Search

The diagnosis of leukemic B-cell lymphoproliferative disorders (B-LPDs) is made by integrating clinical, cytological, cytometric, cytogenetic, and molecular data. This leaves room for differences and inconsistencies between experts. In this study, we examine methodological and conceptual aspects of the flow cytometric classification of leukemic B-LPDs that could explain them. Among methodological aspects, we discuss (1) the different statistical tests used to select and evaluate markers, (2) how these markers are analyzed, (3) how scores are interpreted, (4) different degrees to which diagnostic information is used, and (5) and the impact of differences in study populations. Among conceptual aspects, we discuss (1) challenges to integrating different biological data points, (2) the under examination of the costs of misclassification (false positives and false negatives), and finally, (3) we delve into the impact of the lack of a true diagnostic gold standard and the indirect evidence suggesting poor reproducibility in the diagnosis of leukemic B-LPDs. We then outline current harmonization efforts and our personal approach. We conclude that numerous flow cytometry scores and diagnostic systems are now available; however, as long as the considerations discussed remain unaddressed, external reproducibility and interobserver agreement will not be achieved, and the field will not be able to move forward if a true gold standard is not found.

Kikuchi Fujimoto Disease, originally discovered in 1972, is a rare lymphoproliferative disorder traditionally characterized by cervical lymphadenopathy, fevers, parotid gland enlargement, and several other nonspecific manifestations. Differentials include lymphoma, other viral diseases such as Epstein-Bar Virus, as well as other autoimmune conditions such as Systemic Lupus Erythematosus. Central nervous system involvement is exceptionally rare, with manifestations including meningitis as well as subdural effusions, as presented in this case. This review will summarize a case of a 24-year-old man with recurrent subdural effusions requiring intervention, subsequent relapse with abdominal lymphadenopathy, and possible IgG4 related disease. The background epidemiology, radiology, and potential pathophysiology will be reviewed.

Iatrogenic immunodeficiency-associated lymphoproliferative disorders (IA-LPD) may arise in patients treated with immunosuppressive drugs for autoimmune disease or other conditions. Polymorphic EBV-positive B-lymphoproliferations often have features mimicking Hodgkin lymphoma and typically a self-limited, indolent course. We present an unusual case with isolated, intracerebral manifestation of polymorphic B-LPD with features of classic Hodgkin-lymphoma in an immunosuppressed patient treated with methotrexate and infliximab, including clinical-radiological features and a detailed description of morphological findings, together with a literature review on reported cases of primary CNS manifestation of cHL and IA-LPD with Hodgkin-like morphology. The patient achieved complete remission following neurosurgery with gross total tumor resection and drug withdrawal without any additional treatment. Post-operative staging revealed no evidence for focal relapse or systemic disease during the 18 months follow-up period. Among the previously reported 24 cases of primary, isolated Hodgkin lymphoma in the central nervous system, three similar cases of iatrogenic, IA-LPDs were identified and are discussed here. Polymorphic B-LPD are destructive lesions with a range of morphologic features and disease manifestations. It is clinically important to recognize the spectrum of proliferations with features of classic Hodgkin lymphoma in immunodeficiency, iatrogenic settings, because they are likely to impact the choice of treatment strategies. Funding Agencies|Karolinska InstituteKarolinska Institutet

International audience; Hepatitis C virus (HCV) has been shown to induce many B-cell lymphoproliferative disorders. B lymphocytes are specialized in producing immunoglobulins, and within chronic HCV infection they can cause a range that goes from polyclonal hypergammaglobulinemia without clinical repercussions, passing by mixed cryoglobulinemic vasculitis and eventually reaching B-cell non-Hodgkin lymphoma. This spectrum is supported by substantial epidemiological, pathophysiological and therapeutic data. Many, although not all, pathogenic pathways leading from one extreme to another have been decrypted. Chronic viral antigen stimulation of B lymphocytes has a central role until the last steps towards overt malignancy. This has direct implications in treatment strategies, which always include the use of direct-acting antiviral agents sometimes associated with immunosuppressants. The role of direct-acting antiviral agents has been well established in patients with cryoglobulinemia vasculitis. Its positive impact on B cell non-Hodgkin lymphoma needs to be confirmed in larger studies with longer follow-up.

© 2022 Elsevier Masson SAS. All rights reserved., Crystalline inclusions in lymphocytes are unusual in chronic lymphocytic leukemia. They represent crystallized immunoglobulin (most frequently IgM-lambda) and their recognition facilitates the diagnosis of a lymphoproliferative disorder.

Introduction Multiple flow cytometry scores/diagnostic systems for the classification of leukemic lymphoproliferative disorders (LPD) have been published but few have been compared between them. Patients and Methods We classified a cohort of leukemic LPD based on eleven published flow cytometry scores/diagnostic systems and compared their classification as chronic lymphocytic leukemia (CLL) or non-CLL LPD. Results 329 patients were included. Patients classified as CLL ranged from 46% to 73%, depending on the score/diagnostic system used. All eleven scores/diagnostic systems agreed in 184/324 (57%) of patients while in 58/324 (18%) at least two scores/diagnostic systems classified the patient differently (from the majority). Fleiss kappa was 0.74, but pairwise agreement was variable (Cohen's kappa: 0.48 to 0.87). Conclusion This study found a suboptimal agreement between published flow cytometry scores/diagnostic systems for the classification of LPD.

Epstein Barr virus (EBV) is associated with a wide range of human lymphoproliferative disorders (LPD) of B, T, and natural killer (NK)-cell lineage. In children, abnormal immune response to primary EBV infection can cause peculiar forms of T/NK- cell LPD of childhood, such as the systemic form of chronic active EBV infection, hydroa vacciniforme-like LPD, severe mosquito bite allergy and systemic T cell lymphoma of childhood. In adults, dysregulation of the immune response to EBV infection, immunosenescence caused by aging, chronic inflammation in a closed space, and iatrogenic immune suppression can lead to EBV-positive LPD of diverse types involving B, T, and NK cells with unique clinical and pathological presentations. This review describes the clinical, pathological, and genetic findings of EBV-positive LPD listed in the revised 2016 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) has been included as a provisional entity in the revised version of the World Health Organization Classification of Tumors of Haematopoietic and Lymphoid Tissue. To increase opportunities to intervene with early diagnosis, treatment, and possible prevention, it is important to consider that BIA-ALCL may evolve from a preexisting lymphoproliferative disorder characterized by (1) an indolent localized (in situ) disease in approximately 80 percent of reported cases; (2) a requirement for external cytokine stimulation for cell survival; (3) CD30 cells in some clinically benign seromas/capsules; (4) undetected T-cell clonality in some cases; (5) JAK/STAT mutations in only a minority of cases; and (6) cure by capsulectomy and implant removal in most cases. BIA-ALCL resembles CD30 cutaneous lymphoproliferative disorder: ALK, CD30 anaplastic cells with an aberrant T-cell phenotype; overexpression of oncogenes (JUNB, SATB1, pSTAT3, SOCS3) in lymphomatoid papulosis; frequent apoptosis; complete spontaneous regression in lymphomatoid papulosis; and partial spontaneous regression in cutaneous ALCL. Unlike CD30 cutaneous lymphoproliferative disorder, BIA-ALCL cannot be readily observed over time to study the different steps in progression to ALCL. BIA-ALCL also shares features of lymphomas of mucosa-associated lymphoid tissue, which are clinically indolent, initially localized, antigen driven, and caused by Gram-negative bacteria. Further studies of cytokines, clonality, mutations, and other biomarkers are needed to identify possible premalignant steps in the evolution of benign late seromas to BIA-ALCL.

Successful treatment of indolent T-cell lymphoproliferative disorder of the gastrointestinal tract (ITLPDGI) by chemotherapy is rare and watchful waiting is often performed for asymptomatic patients. We report a case of ITLPDGI successfully treated by involved field radiotherapy (IFRT). The patient presented with slow ITLPDGI localised to the stomach with mild symptoms. IFRT (30 Gy/20f) was administered, after which endoscopy revealed resolution of lesions and blood vessel appearance, and absence of proliferating abnormal lymphocytes was confirmed by biopsy. The patient remains lymphoma-free 1 year post-treatment. Although long-term follow-up and additional cases are essential for the evaluation of IFRT as a treatment option for localised ITLPDGL, complete remission after relatively low-dose IFRT is promising, particularly as this has been rarely achieved by chemotherapy.

Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder with aggressive systemic presentation and poor prognosis. Here, we present a case of MCD in a 37-year-old Asian American woman with a past medical history of the polycystic ovarian syndrome (PCOS), human papilloma virus (HPV), herpes simplex virus-1 (HSV-1), iron deficiency, and vitamin B12 deficiency-related anemia. The patient underwent surgical resection with good recovery. Hemoglobin and erythrocyte sedimentation rate (ESR) normalized after surgical resection. Although the influence of risk factors such as human immunodeficiency virus (HIV) or human herpesvirus-8 (HHV-8) infections on MCD relapse are not well understood, patient education on MCD risk factors is important, as they may place the patient at greater risk for recurrence. MCD should be considered in patients with chronic inflammation and a mass on imaging.

EBV-associated lymphoproliferative disorders (LPDs) are common in hematopoietic stem cell transplantation (HSCT) with T-cell-depleted grafts, but are extremely rare in HSCT patients with T-cell-replete grafts with post-transplant cyclophosphamide (PTCy). Here we present the cases of two pediatric patients who developed EBV-related LPD after T-cell-replete haplo-HSCT with PTCy. One of these is the first reported case of EBV-positive mucocutaneous ulcer (EBVMCU) developing after PTCy. EBV-related diseases are rare in T-cell-replete haplo-HSCT patients with PTCy. However, in patients with risk factors, it is reasonable to screen for EBV viremia for LPD. WOS:000722865400001 34826107 Q3

Methotrexate (MTX) is known as a first-line synthetic disease-modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). Although the risk of LPD development increases by RA inflammation itself, observation of spontaneous regression of LPD after MTX discontinuation lead to the theory of lymphomagenic role of MTX. In this review, we focused on the several immune response involved in LPD that developed under MTX administration in RA patients.

In the current revised 4th edition of the World Health Organization (WHO) classification, ‘other iatrogenic immunodeficiency-associated lymphoproliferative disorders (Oii-LPDs)’ is listed in the last section in the chapter on immunodeficiency-associated lymphoproliferative disorders. Oii-LPDs cover a broad spectrum from benign lesions to lymphoma, and correspond to one of the subtypes in the WHO classification for immunocompetent patients. The WHO classification does not clearly indicate the histological subtype of this disease category; however, the framework of subtype classification is similar to the classification of post-transplant lymphoproliferative disorders, and recent studies have attempted to subcategorize Oii-LPDs that fit this unique disease type. In this review, we provide an overview of B-cell-type Oii-LPDs regarding their histopathology and immunophenotype, genetics and clinical behaviors.

Background Epstein‐Barr virus (EBV) is detected in a variety of B‐cell lymphomas (BCLs) and B‐cell lymphoproliferative disorders (B‐LPDs). Immunodeficiency has been considered to play a key role in the pathogenesis of these diseases. In addition, immune escape of tumor cells may also contribute to the development of EBV+ BCLs and B‐LPDs. The PD‐1/PD‐L1 pathway is particularly important for immune escape of tumor cells that contribute to development of lymphoma through suppression of cytotoxic T‐cell function. We now consider PD‐L1 immunohistochemistry (IHC) a very useful method for predicting whether tumor cells of lymphoid malignancies are characterized by the immune escape mechanism. Methods We reviewed articles of EBV+ BCLs and B‐LPDs from the perspective of immune escape and immunodeficiency, particularly focusing on PD‐L1 IHC. Results Based on PD‐L1 IHC, we consider that EBV+ BCL and B‐LPD can be classified into three types: “immunodeficiency”, “immune escape”, and “immunodeficiency + immune escape” type. The immunodeficiency type includes EBV+ diffuse large BCL (DLBCL) of the elderly, EBV+ sporadic Burkitt lymphoma, EBV+ mucocutaneous ulcer, and methotrexate (MTX)‐associated B‐LPD. The immune escape type includes EBV+ classic Hodgkin lymphoma (CHL) and EBV+ DLBCL of the young. The immunodeficiency + immune escape type includes CHL type MTX‐associated LPD and a minor subset of EBV+ DLBCL of the elderly. Conclusions Recently, good results have been reported for immune check‐point inhibitors in treating lymphoma. Lymphomas and LPDs characterized by immune escape are regarded as good candidates for PD1/PD‐L1 blockade therapy. Therefore, from both the clinical and pathological perspective, we suggest that lymphoma diagnosis should be made considering immune escape and immunodeficiency., We now consider PD‐L1 immunohistochemistry (IHC) a very useful method for predicting whether tumor cells of lymphoid malignancies are characterized by the immune escape mechanism. Based on PD‐L1 IHC, we consider that EBV + BCL and B‐LPD can be classified into three types: “immunodeficiency,” “immune escape,” and “immunodeficiency + immune escape” type.

Introduction: Previously, we reported a relatively rare case of methotrexate-related lymphoproliferative disorder (MTX-LPD) that developed in the lumbar spine. At present, we report the follow-up of that case, presenting with relapse of MTX-LPD. Case Report: The participant was a 75-year-old woman who was diagnosed with MTX-LPD of the lumbar spine and in whom remission was obtained 6 months after discontinuing methotrexate (MTX). At 12 months after remission, elevated levels of soluble interleukin-2 receptor, lymph node swelling on plain computed tomography (CT), and fluorodeoxyglucose uptake on positron emission tomography CT were observed, and recurrent MTX-LPD was diagnosed. Doxorubicin, bleomycin, vinblastine, and dacarbazine therapy was initiated, and partial remission was obtained 6 months later. Conclusion: In MTX-LPD, remission is often achieved following discontinuation of MTX alone; however, some patients do not improve, and some patients relapse, as seen in the present case. Such cases are treated using the standard regimen for the observed histologic subtype. Even after remission has been achieved, strict follow-up observation is needed for MTX-LPD. Furthermore, when signs of recurrence are observed during follow-up, practitioners should endeavor to cooperate with other specialists and act without delay. Keywords: Rheumatoid arthritis, methotrexate, lymphoproliferative disorder, lumbar spine, oncology.

Pyelocaliceal obstruction is a diagnostic challenge, and it is important to identify the obstruction cause. Some patients present extra‐renal compressive masses that need further imagiologic investigation and a biopsy, to establish the diagnosis.

Objectives: CD43 can be useful in routine flow cytometry. We conducted a systematic review aiming to describe when CD43 is used by flow cytometry in malignant hematology and to determine its value in these settings. Methods: Systematic review of MEDLINE (search ‘CD43’ AND ‘flow cytometry,’ starting in 2010). Results: Twenty-one of 103 entries retrieved were included in this systematic review. CD43 is used in three settings: 1) in the classification of mature B cell lymphoproliferative disorders, 2) as part of a strategy to quantify residual disease in chronic lymphocytic leukemia (CLL) and 3) to help classify CD10-positive B cell populations. In this section, the published data is summarized, the clinical usefulness in each of these settings is evaluated and illustrative cases are shown. Conclusion: CD43 has a growing role in the diagnosis and management of B cell malignancies; it has become essential for the classification of B cell lymphoproliferative disorders and may be of help in the differential diagnosis of CD10-positive lymphomas by FC. It is also required for optimal quantification of CLL residual disease, which will soon be used to guide therapeutic decisions.

Due to age and comorbidities many patients with CLL receive chlorambucil as front-line treatment. Doses and schedules of this drug vary widely but it is not clear whether this affects outcomes. We performed this retrospective analysis to compare the efficacy and toxicity of continuous high-dose chlorambucil (12-20 mg daily until response or toxicity) (cHD-Clb- R) and intermittent high dose chlorambucil (8-10 mg/m2 daily for 7 days q 4 wk) (iClb-R) in combination with rituximab (375 mg/m2/cycle for 8 cycles) in previously untreated CLL patients. Thirtysix patients received cHD-Clb- R and 32 iClb-R. Median age was 66 years (range 41-80) ; 24 were women and 44 men ; 24 had Binet stage A, 27 B and 17 C ; 5 had del(17p). Most common severe adverse events were granulocytopenia, occurring in 14 ; and infections in 7 patients, one of whom died. One patient stopped treatment due to hepatotoxicity. Both schedules resulted in similar toxicity and efficacy (cHD-Clb-R vs. iClb-R overall survival, progression-free survival and survival without next treatment at 30 mo. 70% vs. 83%, 49% vs. 55% and 67% vs. 75% respectively). Combinations of rituximab and chlorambucil are well tolerated and effective treatments for patients ineligible for fludarabine- based regimens. Outcomes seem to be related more to total drug doses than schedules.

Introduction Fine needle aspiration cytology (FNAC) is a quick, effective and relatively inexpensive technique to evaluate the visibly accessible superficial masses. As cervical, axillary and inguinal lymphadenopathies are commonly encountered clinical problems, in this study, we evaluated the utility of FNAC for assessment of lymphadenopathy. Methods A retrospective observational study was conducted in the Department of Cytopathology, Liaquat National Hospital and Medical College, over the duration of three years. A total of 559 cases were included in the study that underwent FNAC. After palpation, two to three passes were performed with a 22-23 gauge needle along with a plunger for FNAC. The obtained material was spread on three slides that were then stained with hematoxylin and eosin (H & E), Papanicolaou (PAP), and Diff-Quik methods. The remaining material was used for cell block preparation. Results The mean age of the patients was 37.05±18.03 years. In 98.7% of cases, the material was adequate for a satisfactory cytological examination. The most common site of FNAC was the cervical lymph node and tuberculous lymphadenitis (37%) was the most common diagnosis on FNAC, followed by reactive lymphadenitis (27.2%). Reactive lymphadenitis was seen more frequently in the younger age group (50 years). Tuberculous lymphadenitis was noted more frequently in the middle age group (16-35 years). Moreover, tuberculous lymphadenitis was noted more commonly in cervical lymph nodes, while metastatic carcinoma was more frequently observed in axillary and inguinal lymph node FNACs. Conclusion FNAC is a quick and reliable method to categorize the cause of lymphadenopathy into reactive, inflammatory/infectious, metastatic, and lymphoproliferative, avoiding the necessity of an incisional/trucut biopsy. Moreover, age, gender, and site of involvement are useful predictors of the cause of lymphadenopathy. We noted that in the younger age group, reactive lymphadenitis was more common, whereas tuberculous lymphadenitis and metastatic carcinoma were more frequent in middle and older age groups, respectively. On a similar note, tuberculous lymphadenitis was more frequent in cervical lymph nodes than axillary and inguinal lymph nodes, while metastatic carcinoma was more common in these latter two sites.

The use of viruses for tumour treatment has been imagined more than one hundred years ago, when it was reported that viral diseases were occasionally leading to a decrease in neoplastic lesions. Oncolytic viruses (OVs) seem to have a specific tropism for tumour cells. Previously, it was hypothesised that OVs’ antineoplastic actions were mainly due to their ability to contaminate, proliferate and destroy tumour cells and the immediate destructive effect on cells was believed to be the single mechanism of action of OVs’ action. Instead, it has been established that oncolytic viruses operate via a multiplicity of systems, including mutation of tumour milieu and a composite change of the activity of immune effectors. Oncolytic viruses redesign the tumour environment towards an antitumour milieu. The aim of our work is to evaluate the findings present in the literature about the use of OVs in the cure of haematological neoplastic pathologies such as multiple myeloma, acute and chronic myeloid leukaemia, and lymphoproliferative diseases. Further experimentations are essential to recognize the most efficient virus or treatment combinations for specific haematological diseases, and the combinations able to induce the strongest immune response.

Background Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract is a rare low-grade clonal lymphoid proliferation, included as a provisional entity in the current World Health Organization classification. The disease is generally localized to the gastrointestinal tract, mainly small bowel and colon. Involvement of other organs is infrequently reported. The majority of patients show a protracted clinical course with persistent disease. A prolonged survival, even without treatment, is common. Case presentation A 28-year-old woman had a 2-year history of dyspepsia and lactose intolerance. Autoimmune diseases and celiac disease were excluded. No gross lesions were identified by endoscopy. Multiple gastric biopsies showed a small-sized lymphoid infiltrate, expanding the lamina propria, with a non-destructive appearance. The lymphoid cells were positive for CD3, CD4, CD5, CD7 and negative for CD20, CD8, CD56, CD103, PD1, CD30, ALK1, CD10, BCL6, perforin, TIA-1, Granzyme B and Epstein-Barr virus-encoded RNA. KI-67 index was low (5%). Molecular analysis revealed a clonal T-cell receptor γ rearrangement. Bone marrow was microscopically free of disease, but molecular testing identified the same T-cell receptor γ rearrangement present in the gastric biopsies. After the diagnosis of indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, the patient received steroid therapy, only for 2 months. She is alive, with a stable disease restricted to the stomach, at 12 months from diagnosis. Conclusions Indolent T-cell lymphoproliferative disorder is usually a disease of adulthood (median age: 51 yrs). The small bowel and colon are the sites most commonly involved. Our case occurred in a young woman and affected the stomach, sparing small intestine and colon. Clonality testing identified involvement of bone marrow, a site infrequently affected in this disease. Our aim is focusing on the main diagnostic issues. If appropriate immunostainings and molecular analysis are not performed, the subtle infiltrate may be easily overlooked. The risk of misdiagnosis as more aggressive lymphomas, causing patient overtreatment, needs also to be considered.

Introduction Pre-analytical and analytical errors can threaten the reliability of flow cytometry (FC) results. A potential solution to some of these is the use of dry, pre-mixed antibodies, such as the ClearLLab 10C system. The purpose of the present study was to compare the diagnostic performance of the ClearLLab 10C B cell tube with that of our standard laboratory practice. Methods We compared the diagnoses made with the ClearLLab 10C B cell tube (experimental strategy) with those made with standard laboratory practice (standard strategy). Samples were selected aiming for representation of the full spectrum of B cell disorders, with an emphasis on mature B cell malignancies, as well as healthy controls. Results We included 116 samples (34 normal controls, 4 acute lymphoblastic leukemias, 54 mature lymphoproliferative disorders in peripheral blood and bone marrow, 3 myelomas, 6 bone marrow samples with involvement by lymphoma and 1 with elevated hematogone count, 14 lymph node samples, 1 cerebrospinal fluid, and 1 pleural effusion). There were two diagnostic errors (1.7%). The agreement between the two strategies in the percentage of CD19 cells and fluorescence intensity of CD5, CD19, CD20, CD200, and CD10 was very good. Conclusions In this study, the ClearLLab 10C B cell tube performed similarly to our standard laboratory practice to diagnose and classify mature B cell malignancies.

Background Within the hematopoietic compartment, fibromodulin (FMOD) is almost exclusively expressed in chronic lymphocytic leukemia (CLL) lymphocytes. We set out to determine whether FMOD could be of help in diagnosing borderline lymphoproliferative disorders (LPD). Methods We established 3 flow cytometry-defined groups (CLL [n= 65], borderline LPD [n= 28], broadly defined as those with CLLflow score between 35 and -20 or discordant CD43 and CLLflow, and non-CLL LPD [n= 40]). FMOD expression levels were determined by standard RT-PCR in whole-blood samples. Patients were included regardless of lymphocyte count but with tumor burden >= 40%. Results FMOD expression levels distinguished between CLL (median 98.5, interquartile range [IQR] 37.8-195.1) and non-CLL LPD (median 0.012, IQR 0.003-0.033) with a sensitivity and specificity of 1. Most borderline LPDs were CD5/CD23/CD200-positive with no loss of B-cell antigens and negative or partial expression of CD43. 16/22 patients with available cytogenetic analysis showed trisomy 12. In 25/28 (89%) of these patients, FMOD expression levels fell between CLL and non-CLL (median 3.58, IQR 1.06-6.21). Discussion This study could suggest that borderline LPDs may constitute a distinct group laying in the biological spectrum of chronic leukemic LPDs. Future studies will have to confirm these results with other biological data. Quantification of FMOD can potentially be of help in the diagnosis of phenotypically complex LPDs.

Castleman's disease is a rare lymphoproliferative disorder of poorly understood etiology. It is most commonly located in the mediastinum. Castleman's disease mimicking adrenal neoplasm is a very rare differential diagnosis and unusual presentation. We report a rare suprarenal unicentric hyaline vascular variant of the disease in a 16-year-old boy with atypical symptoms mimicking an adrenal neoplasm.

BACKGROUND: The concept of borderline lymphoproliferative disorder (LPD) has not been clearly defined. METHODS: This study aimed to classify patients with leukemic LPD (n = 597, excluding hairy cell leukemia, mantle cell lymphomas, and CD10-positive LPDs) into CLL or non-CLL applying three diagnostic strategies (the D'Arena and CLLflow scores and CD43 expression) and to better characterize unclassified patients. RESULTS: Patients with concurring CLL-like (n = 441) or non-CLL like (n = 99) results with the three diagnostic strategies were determined to have CLL and non-CLL, respectively. Patients with discordant results (n = 57) were analyzed taking into consideration each individual cytometric marker and cytogenetic data: 41 were classified (11 CLL, 30 non-CLL) and 16 (2.7% of the entire series) could not and were considered borderline LPD. Excluding borderline LPD, the CLLflow score had the highest accuracy of the three strategies. With the addition of CD43 no patient was misclassified. With the aid of hierarchical clustering, 12 of the 16 borderline patients seemed to fall into two well-defined antigenic groups. None of the diagnostic strategies could reliably pick out borderline LPD. CONCLUSION: The combination of the CLLflow score and CD43 generally has a high diagnostic accuracy for leukemic LPD but it is not reliable to identify or diagnose borderline LPD. This latter group needs further study to determine its underlying biology. © 2018 International Clinical Cytometry Society.

The number of patients with methotrexate-associated lymphoproliferative disorder (MTX-LPD) is increasing. We describe a case of MTX-LPD of the stomach. After treatment with methotrexate for rheumatoid arthritis, the patient developed left cervical lymphadenopathy and an ulcerative lesion in the stomach, which was presumed to be a mucosa-associated lymphoid tissue (MALT) lymphoma. However, we suspected MTX-LPD, based on the clinical course and the positivity of in situ hybridization for the detection of the Epstein-Barr encoding region. After the cessation of MTX, the left cervical lymphadenopathy and the gastric lesion disappeared. This is first report of gastric MTX-LPD that was presumed to be MALT lymphoma.

Methotrexate-related lymphoproliferative disorder (MTX-LPD) is a rare disorder caused by long-term MTX therapy for autoimmune diseases. There has been no report of the dermoscopic features of MTX-LPD to date. A 64-year-old female presented with a slightly elevated indurated erythematous plaque with scales on her right thigh. The patient had been treated for rheumatic arthritis with MTX and prednisolone for more than 15 years, and 18 mg/week MTX without prednisolone had been administered in the last year. Dermoscopy revealed dotted vessels and glomerular vessels on pink homogeneous areas and multiple surface scales. Enhanced computed tomography showed multiple nodules and lymphadenopathies at the mediastinum and axillae. Histopathological examination revealed telangiectasia in the superficial dermis. Atypical lymphoid cells were scattered in the whole dermis and subcutaneous tissue. A perivascular infiltrate of atypical lymphocytes and histiocytoid cells partially destroyed the vessel walls. Epstein-Barr virus in situ hybridization showed a positive result. The cessation of MTX reduced the erythematous plaque, and lymphadenopathies at the neck, mediastinum, and axillae were not palpable. We discuss the relevance of these dermoscopic and histopathological features. The accumulation of such cases will reveal the dermoscopic features of MTX-LPD and the utility of dermoscopy for the diagnosis of MTX-LPD.

Highlights • Castleman disease: heterogeneous group of hyperimmune lymphoproliferative disorders. • Unicentric type: localized disease; surgery is primary treatment; good prognosis. • Multicentric type: Serious systemic disease; 70% linked to HHV8; antiviral therapy. • Idiopathic Multicentric type: diagnosis by exclusion; Interleukin-6 blockade useful., Castleman Disease (CD) is a rare, heterogeneous group of hyperimmune lymphoproliferative disorders, not very familiar to surgeons. Unicentric Castleman Disease (UCCD) at one end of the spectrum is a localized disease, with little or no systemic symptoms. It may be an incidental radiological finding or detected while investigating for a symptomatic lymph node mass. Surgery is the primary treatment and has good long term prognosis. Multicentric Castleman Disease (MCCD) is a more serious systemic condition, often associated with constitutional symptoms. Exaggerated systemic inflammatory response secondary to “Cytokine storm” involving Interleukin-6 (IL-6) may cause multi-organ dysfunction. In addition, immunosuppression or malignant transformation can prove lethal. Human Herpes Simplex Virus 8 (HHV8) associated MCCD is a major subgroup occurring in immunocompromised individuals due to the viral trigger. Antiviral therapy is important in its treatment. Idiopathic MCCD (IMCCD) has no known biomarker and is diagnosed after excluding infective, autoimmune and malignant conditions of lymphoid tissue. IMCCD requires systemic therapy. We report a patient of UCCD who presented as a retroperitoneal mass in right iliac fossa causing pressure on femoral nerve. Following successful surgical excision she had good recovery. We report another patient who had large inguinal lymph node mass with constitutional symptoms. IMCCD was diagnosed after excision biopsy and comprehensive work up. Patient was started on corticosteroids followed by CD-20 targeted therapy. These two cases showcase the two ends of the clinical spectrum of CD requiring different management protocols. Awareness among surgeons and diligent work-up is imperative for early diagnosis and best outcome.

Fine-needle cytology (FNC) is a useful diagnostic tool in the first line evaluation of lymphadenopathy of unknown aetiology. Nevertheless, considering the large number of conditions presenting as lymphadenopathy, lymph node cytology represents a challenging scenario. Recently, an expert panel published the proposal of the Sydney system for performing classification and reporting of lymph node cytopathology, the aim of the present study was to evaluate the applicability of this system. Thus, 300 lymph node FNCs performed over 1 year were reviewed and categorized according to the Sydney system classification. Overall, n = 20 cases (6.7%) were categorized as L1-inadequate/non-diagnostic, n = 104 (34.7%) as benign (L2), n = 25 (8.3%) as atypical (L3), n = 13 (4.3%) as suspicious (L4), and n = 138 (46%) as malignant (L5). FNC diagnoses were correlated with histopathologic and clinical follow-up to assess the diagnostic accuracy and the risk of malignancy (ROM) for each diagnostic category. Statistical analysis showed the following results: sensitivity 98.47%, specificity 95.33%, positive predictive value 96.27%, negative predictive value 98.08%, and accuracy 97.06%. The ROM was 50% for the category L1, 1.92% for L2, 58.3% for L3, and 100% for L4 and L5. In conclusion, FNC coupled with ancillary techniques ensures satisfactory diagnostic accuracy and the implementation of the Sydney system may improve the practice of cytopathologists.

Castleman's disease is a rare disease of the lymph nodes and related tissues, presenting as angiofollicular or giant lymph node hyperplasia. Although various skin manifestations have been reported to occur in Castleman's disease, a comprehensive study of cutaneous disorders in Castleman's disease is lacking. Therefore, the aim of this study was to investigate Castleman's disease-associated cutaneous disorders. The medical records of 57 patients with Castleman's disease who visited our hospitals from January 2007 to May 2018 were analysed retrospectively. Patients were classified according to the presence of skin involvement. Plasma variant-type Castleman's disease and multicentric Castleman's disease were more commonly found in patients with Castleman's disease with a cutaneous disorder than in those without a cutaneous disorder. In addition, the skin disorders were classified according to pathomechanisms: immune complex-related (paraneoplastic pemphigus, xanthogranulomas), cytokine-related (vasculitis-like lesion, cherry angioma, hyperpigmentation), and non-specific (pruritus). This study builds on previous case reports of cutaneous disorders in Castleman's disease and proposes a new classification system.

A 28-year-old female presented with an incidentally detected mediastinal mass, found on routine chest X-ray. 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) was advised to plan course of further management. FDG-PET/CT findings were suggestive of an FDG-avid soft-tissue mass in the left posterior mediastinum in paravertebral location with left pleural effusion. Overall, PET/CT scan findings favored the possibility of a nerve sheath tumor. However, histopathology along with immunohistochemistry confirmed the diagnosis of Castleman disease.

Reactivation of hepatitis B virus (HBV) replication is characterized by increased HBV-DNA serum values of about 1 log or by HBV DNA turning positive if previously undetectable in serum, possibly associated with liver damage and seldom life-threatening. Due to HBV reactivation, hepatitis B surface antigen (HBsAg)-negative/anti-HBc-positive subjects may revert to HBsAg-positive. In patients with hemo-lymphoproliferative disease, the frequency of HBV reactivation depends on the type of lymphoproliferative disorder, the individual's HBV serological status and the potency and duration of immunosuppression. In particular, it occurs in 10%-50% of the HBsAg-positive and in 2%-25% of the HBsAg- negative/anti-HBc-positive, the highest incidences being registered in patients receiving rituximab-based therapy. HBV reactivation can be prevented by accurate screening of patients at risk and by a pharmacological prophylaxis with anti-HBV nucleo(t)sides starting 2-3 wk before the beginning of immunosuppressive treatment and covering the entire period of administration of immunosuppressive drugs and a long subsequent period, the duration of which depends substantially on the degree of immunodepression achieved. Patients with significant HBV replication before immunosuppressive therapy should receive anti-HBV nucleo(t)sides as a long-term (may be life-long) treatment. This review article is mainly directed to doctors engaged every day in the treatment of patients with onco-lymphoproliferative diseases, so that they can broaden their knowledge on HBV infection and on its reactivation induced by the drugs with high immunosuppressive potential that they use in the care of their patients.

Neoplastic B cells may have cytoplasmic inclusions that are visible in routine peripheral blood smears by light microscopy.

Background Castleman disease is a lymphoproliferative disorder that can present in multiple locations throughout the body. While considered a benign entity, Castleman disease in the pediatric head and neck can resemble other common childhood malignancies. Methods This report describes a case of Castleman disease in a 10-year-old male who presented with a progressively enlarging facial mass; work-up revealed aggressive histopathological and imaging features concerning for rhabdomyosarcoma. The patient ultimately required surgical resection for definitive diagnosis. Results The facial mass was successfully resected without complication. A diagnosis of unicentric Castleman disease was made based on final histopathological evaluation of the permanent specimen. The mass has not recurred one year postoperatively. Conclusions Castleman disease in the head and neck should be included in the differential diagnosis of a pediatric facial mass. Balancing the appropriate degree of diagnostic intervention and treatment is essential in ensuring the best possible outcome with the least morbidity.

The therapeutic armamentarium for the treatment of patients with lymphoproliferative diseases has grown considerably over the most recent years, including a large use of new immunotherapeutic agents. As a consequence, the epidemiology of infectious complications in this group of patients is poorly documented, and even more importantly, the potential benefit of antimicrobial prophylaxis remains a matter of debate when considering the harmful effect from the emergence of multidrug resistant pathogens. The present position paper is addressed to all hematologists treating patients affected by lymphoproliferative malignancies with the aim to provide clinicians with a useful tool for the prevention of bacterial, fungal and viral infections.

Highlights • Lymphoproliferative disorders (LPD) in cardiac myxomas (CM) has been occasionally reported, and chronic inflammation in response to viral infection may be the key. • CM can upregulate autophagy, creating a favorable environment for Epstein Barr Virus (EBV)-driven oncogenesis. • P62 accumulates when autophagy is inhibited, and aberrant excessive p62 may result from autophagy defect, causing oxidative stress and tumorigenesis. • NanoString technology is a relatively new method for capturing tumor-immune signaling in tissues exploring how the signaling axis is associated with inflammation., Cardiac myxomas (CM) and primary cardiac lymphoproliferative disorders (LPD) are rare primary cardiac neoplasms. The composite occurrence of LPD in CM has been occasionally reported, and chronic inflammation in response to viral infection has been suggested to be at the basis of oncogenesis. Cancers can upregulate autophagy to endure microenvironmental stress and to increase local growth and aggressiveness. CM exhibit a dichotomous separation in low and high inflammatory grades (LIG vs. HIG). We studied 23 CMs using autophagy-related proteins and NanoString technology for gene expression. Autophagy-related proteins (Beclin-1, LAMP-1, LC3, and p62) were demonstrated in both tumor and stromal cells. ATG genes showed a progression of involvement in CM using an 8-gene signature. They were associated with Epstein-Barr virus (EBV) encoded latent membrane protein 1 (EBV LMP1) activation. We suggest that CM can upregulate autophagy, creating a favorable environment for EBV-driven oncogenesis. To the best of our knowledge, the present study is the first to report on the TME using the expression of autophagy-related genes and proteins in CM. The microenvironment of CM is dynamic, with a variety of cell types and different molecular pathways at play, and this study may clearly warrant further investigation.

Syringolymphoid hyperplasia (SLH) is an extremely rare histopathological entity with fewer than 40 cases reported in the literature. SLH have been seen as both benign lesions and in association with T-cell lymphoproliferative lesions. A 20-year-old male presented with a solitary, infiltrated plaque on the left cheek initially diagnosed as a sebaceous carcinoma at an external institution. A repeat biopsy demonstrated prominent follicular mucinosis (FM), squamous metaplasia of the eccrine coils, and a moderately dense perieccrine lymphocytic infiltrate mimicking eccrine carcinoma. The lesion was subsequently diagnosed as SLH with associated FM, an entity that has been previously reported in 12 cases, including this current case. This case highlights the characteristic features of a rare entity, emphasizes the potential for misdiagnosis of SLH, and adds to the current series of SLH described in the literature.

Background: Lymphoproliferative disorders (LPD), including malignant lymphoma, is a relatively rare but life-threatening complication in RA patients under methotrexate (MTX) therapy. Spontaneous regression of LPD after MTX withdrawal is regarded as a distinct characteristic in part of such LPDs. Objective: The present study aimed to investigate the immunological difference in regressive LPD and persistent LPD. Methods: We studied RA patients who developed LPD during MTX administration (n = 35) and clinically matched controls (n = 35). The time of MTX cessation was defined as week 0, and LPD patients were divided into two groups according to LPD status at week 12: regressive group (n = 22) and persistent group (n = 13). Flow cytometric analysis of whole blood samples and serum cytokine assays were conducted for LPD (n = 10) and control patients (n = 10) at weeks 0, 4 and 12. Results: There was a significant decrease in peripheral lymphocytes and the proportion of T helper 1 cells (Th1 cells), effector memory CD8+ T cells (EMCD8+ T) and Epstein–Barr virus (EBV)-specific CD8+ T cells at the time of LPD diagnosis, and a significant increase after MTX cessation was observed in the regressive group but not in the persistent group. The expansion of Th1 cells and EMCD8+ T cells significantly correlated with an increase in serum interferon (IFN)-γ concentration. Conclusion: Changes in Th1 cells, EMCD8+ T cells and EBV-specific CD8+ T cells, which coincided with an increase in IFN-γ, were significantly different between regressive LPD and persistent LPD after MTX cessation.

Castleman disease is a lymphoproliferative disorder with unknown etiology and pathogenesis. While the disease may involve all parts of the body, the mediastinum appears to be the most common part of involvement. In this study, we present two cases of Castleman disease with different localizations that mimicked malignancy. A 62-year-old female patient presented with jaundice. Laboratory analysis indicated aspartate aminotransferase: 250 U/L, total bilirubin: 4 mg/dl, and carbohydrate antigen (CA) 19-9: 900 U/ml. Computerized tomography (CT) of the abdomen showed a mass originating from the pancreas head which resulted in a biliary tract obstruction. A positron emission tomography-computed tomography (PET/CT) showed that the only site of involvement was the pancreas head. A decision was made to perform pancreaticoduodenectomy. During intra-abdominal exploration, lymphadenopathies were identified in the surroundings of the retropancreatic portal vein and the hepatic artery. Histopathological investigation of the dissected lymph nodes demonstrated findings consistent with granulomatous plasma-cell-rich Castleman disease. A 55-year-old female patient presented with abdominal pain, nausea, and vomiting. Computerized tomography of the abdomen showed an abdominal mass of 7 cm, originating from the mesenterium, with high-contrast uptake in the mesenterium in the lower abdominal quadrant. The mesenteric mass was resected along with segmentary small intestine resection. Histopathological investigation of the mass showed a giant granulomatous structure that consisted of plasma cells consistent with Castleman disease. Castleman disease should be kept in mind during differential diagnosis of locally advanced lymph nodes observed during preoperative investigations and intraoperative exploration.

BACKGROUND: CD43 has been used on histological samples for the differential diagnosis of lymphoproliferative disorders but there is scarce data on its use by flow cytometry (FC). We set out to characterize the expression of CD43 by FC in B-cell lymphoproliferative disorders and to determine its possible role in the differential diagnosis of these malignancies. METHODS: We analyzed the expression of CD43 in clonal B-cell lymphoproliferative disorders with exclusive peripheral blood and/or bone marrow involvement based on their Moreau chronic lymphocytic leukemia (CLL) score with particular emphasis on Moreau CLL score 3 (MS3) cases, which often present a diagnostic challenge. The cohort included 433 CLL (score 4-5), 34 MS3 and 166 lymphoproliferative disorders with lower scores. RESULTS: Generally, the higher the Moreau CLL score, the higher CD43-positivity (425/443 [96%] for CLL, 23/34 [67%] for MS3 and 18/166 [11%] for cases with lower scores). MS3 cases constituted 5.4% of all cases and were more frequently CD5, CD200, CD43-positive and had del(q13) than score 0-2 cases. Among MS3 cases, del(13q) cases were predominantly CD43-positive (12/13). CONCLUSIONS: The frequency of CD43-positivity increases sharply with the Moreau score. MS3 cases seem to include both CLL and non-CLL lymphoproliferative disorders and CD43 could aid in the differential diagnosis between the two. However, studies analyzing the correlation between CD43 expression and the underlying biologic changes of these cases are warranted. © 2017 International Clinical Cytometry Society.

Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPDs) sometimes occur following Anti-thymocyte globulin (ATG) administration for allogenic stem cell transplantation but are rare in aplastic anemia (AA) patients. A 55-year-old woman with AA following ATG developed refractory fever and was diagnosed with EBV-LPD. She was successfully treated with weekly rituximab monotherapy; however, she developed EBV encephalitis. She was admitted to the intensive care unit and finally recovered from unconsciousness. EBV-LPD should be considered after ATG for AA when symptoms appear. Because EBV-LPD following ATG for AA can rapidly progress, weekly monitoring of EBV-DNA and early intervention may be necessary.

Background Immunotactoid glomerulopathy (ITG) is a rare cause of proteinuria characterized by organized microtubular deposits in the glomerulus. ITG has been associated with underlying lymphoproliferative disorders and any renal impairment may be reversible with treatment of the concomitant hematologic malignancy. This case is the first reported in literature where diffuse large B cell lymphoma developed two years following the initial ITG diagnosis. Case presentation A 55-year-old woman with a history of well-controlled diabetes mellitus and thalassemia trait presented with proteinuria (830 mg/day) in 2010. Initially, she was managed with renin-angiotensin-aldosterone-system blockade. In 2012, the proteinuria worsened (4.3 g/day) and a renal biopsy showed immunotactoid glomerulopathy (Fig. 1). Despite extensive work up, no lymphoproliferative disorder was initially found. In January 2014, the patient presented with a soft-palate mass found on biopsy to be diffuse large B-cell lymphoma. She received 6 cycles of R-CHOP, 4 cycles of high dose methotrexate chemotherapy for CNS prophylaxis and 30 Gy of Intensity Modulated Radiation Therapy. Follow-up revealed complete remission of diffuse large B-cell lymphoma and resolution of proteinuria from the ITG. Conclusion As we recognize that patients with ITG may develop hematopoietic neoplasms, close long-term monitoring is important. Moreover, treatment of the lymphoproliferative disorder can allow for complete remission of ITG.

Objectives Epstein-Barr virus (EBV) is involved in the pathogenesis of approximately 40% of lymphoproliferative disorders (LPDs) arising in patients receiving immunosuppressive treatment (IST) for rheumatic diseases, but data from large cohorts are still not available. We aimed to identify clinicopathological features, management and outcome of this condition. Methods We reviewed all published cases of EBV-encoded RNA (EBER)-positive LPDs and included in our analysis one unpublished patient diagnosed in our Hospital. We excluded those cases without an underling rheumatic condition, a specific IST or not reporting univocal data. Results In the cumulative cohort of 159 patients, most were affected by rheumatoid arthritis (83.0%) and treated with methotrexate (75.4%). 68.5% of LPDs developed between the age of 40 and 70 years, after 13.3 ± 9.6 years from rheumatic disease onset and 58.7 ± 47.0 months of IST. LPDs were mostly B-cell lineage derived (39.0%), Ann Arbor disease's stage I (38.3%) and presented with extra-nodal involvement in 63.1%, which was most frequently represented by central nervous system (17.6%). The most common approach was IST withdrawal (93.3%), variably associated with radiotherapy(RT)/chemotherapy(CT) in 38.3% of cases. Overall, 61.7% of patients achieved a complete remission (CR; 30.2 ± 24.0 months). Among published cases of patients that only suspended IS as first line treatment approach, 67.2% achieved CR. No significant demographic, clinical and histological differences between patients who achieved CR and who did not, and between who achieved CR by IST withdrawal alone and who did not were observed ( P > 0.05 in all comparison). Conclusions The current study reviews all the published evidences of EBV-induced LPDs in patients receiving IST treatment for rheumatic conditions.

Purpose To analyze ocular surface parameters in patients before hematopoietic stem cell transplantation (HSCT) and to correlate them with hematological characteristics. Methods This is a retrospective analysis of prospectively collected data from 203 patients undergoing HSCT. Demographic data and hematological parameters (disorder type and stage) were collected from clinical charts. Ocular surface parameters (ocular surface disease index; Schirmer test I; tear film break-up time; corneal esthesiometry; and corneal and conjunctival staining) were analyzed the day before beginning the conditioning treatment for HSCT preparation. Results A high prevalence of dry eye (DE) was found: 116 patients (57.2%) were diagnosed as not suffering from DE, whereas 87 patients (42.8%) were diagnosed as having DE. Of these, 26 were classified as dry eye workshot (DEWS) severity score 1, 46 as DEWS score 2, and 15 as DEWS score 3. Tear film break-up time was found to be the only parameter statistically worse in the chronic lymphoproliferative disorder group compared with the stem cell malignancy group. Older age [odds ratio (OR) 1.03], female sex (OR 2.03), advanced stage of hematological disease (OR 1.4), and previous auto- or allo-HSCT (OR 1.9) showed a significant positive association in predicting DE onset before transplantation. Conclusions DE was already present in a significant number of patients suffering from hematological disease before HSCT. Some hematological parameters seemed to influence this percentage. These results highlight the role of ocular surface examination by an ophthalmologist in hematological patients before HSCT, with the aim of diagnosing and, if necessary, treating DE patients early.

Introduction: PAX5 is an immunomarker of B-cell origin and useful in the diagnosis of lymphoma. There is hardly any study on PAX5 expression in Indian patients with lymphoma. Aim: To evaluate the diagnostic utility of PAX5 as an adjunct immunohistochemical marker in the diagnosis of Hodgkin Lymphoma (HL) and Non-Hodgkin Lymphoma (NHL). Materials and Methods: Immunohistochemistry was performed against CD20, CD3, CD15, CD30, and PAX5 on formalin fixed paraffin embedded tissue of 71 cases of lymphoma and CD20, CD3 and PAX5 in control samples of reactive lymph nodes. Frequency, mean values, and percentage were calculated. Fisher’s-exact test and test for analysis of variance were applied. Result: For 24 cases of HL and 47 cases of NHL, the mean age of patients was 17.6±14.8 years and 44.1±21.6 years, respectively. The male: female ratio for both HL and NHL were 1.7:1. Among NHL cases, the numbers of B-cell and T-cell types were 39/47 (83%) and 8/47 (17%), respectively. In comparison to control samples, PAX5+ expression was seen in 23/24 (95.8%) cases of HL (p=1.000) and 32/39 (82%) cases of B-NHL (p=0.0834). All the cases of T-NHL showed negative expression of PAX5 (p

Epstein–Barr virus-positive mucocutaneous ulcer (EBVMCU) comprises part of the spectrum of B-cell lymphoproliferative disorders, reported in settings of immunosenescence and iatrogenic immunosuppression, affecting the oropharyngeal mucosa, skin, and gastrointestinal tract. We report a case of a 59-year-old female, known case of rheumatoid arthritis on methotrexate (MTX) for 15 years, who presented with an ulcer in the inner aspect of her cheek region for 2 years. Clinical examination revealed an infiltrative lesion involving the lower gingivobuccal sulcus of size 2 cm × 3 cm extending to the alveolus with level I lymph nodes, suspicious for carcinoma buccal mucosa. Anti-EBV-capsid antigen-immunoglobulin M and qualitative EBV polymerase chain reaction of peripheral blood were negative. Histopathological examination revealed atypical lymphoid cells with enlarged vesicular nuclei, prominent nucleoli, and moderate eosinophilic cytoplasm, few with binucleation (CD20 focally positive, CD79a focally positive, CD30+, EBV LMP-1+, MIB-I 60%) consistent with EBVMCU, MTX-associated. This is the first case report from India.

Epstein-Barr virus (EBV) was discovered 50 years ago from an African Burkitt lymphoma cell line. EBV-associated lymphoproliferative disorders (LPDs) are life-threatening diseases, especially in children. In this article, we review EBV-associated LPDs, especially in the area of primary immunodeficiency disease (PID). We searched PubMed for publications with key words including EBV infection, lymphoma, LPDs and PID, and selected the manuscripts written in English that we judged to be relevant to the topic of this review. On the basis of the data in the literature, we grouped the EBV-associated LPDs into four categories: nonmalignant disease, malignant disease, acquired immunodeficiency disease and PID. Each category has its own risk factor for LPD development. EBV-associated LPD is a complex disease, creating new challenges for diagnosis and treatment.

Background: Optimal management of posttransplant lymphoproliferative disease (PTLD) remains to be defined due to heterogeneity of this condition and lack of predictors of the outcome. Here we report our experience with pediatric PTLD nonresponsive to immunosuppression (IS) withdrawal, managed after stratification into high and low risk according to the presenting features. Methods: This is a single-center retrospective review of prospectively enrolled patients. From 2001 to 2011, 17 children were diagnosed with severe B-lineage, CD20+, PTLD after a median of 37 months (range, 5-93) from liver (12), heart (4), or multiorgan (1) transplantation. Treatment was tailored on 2 risk groups: (1) standard-risk (SR) patients received IS reduction and rituximab; (2) high-risk (HR) patients received IS discontinuation, rituximab and polychemotherapy. Results: The cumulative incidence of rejection at 1 and 5 years after the diagnosis of PTLD was 35% (95% confidence interval [95% CI], 18-69%) and 53% (33-85%), respectively, whereas the disease-free survival at 1 and 5 years was 94% (95% CI, 65-99%) and 75% (45-90%), respectively. Three children died, PTLD-free, from different transplant-related complications: primary nonfunction after retransplantation (liver), cytomegalovirus disease 21 months after PTLD treatment (liver), graft dysfunction 25 months after PTLD (heart). Conclusions: Severe B-lineage PTLD after solid organ transplantation may be classified as SR or HR and treated accordingly with a tailored protocol obtaining a satisfactory long-term outcome. This approach accomplishes the control of lymphoproliferation in severe forms as well as the minimization of toxicity in milder PTLDs.

OBJECTIVE Monoclonal gammopathies (MGs) associated with HIV infection are frequent but their evolution and significance are uncertain in this population at high risk of lymphoproliferative disorder. Our aim was to describe the long-term evolution of MG in HIV-infected subjects under antiretroviral therapy. METHODS Retrospective study of HIV-1-infected adults, with a monoclonal (M) protein detected by serum protein electrophoresis and confirmed by immunofixation. Logistic regression was used to analyze factors associated with peak disappearance. RESULTS Between September 1997 and November 2012, 1219 serum protein electrophoreses were performed on our HIV cohort, and 137 (11.3%) MGs were detected. Seventy-seven subjects met the inclusion criteria: 68% male, median age 41 years, 47% AIDS stage, median CD4 count 237 per cubic millimeter, 81% uncontrolled HIV infection with HIV viral load over 400 copies per milliliter, 32% chronic hepatitis C, and 9% chronic hepatitis B. Eighteen subjects were not included because of previous or concomitant hemopathy. With a median follow-up of 6.8 years (interquartile range, 3.9-9.1), 66.2% of subjects showed a peak disappearance. In multivariate analysis, MG disappearance was associated with HIV virologic control (odds ratio, 5.98; 95% confidence interval: 1.63 to 21.87; P = 0.007) and the absence of hepatitis C virus replication at the end of follow-up (odds ratio, 10.16; 95% confidence interval: 2.36 to 43.69; P = 0.002). One subject developed a myeloma 3 years after the diagnosis of an IgA kappa MG. CONCLUSIONS MG associated with HIV infection concerned a young population and had favorable evolution on antiretroviral therapy in most cases. M protein disappearance was associated with HIV virologic control and the absence of chronic hepatitis C virus.