Age-related EBV-associated B-cell lymphoproliferative disorders and other EBV + lymphoproliferative diseases: New insights into immune escape and immunodeficiency through staining with anti-PD-L1 antibody clone SP142.

Epstein-Barr virus (EBV) is prevalent among healthy individuals, and is implicated in numerous reactive and neoplastic processes in the immune system. The authors originally identified a series of senile or age-related EBV-associated B-cell lymphoproliferative disorders (LPD) bearing a resemblance to immunodeficiency-associated ones. These LPDs may be associated with immune senescence and are now incorporated into the revised 4th edition of 2017 WHO lymphoma classification as EBV-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS). These EBV+ B-cells often have a Hodgkin/Reed-Sternberg (HRS)-like appearance and are shared beyond the diagnostic categories of mature B-cell neoplasms, mature T-cell neoplasms, classic Hodgkin lymphoma, and immunodeficiency-associated LPD. In addition, peculiar new diseases, such as EBV+ mucocutaneous ulcer and EBV+ DLBCL affecting the young, were recognized. On the other hand, lymphoma classification is now evolving in accord with deeper understanding of the biology of programmed death ligand 1 (PD-L1). Assessing PD-L1 positivity by staining with the anti-PD-L1 monoclonal antibody SP142 provides new insight by discriminating between immune evasion and senescence or immunodeficiency. The aim of the present review is to briefly summarize the diagnostic use of immunostaining with SP142 in malignant lymphomas and/or LPDs that feature tumor and nonmalignant large B-cells harboring EBV.

Novel therapeutic agents for relapsed classical Hodgkin lymphoma.

Hodgkin Lymphoma (HL) is a B-cell lymphoproliferative disorder with an excellent prognosis for the majority of patients who are treated with multi-agent chemotherapy, with or without radiation. A subset of patient, however, does not respond to therapy or relapses after accomplishing an initial response. Their outcome is poor and new treatment strategies are urgently needed for this patient population. Recent advances in the understanding of the tumour biology of HL and its microenvironment have ushered a new era of targeted- and immuno-therapies with remarkable activity. Most notably, the antibody-drug conjugate brentuximab-vedotin, and the immune checkpoint blockers pembrolizumab and nivolumab have recently been approved by the US Food and Drug Administration and have transformed the therapeutic landscape of this disease. Other novel drug compounds are being investigated either as single agents or in combination and hold promise to further the field.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma arising in patient with a history of EBV-positive mucocutaneous ulcer and EBV-positive nodal polymorphous B-lymphoproliferative disorder.

Elderly patients with Epstein-Barr virus (EBV) infection are at increased risk for developing B-cell lymphoproliferative disorder (B-LPD) due to immunosenescence. Here, we describe a case of a 75-year-old man who developed an EBV-positive (EBV+) mucocutaneous ulcer (EBVMCU) in the gingiva with spontaneous regression. Eighteen months after regression, he had a cervical lymph node enlargement that was diagnosed as EBV+ nodal polymorphous B-LPD, Ann Arbor stage IA. Clinicians decided to observe his clinical course without any treatment. Fourteen months later, the patient developed EBV-positive diffuse large B-cell lymphoma (DLBCL), Ann Arbor stage IIA, and received six courses of age-adjusted dose chemotherapy and achieved a complete remission. No evidence of a clonal relationship was found among these three lesions by standard polymerase chain reaction (PCR) analysis for immunoglobulin heavy chain. However, they all had expression of PD-L1 in the EBV+ large B-cells and Hodgkin Reed-Sternberg-like cells. This is the first case report of a PD-L1-positive (PD-L1+) EBVMCU and the development of multiple EBV-driven B-LPDs in the setting of immunosenescence within a 32-month period.

Iatrogenic immunodeficiency-associated lymphoproliferative disorder in a child with B-cell acute lymphoblastic leukemia.

Iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPDs) are a group of lymphoid proliferations or lymphomas that are well known to be associated with an immunosuppressed state. These disorders most commonly occur following hematopoietic or solid organ transplantation (called post-transplant lymphoproliferative disorders or PTLD), but cases have also been described during the treatment of autoimmune and rheumatologic disorders by immunosuppressive and immunomodulatory medications. These disorders are strongly associated with infection by the Epstein-Barr virus (EBV) as a result of impaired immune function in the immunosuppressed state. While this phenomenon has been well documented in autoimmune conditions, cases affecting pediatric patients while on anti-leukemia chemotherapy are lacking. In this report, we describe a case of a pediatric immunosuppressed patient with recurrent sinusitis found to have a nasopharyngeal mass consistent with EBV-positive B-cell lymphoproliferative disorder resembling a polymorphic PTLD during the maintenance phase of B-cell Acute Lymphoblastic Leukemia (ALL) therapy. The patient was successfully treated with rituximab without any cytotoxic chemotherapy, highlighting the importance of recognizing this clinical entity in non-transplant patients with hematologic malignancies.

Consistency of the Moreau CLL score.

BACKGROUND: The Moreau score is essential for the diagnosis of B-cell lymphoproliferative disorders (B-LPD). METHODS: We assessed the consistency of the Moreau score in a series of 138 patients with at least two samples involved by a B-LPD (316 samples) other than germinal center-derived malignancies, hairy cell leukemia, and mantle cell lymphomas. Patients with evidence of two distinct B-LPDs were also excluded. RESULTS: We found 53 inconsistencies in 44 of 138 (32%) patients. FMC7 was the most inconsistent (18 cases) and CD5 the least (5 cases). CD200 was inconsistent in 6 of 67 (9%) cases. The most important predictive factor for the finding of antigenic inconsistencies was sampling of a different anatomic site. Other factors, including number of samples, time between samples, or cytogenetic group, were not predictive. For the most part, these inconsistencies did not appear to be clinically relevant. CONCLUSION: Inconsistencies in the Moreau score are common, supporting the importance of integrated laboratory diagnosis. However, the practical implications of these antigenic inconsistencies are probably limited.

Proliferative Glomerulonephritis With Monoclonal IgG1κ Deposits in a Hepatitis C Virus-Positive Patient.

Hepatitis C virus infection is associated with several glomerular diseases, most commonly cryoglobulinemic glomerulonephritis, which is typically secondary to type II mixed cryoglobulinemia. We present a patient with hepatitis C virus infection and cryoglobulinemic glomerulonephritis secondary to type I (monoclonal) cryoglobulinemia that is likely related to a concurrent hepatitis C virus infection-associated lymphoproliferative disorder. We list the differential diagnosis of cryoglobulinemic glomerulonephritis. Additionally, the case draws attention to the possibility that, rarely, even clinically undetectable "occult" B-cell lymphoproliferative disorders may result in significant kidney disease.

Kidney diseases associated with monoclonal immunoglobulin M-secreting B-cell lymphoproliferative disorders: a case series of 35 patients.

BACKGROUND: Kidney diseases associated with immunoglobulin M (IgM) monoclonal gammopathy are poorly described, with few data for patient outcomes and renal response. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 35 patients from 8 French departments of nephrology were retrospectively studied. Inclusion criteria were: (1) detectable serum monoclonal IgM, (2) estimated glomerular filtration rate (eGFR) < 60mL/min/1.73m(2) and/or proteinuria with protein excretion > 0.5g/d and/or microscopic hematuria, and (3) kidney biopsy showing monoclonal immunoglobulin deposits and/or lymphomatous B-cell renal infiltration. All patients received chemotherapy, including rituximab-based regimens in 8 cases. PREDICTORS: Patients were classified into 3 groups according to renal pathology: glomerular AL amyloidosis (group 1; n=11), nonamyloid glomerulopathies (group 2; n=15, including 9 patients with membranoproliferative glomerulonephritis), and tubulointerstitial nephropathies (group 3; n=9, including cast nephropathy in 5, light-chain Fanconi syndrome in 3, and isolated tumor infiltration in 1). OUTCOMES: Posttreatment hematologic response (≥50% reduction in serum monoclonal IgM and/or free light chain level) and renal response (≥50% reduction in 24-hour proteinuria or eGFR≥30mL/min/1.73m(2) in patients with glomerular and tubulointerstitial disorders, respectively). RESULTS: Nephrotic syndrome was observed in 11 and 6 patients in groups 1 and 2, respectively. Patients in group 3 presented with acute kidney injury (n=7) and/or proximal tubular dysfunction (n=3). Waldenström macroglobulinemia was present in 26 patients (8, 12, and 6 in groups 1, 2, and 3, respectively). Significant lymphomatous interstitial infiltration was observed in 18 patients (4, 9, and 5 patients, respectively). Only 9 of 29 evaluable patients had systemic signs of symptomatic hematologic disease (2, 5, and 2, respectively). In groups 1, 2, and 3, respectively, hematologic response was achieved after first-line treatment in 3 of 9, 9 of 10, and 5 of 6 evaluable patients, while renal response occurred in 5 of 10, 9 of 15, and 5 of 8 evaluable patients. LIMITATIONS: Retrospective study; insufficient population to establish the impact of chemotherapy. CONCLUSIONS: IgM monoclonal gammopathy is associated with a wide spectrum of renal manifestations, with an under-recognized frequency of tubulointerstitial disorders.

IgG4-Related Retroperitoneal Fibrosis in a Patient With B-Cell Lymphoproliferative Disorder.

We report an interesting case of a 25-year-old male patient who presented with a complaint of pain in the abdomen for six months, which was not associated with any other symptom, the patient was diagnosed with IgG4-related retroperitoneal fibrosis (RF) via endoscopic ultrasound (EUS)-guided biopsy. He was prescribed steroids and proton pump inhibitors. Due to the limited presentation and rarity of RF, diagnosis of this disease requires extensive diligence and care. In this case report, we underscore the importance of considering the differential diagnosis of RF or Ormond's disease when a patient presents with vague symptoms of pain in the abdomen. According to our knowledge, this is the first case of IgG4-related RF in a patient with B-cell lymphoproliferative disorder reported from Pakistan.

HIV-associated CD8+ T-cell Skin Infiltrative Disease and EBV-associated Polymorphic B-cell Lymphoproliferative Disorder in an AIDS Patient Who Improved Dramatically with Antiretroviral Therapy Alone.

Human immunodeficiency virus (HIV)-associated CD8+ T-cell skin infiltrative disease with severe erythroderma has rarely been reported. While HIV-positive patients are prone to develop lymphoma, which is often associated with Epstein-Barr virus, polymorphic lymphoproliferative disorder is rare, accounting for <5% of cases. We herein report a 41-year-old HIV-positive man who presented with a fever, erythroderma, and lymphadenopathy and was diagnosed with the coexistence of both diseases. His condition improved significantly with continued antiretroviral therapy. This case suggests that HIV-induced immunodeficiency is central to the pathogenesis of both entities and that improvement of the immunodeficient state is an effective treatment.

Hairy Cell Leukemia: Hematological and Immunophenotypic Profile of 13 Patients.

INTRODUCTION: Hairy cell leukemia (HCL) is a rare lymphoproliferative disorder of the mature B-cells, mostly seen in men, and is characterized by cytopenia, splenomegaly, myelofibrosis, and the presence of atypical lymphoid cells showing the cytoplasmic hairy projection in the peripheral blood, bone marrow, and spleen. The immunophenotypic (IPT) profile shows the clonal expansion of B-cells with CD19, CD20, and CD22 showing bright expression. The diagnosis requires two hairy cell markers out of CD103, CD123, CD25, and CD11c to be positive. The HCL variant (HCL-v) has a different IPT profile with negative CD25 in most cases. AIM: The aim was to study the hematological and IPT of classical HCL and HCL variants. METHODS: This cross-sectional study included all the cases of HCL diagnosed over a retrospective period of eight years from 1st January 2015 to 31st December 2022 in a tertiary care hospital in north India. The patients included in the study were those for whom immunophenotyping; that is, flow cytometry and/or immunohistochemistry (IHC) were done for diagnosis. Bone marrow slides, IHC slides, and flow cytometric IPTs were reviewed. RESULTS: The study included 13 patients who were diagnosed to have HCL, of which 12 were classical HCL and one was HCL-variant (HCL-v). Among classical HCL, IPT was done by flow cytometry in 10 patients, while in two patients, it was done by IHC. CD19, CD20, and CD22 were positive in all patients of classical HCL (10/10, 10/10, and 5/5, respectively), while CD123, CD103, CD25, and CD11C were positive in 100%, 89%, 80%, and 100% cases, respectively. One patient of HCL-v had CD103 and CD123 positive, while CD25 and CD123 were negative. CONCLUSION: The diagnosis of HCL requires a multipronged approach. The use of clinical features, morphology, and immunophenotyping combined with ancillary techniques provides higher diagnostic accuracy and enables its distinction from other B-cell lymphoproliferative disorders (BCLPDs), leading to better patient management and treatment.

Uncommon Presentation of Undiagnosed B-Cell Lymphoproliferative Disorder as Nodular Pulmonary Amyloidosis.

B-cell lymphoproliferative disorders are characterized by the accumulation of mature B lymphocytes in the bone marrow, lymphoid tissues, and/or peripheral blood. They can cause amyloid deposits in the lungs. In rare cases, lung nodules can be the first sign of this disorder. We present the case of an 89-year-old woman with stable shortness of breath and lung nodules on imaging. A positron emission tomography-computed tomography (PET-CT) scan showed the most intense hypermetabolic nodule in the patient's lung, which was 1.5 × 1.4 cm. A biopsy of this nodule showed amyloid material with trapped plasma cell infiltrate on microscopy. Congo red stain under polarizing microscopy showed apple-green birefringence, which is diagnostic for amyloidosis. Immunohistochemistry showed a mixture of kappa-positive and lambda-positive cells. B-cell gene rearrangement-clonal gene rearrangements were detected in the immunoglobulin heavy chain (IgH) gene and the kappa light chain (IGK). These findings suggest a B-cell lymphoproliferative disorder, such as a plasmacytoma or a marginal cell lymphoma with plasma cell differentiation. The patient was diagnosed with a B-cell lymphoproliferative disorder and pulmonary amyloidosis. Isolated amyloidosis in the lungs usually has a good prognosis, but it can be a sign of autoimmune diseases or B-cell lymphoproliferative disorders, as in this case. Early diagnosis of B-cell lymphoproliferative disorder can lead to successful treatment and prevents complications.

Commercial DURAClone panels for extending the repertoire of multicolour immunophenotypic panels in an academic flow cytometry laboratory in South Africa.

Background: Commercial multicolour fixed immunophenotyping panels can improve flow cytometric diagnostic immunophenotyping repertoire. Objective: This study validated the commercially available, standardised Beckman Coulter lyophilised DURAClone RE panels to discriminate specific haematolymphoid subtypes. Methods: We compared the diagnostic capability of the DURAClone acute leukaemia B (ALB), chronic leukaemia B (CLB), and plasma cells (PC) panels to the predicate second-line panels in Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa, from April to August 2020. Clinical diagnostic concordance between the in-house second-line immunophenotyping (the predicate method) and DURAClone was established. The ALB panels tested for precursor B-cell acute lymphoblastic leukaemia (n = 11) or normal bone marrow haematogones (n = 9); CLB panels established haematolymphoid subtypes of mature B-cell lymphoproliferative disorders (B-LPD) (n = 20), while PC panels detected plasma cell dyscrasias (PCD) (n = 17). Flow cytometer setup and data interpretation to discriminate normal and aberrant immunophenotypes were per manufacturer's instructions. Results: There was 100% clinical diagnostic concordance between the predicate and the test panels for second-line diagnostic investigation of B-ALL (with additional CD56), mature B-LPD (with additional discernment of CD81, ROR-1, CD79b and CD43) and PCD. Conclusion: The DURAClone CLB exceeded the predicate second-line performance, offering extended second-line diagnostic discernment of mature B-LPD subtypes and discernment of CD5+ B-LPD from other non-CD5+ (or CD5-) B-LPD; likewise, the PC panels enabled discovery of PCD. While ALB testing offered no additional diagnostic advantage over existing predicate investigation, CD58 did offer additional information to discern haematogones from B-ALL.

Lymphomatoid granulomatosis of the central nervous system (CNS-LYG) posing a management challenge.

Isolated central nervous system lymphomatoid granulomatosis (CNS-LYG) can mimic aggressive glioblastomas. We describe a complex presentation of CNS-LYG coexisting with immune thrombocytopenia successfully managed with rituximab and ultra-low-dose radiation therapy.

Differential Expression of CD43, CD81, and CD200 in Classic Versus Variant Hairy Cell Leukemia.

BACKGROUND: Hairy cell leukemia (HCL) and hairy cell leukemia variant (HCLv) are rare diseases with overlapping clinicopathological features. Features distinguishing HCL from HCLv include expression of CD25, CD123, CD200, annexin-A1, and the presence of BRAF V600E mutation. HCLv typically lacks these markers, but they may occur in a subgroup of HCL patients with an aggressive clinical course. We examined CD43, CD81, CD79b, and CD200 expression in HCL and HCLv. METHODS: Multiparametric flow cytometry (FCM) was performed on blood from 59 HCL and 15 HCLv patients for protocol entry. Mean fluorescent intensity (MFI) of CD43, CD79b, CD81, and CD200 was determined (for CD200, n = 17 and 7, respectively). RESULTS: Median MFI of HCL vs HCLv was 545 vs 272 for CD43, 602 vs 2,450 for CD81, 4,962 vs 1,969 for CD79b, and 11,652 vs 1,405 for CD200, respectively. Analysis of the median differences, HCL minus HCLv (and their 95% confidence intervals and P-values) indicated that CD43 MFI (estimated median difference (95% CI): 212 [72-413; P = 0.0027) and CD200 MFI (9,883 [3,514-13,434]; P < 0.0001) were higher in HCL than in HCLv, while CD81 MFI (-1,858 [-2,604 to -1,365]; P < 0.0001) was lower in HCL than in HCLv. CD79b MFI HCL median was more than double that of HCLv, but the observed difference (1,571 [-739 to 4,417]) was consistent with the null hypothesis of no difference (P = 0.13). CONCLUSIONS: CD200, CD43, and CD81 are likely differentially expressed between HCL and HCLv, reflecting their differing disease biology. Inclusion of these markers in FCM is potentially informative. © 2019 International Clinical Cytometry Society.

Quadravalvular Noninfectious Endocarditis.

Nonbacterial thrombotic endocarditis is characterized by sterile thrombi on cardiac valves. This report describes the case of nonbacterial endocarditis without pathologic findings of fibrin or platelet deposition. Quadrivalvular endocarditis was found to be due to immunoglobulin M heavy chain deposition. This was a case of nonbacterial, nonthrombotic quadrivalvular endocarditis, which was termed noninfective endocarditis. (Level of Difficulty: Intermediate.).

Usefulness of the CLLflow score.

BACKGROUND: The CLLflow score was recently suggested as an improvement over the Moreau score (MS) for the diagnosis and classification of B-cell lymphoproliferative disorders (B-LPD). METHODS: We determined the CLLflow score in peripheral blood or bone marrow of a series of cases with an inconclusive immunophenotype, including samples with a MS of 3 (n = 52) and CD5-positive with a score of 2 (n = 38). As controls, B-LPD with a MS of 0-1 (n = 95), CD5-negative score 2 (n = 24), and score 4-5 (i.e., chronic lymphocytic leukemia [CLL], n = 166) were included. RESULTS: The CLLflow score was positive (suggestive of CLL) in all CLL cases and negative in all MS <2, regardless of CD200-positivity, which occurred in 31% (29/95) of cases. The CLLflow score was positive in 71%, 29%, and 8% of samples with a MS 3, CD5-positive score 2, and CD5-negative score 2, respectively. DISCUSSION: Our results suggest that the CLLflow is useful in the differential diagnosis of cases with inconclusive immunophenotype. © 2018 International Clinical Cytometry Society.

Hairy Cell Lymphoma: A Potentially Under-Recognized Entity.

Hairy cell leukemia (HCL) is a low grade B-cell lymphoproliferative disorder that typically presents with splenomegaly, cytopenias, and diffuse bone marrow infiltration. There have been few cases in the literature of HCL presenting as lymphomas in extra-nodal locations, such as soft tissues and bones without circulating leukemic cells, splenomegaly, or iliac crest bone marrow involvement. We present an additional case presenting as a thoracic mass, and discuss potential diagnostic pitfalls and management of these rare cases.

Hairy B-Cell Lymphoproliferative Disorder and its Differential Diagnosis: a Case with Long-Term Follow-Up.

Hairy B-cell lymphoproliferative disorder (HBLD) is one of chronic polyclonal B-cell lymphocytosis. We report a 47-year-old female Japanese patient diagnosed as having HBLD based on lymphocytosis with hairy cell appearance and characteristic phenotypes including CD11c+ and without B-cell monoclonality. She was a non-smoker and possessed HLA-DR4. She has been closely followed up without treatment and lymphoma development for over five years. Although this disease is quite rare and has been reported, to our knowledge, in only 13 Japanese cases, an accurate diagnosis, particularly differential diagnosis from persistent polyclonal B-cell lymphocytosis or hairy cell leukemia-Japanese variant is essential for the prevention of unnecessary treatments.