How I treat posttransplant lymphoproliferative disorder.

Posttransplant lymphoproliferative disorder (PTLD) is an important and potentially life-threatening complication of solid organ transplant and hematopoietic stem cell transplant (HSCT). Given the heterogeneity of PTLD and the risk of infectious complications in patients with immunosuppression, the treatment of this disease remains challenging. Monomorphic PTLD and lymphoma of B-cell origin account for the majority of cases. Treatment strategies for PTLD consist of response-adapted, risk-stratified methods using immunosuppression reduction, immunotherapy, and/or chemotherapy. With this approach, ∼25% of the patients do not need chemotherapy. Outcomes for patients with high risk or those who do not respond to frontline therapies remain dismal, and novel treatments are needed in this setting. PTLD is associated with Epstein-Barr virus (EBV) infection in 60% to 80% of cases, making EBV-directed therapy an attractive treatment modality. Recently, the introduction of adoptive immunotherapies has become a promising option for refractory cases; hopefully, these treatment strategies can be used as earlier lines of therapy in the future.

Decoding the molecular heterogeneity of pediatric monomorphic post-solid organ transplant lymphoproliferative disorders.

Posttransplant lymphoproliferative disorders (PTLDs) represent a broad spectrum of lymphoid proliferations, frequently associated with Epstein-Barr virus (EBV) infection. The molecular profile of pediatric monomorphic PTLDs (mPTLDs) has not been elucidated, and it is unknown whether they display similar genetic features as their counterpart in adult and immunocompetent (IMC) pediatric patients. In this study, we investigated 31 cases of pediatric mPTLD after solid organ transplantation, including 24 diffuse large B-cell lymphomas (DLBCLs), mostly classified as activated B cell, and 7 cases of Burkitt lymphoma (BL), 93% of which were EBV positive. We performed an integrated molecular approach, including fluorescence in situ hybridization, targeted gene sequencing, and copy number (CN) arrays. Overall, PTLD-BL carried mutations in MYC, ID3, DDX3X, ARID1A, or CCND3 resembling IMC-BL, higher mutational burden than PTLD-DLBCL, and lesser CN alterations than IMC-BL. PTLD-DLBCL showed a very heterogeneous genomic profile with fewer mutations and CN alterations than IMC-DLBCL. Epigenetic modifiers and genes of the Notch pathway were the most recurrently mutated in PTLD-DLBCL (both 28%). Mutations in cell cycle and Notch pathways correlated with a worse outcome. All 7 patients with PTLD-BL were alive after treatment with pediatric B-cell non-Hodgkin lymphoma protocols, whereas 54% of patients with DLBCL were cured with immunosuppression reduction, rituximab, and/or low-dose chemotherapy. These findings highlight the low complexity of pediatric PTLD-DLBCL, their good response to low-intensity treatment, and the shared pathogenesis between PTLD-BL and EBV-positive IMC-BL. We also suggest new potential parameters that could help in the diagnosis and the design of better therapeutic strategies for these patients.

CD27/CD70 pathway activation in primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder.

Primary cutaneous CD4+ small or medium T-cell lymphoproliferative disorder (PCSM-LPD) is a clonal T-cell proliferation disease confined to the skin. PCSM-LPD shares expression of T follicular helper (Tfh) cell markers with various mature T-cell lymphomas. However, the benign presentation of PCSM-LPD contrasts the clinical behavior of other Tfh-lymphomas. The aim of our study was to delineate the molecular similarities and differences between PCSM-LPD and other Tfh-derived lymphomas to explain the clinical behavior and unravel possible pathological mechanisms. We performed targeted next-generation sequencing of 19 genes recurrently mutated in T-cell neoplasms in n = 17 PCSM-LPD with high and in n = 21 PCSM-LPD with low tumor cell content. Furthermore, gene expression profiling was used to identify genes potentially expressed in the PD1-positive (PD1+) neoplastic cells. Expression of some of these genes was confirmed in situ using multistain immunofluorescence. We found that PCSM-LPD rarely harbored mutations recurrently detected in other T-cell neoplasms. PCSM-LPD is characterized by the invariable expression of the T-cell-receptor-associated LCK protein. CD70 and its ligand CD27 are co-expressed on PD1+ PCSM-LPD cells, suggestive of autoactivation of the CD70 pathway. In conclusion, PCSM-LPD differs from disseminated lymphomas of Tfh origin by their mutation profile. Activation of CD70 signaling also found in cutaneous T-cell lymphoma represents a potential driver of neoplastic proliferation of this benign neoplasia of Tfh. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The nuclear matrix protein CIZ1 facilitates localization of Xist RNA to the inactive X-chromosome territory.

The nuclear matrix protein Cip1-interacting zinc finger protein 1 (CIZ1) promotes DNA replication in association with cyclins and has been linked to adult and pediatric cancers. Here we show that CIZ1 is highly enriched on the inactive X chromosome (Xi) in mouse and human female cells and is retained by interaction with the RNA-dependent nuclear matrix. CIZ1 is recruited to Xi in response to expression of X inactive-specific transcript (Xist) RNA during the earliest stages of X inactivation in embryonic stem cells and is dependent on the C-terminal nuclear matrix anchor domain of CIZ1 and the E repeats of Xist CIZ1-null mice, although viable, display fully penetrant female-specific lymphoproliferative disorder. Interestingly, in mouse embryonic fibroblast cells derived from CIZ1-null embryos, Xist RNA localization is disrupted, being highly dispersed through the nucleoplasm rather than focal. Focal localization is reinstated following re-expression of CIZ1. Focal localization of Xist RNA is also disrupted in activated B and T cells isolated from CIZ1-null animals, suggesting a possible explanation for female-specific lymphoproliferative disorder. Together, these findings suggest that CIZ1 has an essential role in anchoring Xist to the nuclear matrix in specific somatic lineages.

Indolent T-Cell/Natural Killer-Cell Lymphomas/Lymphoproliferative Disorders of the Gastrointestinal Tract-What Have We Learned in the Last Decade?

Primary gastrointestinal (GI) T-cell and natural killer (NK)-cell lymphomas/lymphoproliferative disorders (LPD) are uncommon, and they are usually aggressive in nature. However, T-cell and NK-cell lymphoma/LPD of the GI tract with indolent clinical course has been reported over the past 2 decades. Indolent T-cell LPD was formally proposed a decade ago in 2013 and 4 years later recognized as a provisional entity by the revised fourth edition of WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues in 2017. Indolent T-cell LPD of the GI tract has been changed to indolent T-cell lymphoma of the GI tract as a distinct entity by the fifth edition of WHO Classification of Haematolymphoid Tumours, but the International Consensus Classification of mature lymphoid neoplasms prefers indolent clonal T-cell LPD of the GI tract instead. In the past decade, indolent lymphoma/LPD of the GI tract has been expanded to NK cells, and as such, indolent NK-cell LPD of the GI tract was recognized as an entity by both the fifth edition of WHO Classification of Haematolymphoid Tumours and the International Consensus Classification. The underlying genetic/molecular mechanisms of both indolent T-cell lymphoma/LPD of the GI tract and indolent NK-cell LPD of the GI tract have been recently discovered. In this review, we describe the history; salient clinical, cytohistomorphologic, and immunohistochemical features; and genetic/genomic landscape of both entities. In addition, we also summarize the mimics and differential diagnosis. Finally, we propose future directions with regard to the pathogenesis and clinical management.

KSHV/HHV8-mediated hematologic diseases.

Kaposi sarcoma (KS) herpesvirus (KSHV), also known as human herpesvirus 8, is the causal agent of KS but is also pathogenetically related to several lymphoproliferative disorders, including primary effusion lymphoma (PEL)/extracavitary (EC) PEL, KSHV-associated multicentric Castleman disease (MCD), KSHV+ diffuse large B-cell lymphoma, and germinotropic lymphoproliferative disorder. These different KSHV-associated diseases may co-occur and may have overlapping features. KSHV, similar to Epstein-Barr virus (EBV), is a lymphotropic gammaherpesvirus that is preferentially present in abnormal lymphoid proliferations occurring in immunecompromised individuals. Notably, both KSHV and EBV can infect and transform the same B cell, which is frequently seen in KSHV+ EBV+ PEL/EC-PEL. The mechanisms by which KSHV leads to lymphoproliferative disorders is thought to be related to the expression of a few transforming viral genes that can affect cellular proliferation and survival. There are critical differences between KSHV-MCD and PEL/EC-PEL, the 2 most common KSHV-associated lymphoid proliferations, including viral associations, patterns of viral gene expression, and cellular differentiation stage reflected by the phenotype and genotype of the infected abnormal B cells. Advances in treatment have improved outcomes, but mortality rates remain high. Our deepening understanding of KSHV biology, clinical features of KSHV-associated diseases, and newer clinical interventions should lead to improved and increasingly targeted therapeutic interventions.

Chronic lymphoproliferative disorder of natural killer cells-related neurolymphomatosis with severe autonomic dysfunction: a case report.

BACKGROUND: Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK) is a rare disease characterized by a persistent increase in NK cells in peripheral blood and is generally asymptomatic. If present, symptoms may include fatigue, B symptoms (fever, night sweats, and unintentional weight loss), autoimmune-associated diseases, splenomegaly, and infection due to neutropenia. Peripheral neuropathy, however, is uncommon with an incidence of 3%. Neurolymphomatosis is a neurological manifestation of non-Hodgkin lymphoma and leukemia in which neurotropic neoplastic cells infiltrate the nerves. Moreover, neurolymphomatosis caused by CLPD-NK is extremely rare, with even fewer cases of autonomic dysfunction. We report a case of neurolymphomatosis associated with CLPD-NK and developed autonomic dysfunction, including orthostatic hypotension and gastrointestinal symptoms. CASE PRESENTATION: The patient was a 61-year-old male who was referred to our hospital for leukocytosis. He was diagnosed with CLPD-NK; however, was untreated since he had no hepatosplenomegaly, and other systemic symptoms. He later developed numbness in his lower extremities. Cerebral spinal fluid examination revealed a markedly elevated protein level of 140 mg/dL, and contrast-enhanced magnetic resonance imaging showed bilateral L4 and 5 nerve roots with enlargement and contrast effect. An immune-mediated polyradiculoneuropathy was suspected, and he was treated with intravenous methylprednisolone and immunoglobulin followed by oral prednisolone and cyclosporine. Although his symptoms were relieved by the immunotherapy, significant autonomic dysfunction, including intractable diarrhea, decreased sweating, and orthostatic hypotension, appeared. Additionally, tests for onconeuronal antibodies, ganglionic nicotinic acetylcholine receptor (gAChR) antibody, NF155, CNTN1, Caspr1 antibody, and anti-ganglioside antibodies were all negative. A sural nerve biopsy revealed lymphocytic infiltration, and immunohistochemical staining of lymphocytes confirmed the infiltration of NK and T cells. Therefore, a diagnosis of neurolymphomatosis caused by CLPD-NK was made, and chemotherapy led to partial symptom improvement. CONCLUSIONS: We experienced a case of pathologically diagnosed neurolymphomatosis with autonomic dysfunction associated with CLPD-NK. In cases of subacute to chronic autonomic dysfunction, paraneoplastic neuropathy, amyloidosis, and autoimmune autonomic ganglionopathy are considered; however neurolymphomatosis caused by CLPD-NK, an important cause of autonomic dysfunction, is not. In difficult to make diagnosis, aggressive nerve biopsy is required.

Intraoral primary syphilis mimicking lymphoproliferative disorder.

Syphilis can mimic, clinically and microscopically, many other diseases. By microscopy, typically syphilis presents with plasma cell infiltration, admixed with lymphocytes and macrophages, in lichenoid and/or perivascular/perineural distribution pattern. When exuberant, this inflammatory infiltrate can mimic a lymphoproliferative disorder (LPD), notably plasma cell neoplasia or lymphoma. To date, about 12 cases of secondary syphilis, all but one in extraoral location, suggesting initially a LPD, have been published. Here, to our knowledge, we report an unusual case of intraoral primary syphilis initially suggesting LPD, notably lymphoid hyperplasia (pseudolymphoma); however, mucosa-associated lymphoid tissue (MALT) lymphoma and follicular lymphoma could not be disregarded. Polyclonality of plasma cells on immunohistochemistry, in strict clinical correlation, was essential to arrive at the correct diagnosis.

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.

Primary cutaneous marginal zone lymphoproliferative disorder following COVID-19 vaccination.

During the coronavirus disease 2019 (COVID-19) pandemic, COVID-19 vaccines were administered worldwide. A number of skin reactions, including primary cutaneous T-cell lymphoproliferative disorders (LPDs) were reported following COVID-19 vaccination. We report a case of primary cutaneous marginal zone lymphoproliferative disorder (PCMZLPD) secondary to COVID-19 vaccination. A 57-year-old man presented with an erythematous nodule on his left arm at the site of vaccine inoculation following his first dose of the Moderna (mRNA-1273) vaccine a few weeks prior. The nodule continued to progress in size after the second dose. A skin biopsy specimen of the nodule showed a diffuse dermal infiltrate of small to medium-sized lymphocytes with plasma cells and histiocytes. The infiltrate was composed of CD3+ T cells with CD20+ and CD79a+ B cells. The neoplastic B cells reacted with BCL-2 and were negative for BCL-6 and CD10. Kappa light chain restriction was identified by in situ hybridization. Gene rearrangement studies revealed kappa light chain monoclonality, confirming the diagnosis of PCMZLPD. The temporal association with the Moderna vaccination and the occurrence of the lesion at the inoculation site indicate a COVID-19 vaccination-induced PCMZLPD. This is one of the rare cases of PCMZLPD following COVID-19 vaccination.

Primary cutaneous lymphoproliferations in the gray zone between marginal zone lymphoma and CD4+ small/medium T-cell lymphoproliferative disease.

BACKGROUND: Primary cutaneous marginal zone lymphoma (PCMZL) and primary cutaneous CD4+ small/medium T-cell lymphoproliferative disease (CD4+ TLPD) are two distinct entities with excellent prognosis; however, they show profound clinical and histopathological similarities, leading to differential diagnostic uncertainty. AIMS: Our aim was to review and reanalyze cases of primary cutaneous lymphoproliferations diagnosed at Semmelweis University, featuring characteristics of PCMZL and CD4+ TLPD. MATERIALS AND METHODS: Cutaneous lymphoma biopsy specimens between 2018 and 2022 were collected and re-evaluated. Medical history, clinical picture, imaging, and laboratory findings were collected. Immunohistochemical staining for CD20, CD3, BCL6, CD10, PD1, CD3, CD4, CD8, and PCR tests for IGH, IGK, TCRB, and TCRG were repeated in selected cases. RESULTS: Among 55 cases diagnosed as PCMZL (16) or CD4+ TLPD (39), 3 patients had been diagnosed with both LPDs at different time points of their disease course. Four additional patients were identified with single lesions featuring overlapping histopathological characteristics of both LPDs and both monoclonal IGH and TCR rearrangements. All patients are currently in complete remission with local treatment. CONCLUSION: We propose that besides the overlapping histopathological, molecular, and clinical features, the subsequent appearance of PCMZL and CD4+ TLPD in a short timeframe in the same patients may suggest a common pathogenic background.

Stenotrophomonas maltophilia skin infection in an immunocompetent patient: Primary cutaneous CD30+ T-cell lymphoproliferative disorder or pseudolymphoma?

Cutaneous pseudolymphomas are a wide group of diseases mimicking cutaneous lymphoma. They comprise several skin conditions with different etiopathogenesis, clinical-pathological features, and prognosis, which may occur in the absence of an identifiable trigger factor or after administration of medications or vaccinations, tattoos, infections, or arthropod bites. They present with different manifestations: from solitary to regionally clustered lesions, up to generalized distribution and, in rare cases, erythroderma. They persist variably, from weeks to years, and resolve spontaneously or after antibiotics, but may recur in some cases. CD30+ T-cell pseudolymphomas are characterized by the presence of large, activated lymphoid cells, generally in response to viral infections, arthropod assault reactions, and drug eruptions. Stenotrophomonas maltophilia is a ubiquitous Gram-negative bacillus responsible for opportunistic infections in immunocompromised patients. Infection of intact skin in immunocompetent patients is particularly rare. Here, we report a case of a man presenting an isolated nodule histopathologically mimicking a primary cutaneous CD30+ T-cell lymphoproliferative disorder.

The first autopsy case of Epstein-Barr virus-positive marginal zone lymphoma that deteriorated after COVID-19 vaccination.

This is the first autopsy case of Epstein-Barr virus-positive marginal zone lymphoma (EBV + MZL) with an other iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPD) (methotrexate [MTX]-associated LPD) that deteriorated after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. This case had a unique immunophenotype. A 71-year-old female patient with rheumatoid arthritis receiving MTX presented with fatigue 1 week after the SARS-CoV-2 vaccination. She was hospitalized due to hepatorenal dysfunction and pancytopenia. Computed tomography revealed systemic lymphadenopathy. Her physical condition deteriorated, and the patient died. The autopsy revealed systemic lymphadenopathy comprising medium-sized atypical lymphocytes and scattered Hodgkin/Reed-Sternberg (H/RS)-like cells. An immunohistochemical examination showed that atypical lymphocytes were positive for CD79a and MUM-1 and some were positive for CD20 and IRTA-1. H/RS-like cells were immunoreactive for CD30 and CD15 and ringed by T cells. Both cell types were positive for EBV-encoded small RNA. The majority of H/RS-like cells were positive for CD20, whereas a small number of CD3-positive cells were admixed. We herein presented the first autopsy case of EBV + MZL that deteriorated after the SARS-CoV-2 vaccination.

Polymorphic lymphoproliferative disorder arising in a rheumatoid arthritis patient, presenting as fibrin-associated large B-cell lymphoma-like lesions in aortic and mitral valves.

We herein report a case of methotrexate-associated lymphoproliferative disorder (MTX-LPD) showing fibrin-associated large B-cell lymphoma-like heart valve lesions, and Epstein-Barr virus (EBV)-positive mucocutaneous ulcer-like cutaneous and oral mucosal lesions. MTX-LPD is a critical complication that can occur in RA patients who are treated with MTX. EBV also plays a defining or important role in LPDs. Among the sites of MTX-LPD, 40-50% occur in extranodal sites, including the gastrointestinal tract, skin, liver, lung, and kidney. There are few reports of MTX-LPDs involving the heart valves, and to the best of our knowledge, this is the first case to be reported in the English literature. The possibility of EBV-positive LPD should be considered in RA patients, even in patients with an atypical site, as in this case.

Experimental infection of domestic turkeys with lymphoproliferative disease virus of North American origin.

Lymphoproliferative disease virus (LPDV) was first documented in wild turkeys in North America in 2009. LPDV infection is often subclinical but can manifest as lymphoid proliferation or round cell neoplasia. Despite high prevalence across many sampled areas corresponding to declining populations of wild turkeys, knowledge regarding LPDV pathogenesis, risk factors for disease development, and associated impacts on population dynamics are unknown. To understand transmission, viral shedding, and tissue tropism, we inoculated 21 domestic turkeys via the oral cavity, crop, nasal cavity, subcutis, or coelomic cavity. For 12 weeks, oropharyngeal swabs, cloacal swabs, and whole blood were collected weekly. At 1 week postinoculation, 3 turkeys (3/21; 14%) had detectable LPDV proviral DNA in blood by polymerase chain reaction, and 10 developed DNAemia (50%; 10/20) by 12 weeks. LPDV proviral DNA was intermittently detected in oropharyngeal and cloacal swabs. Splenomegaly was the most consistent gross finding in DNAemic birds (8/11; 73%). Lymphoid hyperplasia in the spleen was the most significant microscopic finding (9/11; 82%). Three turkeys (3/11; 27%) developed round cell neoplasia characterized by sheets of pleomorphic, round to polygonal cells in the adrenal gland, bone marrow, skin, small intestine, and/or spleen. LPDV was detected in the spleen and bone marrow from all turkeys with DNAemia and all neoplasms. Our study establishes that infection and disease with North American LPDV from wild turkeys can be experimentally reproduced in domestic turkeys, laying the groundwork for future investigations into LPDV pathogenesis, development of diagnostic techniques, and understanding the impacts of LPDV on wild turkey populations.

Hydroa Vacciniforme Lymphoproliferative Disorder in a Young Spanish Woman: An Infrequent Case With Fatal Outcome.

ABSTRACT: Hydroa vacciniforme (HV) lymphoproliferative disorder is a rare NK/T-cell lymphoma mainly affecting children and with a clinical resemblance to HV, which is mostly reported in Latin American and some Asian countries. Overall, the mature T cell and NK-cell neoplasms are now grouped into 9 families based on diverse concepts: cell of origin/differentiation state, clinical scenario, disease localization, and cytomorphology. HV lymphoproliferative disorder is listed within the group of Ebstein Barr Virus-positive T-cell and NK-cell lymphoid proliferations and lymphomas of childhood according to the fifth edition of the World Health Organization Classification of mature lymphoid neoplasms. We report the extraordinary case of a 22-year-old white woman, native of Spain, first presented in 2016 when she started suffering from recurrent facial edema. Four years later, the disease progressed with lymph node spreading and a fatal outcome. Here, we describe the clinical and histological presentation of the lymphoma throughout its evolution. Cases like this can be difficult to classify posing a real challenge to clinicians and pathologists. So, it is vital to be aware of the rare presentation of this disease to be able to identify the clinical and histological picture to make a correct diagnosis and establish an early treatment.

Classifications of cutaneous lymphomas and lymphoproliferative disorders: An update from the EORTC cutaneous lymphoma histopathology group.

The classification of primary cutaneous lymphomas and lymphoproliferative disorders (LPD) is continuously evolving by integrating novel clinical, pathological and molecular data. Recently two new classifications for haematological malignancies including entities of cutaneous lymphomas were proposed: the 5th edition of the WHO classification of haematolymphoid tumours and the International Consensus Classification (ICC) of mature lymphoid neoplasms. This article provides an overview of the changes introduced in these two classifications compared to the previous WHO classification. The main changes shared by both classifications include the downgrading of CD8+ acral T-cell lymphoma to CD8+ acral T-cell LPD, and the recognition of entities that were previously categorized as provisional and have now been designated as definite types including primary cutaneous small or medium CD4+ T-cell LPD, primary cutaneous gamma/delta T-cell lymphoma, primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma, Epstein-Barr virus-positive mucocutaneous ulcer. Both classifications consider primary cutaneous marginal zone B-cell clonal neoplasm as an indolent disease but use a different terminology: primary cutaneous marginal zone lymphoma (WHO) and primary cutaneous marginal zone LPD (ICC). The 5th WHO classification further introduces and provides essential and desirable diagnostic criteria for each disease type and includes chapters on reactive B- or T-cell rich lymphoid proliferations formerly referred as cutaneous pseudolymphomas, as well as histiocyte and CD8 T-cell rich LPD in patients with inborn error of immunity. As already emphasized in previous lymphoma classifications, the importance of integrating clinical, histological, phenotypic and molecular features remains the crucial conceptual base for defining cutaneous (and extracutaneous) lymphomas.

Epstein-Barr virus latency patterns in polymorphic lymphoproliferative disorders and lymphomas in immunodeficiency settings: Diagnostic implications.

Epstein-Barr virus (EBV) is responsible for many B cell lymphoproliferative disorders (LPD) spanning subclinical infection to immunodeficiency-related neoplasms. EBV establishes a latent infection in the host B cell as defined histologically by the expression of EBV latent membrane proteins and nuclear antigens. Herein, we characterize the latency patterns of immunodeficiency-related neoplasms including post-transplant lymphoproliferative disorders (PTLD) and therapy-related LPD (formerly iatrogenic) with latent membrane protein-1 (LMP-1) and EBV nuclear antigen-2 (EBNA-2) immunohistochemistry. The latency pattern was correlated with immunodeficiency and dysregulation (IDD) status and time from transplant procedure. 38 cases of EBV+ PTLD in comparison to 27 cases of classic Hodgkin lymphoma (CHL) and diffuse large B cell lymphoma (DLBCL) arising in either the therapy-related immunodeficiency setting (n = 12) or without an identified immunodeficiency (n = 15) were evaluated for EBV-encoded small RNAs by in situ hybridization (EBER-ISH) and for LMP-1 and EBNA-2 by immunohistochemistry. A full spectrum of EBV latency patterns was observed across PTLD in contrast to CHL and DLBCL arising in the therapy-related immunodeficiency setting. Polymorphic-PTLD (12 of 16 cases, 75 %) and DLBCL-PTLD (9 of 11 cases, 82 %) showed the greatest proportion of cases with latency III pattern. Whereas, EBV+ CHL in an immunocompetent patient showed exclusively latency II pattern (13 of 13 cases, 100 %). The majority of EBV+ PTLD occurred by three years of transplant procedure date and were enriched for latency III pattern (21 of 22 cases, 95 %). Immunohistochemical identification of EBV latency by LMP-1 and EBNA-2 can help classify PTLD in comparison to other EBV+ B cell LPD and lymphomas arising in therapy-related immunodeficiency and non-immunodeficiency settings.

Monomorphic T-cell post-transplant lymphoproliferative disorder with features of HHV8-negative primary effusion lymphoma: an autopsy case and review of the literature.

A 67-year-old man underwent renal transplantation in his twenties. He developed refractory pleural effusion, with many large lymphocytes with severe atypia and mitosis in the effusion, indicating malignant lymphoma. He finally died of respiratory failure. An autopsy revealed atypical lymphocytes positive for CD3, CD4, and CD30 and negative for CD8, CD20, PAX5, human herpesvirus (HHV) 8, and Epstein-Barr virus-encoded small RNAs by immunohistochemistry and in situ hybridization. Atypical lymphocytes also had T-cell receptor gene rearrangements Jß2, Jγ2, and Jδ1 and chromosomal aberrations der(8)t(1;8)(q21;p21), add(13)(q12), add(14)(q32), and add(16)(q12-13). A few atypical lymphocytes were present at other sites. We finally diagnosed this case as monomorphic T-cell post-transplant lymphoproliferative disorder with features of HHV8-negative primary effusion lymphoma. A literature review only identified six cases (four HHV8-negative, two HHV8-positive) of effusion lymphoma of T-cell type, including the present case. Interestingly, about half of HHV8-negative and HHV8-positive cases had a history of renal transplantation in their twenties. All cases showed tumor CD30 expression, whereas CD4 and CD8 expressions were inconsistent. These findings indicated that this lymphoma may be associated with post-transplant lymphoproliferative disorder by renal transplantation at a young age, although further cases need to be analyzed.

[Interpretation of lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation in the 5th edition WHO classification of haematolymphoid tumours].

The fifth edition of the World Health Organization (WHO) classification of lymphohematopoietic system tumors updated the terminology, types of lesions, diagnostic criteria, nomenclature, and other aspects of lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation. The important updates and main changes in this section were briefly introduced, in order to guide the precise classification of lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation, and standardize pathological reports.