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Objective: To investigate the clinicopathological features and prognosis of skeletal-muscle cytotoxic T-cell lymphoma (CTL). Methods: The clinical data of 14 cases of skeletal muscle CTL and 47 cases of non-skeletal muscle extranodal CTL patients in Beijing Friendship Hospital Affiliated to Capital Medical University and the 989 Hospital of the joint logistics support force of the people's Liberation Army (the former 152 hospital) from 2008 to 2019 were collected retrospectively. Immunophenotype, EBV infection status and T-cell receptor (TCR) clonality of tumor cells were evaluated. The clinicopathological features and prognosis of the two groups were compared. Results: Skeletal-muscle CTL accounted for 23.0% (14/61) of extranodal CTL in the same period. The median age of the patients was 42.3 years (range 11-76 years), including six males and eight females. The main clinical manifestations were painless masses. Two patients (2/14) had B symptoms. The tumors occurred in the cheek (7 cases), the tongue (4 cases), the lower lip (3 cases) and the left upper arm (2 cases), and in two cases had two sites. Ten cases were of stage ⅠE and four cases stage ⅡE. Compared with non-skeletal-muscle extranodal CTL, many patients of skeletal-muscle CTL did not have B symptoms, the clinical stage was lower, and the tumor mainly involved the oral cavity (cheek, tongue and lip, P <0.05). Morphologically, the tumor showed diffuse infiltration of heterotypic lymphocytes in skeletal muscle. Immunohistochemistry showed that in 11/14 cases, there were reduced or loss of expression of some the T cell antigens (CD2, CD3, CD5, CD7). TIA-1, Gr B and CD8 (CD8 + >CD4 + ) were expressed in all cases, and CD56 was negative. The median Ki-67 proliferation index was 35.0% (range 5%-60%). EBER in situ hybridization was negative in all cases. The results of TCR clonality analysis showed clonal TCR gene rearrangement were detected in eight cases. The median follow-up time was 40 months (range 10-67 months). Ten patients were tumor free; the 5-year survival rate of skeletal-muscle CTL was 100%. Compared with non-skeletal-muscle extranodal CTL (5-year overall survival rate was 35.9%), the difference was statistically significant (χ²=8.277, P =0.004). Conclusions: Skeletal-muscle CTL mostly occurs in the skeletal muscle of cheek and mouth. Tumor cells show morphologic characteristics of muscle invasion and myositis-like feature. It also shows CD8 + >CD4 + immunophenotype, cytotoxic molecular pattern and is associated with low clinical stage and good prognosis.

Objective: To investigate the clinicopathological features of EBV-positive T/NK cell lymphoproliferative diseases (EBV(+) T/NK-LPD). Methods: The clinical characteristics of 156 cases of EBV(+) T/NK-LPD were collected from August 2002 to March 2015 at Beijing Friendship Hospital, Capital Medical University. Immunohistochemical staining, EBER in situ hybridization and clonal analysis of TCR gene were performed. All patients were followed up. Results: There were 106 male and 50 female patients; patients' age ranged from 1 to 75 years (median 20 years). The course of the diseases before diagnosis ranged from 2 to 540 months (median 20 months). Fever was noted in 122 patients (78.2%), 108 patients had lymphadenopathy (69.2%), and 75 patients had hepatosplenomegaly (48.1%). Thirty-three cases were grade 1, 68 cases were grade 2, and 55 cases were grade 3. TCR gene arrangement analysis was performed in 45 cases, and 33 cases (73.3%) showed clonal rearrangement. The follow-up period ranged from 1-134 months, and 44 patients (28.2%) died. There was a trend of increased death rate associated with increasing grade ( P >0.05). Conclusions: There are many types of EBV(+) T/NK-LPD, and they can be classified as systemic, relatively localized and localized. The prognosis should be based on a comprehensive analysis of pathology and clinical data. There is no significant correlation between morphological grade and mortality. An important goal of therapy is to prevent serious complications.

In recent years, there are increasing articles concerning Epstein-Barr virus associated lymphoproliferative disorder (EBV+ LPD), and the name of EBV+ LPD is used widely. However, the meaning of EBV+ LPD used is not the same, which triggered confusion of the understanding and obstacles of the communication. In order to solve this problem. Literature was reviewed with combination of our cases to clarify the concept of EBV+ LPD and to expound our understanding about it. In general, it is currently accepted that EBV+ LPD refers to a spectrum of lymphoid tissue diseases with EBV infection, including hyperplasia, borderline lesions, and neoplastic diseases. According to this concept, EBV+ LPD should not include infectious mononucleosis (IM) and severe acute EBV infection (EBV+ hemophagocytic lymphohistiocytosis, fatal IM, fulminant IM, fulminant T-cell LPD), and should not include the explicitly named EBV+ lymphomas (such as extranodal NK/T cell lymphoma, aggressive NK cell leukemia, Burkitt lymphoma, and Hodgkin lymphoma, etc.) either. EBV+ LPD should currently include: (1) EBV+ B cell-LPD: lymphomatoid granulomatosis, EBV + immunodeficiency related LPD, chronic active EBV infection-B cell type, senile EBV+ LPD, etc. (2) EBV+ T/NK cell-LPD: CAEBV-T/NK cell type, hydroa vacciniforme, hypersensitivity of mosquito bite, etc. In addition, EBV+ LPD is classified, based on the disease process, pathological and molecular data, as 3 grades: grade1, hyperplasia (polymorphic lesions with polyclonal cells); grade 2, borderline (polymorphic lesions with clonality); grade 3, neoplasm (monomorphic lesions with clonality). There are overlaps between EBV+ LPD and typical hyperplasia, as well as EBV+ LPD and typical lymphomas. However, the most important tasks are clinical vigilance, early identification of potential severe complications, and treating the patients in a timely manner to avoid serious complications, as well as the active treatment to save lives when the complications happened.

Objective: To study the clinicopathologic features, diagnosis and differential diagnosis of systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease of childhood (CSEBV(+)T-LPD)., Methods: Thirty cases of CSEBV(+)T-LPD were retrospectively studied by light microscopy, immunohistochemistry and in-situ hybridization for EBV-encoded RNA (EBER). The clinical information and follow-up data were analyzed., Results: Nineteen of the 30 patients were males and 11 females. The median age of disease onset was 9 years (range = 1.5 to 32 years). The average duration between disease onset and diagnosis was 14 months. The major clinical manifestations were fever (96.7%), lymphadenopathy (83.3%) and hepatosplenomegaly (66.7%). Cutaneous manifestations were not uncommon, which included hypersensitivity to mosquito bite (13.3%) and skin rash (20.0%). Six of the 20 patients died on follow up. Histologically, the lymph nodes showed expansion of T zone, with diminished or effaced lymphoid follicles. The lymphoid cells were of small to medium size. Scattered large lymphoid cells were also identified in the expanded T zone. Furthermore, the liver and spleen showed mild to marked sinusoidal infiltration. In some cases, various degrees of sinus histiocytosis with erythrophagocytosis were present. Skin biopsies showed mild to marked degree of lymphocytes infiltration in dermis. Immunohistochemical study and in-situ hybridization showed that the EBER-positive cells were of T lineage and CD3 positive. They also expressed cytotoxic molecules granzyme B and TIA-1. Seven of the 8 cases examined were CD8 positive, while the remaining case was mainly CD4 positive. Thirteen of 15 cases were shown to be CD56 negative. The number of EBER-positive cells ranged from 5 to more than 500 per high-power field. These cells included small to large lymphoid cells located mostly in the expanded T zone and sometimes in the germinal centers. Nine of the 30 cases, which consisted mainly of medium to large-sized lymphoid cells, were also EBER positive., Conclusions: Systemic EBV-positive T-cell lymphoproliferative disease of childhood occurs most often in children and young adults, with a median age of 9 years. It has a subacute or chronic clinical course. Most of the patients have evidence of systemic disease, often with lymph node, liver, spleen and skin involvement. It carries a poor clinical outcome and can be life-threatening. The disease is characterized by a clonal proliferation of EBV-infected T cells with cytotoxic immunophenotype. Definitive diagnosis requires correlation between clinical, pathologic and ancillary investigation findings.

Objective: To study the clinical and morphological features, immunophenotype and in situ detection of Epstein-Barr virus (EBV) infection in infectious mononucleosis (IM) to enhance the knowledge and diagnosis of the disease., Method: Using routine haematoxylin and eosin staining, immunohistochemistry and EBER in situ hyhridization together with clinical data analysis, 15 cases of IM were evaluated for their clinical features, morphology, immunophenotype and EBV infection status., Results: IM was common in children and young adults with a median age of 18 years. It was an acute disease with lymphadenopathy and frequently fever. Most of the patients had a rapid recovery. Every case showed a markedly T zone expansion with a mottling pattern, composing of small to large lymphocytes, plasma cells and histiocytes. The cells also showed a B-cell differentiation profile ranging from activated lymphoblastoid cells, immunoblasts, plasmablasts, plasma-like cells and plasma cells. Many small lymphocytes in the expanded T zone expressed CD3. Some of the activated lymphoblastoid cells and immonoblasts were CD20 and CD30 positive with variable intensity signals. EBER positive (nuclear staining) cells were seen in every case. The number of EBER positive cells ranged from 10 to more than 100 per high power field. These cells included small to large lymphocytes locating mostly in the expanded T zone and a few were in the follicular germinal centers., Conclusions: IM is an EBV related acute sell-recovering lymphoproliferative disease, having distinct clinical, morphological and immunophenotypic characteristics as well as EBV infection. Taking these features into consideration will facilitate the correct diagnosis of IM.

Background: The Epstein-Barr virus (EBV) is thought to be involved in the pathogenesis of some Hodgkin disease (HD) cases. EBV may be associated particularly with childhood HD, a disease rare in the West compared with developing countries. In this study, a large series of Chinese pediatric HD cases has been examined to determine the age-specific prevalence of EBV., Methods: Paraffin sections from 104 pediatric and 52 adult Chinese HD cases were examined for EBV-RNA (EBERs) and EBV latent membrane protein-1., Results: Most pediatric cases arose in boys and showed an histology of mixed cellularity. Prominent interfollicular involvement was seen frequently in the childhood cases. EBV was identified in tumor cells in 113 of 156 (72%) HD cases but was more frequent in pediatric cases (93 of 104; 89%) compared with adult cases (20 of 52; 38%) (P < 0.01; chi-square test). EBV was found in 86 out of 91 (95%) cases in children aged 3-10 years and in 7 out of 13 (54%) cases in children aged 11-14 years (P < 0.01; chi-square test). The virus was less frequent in cases in young adults than in old adults, although this trend was not significant (P > 0.05; chi-square test). Pediatric HD was associated with EBV irrespective of histologic subtype. In adults, EBV was associated more frequently with mixed cellularity than with other subtypes., Conclusion: To the authors' knowledge, this is to date the largest series of pediatric HD cases studied for EBV. Study findings provided further evidence that HD is etiologically heterogeneous. The authors believe that pediatric HD now should be regarded as a distinctive EBV-related lymphoma., (Copyright 2001 American Cancer Society.)

Epstein--Barr virus (EBV) is associated with several malignancies. Specific EBV gene variants, e.g. the BamHI f configuration, a C-terminal region 30 bp deletion in the latent membrane protein-1 (LMP1) gene (del-LMP) and the loss of an XhoI site in LMP1 (XhoI-loss), are found in Chinese cases of nasopharyngeal carcinoma (NPC), suggesting that EBV sequence variation may be involved in oncogenesis. In order to understand better the epidemiology of these EBV variants, they were studied in virus isolates from EBV-positive Chinese cases of Hodgkin's disease (HD; n=71) and donor throat washings from healthy CHINESE: Sequencing was performed of 15 representative EBV isolates, including the first analysis of the LMP1 promoter in Asian wild-type EBV isolates. The following observations were made. (i) Three EBV LMP1 variants were identified, designated Chinese groups (CG) 1--3. In both EBV-associated HD and in healthy Chinese, CG1-like viruses showing del-LMP1 and XhoI-loss were predominant. (ii) CG1viruses were distinct from European and African variants, suggesting that this profile is useful for epidemiological studies. (iii) Specific patterns of mutations were present in the LMP1 promoter in both CG1 and CG2. (iv) The BamHI f variant was not found in Chinese HD, in contrast to Chinese NPC and European HD. This study confirms that EBV isolates in Chinese HD and other tumours differ from those reported in Western cases. However, this reflects the predominant virus strain present in the healthy Chinese population, suggesting that these are geographically restricted polymorphisms rather than tumour-specific strains.

Aims: To study the distribution of Epstein-Barr virus (EBV) variants containing mutations in the latent membrane protein 1 (LMP-1) oncogene and promoter in EBV associated Hodgkin's disease and infectious mononucleosis compared with previous findings in asymptomatic EBV carriers., Methods: Sequence analysis of the EBV LMP-1 promoter and gene in isolates from Danish patients with Hodgkin's disease (n = 61) and infectious mononucleosis (n = 10)., Results: Viruses (previously designated group D) that contain two mutations in the activating transcription factor/cAMP response element (ATF/CRE) in the LMP-1 promoter, which are known to decrease promoter activity greatly, were significantly less frequent in Hodgkin's disease than in both infectious mononucleosis (p = 0.0081) and asymptomatic EBV carriers (p = 0.0084). In some cases, the LMP-1 gene contained mutations in a recently identified cytotoxic T cell (CTL) epitope. Most viral isolates contained mutations shown to increase nuclear factor kappa B (NF-kappa B) activation and had one of two newly identified C-terminal activation regions 3 (CTAR-3) deleted. The exon 1 Xho-I restriction site in the LMP-1 gene could be lost through a range of different mutations., Conclusions: These findings indicate selection pressure against EBV strains with weak LMP-1 promoter activity in Hodgkin's disease and thus provide further strong circumstantial evidence for the pathogenic role of EBV (and LMP-1) in this disease. Mutation of the CTL epitope suggests immune selection of EBV strains. Many EBV isolates contain functionally important mutations in the LMP-1 gene. Loss of the Xho-I restriction site should not be used as a marker of specific LMP-1 variants.

Sequence variations in the Epstein-Barr virus (EBV) encoded latent membrane protein-1 (LMP-1) gene have been described in a Chinese nasopharyngeal carcinoma-derived isolate (CAO), and in viral isolates from various EBV-associated tumors. It has been suggested that these genetic changes, which include loss of a Xho I restriction site (position 169425) and a C-terminal 30-base pair (bp) deletion (position 168287-168256), define EBV genotypes associated with increased tumorigenicity or with disease among particular geographic populations. To determine the frequency of LMP-1 variations in European wild-type virus isolates, we sequenced the LMP-1 promoter and gene in EBV from lymphoblastoid cell lines from healthy carriers and patients without EBV-associated disease. Sequence changes were often present, and defined at least four main groups of viral isolates, which we designate Groups A through D. The widespread prevalence of LMP-1 sequence variations, particularly the Xho I polymorphism and the 30-bp deletion, indicate that they cannot be used as simple markers for oncogenic viruses related to particular forms of EBV-associated tumor. Several of the structural changes detected occur, however, at sites where they may affect transcription, translation, or function of LMP-1. Future in vitro studies should aim to establish the functional importance of variations at these sites.

Specimens from 82 children with Hodgkin's lymphoma were studied by immunohistochemical technique for Epstein-Barr virus encoded latent membrane protein (LMP). LMP was demonstrated in 67 cases 81.7%, the positive rate for the mixed cellular subtype was 90.9%. The positive rate for the 3-5 year old group of patients was 100%, 75% for the 6-10 year old group and only 62.5% for the 11-14 year old group. These findings suggest that Epstein-Barr virus is strongly associated with Hodgkin's lymphoma, the younger the age, the stronger the association. Mixed cellular subtype of Hodgkin's lymphoma had the strongest association with Epstein-Barr virus among all subtypes.

Forty-two cases of Chinese T-cell lymphoma were studied for expression of Epstein-Barr virus (EBV) encoded RNA (EBER-1) and EBV latent membrane protein-1 (LMP-1) using in situ hybridization and immunohistochemistry, respectively. EBV was detected in tumour cells in 24/39 peripheral T-cell lymphomas (62%), comprising 18/27 pleomorphic, medium and large cell lymphomas (67%), 4/6 angioimmunoblastic lymphadenopathy-like lymphomas (67%), 2/2 Lennert's lymphomas, 0/2 anaplastic large cell lymphomas, and 0/2 T-zone lymphomas. EBV was not found in three T-lymphoblastic lymphomas. EBV was associated with 12/24 nodal (50%) compared with 12/15 extranodal (80%) peripheral T-cell lymphomas. In EBV positive nodal lymphomas, 9/12 cases (75%) contained less than 10% EBER positive tumour cells. In EBV positive extranodal lymphomas, 9/11 cases (82%) showed EBV gene expression in more than 50% of the tumour cells, and in five of these almost all tumour cells were positive. Lymphomas of the nasopharynx (mainly midline granuloma-type) showed EBER-1 expression in nearly all tumour cells. LMP-1 was detected in 19/23 EBER positive peripheral T-cell lymphomas (83%). Our results show that EBV is strongly associated with peripheral T-cell lymphomas in Chinese. An important role for the virus is suggested in lymphomas of the nasopharynx. The significance of EBV in T-cell lymphomas that contain only a minor population of virally infected tumour cells is currently unclear.

Epstein-Barr virus (EBV) can be detected in Hodgkin and Reed-Sternberg (HRS) cells in about one-half of cases of Hodgkin's disease (HD) in Western countries. To determine whether EBV is also associated with HD in a developing country such as China, we studied paraffin sections from 28 Chinese cases of HD for expression of latent membrane protein-I (LMP-I) and EBV-encoded small RNA (EBER-I), using immuno-histology and RNA/RNA in situ hybridization respectively. The cases were selected from a large series of Chinese lymphomas following histological and immunophenotypical revision. EBV gene expression was found in HRS cells in 17/28 cases, and was related to histological sub-type, being present in 10/11 of mixed cellularity, 6/14 nodular sclerosis, 0/1 lymphocytic predominance, 0/1 lymphocytic depletion, and 1/1 unclassified HD. The 2 methods for detecting EBV gene expression gave similar results, except in one case of nodular sclerosis, in which HRS cells were negative for EBER-I, but weakly positive for LMP-I. In 5/12 cases with EBER-negative HRS cells, rare small or medium-sized lymphocytes expressed EBER-I but not LMP-I. These results suggest that (i) Chinese HD is frequently associated with EBV; (ii) the proportional frequency and sub-type distribution of EBV-positive HD are similar in China and in the West; (iii) both LMP-I immunohistology and EBER in situ hybridization reliably detect EBV in HRS cells in routine biopsies, but the former is simpler and less resource-consuming to perform.