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.     

Nodal T/NK-cell lymphoma of nasal type: a clinicopathological study of six cases

Aims:  To investigate the clinicopathological features of six unusual cases of nodal CD56+ and Epstein–Barr virus (EBV)+ T/natural killer (NK)-cell lymphoma, a putative nodal counterpart of nasal NK/T-cell lymphoma (nodal T/NK-cell lymphoma of nasal type) in comparison with nasal NK/T-cell lymphoma with secondary lymph node involvement ( n  = 24) and peripheral T-cell lymphoma (PTCL) of cytotoxic molecule (CTM)+ and EBV+ type ( n  = 21).
Methods and results:  All cases of nodal T/NK-cell lymphoma of nasal type exhibited diffuse infiltration of pleomorphic medium-sized to large tumour cells, reminiscent of those in CTM+ EBV+ PTCL. The tumour cells had a typical phenotype of nasal NK/T-cell lymphoma: CD2+, CD3ε+, CD4−, CD5−, CD56+, T-cell intracellular antigen-1+, granzyme B+, perforin+ and EBV+. However, four of six cases demonstrated clonal T-cell receptor γ-gene rearrangement on polymerase chain reaction analysis, unlike nasal NK/T-cell lymphoma. Comparison of clinical parameters and overall survival among the three groups demonstrated only minor differences.
Conclusions:  Nodal T/NK-cell lymphoma may occupy the grey zone between extranodal nasal-type NK/T-cell lymphoma and nodal CTM+ PTCL in a spectrum of NK to T-cell lymphomas that are EBV+. The close relationship between NK/T-cell lymphomas and cytotoxic T-cell lymphomas was also substantiated.     

Intestinal T-cell and natural killer-cell lymphomas in Taiwan with special emphasis on 2 distinct cellular types: natural killer-like cytotoxic T cell and true natural killer cell

Primary intestinal lymphomas are rare, especially the T-cell and natural killer (NK)-cell types. Enteropathy-type T-cell lymphoma (ETL) is the most characteristic of the intestinal T-cell and NK-cell lymphomas (ITNKLs) defined in the World Health Organization classification. However, typical ETL is rare in nonendemic areas for celiac disease, which include Taiwan. With the exception of ETLs, ITNKLs comprise heterogeneous subtypes such as anaplastic large cell lymphoma, nasal-type NK/T-cell lymphoma and peripheral T-cell lymphoma, unspecified. Furthermore, the literature results with respect to the association between Epstein-Barr virus (EBV) and ITNKL are contradictory. To define the clinicopathological features of primary ITNKLs and develop a better understanding of their relationship with EBV in Taiwan, therefore, we investigated a sample of 11 patients based on the new World Health Organization classification using immunostaining, in situ hybridization for EBV detection, and polymerase chain reaction (PCR) for evaluation of T-cell receptor clonality. In conclusion, 2 distinct groups of primary ITNKLs were identified in our Taiwanese sample. The 6 group A cases were non-EBV-associated ETLs, prevalent in the jejunum and/or ileum. They were composed of monotonous round-ovoid medium-sized nuclei and had little pale cytoplasm. The immunophenotypes of these tumors were consistently CD3+, CD4-, CD8+, CD56+, T-cell intracellular antigen 1+, and Epstein-Barr early region- and monoclonal for T-cell receptor PCR, which indicated NK-like cytotoxic T-cell origin. The 5 group B cases were EBV-associated nasal-type NK/T-cell lymphomas prevalent in the ileum or cecum of younger patients. The neoplastic cells had polymorphous medium to large angulated nuclei and moderate cytoplasm, with immunologic phenotypes of CD4-, CD8-, variable cytoplasmic CD3varepsilon+, CD56+, T-cell intracellular antigen 1+, and Epstein-Barr early region 1+, and germ line PCR result for T-cell receptor, which indicated true NK-cell origin. The grave prognoses for the 2 groups did not differ significantly.     

Pediatric oral Epstein-Barr virus associated self-remitting CD30+ lymphoproliferative disorder: A distinct entity

Epstein-Barr virus (EBV) has a well-known association with lymphoproliferative disorders of B and T cell origin. EBV-related B cell lymphoproliferative disorders include Hodgkin and Burkitt lymphomas, lymphomatoid granulomatosis, EBV positive diffuse large cell B cell lymphoma of the elderly, as well as B cell lymphomas associated with solid organ transplantation and methotrexate use. EBV-related T cell disorders are primarily represented by NK/T- cell lymphoma. In a subset of patients, EBV has been implicated in CD30 positive B cell lymphoproliferative disorders of the oral mucosa falling under the rubric of the mucocutaneous ulcer of the oral cavity. We previously reported on an index series of endogenous CD30 positive T cell lymphoproliferative disorder of the oral cavity resembling borderline type C lymphomatoid papulosis. The clinical manifestation of type C oral lymphomatoid papulosis is that of a recurrent self-remitting ulcer of the oral mucosa, which histologically resembles anaplastic large cell lymphoma. Such cases can be misdiagnosed as aggressive lymphoma leading to unnecessary treatment with aggressive chemotherapeutic regimens. Whereas none of the patients in our index series exhibited EBV positivity, here we discuss a very unique example of a 14-year-old girl diagnosed with EBV positive CD30 positive lymphoproliferative disorder strongly resembling the cases of intra-oral type C lymphomatoid papulosis. The patient was initially diagnosed by a senior hematopathology consultant as having EBV positive aggressive NK/T-cell lymphoma. The significance of raising physician awareness regarding pediatric oral EBV associated CD30 positive lymphoproliferative disease of the oral cavity lies in preventing inadvertent exposure to toxic chemotherapeutic agents intended for treatment of aggressive look-alikes, namely anaplastic large cell lymphoma. Additionally, we include a literature review of similar reports of pediatric intra-oral EBV positive CD30 positive T cell lymphoproliferative disease.     

Characteristics of Epstein-Barr virus associated childhood non-Hodgkin’s lymphoma in the Republic of Korea

To analyze the clinicopathologic characteristics of childhood non-Hodgkins lymphoma (NHL) associated with Epstein-Barr virus (EBV), EBER in situ hybridization was performed in 80 cases of NHLs. EBER-positive lymphomas account for 25% (20/80) and include NK/T-cell lymphoma (6/6), aggressive NK-cell leukemia (1/1), peripheral T cell lymphoma (5/11), diffuse large B-cell lymphoma (5/14), hydroa-like T-cell lymphoma (1/1), marginal zone B-cell lymphoma (1/2), and post-transplantation lymphoproliferative disorder (1/1). Other types including 19 cases of Burkitts lymphoma were negative. For 9 EBER-positive cases, immunohistochemical staining for LMP-1, and EBNA-2 was performed to determine the EBV latency pattern. Two of nine EBER-positive cases expressed both LMP-1 and EBNA-2. Clinically, patients with EBV-positive B-cell lymphomas were cured with chemotherapy, whereas EBV-associated NK- and T cell lymphomas pursued fatal clinical course. In conclusion, EBVs infected in childhood NHLs are frequently associated not only with NK- and T- cell lymphomas but also large B-cell lymphomas.     

Nasal natural killer/T-cell lymphoma and its association with type "i"/XhoI loss strain Epstein-Barr virus in Chile

BACKGROUND: Nasal T/natural killer (NK)-cell lymphoma is an aggressive type of non-Hodking's lymphoma associated with Epstein-Barr virus (EBV) and striking geographical variations worldwide. AIM: To characterise nasal NK/T-cell lymphoma associated with genotypes of EBV in Chile, a Latin American country, where multiple strains of EBV, including two new recombinant strains, in healthy individuals were recently found. METHODS: Cases with diagnosis of primary nasal lymphoma were selected for histological and immunohistochemical analysis (CD3, CD3e, CD4, CD8, CD79a, CD56, CD57 and TIA-1) and in-situ hybridisation, serology and genotyping analysis for EBV. RESULTS: Out of 22 cases, 9 (41%) cases fulfilled the World Health Organization criteria for nasal NK/T-cell lymphoma; of these 7 (78%) cases were positive for EBV. Genotyping analysis revealed 6 cases of type 1 EBV and wildtype F at the BamHI-F region, 4 cases type "i" EBV at the BamHI-W1/I1 region; XhoI wild type was found in 2 and XhoI loss in 4 cases, respectively. Cosegregation analysis of the BamHI-W1/I1 region and XhoI restriction site showed the new recombinant strain type "i"/XhoI loss in 3 cases and type "i"/XhoI wild-type strain in 1 case. Most patients were treated with combined anthracycline-containing regimens. Half of the cases attained complete remission. CONCLUSION: Although nasal NK/T-cell lymphomas from Chile share similar clinicopathological features, high association with EBV and unfavourable prognosis with those described elsewhere, genotype analysis shows that the new recombinant type "i"/XhoI loss strain might contribute to explain the intermediate incidence of nasal NK/T-cell lymphomas in Latin America.     

Host ethnicity influences non-Hodgkin''s lymphoma subtype frequency and Epstein–Barr virus association rate: the experience of a multi-ethnic patient population in Malaysia

AIMS: The pattern of malignant lymphoma is known to vary in different populations. This study aims to elucidate the effect of ethnicity on subtype frequency of non-Hodgkin's lymphoma and EBV association rate. METHODS AND RESULTS: A total of 232 reconfirmed lymphoma cases in Malaysian patients were retrieved from the archives in the Department of Pathology, University Hospital, Kuala Lumpur. There were 24 (10%) Hodgkin's and 208 (90%) non-Hodgkin's lymphomas, 173 of the latter were in adult group (aged > or = 15 years). The ethnic composition were 41 Malays, 107 Chinese, 21 Indians and four none of the above. A male : female ratio of 2.4 : 1 was observed. Complete immunohistochemical studies in 158 cases revealed 36 (23%) T-cell, 121 (76%) B-cell and one (1%) null-cell phenotype. Seventy-five percent of the T-cell lymphomas were peripheral T/NK-cell types. Among the classifiable lesions, low-grade/indolent lymphomas constituted 17%: 2% were the lymphocytic subtype and 10% were follicular lymphomas. Approximately one-third of the follicular lymphomas occurred in Indian patients. The largest group of high-grade lymphoma was diffuse large B-cell type (46%), followed by peripheral T/NK-cell (18%). A predominance of NK/T-cell lymphomas occurred in Chinese (5/7), and all were EBV associated. Burkitt's lymphoma accounted for 5% (eight cases), all were Chinese males, with a 38% EBV-association rate. The frequency of EBV-associated B-cell lymphoma is three times more common in Chinese than Malays. The EBV positivity rate among lymphomas in ethnic Malay, Chinese and Indian patients was 5%, 15% and 22%, respectively, and in T- and B-cell lymphomas was 36% and 7%, respectively. CONCLUSIONS: This Malaysian series reveals differences in the subtype frequencies of non-Hodgkin's lymphomas and EBV association rate amongst patients of various ethnic groups residing in the same environment.     

NK and NK-like T-cell lymphoma in extranasal sites: a comparative clinicopathological study according to site and EBV status

AIMS: To analyse the clinicopathological findings of extranasal CD56+ cytotoxic T- or NK-cell lymphomas in different organs and to compare Epstein-Barr virus (EBV)+ and EBV- lymphoma of non-blastoid cytomorphology. METHODS AND RESULTS: Fifty-one cases of cCD3+ T-cell intracellular antigen (TIA-1)+ CD56+ lymphomas of extranodal/extranasal origin were included in the study. The primary sites of the CD56+ tumours were soft tissue (n = 10), the gastrointestinal (GI) tract (n = 13), the skin (n = 15), upper aerodigestive tract excluding nasal and nasopharyngeal regions (n = 11), the testis (n = 1), and parotid gland (n = 1). TCR gene rearrangement was detected in seven of 47 cases examined (16%). EBV was positive in 39 of 51 cases (76%). The positive rate of EBV was higher in tumours of soft tissue (80%), GI tract (92%), and skin (80%), and lowest in the upper aerodigestive tract excluding the nasal and nasopharyngeal region (50%). Tumours of the soft tissue and the upper aerodigestive tract tended to present with localized disease (P = 0.002). The 2-year survival rate was lowest for tumours of the GI tract (P = 0.0256). EBV- TCR- lymphoma showed less necrosis (P = 0.0133) and a better 2-year survival rate (P = 0.0066) than EBV+ TCR- lymphoma. Patients with EBV+ TCR+ lymphomas tended to present with localized disease, more often than EBV+ TCR- lymphoma (P = 0.0186). Significant prognostic factors in all CD56+ lymphomas were the site (P = 0.0256), EBV status (P = 0.0026), necrosis with or without perforation (P = 0.0338) and the presence of pleomorphic large tumour cells (P = 0.0428). Cox's regression analysis adjusting for other pathological parameters showed EBV status to be the only independent prognostic factor (P = 0.018). CONCLUSIONS: Extranodal CD56+ EBV- lymphoma at extranasal sites is a clinically less aggressive malignancy and displays less necrosis than CD56+ EBV+ lymphoma. Because CD56+ EBV+ TCR+ lymphomas show similar pathological and clinical findings to CD56+ EBV+ TCR- lymphomas, nasal-type NK/T-cell lymphomas at extranasal sites should be diagnosed as such on the basis of EBV+, cytotoxic T or NK phenotype irrespective of the genotype determined by molecular study.     

T-cell/histiocyte-rich large B-cell lymphoma is a disseminated aggressive neoplasm: differential diagnosis from Hodgkin's lymphoma

AIMS: An accurate diagnosis of T-cell/histiocyte-rich large B-cell lymphoma needs to take into consideration those forms of Hodgkin's lymphoma also characterized by a predominance of small lymphocytes and histiocytes, i.e. nodular lymphocyte predominance Hodgkin's lymphoma and lymphocyte-rich classical Hodgkin's lymphoma. We have studied the clinical, phenotypic and genetic features of a series of 12 cases of T-cell/histiocyte-rich large B-cell lymphoma along with 18 cases of Hodgkin's lymphoma for comparative purposes. METHODS AND RESULTS: Of the Hodgkin's lymphoma cases, there were 11 lymphocyte predominance type and seven classic type. T-cell/histiocyte-rich large B-cell lymphomas presented usually in advanced stages (III or IV in 11/12 cases), frequently with 'B' symptoms (6/9 cases), and followed a more aggressive course than Hodgkin's lymphoma (4/8 patients died due to the tumour in T-cell/histiocyte-rich large B-cell lymphoma versus 0/15 in Hodgkin's lymphoma). T-cell/histiocyte-rich large B-cell lymphoma cases showed diffuse effacement of the nodal architecture by a proliferation of scattered large atypical B-cells obscured by a background of small T-lymphocytes (more CD8+, TIA1+ than CD57+). Five cases showed also a prominent histiocytic component. The large B-cells expressed CD45 and often EMA (6/10 cases). On the other hand, CD 30, CD15 and latent infection by Epstein-Barr virus (EBV) were generally lacking. bc l6 and CD10 were, respectively, detected in 6/6 and 1/5 cases. Conventional polymerase chain reaction (PCR) showed monoclonal immunoglobulin heavy chain (IgH) gene rearrangements in all T-cell/histiocyte-rich large B-cell lymphomas studied (5/5), but did not detect any case with t(14;18) involving the major breakpoint region (0/4). CONCLUSIONS: The differential diagnosis of T-cell/histiocyte-rich large B-cell lymphoma from Hodgkin's lymphoma is facilitated by the integration of different immunophenotypic, molecular and clinical findings. T-cell/histiocyte-rich large B-cell lymphoma is a monoclonal neoplasm of bc l6+ B-cells with a phenotypic profile similar to lymphocyte predominance Hodgkin's lymphoma, suggesting a germinal centre origin and a possible relation to this disease. Therefore, in order to distinguish it from lymphocyte predominance Hodgkin's lymphoma, characterization of the reactive background, IgH gene rearrangement studies by conventional PCR and clinical features are more useful. In contrast, T-cell/histiocyte-rich large B-cell lymphoma can be distinguished from classical Hodgkin's lymphoma thanks to the presence of monoclonal IgH rearrangement and the CD 30-CD15-CD45+EMA+ immunophenotypic profile of the neoplastic cells in T-cell/histiocyte-rich large B-cell lymphoma.     

Clinical, immunohistochemical and phenotypic features of aggressive nodal cytotoxic lymphomas, including α/β, γ/δ T-cell and natural killer cell types

Cytotoxic cells include natural killer (NK) cells and cytotoxic αβ and γδ T lymphocytes (CTLs). These cells express cytotoxic molecules of T-cell restricted intracellular antigen(TIA-1), and activated cytotoxic molecules of perforin, granzyme B, and FasL. Recent studies suggest that most extranodal T-cell lymphomas are derived from CTLs, and that NK cell lymphomas are extranodal. However, only a few nodal NK and cytotoxic lymphomas have been described so far. We present here the clinicopathological features of seven cases of nodal cytotoxic T and NK cell lymphomas. The study excluded anaplastic large-cell lymphomas expressing cytotoxic molecules. The neoplastic cells of all cases contained activated cytotoxic molecules of TIA-1, granzyme B, Fas ligand, and/or perforin. Phenotypically and genotypically, four cases showed αβ T cell type [CD2+, CD3+, T-cell receptor (TCR) δ-1–, βF1+, and TCR gene rearrangement], two cases showed γδ T-cell type [CD2+, CD3+, T-cell receptor (TCR)δ–1+, βF1–, and TCR gene rearrangement], and one case showed NK cell type [CD2+, CD3-, CD56+, T-cell receptor (TCR)δ-1–, βF1–, and TCR gene germline]. Using Southern blot analysis, Epstein-Barr virus (EBV) sequences were detected in six cases, and monoclonal terminal repeat proliferation was confirmed. In addition, in situ hybridization (ISH) studies for EBV showed EBV infection in almost all neoplastic cells. Clinically, all patients presented with peripheral lymphadenopathy in high clinical stages and showed an aggressive course. Hepatosplenomegaly was detected in six cases. During the course of the disease, bone marrow and extranodal invasion were noted in five cases. The nodal type showed an aggressive clinical course in all cases but one, as did the extranodal type. The nodal type varied in phenotype, but was closely associated with EBV infection.     

Primary lymphoma arising in the nasal cavity among Japanese

AIMS: Most lymphomas arising in the nasal cavity are thought to be of natural killer (NK) cell origin. However, some reports indicate that T- and B-cell lymphomas may also primarily arise in the nasal cavity. We therefore studied lymphomas arising in the nasal cavity both histologically and immunohistochemically. METHODS AND RESULTS: Of the 32 cases investigated, 20 cases were also available as fresh frozen specimens. We diagnosed 31 cases as extranodal NK/T-cell lymphoma and one as plasmacytoma. The neoplastic cells were immunoreactive for CD3 (polyclonal) 31/31, LMP-1 12/31, CD20 (L26) 0/31, granzyme B 30/31, TIA-1 30/30, CD56 (123C3) 29/31, CD4 0/31 and CD8 3/31. In situ hybridization for Epstein-Barr virus-encoded small RNA-1 (EBER-1) was detected in 31/31. In frozen tissue sections, neoplastic cells mostly showed CD3 (Leu4)-, CD4 (Leu3a)-, CD5 (Leu1)-, CD8 (Leu2)-, CD16 (Leu11)-, CD56 (Leu19)+, betaF1-, TCRdelta1-, perforin+, CD94+ phenotypes. These immunohistochemical findings indicate their NK cell origin. In three cases, neoplastic cells were positive for CD8. In one of these cases, neoplastic cells were positive for CD8beta and Valpha24, suggesting their NKT-cell origin. CONCLUSIONS: Our present study indicates that primary lymphomas arising in the nasal cavity are mostly of NK cell derivation. Our present study also suggests that a small number of cases are derived from NKT-cells.     

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.     

Genotypic and phenotypic alterations in Epstein-Barr virus-associated lymphoma

AIMS: Epstein-Barr virus (EBV) is associated with numerous reactive and neoplastic lymphoproliferative disorders. In vitro, EBV infection can transform B-lymphocytes and induce phenotypic alterations. This study presents the clinicopathological features of four cases with malignant lymphoma, which showed phenotypic and/or genotypic alterations during the course of the disease. METHODS AND RESULTS: To determine the type of EBV genotype, we performed polymerase chain reaction (PCR) for lymphocyte-defined membrane antigen (LYDMA) of EBV, subtype A/B and latent membrane protein (LMP)-1 deletion. In addition, we analysed the terminal repeat (TR) band of EBV and receptor genes (T-cell receptor gene, TCR; immunoglobulin gene heavy chain, IgH) for EBV-infected cell clonality. Double staining of cell markers (B, T-lymphocytes; histiocytes), and in-situ hybridization (ISH) for EBV were performed using tissues obtained during the course of the disease. The first case showed genotypic and phenotypic alterations of T-cell type to B-cell type. The first TCR rearrangement and T-cell markers (CD3+, CD4+, CD8-) were lost and IgH rearrangement and B-cell markers (CD19+, CD20+) were identified. During the course of the disease, EBV-TR bands changed in size; however, the EBV genotype type B, LMP1 deletion type, and single LYDMA band remained the same. The initial T-cell lymphoma clone was considered to be different from the latter B-cell lymphoma clone. The second case showed phenotypic alterations. The first B-cell marker (CD19+, CD20+, CD68-) changed to histiocytic markers (CD19-, CD20-, CD68+). However, IgH rearrangement and EBV-TR bands remained the same throughout the course of the disease and EBV genotype type A, LMP1 deletion type, and single LYDMA band remained unchanged. The third case showed phenotypic alterations. The B-cell marker (CD20+) was lost; however, IgH rearrangement of PCR and EBV genotype remained the same. In the second and third cases, the initial lymphoma clones were considered to be same as the latter clones. The last case showed lineage alterations from Hodgkin's disease to natural killer (NK) cell leukaemia. However, EBV genotype did not change. The second case and Hodgkin's disease showed LMP expression, but the first and third cases showed no LMP, and EBNA2 was not detected in all cases. CONCLUSIONS: We report the genotypic and/or phenotypic alterations in four patients with EBV-associated lymphoma/leukaemia. However, EBV genotype did not change in all four. These findings suggest that EBV might induce the cell marker and lineage alteration in vivo, as in vitro.     

CD8+, CD56+ (natural killer-like) T-cell lymphoma involving the small intestine with no evidence of enteropathy: clinicopathology and molecular study of five Japanese patients

The present study reports five CD8+, CD56+ (natural killer (NK)-like) T-cell lymphomas involving the small intestine without evidence of enteropathy, from Japan. Three were intestinal T-cell lymphoma. The site of origin of the other two was not definitive. Four of five patients underwent emergency operation because of intestinal perforation. The small intestines of these patients had multiple ulcerative lesions with or without demarcated tumors. Histologically, the lymphoma cells were monomorphic or slightly pleomorphic and displayed epitheliotropism of varying degrees. Lymphoma cells of all patients shared the common phenotype: CD3+, CD4-, CD5-, CD8+, CD56+, CD57-, T-cell intracellular antigen-1+, granzyme B+. In contrast to nasal/nasal type NK-cell lymphomas, they had clonal rearrangement of T-cell receptor(TCR) genes and were negative for EBV-encoded RNA. Immunohistochemistry and genetics suggested that three cases were of alpha beta T-cell origin and two cases were of gamma delta T-cell origin. There was no evidence of enteropathy in any patient. The cases followed a clinically aggressive course with a frequent involvement of lung. According to the classification based on the recent genetic studies of European enteropathy-type intestinal T-cell lymphoma (ETL), the present cases could be classified as type 2 ETL.     

Classification of cell lineage and anatomical site, and prognosis of extranodal T-cell lymphoma – natural killer cell, cytotoxic T lymphocyte, and non-NK/CTL types

Due to their minority among the non-Hodgkin lymphomas, classification of extranodal T-cell lymphomas, including those of the natural killer (NK) cell type, has long been controversial and unclear, and the clinical outcome is not well clarified. Recently, new well-defined disease entities have been described based on tumor cell biology combined with anatomical site, clinical features, Epstein-Barr virus (EBV) status, and cell lineage as determined by immunophenotype and genotype. Cytological features are usually not specific, and there are no morphologic correlates with the classification of extranodal T/NK-cell lymphomas. From a human T-cell lymphotropic virus type 1 (HTLV-1) endemic area in Japan, we report here the analysis of 144 cases of extranodal T-cell lymphoma, from which fresh tissues were available. As the clinicopathological features were known, we simply reclassified the cases according to cell lineage and anatomical site. The extranodal T-cell lymphomas were classified into three types on the basis of cell lineage: (1) natural killer cell (NK) type [sCD3-, CD56+, T-cell receptor gene (TCR) germline], (2) cytotoxic T lymphocyte (CTL) type [sCD3+, TIA-1+, TCR rearranged, CD8+/-, CD4-/+], and (3) non-NK/CTL type [sCD3+, TIA-1-, TCR rearranged, CD4+/-, CD8-/+]. In addition to cell lineage, the anatomical site and clinical features were added for subclassification. NK type tumors (35 cases) included the lymphoblastic type, nasal/nasal-type NK lymphoma, and NK leukemia. The CTL type (46 cases) included anaplastic large cell lymphoma (ALCL), cutaneous type, intestinal, gamma delta T-cell type, and an unspecified type. The non-NK/CTL type (63 cases) included adult T-cell leukemia/lymphoma (ATLL), mycosis fungoides (MF), and an unspecified type. With the exception of ATLL and MF, most extranodal T-cell lymphomas had a cytotoxic phenotype of NK type or CTL type and were often associated with EBV infection. MF and the unspecified type within the non-NK/CTL tumors, with the exception of ATLL, had a favorable prognosis. However, NK and CTL types, with the exception of ALCL, were associated with a poor prognosis. Our results indicate that anatomical site and cell lineage are useful predictors of clinical outcomes of extranodal T-cell lymphomas.     

Therapeutic outcome of Epstein-Barr virus positive T/NK cell lymphoma in the upper aerodigestive tract

Expression of the natural killer (NK) cell antigen CD56 is uncommon in malignant lymphoma, but when it is, it is almost exclusively of the non-B cell lineage and show a preference for the nasal and nasopharyngeal region. T/NK cell lymphoma is known to be aggressive and refractory to treatment. It is highly associated with the Epstein-Barr Virus (EBV), but clinical investigations are rarely reported, that is until recently. We report here, on the clinical features and therapeutic outcomes of patients with T/NK cell lymphomas and its association with EBV. We reviewed fifty-four cases with peripheral T cell lymphomas in the upper aerodigestive tract between Jan. 1987 and Aug. 1998 from the Severance Hospital, Yonsei University College of Medicine. The diagnosis of T/NK cell lymphoma was made according to the expression of the NK cell markers, CD56 antigen and cytoplasmic CD3epsilon, in tumor specimens, by immunohistochemistry. Epstein-Barr early region (EBER) RNA was detected using in situ hybridization on paraffin-embedded sections. Among the 54 cases with malignant lymphomas occurring in the upper aerodigestive tract, 20 had T/NK cell lymphoma (37%). The primary sites of T/NK cell lymphomas were the nasal cavity, 12 cases (60%), the tonsils, 4 cases (20%), the nasopharynx, 2 cases (10%), and the oropharynx, 2 case (10%). There were no differences between the features, at diagnosis or therapeutic modalities for patients with T/NK cell lymphoma and non-T/NK cell lymphoma. The complete remission rate of T/NK cell lymphomas was lower than non-T/NK cell lymphomas (65% vs 85%, p=0.02). The overall survival of T/NK cell lymphomas was 13 months (1-74 month), which was significantly lower than non-T/NK cell lymphomas [60.6% with a median follow up of 22 months (1-101 month, p=0.02)]. Disease free survival of T/NK cell lymphomas was 22 months (4-66 month), significantly lower than non-T/NK cell lymphomas [73.8% with a median follow up of 22 months (2-95 month), p=0.04]. The overall survival rates for T/NK cell lymphomas were significantly lower than for EBV positive non-T/NK cell lymphomas (p=0.018). EBER RNA was detected in the paraffin-embedded tissue sections of all T/NK cell lymphomas, compared to only 17.6% (6 of 34 cases) for non- T/NK cell lymphomas. In conclusion, as patients with T/NK cell lymphomas showed poor clinical outcomes, and a high association with EBV positivity, clinical trials with more investigational therapeutic strategies, and further research into the relationship of EBV infection with pathogenesis of T/NK cell lymphoma is warranted.     

鼻及咽部非霍奇金淋巴瘤158例临床特点及其与EB病毒感染的关系

目的探讨鼻及咽部原发性非霍奇金淋巴瘤（NHL）的临床特点、免疫表型及其与EB病毒感染的关系。方法对158例鼻及咽部原发性NHL进行了HE和免疫组织化学SP法（CD3、CD20、CD56、CD57）检查,按WHO2001年《造血和淋巴组织肿瘤的病理学和遗传学》标准进行分类;并对其中99例进行了EBER-1原位杂交的检测。结果158例鼻及咽部原发性NHL中,原发于鼻腔84例（53．2％）,扁桃体39例（24．7％）,咽部35例（22．1％）。结外鼻型NK／T细胞淋巴瘤101例（63．9％）、非特异性外周T细胞淋巴瘤23例（14．6％）,B细胞淋巴瘤34例（21．5％）。99例EBER-1原位杂交结果显示阳性率：结外鼻型NK／T细胞淋巴瘤为98．6％（70／71）,而非特异性外周T细胞淋巴瘤为66．7％（8／12）,B细胞淋巴瘤为43．8％（7／16）。结论鼻及咽部NHL中结外鼻型NK／T细胞淋巴瘤最为多见,与EB病毒密切相关,其病理诊断需结合其免疫表型特征及肿瘤部位。     

Hepatosplenic gammadelta T-cell lymphoma: relation to Epstein-Barr virus and activated cytotoxic molecules

AIMS: Hepatosplenic gammadelta T-cell lymphoma (TCL) is a rare, aggressive subset of peripheral TCL that presents with hepatosplenomegaly and cytopenia. Epstein-Barr virus (EBV) infection and activated cytotoxic molecules (granzyme and perforin) are uncommon in hepatosplenic gammadelta CTL. EBV infection and activated cytotoxic molecules are occasionally detected in non-hepatosplenic gammadelta TCL. We describe the clinicopathological features of three Japanese cases who were not immunodeficient. METHODS AND RESULTS: All cases showed gammadelta T-cell type (CD2+, CD3+, T-cell receptor (TCR)delta-1+, betaF1-). Two cases expressed natural killer (NK) cell-associated antigens (CD8-, CD16+, CD56+; CD8-, CD16-, CD56+), and one expressed CD8 (CD8+, CD16-, CD56-). All cases expressed cytotoxicity-associated molecules (perforin, granzyme B, TIA-1 and Fas ligand). However, perforin and Fas ligand were not detected in one case. In-situ hybridization analysis with EBER probes revealed strong nuclear positivity in all neoplastic cells. In addition, two cases showed clonal bands of the EBV terminal repeat (TR) gene. Cytologically, instead of the presence of monomorphic medium-sized cells, our three cases showed pleomorphic medium-sized and large cells. CONCLUSIONS: Our gammadelta TCL cases were clinicopathologically considered to be compatible with hepatosplenic gammadelta T-cell lymphoma. However, with regard to EBV association, activated cytotoxic profile and cytological features they resembled non-hepatosplenic gammadelta TCL. EBV may play a role in this disease by inducing cellular activation.     

Histological and immunophenotypic profile of nasal NK/T cell lymphomas from Peru: high prevalence of p53 overexpression.

Nasal NK/T-cell lymphoma is a unique form of lymphoma highly associated with Epstein-Barr virus (EBV). These lymphomas are rare in Western populations and much more prevalent in some Asian and Latin American countries. Although there are several sizable studies from Asian countries, the same is not true from South America. The aim of this study was to analyze a series of 32 cases of nasal T-cell lymphoma from Peru and to further extend the characterization of this disease. Immunohistochemistry was performed on paraffin sections using the following antibodies: CD20 (L26), CD45RO, CD3, Ki67, CD57, CD56, TIA-1, bcl-2, and p53. The presence of EBV was investigated with immunohistochemical analysis for latent membrane protein (LMP)-1 and in situ hybridization using an antisense riboprobe to EBER 1. The 32 patients included 18 men and 14 women (M:F ratio, 1.2:1), with a median age of 43 years (11 to 72). Three categories were identified: (1) Nasal NK/T cell lymphomas (28 cases): The morphology ranged from small or medium-sized cells to large transformed cells. Necrosis was present in 86% of the cases, and angioinvasion was seen in 36% of the cases. All cases were positive for CD45RO, CD3, and for TIA-1. CD56 was positive in 21 of 27 cases (78%), and CD57 was negative in all cases. EBER 1 positivity was identified in most of the tumor cells in 27 of 28 cases (96%), including the six cases in which CD56 was negative. Overexpression of p53 was detected in 24 cases (86%). (2) Blastic NK cell lymphoma (1 case): The neoplastic cells resembled those of lymphoblastic lymphoma. CD56 and CD45RO were positive; TIA-1, TdT, and EBER-1 were negative. (3) Peripheral T-cell lymphoma (PTCL) unspecified (3 cases): CD56, TIA-1, and EBER-1 were negative. Nasal lymphomas from Peru with a T cell phenotype are predominantly EBV-associated NK/T cell lymphomas, similar to those described in Asian countries. The expression of CD56, TIA-1, and EBER-1, in combination, are very useful markers for the diagnosis of nasal NK/T cell lymphoma in paraffin-embedded tissue. The differential diagnosis of T-cell lymphomas in the nasal region should include rare cases of PTCL unspecified and the blastic variant of NK cell lymphoma. P53 is overexpressed in 86% of the cases. The significance of this finding with regard to clinical behavior and prognosis remains to be determined.