid was used for each assay. Upon limited proteolysis, dLCCD signal was detected in 32 of 35 AL plasmas, including two samples from patients with AL-associated IgM lymphoplasmacytic lymphoma (LPL). Of the three dLCCD negative AL samples, one presented with monoclonal IgAλ, and two cases were bi-clonal on serum immunofixation electrophoresis. dLCCD signal was not detected in 18 of 19 MM plasma samples. Similarly, dLCCD signal was undetectable in 23 normal plasmas. Overall, the dLCCD signals detected in AL plasmas were 10x-200x above that of normal control and most MM samples (Fig. 1). The low limit of quantification of the MSD assay was ~0.4 ng/dL (1.4 pM), with >500x dynamic range, enabling sensitive and robust quantification of λ aFLCs in biosamples. Analysis of Proteinase K recognition potential of the cleavage site of 389 λ LC sequences from the AL-Base, a database of amyloidogenic LC sequences (https://wwwapp.bumc.bu.edu/BEDAC_ALBase/) predicted that the dLCCD assay can detect λ aFLCs in up to 99% of λ AL patients, irrespective of the FLC sequences. This was confirmed with the 100% detection rate of the dLCCD signal in a validation cohort of 35 additional monoclonal λ-restricted AL samples. In summary, we have developed a quantitative blood-based immunoassay that is sensitive and highly specific for λ aFLC irrespective of the protein sequences. The preliminary data demonstrates the potential of our assay for AL diagnostics. Additional clinical applications for future exploration will include (i) monitoring and early detection of AL amyloidosis in plasma cell dyscrasias (monoclonal gammopathy of unknown significance, MM, and smoldering MM) and lymphoproliferative disorders, including LPL; and (ii) clinical management of patients with AL amyloidosis via the assessment and monitoring of minimal residual disease and therapeutic responses. The utility of the dLCCD assay in the quantification of λ aFLCs in bi-clonal AL cases warrants further investigation.

Establishment of Epstein-Barr Virus (EBV) Latent Gene-Expressing T-Cell Lines with an Expression Vector Harboring EBV Nuclear Antigen 1.

Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is characterized by chronic or recurrent infectious mononucleosis-like symptoms and is associated with EBV-associated T/natural killer (NK)-cell lymphoproliferative disorders, which frequently lead to the development of life-threatening complications, such as virus-associated hemophagocytic syndrome and EBV-positive apparent leukemia/lymphoma mainly in T- and NK-cell lineages. In order to clarify the EBV genes responsible for the diseases, we introduced the plasmid coding sequences of EBV-encoded small RNAs (EBERs) and/or latent membrane protein (LMP) 1 into human T-lymphocyte virus-I-negative human T-cell lines using a gene expression vector harboring EBV nuclear antigen 1, established the G418-resistant transformants of five T-cell lines, and quantitatively examined the expression of EBERs and LMP1 using real-time reverse transcriptase-polymerase chain reaction. The expression levels of EBERs in T-cell transformants with EBER DNA paralleled those in EBV-positive human T- and NK-cell lines, SNTK cells. The expression of LMP1 mRNA varied in SNTK cells and in human T-cell transformants, and the expression of LMP1 mRNA in T-cell lines expressing both EBERs and LMP1 was much lower than that in the same cell line expressing LMP1 mRNA alone. The currently employed gene expression system and currently obtained transformants may be useful for the analyses of the pathophysiology of CAEBV and EBV-positive T/NK-cell lymphoproliferative disorders.

FCRL1 immunoregulation in B cell development and malignancy.

Immunotherapeutic targeting of surface regulatory proteins and pharmacologic inhibition of critical signaling pathways has dramatically shifted our approach to the care of individuals with B cell malignancies. This evolution in therapy reflects the central role of the B cell receptor (BCR) signaling complex and its co-receptors in the pathogenesis of B lineage leukemias and lymphomas. Members of the Fc receptor-like gene family (FCRL1-6) encode cell surface receptors with complex tyrosine-based regulation that are preferentially expressed by B cells. Among them, FCRL1 expression peaks on naïve and memory B cells and is unique in terms of its intracellular co-activation potential. Recent studies in human and mouse models indicate that FCRL1 contributes to the formation of the BCR signalosome, modulates B cell signaling, and promotes humoral responses. Progress in understanding its regulatory properties, along with evidence for its over-expression by mature B cell leukemias and lymphomas, collectively imply important yet unmet opportunities for FCRL1 in B cell development and transformation. Here we review recent advances in FCRL1 biology and highlight its emerging significance as a promising biomarker and therapeutic target in B cell lymphoproliferative disorders.

A patient with the highly suspected B cell lymphoma accompanied by the erythrocytes cold agglutination: Case report.

Cold agglutinins are related with B cell lymphoproliferative disorder and lymphoma, and can agglutinate red blood cells (RBCs) at an optimum temperature of 3-4°C, which is the undergoing cause of RBCs cold agglutination. RBC cold agglutination may lead to an extreme abnormality of RBC parameters of complete blood count (CBC). The present study reports a case of an old patient with severe infectious fever and anemia presenting extremely abnormal levels of RBC parameters in CBC and a sand-like appearance of blood on tube wall. The validating tests indicated the presence of the RBCs cold agglutination and the highly suspected B cell lymphoma. The 37°C-incubation corrected the CBC results of the patient, and the microscopic observation and flow cytometry analysis of blood and marrow indicated many abnormal B lymphocytes. Subsequently, the patient was diagnosed with a highly suspected B-cell lymphoma. The blood with a sand-like appearance was reanalyzed to validate the cold agglutination by 37°C-water incubation. The smears of peripheral blood and marrow were made for morphological observation by using optical microscopy. Moreover, the clusters of differentiation of the white blood cells were analyzed to confirm the type of abnormal white blood cells with a flow cytometer. The RBCs cold agglutination was validated, and the highly suspected B cell lymphoma was proved as the undergoing cause. This case focuses on the discovery and solutions of RBCs cold agglutination, and emphasizes the importance of microscopic observation in the exploration of undergoing causes of cold agglutination.

KAPPA MYELOMA ANTIGEN (KMA) AND LAMBDA MYELOMA ANTIGEN (LMA) ARE EXPRESSED ON B CELL MALIGNANCIES AND ARE PROMISING NOVEL TARGETS ON MALIGNANT PLASMA CELLS

Introduction: The kappa myeloma antigen (KMA) and the lambda myeloma antigen (LMA) are found on the surface of malignant plasma cells (PCs) in multiple myeloma (MM), other plasma cell dyscrasia patient bone marrow (BM) samples, human myeloma cell lines and in patient BM samples from plasmacytomas, lymphoplasmacytoid and B cell lymphoproliferative disorders (BLPD). KMA and LMA are not present on normal B cells in BM but are found on occasional mononuclear cells in tonsillar tissue and secondary mucosal lymphoid tissue. KappaMab is a therapeutic antibody that specifically targets KMA and a phase IIb study in combination with lenalidomide and dexamethasone has recently been completed. In early clinical trials, KappaMab was shown to have an excellent safety profile, with low-grade infusion-related reactions and no haematological toxicities. Two human therapeutic LambdaMabs (10B3 and 7F11) bind specifically to LMA expressed only on malignant cells in lambda restricted B cell diseases. Here we compare the expression of KMA and LMA to that of BCMA in MGUS, newly diagnosed MM and relapsed, refractory (RRMM) myeloma BM samples. We describe the difference in phenotype between KMA and LMA expressing malignant PCs and their enrichment in RRMM compared to early disease stages. Methods: Patient BM samples (κ = 70 and λ = 40) were analysed using multiparametric FCM immunophenotyping with APC labelled LambdaMab (10B3) and KappaMab Fab’2 fragments, CD38, CD138, CD269 (BCMA), CD319 (SLAM F7), CD56 and CD45 monoclonal antibodies. PCs were identified by initial gating using CD38 and CD138. LMA and KMA expression was determined and compared with the other cell markers. Results: KMA was expressed on the majority of kappa restricted BM PCs from MGUS through to RRMM, on lymphoplasmacytoid cells in 2 out of 3 BM samples and in all 4 plasmacytoma BM samples. LMA was expressed on the surface of BM PCs in lambda restricted MGUS through to RRMM and in all 4 AL amyloidosis BM samples. KMA and LMA antigen densities were both higher than BCMA in the RRMM population: KMA mean 1899 (range 468–7943) versus BCMA mean 1426 (range 350-2630) and LMA mean 2439 (range 263–6664) versus BCMA mean 817 (range 537–1065) molecules of PE/cell. Conclusions: Although there are smaller numbers of samples from other B cell malignancies such as lymphoplasmacytoid, amyloidosis and BLPDs, we have demonstrated that KMA or LMA are expressed on malignant BM PCs. In the myeloma cases, the antigen density of both KMA and LMA was increased compared to BCMA on RRMM BM PCs, which suggests a clonal advantage of KMA and LMA expressing plasma cells that are resistant to standard of care treatments. These data suggest that KappaMab and LambdaMabs have therapeutic potential in RRMM where the combination of high antigen density and restriction of the target antigen to the malignant subpopulation of PCs may confer clinical benefit by retaining normal plasma cells following treatment. Keywords: Immunotherapy, Multiple Myeloma Conflicts of interests pertinent to the abstract D. Gottlieb Consultant or advisory role David sits on the Scientific Advisory Board for HaemaLogiX Ltd. R. Dunn Employment or leadership position: Employee at HaemaLogiX Ltd. Stock ownership: Yes

Analysis of clinical features in primary cutaneous T cell lymphoma

Background: Primary cutaneous T cell lymphoma is a diverse and rare group of diseases with clinical manifestations that, if not biopsied, are easily confused with benign skin diseases. Objective: To determine some clinical features of primary cutaneous T cell lymphomas and classify them according to the 2018 update of World Health Organization and European Organisation for Research and Treatment of Cancer classification. Methods: a case series study with 39 cases of primary cutaneous T cell lymphomas diagnosed at Pathology Department of University Medical Center at Ho Chi Minh city from 01/2018 to 02/2022. Results: Median age at diagnosis is 59 years old. Male:Female ratio is 1:2.3. In order of frequency, diagnoses were: subcutaneous panniculitis-like T cell lymphoma (35.8%), mycosis fungoides (28.2%), primary cutaneous anaplastic large cell lymphoma (15.4%), peripheral T cell lymphoma not otherwise specified (7.7%), extranodal NK/T cell lymphoma, nasal type (7.7%), primary cutaneous CD4+ small/medium T cell lymphoproliferative disorder (2.6%) and primary cutaneous CD8+ aggressive epidermotropic T- cell lymphoma (2.6%). Subcutaneous panniculitis-like T cell lymphoma always presents as subcutaneous nodule-tumor (100%); the most common site is lower extremities (71.4%). Mycosis fungoides has various appearance of skin lesions (36.4%) including patch-plaque (100%), and usually involves in trunk (90.9%). Extranodal NK/T cell lymphoma, nasal type always has skin ulcer (100%). Conclusion: The study documented the frequence and clinical characteristics of each subtype of primary cutaneous T cell lymphoma. The most common were subcutaneous panniculitis-like T cell lymphoma and mycosis fungoides. Although the morphology and location of skin lesions in the subtypes overlap, they still aid in the diagnosis of skin lymphoma. Key words: T-cell lymphoma, primary, cutaneous.

Clinicopathological and molecular features of indolent natural killer-cell lymphoproliferative disorder of the gastrointestinal tract.

Indolent natural killer (NK) cell lymphoproliferative disorder of the gastrointestinal (GI) tract (iNKLPD) is a rare, recently recognised neoplasm. Most of the reported tumours are confined to the GI tract, while a small subset of the tumours harbour JAK3 mutations. We collected four cases of iNKLPD with the goal of adding additional information to the current knowledge of this disease regarding the clinicopathological, immunohistochemical and molecular features. Similar features including medium- to large-sized lymphoid cells with variable amounts of pale or slightly eosinophilic cytoplasm, and no evidence of EBER, TCR rearrangement were found in four cases. JAK3 K563_C565del mutation was found in one of three cases that were subjected to targeted next-generation sequencing. Unique findings of our study include one iNKLPD encountered for the first time in nasopharynx, where lesions could be inadvertently diagnosed as extranodal NK/T cell lymphoma, and one iNKLPD located in the gallbladder extended deeply into muscular and adventitial layers. Exceptional CD8-positive expression was observed in one iNKLPD. In addition, positive staining of phospho-STAT5, phospho-STAT3 and phospho-p38 were found in our cases. None of the four patients received therapy for lymphoma, but all had a benign clinical outcome during a follow-up time of 20-99months. We present four iNKLPDs with clinical, immunohistochemical and molecular features similar to the reported cases, as well as some unusual characters, which expand our knowledge on this disease, and further support the neoplastic nature of iNKLPDs.

Classification of B-Cell Lymphomas and Immunodeficiency-Related Lymphoproliferations: What’s New?

New insights from genomic studies have had an impact on the definition and the diagnosis of several lymphoid tumors including follicular B-cell lymphomas, aggressive diffuse large B-cell lymphomas, and lymphoproliferations associated with acquired and posttransplant immunodeficiencies. Follicular lymphoma (FL) includes tumors whose behavior varies widely from indolent/early lesions to aggressive/transformed lymphomas. Although some large B-cell lymphomas can be subclassified as specific entities, the majority lack the characteristics necessary for subclassification and, thus, are termed diffuse large B-cell lymphoma, NOS. There have been, however, some changes in the classification of specific subtypes of large B-cell lymphoma as well as the addition of new entities, a few of which are highlighted in this article. The immunodeficiency-related lymphoproliferative disorders are currently divided into four major categories based on the clinical setting in which they arose: primary immune deficiency, post-transplant, HIV infection, and iatrogenic immunosuppression. In the two upcoming classifications systems for hematolymphoid neoplasms, International Consensus Classification (ICC) and WHO-HAEM-5, there is a divergence in the approach to categorize these lesions. Furthermore, whereas the WHO-HAEM-5 confirms the ability to classify a spectrum of EBV+ lesions as EBV+ DLBCL, NOS, the ICC has separated out lesions that are composed of a heterogenous cellular infiltrate into a new separate category, “EBV-positive polymorphic B cell lymphoproliferative disorder, NOS”. Both WHO-HAEM-5 and ICC recognize a number of KSHV/HHV8-associated lymphoid lesions and acknowledge that there is significant overlap among the different lesions. In the future, translation of these innovations in general practice requires further validation.

Piddling and Moderate-Primary Cutaneous CD4+ Small/Medium T Cell Lymphoproliferative Disorder

Initially contemplated as a provisional subtype of cutaneous T cell lymphoma (CTCL), primary cutaneous CD4+ small / medium T cell lymphoproliferative disorder manifests as an indolent, solitary cutaneous lesion in the absence of accompanying cutaneous lymphoma as mycosis fungoides. Preponderantly, infiltration of upper dermis with miniature to intermediate, pleomorphic CD4+ T cells in the absence of preceding or concurrent patches and plaques with focal epidermotropism is encountered. Primary cutaneous CD4+ small/medium T cell lymphoproliferative disorder commonly appears in adults as a solitary plaque, tumour or nodule situated upon face, neck, upper trunk or thoracic region. Upon cytology, pleomorphic, miniature, intermediate or occasionally enlarged T lymphoid cells with irregular nuclear contours are variably intermixed with miniature, reactive CD8+ T cells, B cells, plasma cells, histiocytes and monotypic plasma cells. Morphologically, an intense dermal infiltrate of atypical lymphoid cells or small / medium pleomorphic CD4+ T cells extending into subcutaneous tissue appears to configure a diffuse or nodular configuration wherein the enlarged, pleomorphic cells articulate < 30% of neoplastic cellular infiltrate. Neoplastic lymphocytes appear immune reactive to T cell markers as CD3, CD4, CD5 along with T follicular helper markers as CD279 (PD-1), ICOS and CXCL13. Primary cutaneous CD4+ small/medium T cell lymphoproliferative disorder necessitates segregation from mycosis fungoides, cutaneous involvement with systemic T cell lymphoma of T follicular helper immuno-phenotype, benign inflammatory infiltrate, extra-nodal marginal zone (MALT) lymphoma or adult T cell leukaemia /lymphoma. The disorder can be therapeutically managed with intralesional steroids, radiotherapy or surgical extermination of lesion.