Improved prognosis of Epstein-Barr virus associated childhood Hodgkin's lymphoma: study of 47 South African cases

AIM: To study the distribution of Hodgkin's lymphoma in South African children and report the incidence of Epstein-Barr virus (EBV) as regards age, race, sex, and histological subtype; to investigate whether EBV is relevant to survival. METHODS: Immunohistochemistry (IHC) and in situ hybridisation (ISH) to detect EBV were performed on 47 South African children with classical Hodgkin's lymphoma, ranging in age from 3 to 14 years and coming from different ethnic backgrounds. The correlation between the presence of the virus and clinical outcome was assessed. RESULTS: The nodular sclerosing subtype predominated, comprising 89% of cases; the remaining 11% were of the mixed cellularity subtype. EBV was present in 68%. Full clinical data were available for 36 cases; EBV positive patients presented with less aggressive symptoms at diagnosis and had a significantly longer median survival than EBV negative patients. CONCLUSIONS: The distribution of EBV in South African childhood Hodgkin's lymphoma follows a pattern intermediate to that of industrialised and non-industrialized countries. Furthermore, our data suggest that there is an association between poor prognosis and the non-detection of EBV products in South African childhood Hodgkin's lymphoma.     

Primary cerebral lymphoma. A histologic and immunohistochemical study of six cases

Between 1981 and 1985, three male and three female patients (age range, 26 to 65 years) with primary central nervous system lymphoma underwent biopsy procedures and were treated in the Wessex Neurological Centre, Southampton, United Kingdom. The primary nature of the disease was confirmed by extensive clinical and radiologic investigation, and a combined approach of cytologic, histologic, and immunohistochemical studies contributed to the diagnosis and characterization of these tumors. By the Kiel classification, the lesions included five diffuse follicle center cell lymphomas and one T-cell lymphoma. Five of the lesions were present in the cerebral hemispheres, and three of these were multifocal. Only one patient presented with a lesion in the posterior fossa. Despite combinations of surgery, radiotherapy, and chemotherapy, all patients died, the longest postoperative survival being two years.     

原发性硬膜淋巴瘤2例临床病理分析

目的探讨原发性硬膜淋巴瘤的临床病理特点。方法对2例原发性硬膜淋巴瘤大体与镜下形态进行分析并复习文献。结果1例为原发性硬脊膜外中心/中心母细胞淋巴瘤(CD20 ),瘤细胞体积相当于1~3个小淋巴细胞,核卵圆或成角或核膜呈锯齿状,染色质粗密,核较大者可见核仁。1例为原发性硬脊膜下腔大B细胞淋巴瘤,瘤细胞体积大,胞质中等,核圆形,可见核仁。结论现有资料提示硬脊膜外淋巴瘤以高中度恶性居多,硬脑膜外淋巴瘤以低度恶性居多。硬膜淋巴瘤可能源于颅及椎管外淋巴组织迁入硬膜外甚至硬膜下腔隙的淋巴细胞。     

Primary small intestinal lymphoma: a study of 39 cases

Thirty-nine cases of primary small intestinal lymphoma were studied by morphological and immunohistochemical methods. The adjacent uninvolved mucosa was also examined for features suggestive of coeliac disease. Employing the immunogold silver staining (IGSS) technique and polyclonal primary antisera against alpha-l-antitrypsin, lysozyme and kappa and lambda light chains, 29 cases (74.5 per cent) were found to be B-cell lymphomas, seven (18 per cent) histiocytic tumours, one (2.5 per cent) Hodgkin's disease and two (5 per cent) remained unclassified. No specific lymphoma subtype was found to be associated with cases having the histological features of coeliac disease in the uninvolved adjacent mucosa. In 35 cases sufficient clinical information was available to assess the significance of histological type and stage in relation to survival. Although the histological type did not correlate with survival, stage did and tumours extending beyond the local lymph nodes were associated with a significantly worse prognosis.     

Primary brain lymphoma in the immunocompetent host: relation to Epstein-Barr virus

Epstein-Barr virus has been implicated in the pathogenesis of primary brain lymphoma in patients with congenital or acquired immunodeficiency states. To examine its role in central nervous system (CNS) lymphoma in the immunocompetent host, Epstein-Barr virologic studies were performed in six consecutive cases seen at our institutions. Virus DNA sequences were detected in only one of three tumor specimens studied by Southern blot hybridization. Serologic studies from the entire cohort disclosed past virus infection; however, antibody reactivity to virus-specific antigens in cerebrospinal fluid was limited to the patient harboring genome-positive tumor. Immunologic studies revealed hyperimmunoglobulin-E (range, 720 to 1040 micrograms/ml) in each of four patients tested. Our findings suggest that Epstein-Barr virus is an infrequent pathogen in nonimmunosuppressed patients with primary CNS lymphoma. Abnormalities in isotype-specific regulation of IgE production are common in such patients and may have pathogenetic implications.     

Hodgkin lymphoma in a renal transplant recipient associated with low peripheral blood Epstein-Barr virus genome copies.

Posttransplant lymphoproliferative disorders are often accompanied by >500 Epstein-Barr virus (EBV) genome copies/10(5) lymphocytes, and they occur shortly after transplantation. Hodgkin lymphoma occurs rarely after transplantation, appearing a mean of 4.2 years posttransplant, and although Hodgkin lymphoma has strong associations with EBV, no quantitative analysis of peripheral blood EBV genome copies has been reported. A mixed cellularity Hodgkin lymphoma developed in a 17-year-old boy 4 years after a renal transplant. Serial EBV genome copy numbers from blood by competitive polymerase chain reaction had been obtained to assess for lymphoproliferative disease. Epstein-Barr virus genome copy numbers peaked at 500 copies/10(5) lymphocytes 8 months prior to Hodgkin lymphoma diagnosis but fell to 8 copies/10(5) lymphocytes at diagnosis. Reliance on EBV levels greater than 500 copies may result in delay of biopsy and diagnosis of Hodgkin disease in the posttransplant setting.     

Mode of integration of Epstein-Barr virus genome into host DNA in Burkitt lymphoma cells.

The ebv dna integrated into the host genome from cell of an African Burkitt lymphoma biopsy has been compared to the corresponding fraction of EBV DNA from the cell line SU-AmB-2 which is of American Burkitt lymphoma origin. It is shown that while, in the case of the African biopsy, large pieces of EBV DNA sequences are integrated into the host DNA, much smaller pieces of virus DNA are integrated into the DNA of the SU-AmB-2 cells. The possibility that this difference might be related to the fact that EBV is rarely associated with Burkitt lymphomas outside East Africa is discussed.     

原发性中枢神经系统弥漫性大B细胞淋巴瘤主要为活化B细胞亚型

目的 对原发性中枢神经系统弥漫性大B细胞淋巴瘤分型,并探讨其组织起源和预后相关意义.方法 应用免疫组织化学EnVision二步法,检测CD10、bcl-6、MUM-1、CD138和FOXP1在47例原发性中枢神经系统弥漫性大B细胞淋巴瘤中的表达情况.结果 CD10、bcl-6、MUM-1、CD138和FOXPI表达率分别为6.4%、53.2%、91.5%、0和93.6%.47例中有43例(91.5%)为活化B细胞表型:21例(44.7%)为活化的生发中心亚型,22例(46.8%)为活化的非生发中心亚型.该分型及FOXP1的表达与预后无明显相关性(P=0.279和P=0.154).结论 原发性中枢神经系统弥漫性大B细胞淋巴瘤绝大多数为活化B细胞亚型,是系统性弥漫性大B细胞淋巴瘤中一种相对同质性的亚型,推测其组织起源是生发中心末期至后生发中心早期的B细胞.     

Primary angiocentric T-cell intestinal lymphoma with Epstein-Barr virus in a 5-year-old boy

A case of peripheral T-cell lymphoma affecting the small bowel of a 5-year-old boy is reported. The cells did not form a tumoral mass but infiltrated diffusely, arranged in an angiocentric pattern and associated with numerous ulcers, one of which perforated. Immunohistochemistry proved them to be CD45RO-, CD3-, and CD8-positive. CD20, CD4, and CD56 markers were negative. The presence of EBV in the lymphomatous cells was demonstrated by in-situ hybridization. Polymerase chain reaction study revealed T-cell receptor (TCR) gene rearrangement. Notably the hemophagocytic syndrome present on admission reverted after surgery. The authors are not aware of a previous report of intestinal T-cell lymphoma in a child.     

Epstein-Barr virus in pyothorax-associated pleural lymphoma.

Pleural B-cell lymphoma was found in five patients with a history of pyothorax that was the sequelae of tuberculosis 35 to 47 years previously. Epstein-Barr virus (EBV) DNA was detected in all five pleural tumors by polymerase chain reaction and Southern blot hybridization. The lymphoma cells were shown to express the latent membrane protein-1 and the EBV-encoded nuclear antigen-2 by immunocytochemistry and EBV-encoded small RNA by in situ hybridization. Three cases were shown to be EBV subtype A, whereas the remaining two were subtype B, as determined by differences in the EBV-encoded nuclear antigen-2 nucleotide sequence. The patients also had high titers of antibodies against EBV. These findings suggest that EBV is causally associated with the pleural lymphomas that originate at the site of chronic inflammation and fibrosis with a latent period of more than 40 years.     

Epstein-Barr virus in a CD8-positive T-cell lymphoma.

In contrast to its role in B-lymphomagenesis, Epstein-Barr Virus (EBV) only incidentally has been associated with T-cell lymphomas. In the present report we describe a fourth patient with EBV-related T-cell lymphoma. The patient presented with an angio-immunoblastic lymphadenopathy (AILD)-like T-cell lymphoma. Serology was compatible with chronic Epstein-Barr (EBV) infection. After a 1-year period of waxing and waning lymphadenopathy, this lymphoma evolved to an aggressive CD8+ Immunoblastic T-cell lymphoma. A relationship with the chronic EBV infection was indicated by the finding of EBV genome in the tumor tissue by Southern blot analysis. Moreover, EBV nuclear antigen (EBNA) was detected in situ within individually defined CD8+ tumor cells by two-color immunofluorescence. Two alternative possibilities, namely that EBV primarily played a role in lymphomagenesis of the AILD-like T-cell lymphoma or that the virus was an additional oncogenic event in the final process of tumor progression to the immunoblastic lymphoma, are discussed.     

眼部原发性黏膜相关淋巴组织结外边缘区B细胞淋巴瘤的临床病理分析

近年来眼部淋巴瘤日益多见,其中眼附属器淋巴瘤占老年人眼眶原发性恶性肿瘤的首位。根据2001年WHO恶性淋巴瘤分类诊断标准,眼附属器淋巴瘤大多属于黏膜相关淋巴组织结外边缘区B细胞淋巴瘤（MALT淋巴瘤）,其临床和组织病明学表现、治疗及预后均有其特殊性。我们对眼部MALT淋巴瘤的临床和病理资料进行了回顾性分析。     

Different localization of Epstein-Barr virus genome in two subclones of the Burkitt lymphoma cell line Namalwa.

The Epstein-Barr virus genome contained in the Burkitt lymphoma line Namalwa was previously localized to the short arm of chromosome 1. Analysis of a different subline of the same Namalwa line by means of Southern analysis carried out on genomic DNA, as well as in situ hybridization, showed a localization on the X chromosome.     

Two deletions in the Epstein-Barr virus genome of the Burkitt lymphoma nonproducer line Raji

The Epstein-Barr virus genome carried in the Burkitt lymphoma nonproducer cell line Raji was characterized by partial denaturation mapping and by hybridization of cloned viral fragments to filters containing separated Raji DNA fragments. Partial denaturation mapping revealed that the EBV DNA population of Raji cells is homogeneous and that two deletions are observed in distant parts of the genome compared to linear DNA isolated from virus particles of different strains. These deletions were characterized by blot analysis. One deletion of 3.15 kb lies within HindIII-E; the second is 2.4 kb and is located close to the right terminus of linear viral DNA. The two deletions were observed in several cell lines derived from the Raji line. These deletions might contribute to the inability of Raji cells to produce EBV either spontaneously or upon induction.     

Absence of Epstein-Barr virus in anaplastic large cell lymphoma: a study of 64 cases classified according to World Health Organization criteria

The frequency of Epstein-Barr virus (EBV) in anaplastic large cell lymphoma (ALCL) has been controversial. The interpretation of previous studies is complicated by the use of nonuniform EBV detection methods and the inclusion of cases of CD30-positive diffuse large B-cell lymphoma and so-called "ALCL, Hodgkin-like," as defined in the Revised European-American Lymphoma classification scheme. In the current World Health Organization (WHO) classification system, both of these tumors are excluded from the ALCL category. Also, recently developed antibodies (eg, the antibody specific for PAX-5/B-cell-specific activator protein [BSAP]) provide new, sensitive tools for identifying neoplasms of B-cell lineage that can morphologically resemble ALCL. In this study we evaluated 64 cases of ALCL of T- or null-cell lineage, defined according to the WHO classification system, for the presence of EBV. All tumors were negative for B-cell antigens, including PAX-5/BSAP and CD20 or CD79a. The study group included 27 (42%) anaplastic lymphoma kinase (ALK)-positive (18 T-cell and 9 null-cell) and 37 (58%) ALK-negative (30 T-cell and 7 null-cell) tumors analyzed by in situ hybridization for EBV-encoded RNA (EBER) or immunohistochemistry for EBV-latent membrane protein type 1. All 64 cases were negative for EBV. We conclude, based on the current definition of ALCL in the WHO classification, there is no role for EBV in ALCL arising in Western patients. We suggest that published reports of EBV in a small proportion of ALCL cases in Western patients can be explained by the inclusion of tumors no longer considered to be in the current classification of ALCL, such as CD30-positive anaplastic tumors of B-cell origin.     

原发乳腺淋巴瘤的临床病理学特征与预后关系的分析

目的 探讨原发乳腺淋巴瘤(PBL)的临床病理、免疫组织化学特征及其与预后的关系.方法 按Ann Arbor临床分期标准及Wiseman和Liao的诊断标准对40例PBL患者进行分期,按照WHO(2008年)造血和淋巴瘤系统肿瘤分类分型,并进行了随访.采用SP法行免疫组织化学染色.结果 (1)40例患者均为女性,中位年龄47岁,右侧20例,左侧16例,双侧4例.临床症状大部分表现为逐渐增大的乳腺无痛性包块,肿块数量＜3个31例(77.5%,31/40),≥3个9例(22.5%,9/40);Ann Arbor分期:33例(82.5%)为Ⅰ～Ⅱ期,7例(17.5%)为Ⅲ～Ⅳ期.9例(24.3%,9/37)血清乳酸脱氢酶(LDH)水平升高;体力状况美国东部肿瘤协作组(ECOG)评分:0～1分34例(85.0%),2分以上6例(15.0%);国际预后指数(IPI)评分:29例0～1分(7 8.4%,29/37),2例2分(5.4%,2/37),3例3分(8.1%,3/37),3例4分(8.1%,3/37).21例(53.8%,21/39)累及腋窝淋巴结.(2)40例中27例(67.5%)为弥漫性大B细胞淋巴瘤(DLBCL),8例(20.0%)为黏膜相关淋巴组织结外边缘区B细胞淋巴瘤(MALT淋巴瘤,1例伴大细胞转化),2例为滤泡性淋巴瘤(FL,Ⅰ级),1例为淋巴性浆细胞淋巴瘤,1例为淋巴母细胞性淋巴瘤,1例为外周T细胞淋巴瘤.40例细胞角蛋白均呈阴性,95.0%(38/40)的肿瘤细胞表达CD20和(或)CD79a;MUM1(57.6%,19/33)、bcl-6(30.3%,10/33)、bcl-2(72.7%,24/33)呈阳性表达.3例为生发中心B细胞(GCB)亚型,21例为非GCB亚型.(3)37例(92.5%,37/40)获得随访资料,其中23例(62.2%,23/37)存活,14例(37.8%,14/37)死亡.27例DLBCL的5年总生存率为48.0%,5年无病生存率为36.0%.结论 PBL少见,大多为DLBCL,其中又以非GCB亚型为主.LDH水平、肿块数目、IPI指数为影响预后的独立因素.

Abstract：

Objective To study the clinicopathologic features and prognosis of primary lymphoma of breast. Methods Forty cases of primary breast lymphoma, diagnosed according to the 2008 World Health Organization classification of hematopoietic and lymphoid tumors, were retrospectively studied.Immunohistochemistry was performed by SP method. The follow-up data were analyzed. Results ( 1 ) All the patients were females and the median age was 47 years. Unilateral and bilateral breast involvement were noted in 36 and 4 patients, respectively. The number of tumor were 31 cases(77. 5% ,31/40) less than 3 ,and 9 cases (22.5% ,9/40) were 3 and more than 3. According to Ann Arbor staging system, 33 cases (82. 5% ) were in stage Ⅰ to Ⅱ and 7 cases ( 17. 5% ) in stage Ⅲ to Ⅳ. The level of LDH in 9 cases (24. 3% ,9/37) went up. For ECOG scores, 34 cases(85.0% ) were 0 to 1 score and 6 cases ( 15.0%)were more than 2 scores. With respect to international prognostic index, 83. 8% (31/37) were of score 0 to 2 and 16. 2% (6/37) were of score 3 and more than 3. The axillary lymph nodes of 21 patients (53. 8%,21/39) were involved by the malignancy. (2) Histologically, 38 cases (95.0% ,38/40) were classified as B-cell lymphoma [including 27 cases ( 67. 5% ) of diffuse large B-cell lymphoma, 8 cases ( 20. 0% ) of mucosa-associated lymphoid tissue lymphoma, 2 eases of follicular lymphoma and 1 case of lymphoplasmacytic lymphoma]. The remaining cases included one case of peripheral T-cell lymphoma and one case of lymphoblastic lymphoma. Immunohistochemically, expression of CD20 +/- CD79a were demonstrated in the 38 cases ( 95.0% ) of B-cell lymphoma. The staining for CK was negative in all cases.In 33 cases, the positive rates of MUM-1, bcl-6 and bcl-2 were 57. 6% ( 19/33), 30.3% ( 10/33 ) and 72. 7% (24/33), respectively. Three cases were germinal center B cell phenotype and 21 cases were nongerminal center B cell phenotype. (3) Follow-up information was available in 37 patients(92. 5% ,37/40).Twenty-three patients(62. 2% ,23/37) were still alive and fourteen ones (37.8%, 14/37 ) died. For the 27cases with diffuse large B-cell lymphoma, the five-year and disease-free survival rates were 48.0% and 36. 0%, respectively. Conclusions Primary breast lymphoma is a rare disease entity. Diffuse large B-cell lymphoma is the commonest histologic type and the majority show a non-germinal center B cell phenotype.The level of LDH, number of tumor and international prognostic index are of prognostic significance.     

原发性皮肤恶性淋巴瘤的临床病理和免疫组化研究

研究原发性皮肤恶性淋巴瘤的类型及临床病理特点,方法对４２例ＰＣＭＬ作了形态学观察,免疫表型标记和组织学分型。结果原发性皮肤Ｔ细胞性淋巴瘤（ＰＣＴＣＬ）占６９．０％,其中蕈样霉菌病占７．２％（ＭＦ）、血管中心性淋巴瘤占９．５％皮下指明脂膜炎样Ｔ细胞巴瘤占１９．０％,原发性皮肤Ｂ细胞性淋巴瘤（ＰＣＢＣＬ）占３１．０％;ＰＣＭＬ男女之比为２：１,中位年龄３７岁,ＰＣＴＣＬ的发病年龄小于ＰＣＢＣＬ（     

Primary cutaneous diffuse large B-cell lymphoma: a clinicopathologic study of 15 cases

Primary cutaneous diffuse large B-cell lymphoma (DLBCL) is an uncommon lymphoma. Some authors have suggested that large B-cell lymphoma can be segregated based on anatomic site, with tumors of the lower extremity being unique. We report 15 cases of primary cutaneous DLBCL. Each case was analyzed immunohistochemically using antibodies specific for CD3, CD5, CD10, CD20, bcl-2, bcl-6, and p53. Polymerase chain reaction analysis for t(14;18)(q32;q21) also was performed. There were 13 men and 2 women (median age, 64 years). Thirteen tumors were composed predominantly of centroblasts, and 2 were immunoblastic. There was a median follow-up of 72 months. Of the 4 patients with primary cutaneous DLBCL of the lower extremity (thigh, knee, leg), 2 (50%) experienced a recurrence and 1 patient died of disease. In the non-lower extremity cases, 18% (2/11) recurred and no patients died of disease. We conclude that primary cutaneous DLBCL usually occurs in elderly patients with a male predominance. Recurrences are common, but death of disease is rare.