Primary natural killer/T-cell lymphomas of the oral cavity are aggressive neoplasms

Thirty-four cases of primary non-Hodgkin’s lymphoma of the oral cavity were investigated for their clinical findings, histopathological features, immunophenotypes and association with Epstein-Barr virus (EBV). Four cases (12%) were natural killer/T-cell lymphomas, 3 (9%) were T-cell lymphomas and 27 (79%) were B-cell lymphomas. Compared with T- and B-cell lymphomas, NK/T-cell lymphomas had a male predominance (M:F 4:0), and most presented as ulceration of the palate and/or maxillary gingiva. Histologically, the lesions showed diffuse infiltration of medium-sized or large lymphoid tumour cells. Angiocentricity and/or angioinvasion were found in all 4 cases. The immunophenotypes of the NK/T-cell lymphomas were CD3+, CD43+, CD45RO+, CD56+ and TIA-1+. EBV was detected in 2 NK/T-cell lymphomas by in situ hybridization (ISH) and polymerase chain reaction (PCR) methods, and was not detected in T- and B-cell lymphomas. The survival rate of patients with NK/T-cell lymphoma was zero, but the survival rates for patients with T-cell and B-cell lymphomas were 67% and 38%, respectively. It appears that NK/T-cell lymphomas of the oral cavity have a predilection for originating in the palate and maxillary gingiva and are aggressive neoplasms. EBV positivity might be associated with more aggressive behaviour. Received: 21 January 1999 / Accepted: 14 April 1999     

A survey of Epstein-Barr virus gene expression in sporadic non-Hodgkin''s lymphomas. Detection of Epstein-Barr virus in a subset of peripheral T-cell lymphomas.

This study analyzes the association of Epstein-Barr virus (EBV) with non-Hodgkin's lymphoma (NHL) arising in patients without pre-existing overt immunodeficiency. The authors examined 201 lymphomas (105 high-grade B-cell, 82 peripheral T-cell, 7 high-grade non-B-cell, non-T-cell, and 7 hairy-cell leukemia) for EBV gene expression by immunohistologic procedures using monoclonal antibodies to EBV latent, immediate early, and replicative infection antigens. Transformation-associated EBV latent membrane protein 1 (LMP 1) was detected in 13 (6%) NHL, comprising 4 (4%) high-grade B-cell, 8 (10%) peripheral T-cell, and 1 non-B-cell, non-T-cell lymphomas. Anaplastic large-cell lymphoma of T-cell type was consistently LMP 1-negative. EBV nuclear antigen 2 was demonstrated in only three (1%) cases. Induction of replication as defined by expression of the immediate early BamHI Z leftward reading frame 1 (BZLF1) protein was detected in five cases, but early (EA) and late (VCA and MA) lytic cycle antigens were only found in two cases and in one case, respectively. The presence of EBV was confirmed by in situ DNA hybridization in 9 of 11 EBV antigen-positive lymphomas. This study shows the surprisingly frequent presence of EBV in peripheral T-cell NHL in European patients without pre-existing overt immunodeficiency. Interestingly, most sporadic B-cell NHL are not associated with the virus. Furthermore, the usefulness of selected monoclonal antibodies for the routine immunohistological diagnosis of EBV infection was confirmed.     

Malignant lymphomas of the nasal cavity and paranasal sinuses. A clinicopathologic and immunohistochemical study.

The clinicopathologic and immunohistological features of 20 Japanese patients with non-Hodgkin's lymphomas (NHLs) limited to the sinonasal area were studied using a broad panel of T- and B-cell markers on paraffin-embedded and fresh frozen tissue. All cases showed a diffuse growth pattern. Nine cases were B-cell lymphomas (immunoblastic n = 4, centroblastic n = 3, immunocytoma n = 1, centrocytic n = 1), and nine were T-cell lymphomas (pleomorphic medium and large cell n = 8, angioimmunoblastic n = 1). In two cases, the cell lineage could not be determined. No morphologic features of angiocentric/angiodestructive lymphoproliferative lesions or lymphoepithelial lesions in ductal or glandular epithelium were seen in our series. Eight (89%) of the nine T-cell tumors and four (44%) of the nine B-cell neoplasms involved both the nasal cavity and paranasal sinuses. Six of the nine T-cell neoplasms showed a clinical presentation of rhinitis, whereas all of the B-cell neoplasms showed tumor masses in the nasal cavity and/or paranasal sinuses. The two-year survival rate for T-cell lymphomas was poorer than that for B-cell lymphomas. The five-year survival of patients with NHLs involving both the nasal cavity and paranasal sinuses was also poorer than that of patients in whom NHLs were limited to the nasal cavity.     

Malignant lymphoma of the thyroid. A 30-year clinicopathologic experience and an evaluation of the presence of Epstein-Barr virus.

Lymphoma of thyroid is uncommon, and Epstein-Barr virus (EBV) is found in many lymphomas. We studied the clinicopathologic characteristics in Hong Kong Chinese and analyzed the presence of EBV in thyroid lymphomas by reviewing data collected during 3 decades. We studied EBV gene expression by in situ hybridization and immunohistochemistry. Primary thyroid lymphomas were found in 23 patients (diffuse large B-cell lymphoma, 18; marginal zone B-cell lymphoma, 4; plasmacytoma, 1), and secondary lymphomas were found in 9 patients (diffuse large B-cell lymphoma, 3; Burkitt lymphomas, 2; Burkitt-like lymphoma, 1; hairy cell leukemia, 1; nasal T-cell and natural killer cell lymphoma, 1; and intestinal T-cell lymphoma, 1). Primary thyroid lymphomas were large (mean, 7 cm), found commonly in older women, and often misdiagnosed as undifferentiated carcinomas. Fine-needle aspiration was not helpful for diagnosis. Fifteen patients had Hashimoto thyroiditis. A history of thyrotoxicosis was found in 3 patients, and coexistence of 3 diseases (papillary microcarcinomas, primary thyroid lymphoma, and Hashimoto thyroiditis) was found 4 patients. The 5-year survival rate for primary thyroid lymphoma was 53%. Combined surgery and radiotherapy seemed to be the best treatment. Secondary thyroid lymphomas often were asymptomatic. EBV messenger RNAs were detected in 1 primary and 1 secondary thyroid lymphoma. The EBV gene expression in primary thyroid lymphoma showed a type II latency pattern. Thyroid lymphomas in Chinese had important clinicopathologic features. EBV may have a role in a subset of cases.     

Enhanced Autophagy and Reduced Expression of Cathepsin D Are Related to Autophagic Cell Death in Epstein-Barr Virus-Associated Nasal Natural Killer/T-Cell Lymphomas: An Immunohistochemical Analysis of Beclin-1, LC3, Mitochondria (AE-1), and Cathepsin D in Nasopharyngeal Lymphomas

This study investigated autophagy in 37 cases of nasopharyngeal lymphomas including 23 nasal natural killer (NK)/T-cell lymphomas (NKTCL), 3 cytotoxic T-cell lymphomas (cytotoxic-TML) and 9 B-cell lymphomas (BML) by means of antigen-retrieval immunohistochemistry of beclin-1, LC3, mitochondria (AE-1) and cathepsin D. Peculiar necrosis was noted in EBV(+) lymphomas comprising 21 NKTCL, 2 cytotoxic-TML and 1 BML. Lymphomas without peculiar necrosis showed high expression of beclin-1, macrogranular cytoplasmal stain of LC3 with sporadic nuclear stain, a hallmark of autophagic cell death (ACD), some aggregated mitochondria and high expression of cathepsin D, suggesting a state of growth with enhanced autophagy with sporadic ACD. EBV(+) NKTCL with the peculiar necrosis, showed significantly low level of macrogranular staining of LC3, aggregated mitochondria and low expression of cathepsin D in the cellular areas when degenerative lymphoma cells showed decreased beclin-1, significantly advanced LC3-labeled autophagy, residual aggregated mitochondria and significantly reduced expression of cathepsin D, suggesting advanced autophagy with regional ACD. Consequently it was suggested that enhanced autophagy and reduced expression of lysosomal enzymes induced regional ACD under EBV infection in NKTCL.     

Prevalence of Epstein-Barr virus in non-Hodgkin's lymphomas in central region of Tunisia

The purpose of this study was to evaluate the prevalence of EBV in non-Hodgkin's lymphomas occuring in non-immunocopromised patients in Tunisia through a series of 126 cases. EBV was investigated by EBER oligonucleotide in situ hybridization (ISH) and LMP1-immunohistochemistry. Serological study of EBV has been performed before therapy in 28 patients. EBV was detected in tumor cells by ISH in 28/126 (22.2%) cases. Variable proportions of tumor cells were positive. LMP1 was identified in only 8 cases. EBV was more frequently observed in T-cell lymphomas (9/24 patients; 37.5%) than in B-cell lymphomas (19/102 patients; 18.6%) (p=0.04). There was a strong relationship between EBV and small intestine lymphomas (6/8 patients; 75%) and T/NK nasal type lymphomas (3/3 patients; 100%). EBV serological reactivation was noted in 7/13 patients in clinical stages III/IV and in only 1/10 patients in stages I/II (p=0.03). In conclusion, the prevalence of EBV in Tunisian non-Hodgkin's lymphomas is low but variable depending on the histological type and anatomical location with a predilection for small intestine and nasal lymphomas.     

Syndromes mononucléosiques et pathologies hématologiques liés au virus d'Epstein-Barr

The Epstein-Barr virus (EBV), which preferentially infects B cells, persists in the infected subject as a latent asymptomatic infection. In adolescents, infectious mononucleosis is the symptomatic manifestation of primary EBV infection. The viral latency in the memory B-cells, the reservoir cells in peripheral blood in individuals is controlled by CD4 and CD8 positive T-cells. Immunodeficient patients are at high risk of developing EBV driven B-cell lymphomas as the consequence of the expression of oncogenic latency proteins LMP1 and EBNA2. These proteins expressed in infected B cells identify latency III or proliferation program in virus transformed B-cell, leading to lymphoid proliferation. In addition to immunodeficiency-related lymphomas, the most frequent lymphoid malignancies associated with EBV are the endemic Burkitt lymphoma, Hodgkin lymphoma and nasal type T-cell lymphoma.     

EBV in situ hybridization study for non-Hodgkin's lymphomas.

Epstein-Barr virus(EBV) has been implicated in the pathogenesis of B-lymphoproliferative disorders, T-cell lymphomas and Hodgkin''s disease. In this report, we performed an in situ hybridization study on EBV genome in 10 cases of nasal non-Hodgkin''s lymphoma(NHL), 20 cases of Waldeyer''s ring(WR) NHL, and 20 cases of nodal NHLs to document EBV association with lymphomas in Koreans. For immunophenotyping, monoclonal antibodies for CD 20, MB 2, CD 45Ro & CD 43 were used. For in situ hybridization study, EBV DNA probe for Bam HI ''V'' fragment and EBV RNA probe for EBER and BHLF were used. Twenty two cases(44%) of malignant lymphomas were positive for EBV genome. Generally, T-cell lymphomas showed a higher positive rate(61%) than B-cell lymphomas(24%). Among T-cell lymphomas, nasal lymphomas showed a higher positive rate(80%) than WR(50%) or nodal lymphomas(50%). Of 22 EBV genome positive cases, 10 cases were positive for EBER, 10 cases for BHLF, and 2 cases for both EBER and BHLF. The histologic types by Working Formulation(WF) were not correlated with EBV genome positive rate, whereas lymphomas showing the histologic spectrum of polymorphic reticulosis(PR) showed a higher positive rate(65%) than lymphomas without PR-like features(40%). These results indicate that nasal T-cell lymphomas with the histologic spectrum of PR are strongly associated with EBV and that the anatomic site may be an important factor in this association.     

B细胞淋巴瘤与EB病毒关系的观察

为了了解我国非免疫缺陷相关B淋巴瘤是否与EBV有关，我们采用EBVencodedsmallRNA（EBER－1）原位杂交对127例非免疫缺陷相关B淋巴瘤进行了研究。结果显示，其中8例瘤细胞核内有EBER－1的表达（中心母细胞型4例；淋巴浆细胞样型、浆细胞型、免疫母细胞型和不能分型的高度恶性B细胞淋巴瘤各1例），检出率为6．3％。这一结果与欧美的情况一致（5％左右）．但明显低于我国何杰金病（82％）及T淋巴细胞（62％）的检出率，因此提示EBV在非免疫缺陷B淋巴瘤发病中的作用是有限的，主要致病因素还有待进一步研究。     

Epstein–Barr virus-associated primary gastrointestinal lymphoma in non-immunocompromised patients in Korea

We examined 81 cases of primary gastrointestinal lymphomas in Korea, including 64 gastric lymphomas and 17 intestinal lymphomas, for EBV expression by EBER-1 in situ hybridization (ISH) and EBNA-1 PCR. In EBER-1 positive cases, we performed immunohistochemistry for latent membrane protein-1 (LMP-1) and EBV diffuse early antigen (EA(D)) to compare EBV latent gene expression and lytic process.   EBER-1 was detected in 15 of 81 cases of lymphomas. EBER-1 expression showed three different patterns on tumour cells; diffuse 4/81 (5%), localized 4/81 (5%), and a few scattered pattern 7/81 (9%). We regarded diffuse pattern and localized pattern as EBER-1 positive group (8/81: 10%). Diffuse pattern of EBER-1 was shown in all three T-cell lymphomas and one B-cell lymphoma. A localized pattern was seen all in B-cell lymphomas. The EBER-1 expression was 11% in the stomach (7/64) and 6% in the intestine (1/17). Five of the eight EBER-1 positive gastric lymphomas were histologically diffuse large B-cell lymphomas, and the other three were peripheral T-cell lymphoma, unspecified, one angiocentric lymphoma, and one intestinal T-cell lymphoma by REAL classification. Eight MALT type gastric B-cell lymphomas showed no EBV association. EBV nuclear antigen (EBNA-1) was detected in 15 of 45 resected cases (33%) by PCR. EBER-1 positive cases were all EBNA-1 positive. Twelve EBNA-positive/EBER-negative cases consisted of seven cases showing a few scattered EBER-1 positive lymphocytes. LMP-1 and diffuse early antigen (EA(D)) was detected in five and three cases, respectively. Although follow-up information in our series was incomplete, it seemed that there was no significant difference in their staging or prognosis between EBER-positive cases and EBER-negative group. It is concluded that EBV is associated with some lymphomas among Koreans without overt pre-existing immunodeficiency, especially in T-cell lymphomas.     

Non-Hodgkin's lymphoma,coeliac disease,and Epstein–Barr virus: A study of 13 cases of enteropathy-associated T- and B-cell lymphoma

A group of 166 patients with coeliac disease was followed for a period of up to 25 years. During this time, 17 patients developed intestinal tumours that were diagnosed as lymphoma, of which 15 cases were available for review. Eleven of the lymphomas were of T-cell type (enteropathy-associated T-cell lymphoma, EATL) and two were of B-cell type. Two cases were reclassified as undifferentiated carcinoma. The interval between the diagnosis of enteropathy and the onset of lymphoma varied from less than 2 months in four patients to more than 5 years in seven. Seven of the T-cell and both B-cell lymphomas were investigated for the presence of Epstein–Barr virus (EBV) by in situ hybridization (ISH) using probes against Epstein–Barr virus-encoded RNAs (EBERs) and by immuno-histochemistry with EBV-specific monoclonal antibodies. All EATL cases were negative, suggesting that EBV is not an important factor in these cases. In one of the B-cell cases, EBV was detectable by ISH and immunohistochemistry in most tumour cells in the mesenteric lymph nodes, but not in any of the tumour cells in the primary ileal tumour, indicating that in this case EBV infection was a late event in the neoplastic process. These results show that lymphoma may develop any time after the onset of coeliac disease and that in our cases of EATL, EBV was not an important factor. In some cases of EBV-related neoplasia, virus infection may be a late event.     

Expression of natural killer cell markers in non-Hodgkin''s lymphomas

One hundred forty-nine cases of non-Hodgkin's lymphoma were studied with a panel of monoclonal antibodies, including antibodies to natural killer (NK) cells--anti-NKH1, anti-Leu 7, and anti-Leu 11b. There were 95 B-cell, 51 T-cell, and three null cell lymphomas. Seventeen T-cell lymphomas (33 per cent) expressed NKH1, Leu 7, and/or Leu 11b. None of the B- or null cell lymphomas expressed the NK markers. In comparison with the NK-negative T-cell lymphomas, the NK-positive cases showed a predilection for the nasal and paranasal region. There was a more significant loss of the T-cell markers T3 (peripheral T cell) and T4 (T-helper cell) in NK-positive lymphomas. The difference was due to a high proportion of nasal/paranasal lymphomas, which were associated with a frequent loss of T-cell markers, among the NK-positive cases. However, a similar degree of loss of T-cell markers was observed among NK-positive and NK-negative nasal/paranasal lymphomas. We conclude that expression of NK markers occurs exclusively in a proportion of T-cell lymphomas, but not B-cell or null cell lymphomas. The reason this occurs predominantly in nasal and paranasal lymphomas is unknown.     

Malignant lymphomas of the nasal cavity and paranasal sinuses

Summary The incidence of malignant lymphomas in the nasal cavity and paranasal sinuses was found tobe 0.17% of all malignant lymphomas and 0.44% of all extranodal malignant lymphomas registered in the Kiel Lymph Node Registry from 1972 to 1987. Fifty-nine cases of malignant lymphoma presenting in the nasal cavity and paranasal sinuses were investigated with morphological and immunological methods. The median age of the patients was 64.5 years, with a female predominance (m:f=0.87:1). In the 59 cases a marked preponderance of B-cell lymphomas was found (centroblasticn=15, immunoblasticn=8, Burkitt's lymphoman=6, Immunocytoman=3, centrocyticn=1, centroblastic/centrocyticn=1, plasmacyticn=11); only a small number (n=5) was of T-cell lineage (pleomorphic types). Nine further cases could not be assigned with certainty to either the T or B cell system. Angiocentricity with infiltration and destruction of vessel walls by tumour cells was demonstrated only in the T-cell lymphomas; the B-cell lymphomas, in contrast, of ten surrounded and compressed blood vessels with intact endothelium. No similarity to malignant lymphomas of mucosa associated lymphoid tissue, such as those in the gastrointestinal tract, was detected.     

High frequency of EBV association and 30-bp deletion in the LMP-1 gene in CD56 lymphomas of the upper aerodigestive tract

Natural killer (NK)/T-cell lymphomas are frequently associated with Epstein-Barr virus (EBV), and usually lack TCR gene rearrangement. Studies from Asia have reported frequent deletion in the LMP-1 gene in EBV-associated nasopharyngeal carcinoma (NPC). The present study aims to investigate LMP-1 and TCRgamma gene status in upper aerodigestive tract lymphomas. A total of 43 cases were classified into T-, B-, and NK/T-cell tumors based on the phenotype expressions of CD3(+)/CD20(-)/CD56(-), CD3(-)/CD20(+)/CD56(-), and CD3(+)/CD20(-)/CD56(+), respectively. The presence of EBV in the tumor was confirmed by EBV early RNA-in situ hybridization. LMP-1 gene deletion and TCR gamma gene rearrangement were analyzed by polymerase chain reaction on paraffin-embedded tissues. There were 20 NK/T-, eight T-, and 15 B-cell phenotype lymphomas in the present series, and EBV was detected in 19 (95%), two (25%), and three (20%) cases in the respective groups. All EBV+ cases carried 30-bp deletion in the LMP-1 gene, and two of the NK/T-cell cases were infected by both the wild type and deleted strains. Five (25%) of the NK/T-cell phenotype lymphomas showed rearranged TCR gamma gene. The present study revealed a high frequency of EBV association, and a high frequency of 30-bp deletion in the LMP-1 gene in the virus in the present series of lymphoma. The NK/T-phenotype lymphomas are comprised of both NK-cell and cytotoxic T-lymphocyte-derived tumors.     

Epstein-Barr virus-associated B-cell lymphoproliferative disorders in angloimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified

Various patterns of Epstein-Barr virus (EBV)-associated B-cell lymphoproliferation occur in patients with immunodeficiency. We studied 17 cases of T-cell lymphoma displaying extensive EBV-driven B-cell lymphoproliferation or simultaneous/subsequent EBV-associated B-cell lymphoma. In 10 cases of angioimmunoblastic T-cell lymphoma, an uncommonly prominent population of EBV+ atypical, activated, focally confluent large transformed B cells was found in the background of T-cell lymphoma. In 4 cases, an EBV-associated B-cell neoplasm (3 diffuse large B-cell lymphomas, 1 plasmacytoma) occurred in patients with T-cell lymphoma. Three cases were composite lymphomas of a peripheral T-cell lymphoma, unspecified, combined with EBV-associated diffuse large B-cell lymphoma. The transformed B-cell population displayed EBV latency types 2 and 3. Monoclonal and oligoclonal B-cell populations were detected in 5 and 6 cases, respectively. Similar to other states of immunodeficiency, disease-related and therapy-induced immunosuppression in T-cell lymphoma may lead to a prominent EBV-associated B-cell lymphoproliferation and to EBV+ B-cell neoplasms.     

上呼吸道淋巴瘤的病理,免疫表型及其与EB病毒相关性的研究

目的研究中国北方人上呼吸道淋巴瘤的临床病理学、免疫表型及与ＥＢ病毒的关系。方法应用单克隆抗体ＵＣＨＬ１、Ｌ２６、４ＫＢ５及ＣＳ１４进行免疫组化染色,ＥＢ病毒寡核苷酸探针（ＥＢＥＲ１／２）原位杂交,观察１１２例上呼吸道淋巴瘤的免疫表型及ＥＢ病毒感染情况。结果１１２例上呼吸道淋巴瘤病例中７７例为Ｔ细胞淋巴瘤（６８８％）。３５例为Ｂ细胞淋巴瘤（３１．３％）。ＥＢＶＥＢＥＲ１／２原位杂交１０１例中５４例阳性,各例中阳性细胞占肿瘤细胞的１５０％～８５０％,阳性病例中Ｔ细胞淋巴瘤４８例（８８９％）,Ｂ细胞淋巴瘤６例（１１１％）。结论中国北方人上呼吸道淋巴瘤以Ｔ细胞淋巴瘤为多见,且与ＥＢ病毒有较高的相关性。     

NK-cell lymphoma with nodal presentation and expression of cutaneous lymphocyte-associated antigen

Nasal and nasal-type NK/T-cell lymphomas are predominantly extranodal tumors with a specific immunophenotype and a strong association with EBV. The cutaneous lymphocyte-associated antigen (CLA) is the homing receptor for skin-homing T cells and NK cells. In the literature, the prognostic impact of CLA expression in primary cutaneous T-cell lymphomas and nasal NK-cell lymphomas is contradictory. We present 2 non-nasal NK-cell lymphomas with nodal presentation. Both tumors showed the phenotype of CD3+ (cytoplasmic), CD5−, CD7−, CD16+, CD56+, cytotoxic molecules+, EBV+ (by in situ hybridization), and CLA+. They were polyclonal for T-cell receptor γ chain gene rearrangement, indicating an NK cell lineage. The aggressive course in these two patients suggested that in nasal and nasal-type NK-cell lymphomas, CLA expression might be an indicator of poor prognosis. More studies are needed to elucidate the prognostic impact of CLA expression in T cell and NK-cell lymphomas.