EBER Research Articles

Fas/FasL and Complement Activation are Associated with Chronic Active Epstein-Barr Virus Hepatitis.

Chronic active Epstein-Barr virus hepatitis (CAEBVH) is a rare and highly lethal disease characterized by hepatitis and hepatomegaly. This study aimed to investigate the clinicopathological features and pathogenic mechanisms of CAEBVH. Ten patients with confirmed Epstein-Barr virus hepatitis infection were enrolled. The clinicopathological characteristics of these patients were summarized and analyzed. Flow cytometry was utilized to detect peripheral blood immune cell phenotypes and whole exome sequencing was used to explore pathogenic genetic mechanisms. Lastly, immunohistochemical staining was employed to verify pathogenic mechanisms. Clinical features observed in all Epstein-Barr virus hepatitis patients included fever (7/10), splenomegaly (10/10), hepatomegaly (9/10), abnormal liver function (8/10), and CD8+ T cell lymphopenia (6/7). Hematoxylin and eosin staining revealed lymphocytic infiltration in the liver. Positive Epstein-Barr virus-encoded small RNA in-situ hybridization (EBER-ISH) of lymphocytes of liver tissues was noted. Whole exome sequencing indicated that cytotoxic T lymphocytes and the complement system were involved. The expression of CD8, Fas, FasL, and Caspase-8 expression as well as apoptotic markers was enhanced in the Epstein-Barr virus hepatitis group relative to the controls (p<0.05). Lastly, Complement 1q and complement 3d expression, were higher in CAEBVH patients relative to controls (p<0.05). CAEBVH patients developed fever, hepatosplenomegaly, and lymphadenopathy. Histopathological changes were a diffuse lymphocytic sinusoidal infiltrate with EBER-ISH positivity. Fas/FasL and complement activation were involved in CAEBVH patients.

Clinicopathological features of angioimmunoblastic T-cell lymphoma pattern Ⅰ

Objective: To investigate the clinicopathological features of angioimmunoblastic T-cell lymphoma pattern Ⅰ (AITL Pattern Ⅰ). Methods: The clinicopathological data of 11 AITL Pattern Ⅰ cases that were diagnosed at the Beijing Friendship Hospital Affiliated to Capital Medical University (10 cases) and Beijing Lu Daopei Hospital (1 cases) from January 2019 to October 2021 were retrospectively collected. Immunophenotype, Epstein-Barr virus infection status and T cell receptor (TCR) clonality of the tumor cells were tested, and clinicopathological features of cases were analyzed. Results: Among the 11 AITL Pattern Ⅰ cases, the male to female ratio was 1.2∶1.0. The median age was 59 years (range 47-78 years). Seven cases had B symptoms, while eleven cases presented with systemic lymphadenopathy. According to Ann Arbor system staging, two cases were classified as stage Ⅰ-Ⅱ, and 9 cases as stage Ⅲ-Ⅳ. Hepatosplenomegaly was present in two cases (2/11), three cases (3/11) had skin rash and pruritus, and two cases (2/11) had pleural effusion. Previously, 6 cases (6/11) were diagnosed as reactive hyperplasia, 1 case (1/11) as EBV-associated lymphoproliferative disorder, and 4 cases (4/11) as hyperplasia of lymphoid tissue, which was unable to exclude lymphoma. Histologically, all the 11 cases showed hyperplastic follicles in the paracortical regions with well-formed germinal centers. The hyperplastic follicles showed ill-defined borders and attenuated mantle zones in 7 cases. Mantle zones completely disappeared in 4 cases. The follicles were surrounded by a thin layer of atypical lymphocytes with bright or faintly stained cytoplasm. In 2 cases, the clear cells were located between the germinal centers and the thin residual mantle cell layers, showing a circular growth pattern. The cells were medium in size, with irregular karyotype, coarse chromatin and indistinct nucleoli. Immunohistochemically, CD21 staining showed that the meshworks of follicular dendritic cells(FDC)were mainly confined to the follicles. There was a subtle expansion of the meshworks of FDC in 4 cases with ill-defined borders. The atypical cells surrounding the follicles expressed CD3 (11/11), CD4 (11/11), PD-1 (11/11), CXCL13 (6/11), ICOS (10/11) and CD10 (7/11). PD-1 staining showed a strong perifollicular pattern, and a small number of positive cells were scattered around the high endothelial veins in the interfollicular region. CXCL13, ICOS and CD10 showed similar distribution patterns. EBV-encoded small RNA probe (EBER) in situ hybridization showed that EBER positive B lymphocytes were scattered in the interfollicular region (5-20/HPF) in all cases. T cell receptor gene rearrangement was monoclonal in all cases. Conclusions: Diagnosing AITL Pattern Ⅰ may be challenging and requires comprehensive analysis of clinical manifestations, histological morphology, immunophenotype and gene rearrangement results.

Plasmablastic lymphoma: An update.

Plasmablastic lymphoma (PBL) is a highly aggressive B cell non‐Hodgkin lymphoma frequently associated with immunosuppression, particularly human immunodeficiency virus (HIV) infection. Although PBL is rare globally, South Africa has a high burden of HIV infection leading to a higher incidence of PBL in the region. Laboratory features in PBL may overlap with plasmablastic myeloma and other large B cell lymphomas with plasmablastic or immunoblastic morphology leading to diagnostic dilemmas. There are, however, pertinent distinguishing laboratory features in PBL such as a plasma cell immunophenotype with MYC overexpression, expression of Epstein–Barr virus‐encoded small RNAs and lack of anaplastic lymphoma kinase (ALK) expression. This review aims to provide a summary of current knowledge in PBL, focusing on the epidemiology, pathophysiology, laboratory diagnosis and clinical management.

Are Viral Infections Key Inducers of Autoimmune Diseases? Focus on Epstein-Barr Virus.

It is generally accepted that certain viral infections can trigger the development of autoimmune diseases. However, the exact mechanisms by which these viruses induce autoimmunity are still not understood. In this review, we first describe hypothetical mechanisms by which viruses induce some representative autoimmune diseases. Then, we focus on Epstein–Barr virus (EBV) and discuss its role in the pathogenesis of rheumatoid arthritis (RA). The discussion is mainly based on our own previous findings that (A) EBV DNA and its products EBV-encoded small RNA (EBER) and latent membrane protein 1 (LMP1) are present in the synovial lesions of RA, (B) mRNA expression of the signaling lymphocytic activation molecule-associated protein (SAP)/SH2D1A gene that plays a critical role in cellular immune responses to EBV is reduced in the peripheral T cells of patients with RA, and (C) EBV infection of mice reconstituted with human immune system components (humanized mice) induced erosive arthritis that is pathologically similar to RA. Additionally, environmental factors may contribute to EBV reactivation as follows: Porphyromonas gingivalis peptidylarginine deiminase (PAD), an enzyme required for citrullination, engenders antigens leading to the production of citrullinated peptides both in the gingiva and synovium. Anti-citrullinated peptides autoantibody is an important marker for diagnosis and disease activity of RA. These findings, as well as various results obtained by other researchers, strongly suggest that EBV is directly involved in the pathogenesis of RA, a typical autoimmune disease.

Short-term outcomes of three rare cases of intramucosal Epstein-Barr virus-associated gastric cancer treated with endoscopic submucosal dissection.

Epstein–Barr virus-associated gastric cancer (EBVaGC) is a subtype of gastric cancer morphologically characterized by massive lymphocyte infiltration. We herein report the short-term outcomes of three rare cases of intramucosal EBVaGC treated with endoscopic submucosal dissection (ESD). Histologically, the lesions exhibited poorly to moderately differentiated tubular adenocarcinoma without lymphovascular invasion, and in situ hybridization revealed EBV-encoded small RNA. Helicobacter pylori infection was not found in any of the lesions. During the 3 to 12 months of follow-up following ESD, none of the ESD-treated patients showed evidence of local recurrence or distant metastases. Essential characteristics of intramucosal EBVaGC may include lymphocyte infiltration into the mucosal stroma or cancer nests as well as the presence of a lace pattern. We believe that ESD might be a safe and suitable treatment method for intramucosal EBVaGC that avoids needless surgery, particularly in patients with severe comorbidities or a high operational risk.

The clinicopathological characteristics of C-MYC protein in angioimmunoblastic T-cell lymphoma.

To investigate the relationship between expression of C-MYC protein and clinicopathologic characteristics in angioimmunoblastic T-cell lymphoma (AITL), then discuss the prognosis. Patient samples were collected and made into tissue microarray for the same experimental condition. Pathomorphological features and immunohistochemistry of specific markers were used to determine the diagnosis of AITL. Epstein-Barr virus (EBV) infection was detected by EBV-encoded small RNA by in situ molecular hybridizations. B cells atypical hyperplasia was explored by the immunohistochemistry and gene rearrangement, C-MYC protein was expressed by the immunohistochemical staining and C-MYC gene abnormalities were detected by fluorescence in situ hybridization (FISH). 44 AITL patients were divided into two groups and the relation among C-MYC protein, EBV infection and B cells hyperplasia was observed. We followed up the overall survival rate (OS) and progression-free survival (PFS), and analyzed C-MYC protein, and the relationship between the prognosis of survival. Among 44 AITL patients, 29 cases (65.9%) were C-MYC protein-positive, and 32 (32/44, 72.3%) were EBV-positive. The expression rate of C-MYC protein in the high-risk group ranked by international prognostic index (IPI) and stage III-IV were higher than that in the low-risk group and stage I-II (P<0.05). The expression rate of C-MYC protein was higher in B cells excessive proliferation group, including simple hyperplasia, atypical hyperplasia, monoclonal B cells hyperplasia, and the diffuse large B lymphoma than in the low-proliferation group (P<0.05). The expression rate of C-MYC protein in EBV-positive patients was indifferent compared with the negative group (P>0.05). C-MYC gene rearrangement was not found in any samples, while the multi-copies of the C-MYC gene were found in only one case. As followed, 5-year OS was significantly low, and there was no significant difference in OS between the C-MYC protein-positive and negative groups. PFS in the positive group was significantly lower than that of the negative group. The difference in response to treatment between the two groups was statistically significant (P<0.05). We discussed the clinicopathologic characteristics and significance in AITLs, which predominantly express MYC-protein in <50% of cells, lacking C-MYC gene rearrangement. C-MYC protein-positive or negative expression was closely related to B cells excessive proliferation. C-MYC protein may be used as an indicator to judge the malignancy and to predict the prognosis of AITL.

Malar rash with pancytopenia

Malar rash with pancytopenia

Clinicopathological features of Epstein-Barr virus-associated superficial early stage gastric cancer treated with endoscopic submucosal dissection.

Epstein-Barr virus (EBV) is known to be involved in gastric carcinogenesis. EBV-associated early gastric carcinoma (EBVEGC) has a lower incidence of lymph node involvement and could be an expanded indication for endoscopic submucosal dissection (ESD) treatment. To clarify the prevalence and clinicopathological features of EBVEGC. This study reviewed 618 lesions in 519 patients treated with ESD between 2014 and 2016. Tissue microarray sections were subjected to in situ hybridization staining for EBV-encoded small RNA transcripts (EBER). Lesions positive for EBER were compared with control lesions and were retrospectively analyzed. 12 (1.9%) of the 618 lesions were EBVEGC. EBVEGCs were more frequently located near the atrophic border than control lesions in the middle or upper stomach and were reddish. EBVEGC invasion was deeper and more often histologically undifferentiated. On narrow-band imaging magnifying endoscopy, the EBVEGC group significantly more often showed an endoscopic lace pattern, defined as an absent or obscure microsurface pattern and a microvascular pattern of a tiny, dense, and irregular subepithelial capillary network. The rate of curative resection was significantly lower in the EBVEGC group. Only 1.9% of the ESD specimens were EBV-positive. Endoscopic features could raise clinical suspicion of EBV infection.

Virus-Mediated Inhibition of Apoptosis in the Context of EBV-Associated Diseases: Molecular Mechanisms and Therapeutic Perspectives.

Epstein-Barr virus (EBV), the representative of the Herpesviridae family, is a pathogen extensively distributed in the human population. One of its most characteristic features is the capability to establish latent infection in the host. The infected cells serve as a sanctuary for the dormant virus, and therefore their desensitization to apoptotic stimuli is part of the viral strategy for long-term survival. For this reason, EBV encodes a set of anti-apoptotic products. They may increase the viability of infected cells and enhance their resistance to chemotherapy, thereby contributing to the development of EBV-associated diseases, including Burkitt’s lymphoma (BL), Hodgkin’s lymphoma (HL), gastric cancer (GC), nasopharyngeal carcinoma (NPC) and several other malignancies. In this paper, we have described the molecular mechanism of anti-apoptotic actions of a set of EBV proteins. Moreover, we have reviewed the pro-survival role of non-coding viral transcripts: EBV-encoded small RNAs (EBERs) and microRNAs (miRNAs), in EBV-carrying malignant cells. The influence of EBV on the expression, activity and/or intracellular distribution of B-cell lymphoma 2 (Bcl-2) protein family members, has been presented. Finally, we have also discussed therapeutic perspectives of targeting viral anti-apoptotic products or their molecular partners.

Higher viral load of Epstein-Barr virus in gastric cancer compared with non-cancerous gastroduodenal tissues

Epstein-Barr Virus (EBV)-associated gastric cancer is a distinct molecular subtype of gastrointestinal carcinomas as defined by the Cancer Genome Atlas. In the present study 237 samples from Iranian patients diagnosed with gastric cancer and gastroduodenal disease were retrospectively examined for EBV infection by quantitative Real-Time PCR. Of the 237 samples tested, EBV DNA was detected in 37 samples (15.6%), in 13 of the 81 gastric cancer cases (16%), and 24 of the 156 non-cancerous samples (15.4%). The EBV infection rate was found higher in patients with gastric ulcer (35%) and duodenal ulcer (21.9%) compared to patients with gastric cancer (16%) and gastritis (19.6%). The EBV-encoded small RNA (EBER) copy number in the gastric cancer group (mean = 2.14×10-1 with range of 2.14×10-2 to 4.10×10-1 copies/ cell) was higher than gastroduodenal diseases group (mean = 1.39×10-2 with range 1.11×10-3 to 2.35×10-2 copies/ cell), and this difference was statistically significant (P >0.001). The higher number of copies of EBV-EBER in the gastric cancer group compared to the non-cancer group confirmed the possible role of EBV in inducing cancer.

Prognostic Perspectives of STING and PD-L1 Expression and Correlation with the Prognosis of Epstein-Barr Virus-Associated Gastric Cancers.

: Epstein-Barr virus-associated gastric cancers (EBVaGCs) have unique molecular and clinicopathological characteristics. The cyclic GMP-AMP synthase-stimulator of interferon genes (STING) pathway is recently recognized as the critical innate immunity against pathogens and tumors. STING is also a master regulator in the cancer-immunity cycle and targeting STING could synergize with existing immune-checkpoint therapies. However, the role of STING in GC, especially in EBVaGC, and its correlation with programmed death-ligand 1 (PD-L1) remain largely unclear. We collected 78 cases of EBVaGCs and 210 cases of EBV-negative GC (EBVnGC) from a total of 1,443 cases of GC analyzed by EBV-encoded small RNA in situ hybridization. We investigated STING and PD-L1 expression and their concomitant prognostic value in EBVaGCs and EBVnGCs using tissue microarray and immunohistochemistry. The effects of STING and PD-L1 expression on the overall survival of patients with EBVaGC or EBVnGC were assessed by univariate and multivariate analysis. We found that both STING and PD-L1 exhibited significantly higher expression in the EBVaGCs than that in the EBVnGCs. The expression of STING was positively correlated with that of PD-L1 in EBVaGCs. Simultaneous negative expression of STING and PD-L1, and positive expression of STING were independent prognostic risk factors for EBVaGC and EBVnGC, respectively. This is the first prognostic retrospective study of STING and PD-L1 expression and the prognosis among EBVaGC and EBVnGC. The expression and prognostic value of STING and PD-L1 are different in the two types of GCs. STING and PD-L1 are promising prognostic biomarkers and therapeutic targets for EBVaGC and EBVnGC.

Establishment of a patient-derived organoid model and living biobank for nasopharyngeal carcinoma

Background Recurrent nasopharyngeal carcinoma (NPC) remains a major challenge for clinicians and scientists. Tumor organoid is a revelational disease model that highly resembled the heterogeneity and histopathological characteristics of original tumors. This study aimed to optimize the modeling process of patient-derived NPC organoids (NPCOs), and establish a living-biobank of NPCs to study the mechanism and explore the more effective treatment of the disease.MethodsSixty-two fresh NPC tissue samples and 15 normal mucosa samples were collected for 3-dimensional (3D) organoid culture. The organoids were confirmed using hematoxylin and eosin assays. The expression levels of CD133, CD44, BMI-1, and Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) were detected by immunohistochemistry (IHC) and in situ hybridization (ISH). Recurrent NPCOs were frozen in liquid nitrogen for 6 months and then resuscitated and passaged.ResultsWe identified a novel two-step enzymatic strategy for the treatment of NPC and nasal mucosa specimens and an optimal medium for culturing NPCOs and nasal mucosa organoids (NMOs). Organoid cultures were generated from 34 primary NPC samples, 28 recurrent NPC samples, and 15 normal mucosa samples. The success rates for primary NPCO, recurrent NPCO, and NMO formation were 47.06%, 81.25%, and 86.5%, respectively. All the NPCOs were EBER positive and CK7 negative. Recurrent NPCOs had higher expressions of stem cell markers, including BMI-1, CD44, and CD133. Additionally, recurrent NPCOs could be cultured to passage 4 and frozen and revived repeatedly, while primary NPCOs were challenging to culture.Conclusions In summary, we successfully established a living biobank using the NPCO model, which has enormous potential in basic and clinical research on NPC.

Potential Role of Epstein-Barr Virus in Oral Potentially Malignant Disorders and Oral Squamous Cell Carcinoma: A Scoping Review.

Though the oral cavity is anatomically proximate to the nasal cavity and acts as a key reservoir of EBV habitation and transmission, it is still unclear whether EBV plays a significant role in oral carcinogenesis. Many studies have detected EBV DNA in tissues and exfoliated cells from OSCC patients. However, very few studies have investigated the expression of functional EBV proteins implicated in its oncogenicity. The most studied are latent membrane protein 1 (LMP-1), a protein associated with the activation of signalling pathways; EBV determined nuclear antigen (EBNA)-1, a protein involved in the regulation of gene expression; and EBV-encoded small non-polyadenylated RNA (EBER)-2. LMP-1 is considered the major oncoprotein, and overexpression of LMP-1 observed in OSCC indicates that this molecule might play a significant role in oral carcinogenesis. Although numerous studies have detected EBV DNA and proteins from OSCC and oral potentially malignant disorders, heterogeneity in methodologies has led to discrepant results, hindering interpretation. Elucidating the exact functions of EBV and its proteins when expressed is vital in establishing the role of viruses in oral oncogenesis. This review summarises the current evidence on the potential role of EBV in oral oncogenesis and discusses the implications as well as recommendations for future research.

Case Report: Predominant brain superficial location of Epstein-Barr virus-related primary central nervous system diffuse large B cell lymphoma in a young woman with primary Sjögren’s syndrome

Epstein-Barr virus (EBV)- related primary central nervous system (CNS) diffuse large B cell lymphoma (DLBCL) is very rare in young patients without immunodeficiency. The predominant brain superficial location of EBV-related primary CNS DLBCL, and its’ concurrence with EBV-related lumbar-sacral radiculitis are special and have not been described previously. A young female patient presented with multiple cranial neuropathies, radiculopathy of lower limbs, and urinary retention. Her series brain magnetic resonance imaging (MRI) revealed dynamic changes, starting from lesions mainly in cranial nerves to mammillary body, pineal body, meninges, and finally in the bilateral cerebellum and cerebral lobes. Lumber spinal MRI showed enhancement in meninges and cauda equine roots. 18-fluorodeoxyglucose PET-CT revealed remarkably increased glucose metabolism in the lesions shown on the aforementioned brain MRI and lumbar spinal MRI, as well as right axillary lymph nodes. The biopsy of a whole axillary node on right side indicated EBV-related lymphoproliferation. Lumbar meninges and cauda nerves biopsy revealed chronic inflammation. By cerebral spinal fluid cytology and in situ hybridization, EBV-encoded small RNA (EBER) positive large B cell lymphoma was identified. The patient also had primary Sjögren’s syndrome (PSS). The patient died two weeks after treatment with rituximab, lenalidomide and methylprednisolone. She had survived for four and a half months since symptom onset. The patient presented with several stages of EBV-related complications in the nervous system, chronic EBV infection of lumbar-sacral radiculitis, and primary CNS DLBCL, indicating the process from chronic EBV infection to DLBCL in nervous system. Intracranial acute bacterium infection probably exacerbated the progression of CNS DLBCL. The concomitant sufferings of PSS reflected immune-dysfunction might have increased the risk of EBV-related CNS DLBCL in this young patient.

Epstein-Barr virus infection associated polymyositis and coronary artery dilation

BackgroundEpstein-Barr virus (EBV) infects more than 90% of the population worldwide. However, chronic active EBV infection (CAEBV) is one of the EBV-positive T- or NK-lymphoproliferative diseases with high morbidity and mortality. Here, we report a case of a 9-year girl with CAEBV, successively presenting with polymyositis and coronary artery dilation (CAD).Case presentationThe girl complained of fatigue for more than 1 month. Muscle strength examinations had no abnormal findings. Blood chemistries showed elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine kinase (CK). Magnetic resonance imaging (MRI) showed spotty high-intensity signals in thigh muscles, and electromyogram suggested myogenic damage. The significant findings were positive EBV antibodies (EBVEA-IgG, EBVCA-IgG, and EBVNA-IgG), increased EBV DNA copies in B, T, and NK cells, and positive EBV-encoded small RNA in biopsy muscle specimen. The girl received ganciclovir, intravenous immunoglobulin, and methylprednisolone, and her symptoms improved. On the 45th day of hospitalization, echocardiograph revealed CAD. She received additional anticoagulants and Tocilizumab. Her condition improved and continued to be followed up at the clinic preparing for hematopoietic stem cell transplantation.ConclusionsThis is the first reported case of CAEBV successively with polymyositis and CAD. This case makes the diagnoses of autoimmune diseases in children more complicated. Careful investigation of hidden CAEBV should be recommended in children with atypical polymyositis or CAD.

Recent Advances in the Diagnosis and Treatment of Natural Killer Cell Malignancies.

Simple SummaryNatural killer (NK)/T-cell lymphomas are aggressive extranodal Epstein–Barr virus (EBV)-positive malignancies. They can be divided into three subtypes: nasal (involving the nose and upper aerodigestive tract), non-nasal (involving skin, gastrointestinal tract, testis and other organs) and disseminated (involving multiple organs). Lymphoma cells are positive for CD3ε, CD56, cytotoxic molecules and EBV-encoded small RNA. There is a predilection for Asian and Central/South American populations. Genome-wide association studies have identified lymphoma susceptibility loci in Asians. Positron emission tomography computed tomography and plasma EBV DNA quantification are crucial at diagnosis and follow-up. Stage I/II patients receive non-athracycline asparaginse-containing regimens, together with sequential/concurrent radiotherapy. Anthracycline-containing regimens are ineffective. Stage III/IV patients receive asparaginase-containing regimens, followed by allogeneic haematopoietic stem cell transplantation (HSCT). Autologous HSCT does not improve outcome. In relapsed/refractory patients, novel approaches include PD1/PD-L1 targeting, EBV-specific cytotoxic T-cells, and monoclonal antibodies. Small molecules including histone deacetylase inhibitors may be beneficial.Natural killer (NK)/T-cell lymphomas are aggressive malignancies. Epstein–Barr virus (EBV) infection in lymphoma cells is invariable. NK/T-cell lymphomas are divided into nasal, non-nasal, and disseminated subtypes. Nasal NK/T-cell lymphomas involve the nasal cavity and the upper aerodigestive tract. Non-nasal NK/T-cell lymphomas involve the skin, gastrointestinal tract, testis and other extranodal sites. Disseminated NK/T-cell lymphoma involves multiple organs, rarely presenting with a leukaemic phase. Lymphoma cells are positive for CD3ε (not surface CD3), CD56, cytotoxic molecules and EBV-encoded small RNA. There is a predilection for Asian and Central/South American populations. Genome-wide association studies have identified lymphoma susceptibility loci in Asian patients. Positron emission tomography computed tomography and plasma EBV DNA quantification are crucial evaluations at diagnosis and follow-up. Stage I/II patients typically receive non-athracycline regimens containing asparaginse, together with sequential/concurrent radiotherapy. Anthracycline-containing regimens are ineffective. Stage III/IV patients are treated with asparaginase-containing regimens, followed by allogeneic haematopoietic stem cell transplantation (HSCT) in suitable cases. Autologous HSCT does not improve outcome. In relapsed/refractory patients, novel approaches are needed, involving PD1/PD-L1 targeting, EBV-specific cytotoxic T-cells, and monoclonal antibodies. Small molecules including histone deacetylase inhibitors may be beneficial in selected patients. Future strategies may include targeting of signalling pathways and driver mutations.

Decrease of CD38 expression is linked to increase of solitary plasmacytoma pathological grade: a single institution experience from China.

Solitary plasmacytoma (SP) is a rare plasma cell disorder characterized by localized neoplastic proliferation of monoclonal plasma cell. Due to its rarity, further understanding of the spectrum of its clinicopathologic features is needed. A retrospective analysis of cases from a single institution was conducted. Clinical characteristics of the patients were collected; histopathological and semi-quantitative immunohistochemical analyses were performed. Thirteen cases were identified from our pathology archives, including 4 cases of solitary plasmacytoma of bone (SPB) (30.8%) and 9 extraosseous plasmacytoma (EP) (69.2%). The mean age of EP is a decade older than SPB. There is no gender disparity. The most common sites involved are the vertebrae and nasopharynx. Histologically, the tumors can be classified into two grades based on degree of differentiation. Immunohistochemically the tumor cells express CD38, CD138, MUM-1, and exhibit light chain restriction. Ki-67 proliferation index is 30%. In situ hybridization for Epstein-Barr virus-encoded small RNAs (EBER) is negative in six cases tested. Semi-quantitative immunohistochemical analysis showed decreased integrated optical density (IOD) of CD38 in neoplastic cells. IgH gene rearrangement was identified in two cases. SP is a rare plasmacytoid neoplasm that occurs more frequently in older patients. Diagnosis requires a systematic clinical approach combined with the pathological characteristics of plasmacytoid morphology, immunophenotype and light chain restriction. There are more cases of EP than SPB in our series, which is in contrast to that reported in literature. Results from this study suggest that CD38 is a potential immunohistochemical marker associated with prognosis of SP. Further studies with more cases and longer term follow-up may provide more definitive information on risk of progression from SP to multiple myeloma (MM).

Multifocal Oral Epstein-Barr Virus-Positive Mucocutaneous Ulcers Associated with Dual Methotrexate and Leflunomide Therapy: A Case Report.

Epstein–Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) is a unique clinicopathologic entity of lymphoproliferative disorder, occurring in immunosuppressed patients. Due to its rarity, EBVMCU may be under-recognized by clinicians as well as pathologists. In addition, its clinical and histopathologic features overlap with other benign and malignant conditions, making a diagnosis challenging. This report presents an unusual case of multifocal oral EBVMCUs in a 52-year-old female patient with rheumatoid arthritis, receiving the combination of methotrexate and leflunomide for 5 years. The patient presented with persistent multiple large painful ulcers involving her palate and gingiva for 6 months. The histopathologic examination revealed extensive ulceration with diffuse polymorphic inflammatory infiltrate admixed with scattered atypical lymphoid cells showing occasional Hodgkin and Reed/Sternberg-like cell features. These atypical cells showed immunoreactivity for CD20, CD30 and MUM1/IRF4. EBV-encoded small RNA in situ hybridization was positive, validating the presence of EBV-infected cells. Two months after discontinuation of both immunosuppressive medications, oral lesions gradually regressed. At 9-month follow-up, no evidence of relapsing oral EBVMCU has been observed. The multifocal presentation of EBVMCU is rare and could be resulted from the overwhelming immune suppression by long-term use of dual immunosuppressants. Its diagnosis requires comprehensive correlation of patient history, clinical findings, histopathologic, and immunophenotypic features. The ability of EBVMCU to regress following removal of immunosuppressive causes is in drastic contrast to a variety of its potential clinical and histopathologic mimics. Therefore, accurate diagnosis is crucial to avoid unnecessary patient management and achieve optimal patient outcomes.

The CT and PET/CT findings in primary pulmonary lymphoepithelioma-like carcinoma with pathological correlation: a study of 215 cases

To investigate the computed tomography (CT) and integrated positron-emission tomography (PET)/CT findings of primary pulmonary lymphoepithelioma-like carcinoma (PLELC). The imaging and histopathological data of 215 patients with PLELC confirmed at histopathology were analysed retrospectively. All patients underwent CT, and 70 underwent PET/CT. None of the cohort had nasopharyngeal lymphoepithelioma-like carcinoma. The PLELC was demonstrated as a solitary nodule/mass in 188 cases (188/215, 87%), multiple nodules/masses in 12 cases (12/215, 6%), lobar or segmental consolidation in 15 cases (15/215, 7%). The tumour showed a well-defined margin in 171 cases (171/215, 80%), lobular sign in 177 cases (177/215, 82%), and spicule sign in 91 cases (91/215, 42%). Most of the cases showed homogeneous density in unenhanced CT (128/215, 60%), and vascular shadows inside the tumour in the arterial stage were found in 105 cases (105/158, 66%). Involvement of the bronchus was found in 154 cases (154/215, 72%). Hilar or mediastinal lymph nodes were enlarged in 160 patients (160/215, 74%). Seventy cases demonstrated avid 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) uptake on PET/CT. The range of maximum standardised uptake values (SUVmax) was 2.1-28.5 (14±5.93). Microscopic pathological classification of 124 resected specimens included 87 cases of the Regaud type and 37 cases of the Schmincke type. Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) was positive in all 215 cases. PLELC should be suspected when a large, lobulate, well-defined lung tumour with homogeneous density, vascular encasement, and high 18F-FDG uptake is found. Moreover, EBERs are helpful in patients with suspected PLELC.

Bilateral intraocular and lung involvements associated with Nasal NK/T-cell lymphoma.

To report a rare case of nasal natural killer/T (NK/T) cell lymphoma with bilateral intraocular and lung metastasis and to further describe the clinical features of intraocular manifestations. A 54-year-old man presented with a 3-month history of left nasal congestion, and bilateral vision impairment of one week duration. Subsequent maxillary computed tomography (CT) and multiple biopsies confirmed the diagnosis of nasal NK/T-cell lymphoma. EBV-encoded small RNA (EBER) in situ hybridization revealed EBV infection. A comprehensive ophthalmic examination found lymphoma-associated retinopathy and choroidopathy, which presented as bilateral diverse patterns and retinal detachment. In addition, the chest CT showed multiple scattered nodules in both lungs, and soft-tissue mass in the left hilum with mediastinal and axillary lymphadenopathy. The condition of this patient deteriorated rapidly and he died shortly after diagnosis. The rarity of secondary ocular NK/T-cell lymphoma makes it challenging to identify these tumors early. Both otolaryngologist and ophthalmologists should be aware of ocular involvement and other secondary manifestations of NK/T-cell lymphoma.