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.     

Nasal CD56 positive small round cell tumors

CD56-positive nasal and nasal-type natural killer (NK)/T-cell lymphoma is now a well-defined disease entity. Rare cases of blastic NK-cell lymphoma positive for CD56 have been recently reported. However, CD56 expression is also identified in several types of non-hematopoietic small round cell tumors in which lymphoma is included as a differential consideration. Here, we present nine cases of CD56+ small round cell tumors of histological origin unrelated to nasal NK/T-cell lymphoma. Eight of the nine cases presented as solid tumors of the sinonasal region. Clinical, histological, ultrastructural, and immunohistochemical examination and gene analysis for T-cell receptor (TcR) and immunoglobulin heavy chain (IgH) genes and in situ hybridization (ISH) for Epstein-Barr virus (EBV) were performed. Two cases presented with features consistent with blastic NK-cell lymphoma or lymphoblastic lymphoma of NK-cell phenotype. These cases showed features of lymphoblastic lymphoma, phenotypes of sCD3-, cCD3+, CD45+, CD56+, TdT+, and human leukocyte antigen (HLA)-DR+, germline of IgH and TcR genes, and EBV negative reactivity. One case had myeloid/NK-precursor acute leukemia/lymphoma with a phenotype of CD13+, CD33+, CD34+, CD56+, and MPO-. Three cases were neurogenic, including one case of olfactory neuroblastoma and two of primitive neuroectodermal tumors (PNET). It was difficult to differentiate CD56+ PNET from blastic NK-cell lymphoma, especially when only paraffin-embedded sections were available. Myogenic markers, such as HHF35, alpha-sarcomeric actin, and desmin, were positive in three cases of rhabdomyosarcomas. Our findings suggest that as CD56 is used more routinely as a marker in immunohistochemical staining, the differential diagnosis of extranodal lymphohematological malignancies and small round cell tumors will become more complicated.     

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.     

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.     

NK-cell lymphomas and leukemias: a spectrum of tumors with variable manifestations and immunophenotype

Natural killer (NK) cells are lymphocytes that have some phenotypic and functional similarities to cytotoxic T cells but do not express the T-cell receptor complex. NK-cell malignancies may be localized or disseminated at initial examination, and most behave aggressively. The variable presentation of NK-cell lymphomas and leukemias suggests that they represent a spectrum of disease, with Epstein-Barr virus (EBV) implicated in the pathogenesis of most cases. Using cases presented in Session 10 of the 2005 Society for Hematopathology/European Association for Haematopathology Workshop on T-cell and NK-cell malignancies, we discuss outstanding issues in the classification and diagnosis of NK-cell malignancies. These difficulties are related to unusual sites of manifestation, atypical immunophenotypic features, and EBV+ T-cell tumors that resemble classical extranodal NK/T-cell lymphoma, nasal-type (EN-NK/T-NT). Although some of these cases can be grouped into ENNK/T-NT, classification of tumors that have atypical or discordant features will remain controversial, particularly when EBV is absent.     

TIA-1 expression in lymphoid neoplasms. Identification of subsets with cytotoxic T lymphocyte or natural killer cell differentiation.

TIA-I is a 15-kd cytotoxic granule-associated protein expressed in natural killer (NK) cells and cytotoxic T lymphocytes. TIA-1 expression was evaluated by paraffin immunohistochemistry in 115 T- or NK-cell neoplasms, 45 B-cell neoplasms, and 45 Hodgkin''s lymphomas. TIA-1-positive granules were identified within the cytoplasm of neoplastic cells in 6/6 large granular lymphocytic leukemias, 11/11 hepatosplenic T-cell lymphomas, 15/15 intestinal T-cell lymphomas, 6/6 NK-like T-cell lymphomas of no special type, 2/2 NK-cell lymphomas, 8/9 nasal T/NK-cell lymphomas, 7/8 subcutaneous T-cell lymphomas, 4/5 pulmonary T- or NK-cell angiocentric lymphomas (lymphomatoid granulomatosis), 12/19 T-cell anaplastic large-cell lymphomas, 2/12 nodal peripheral T-cell lymphomas, 1/3 CD8+ cutaneous T-cell lymphomas, and 5/38 classical Hodgkin''s disease. All B-cell neoplasms, nodular lymphocyte-predominant Hodgkin''s disease (7 cases), CD4+ cutaneous T-cell lymphomas (6 cases), adult T-cell leukemia/lymphomas (3 cases), T-cell chronic or prolymphocytic leukemias (3 cases), and T-cell lymphoblastic leukemia/lymphomas (7-cases) were TIA-1 negative. These findings indicate that most large granular lymphocytic leukemias, hepatosplenic T-cell lymphomas, intestinal T-cell lymphomas, NK-like T-cell lymphomas, NK-cell lymphomas, nasal T/NK-cell lymphomas, subcutaneous T-cell lymphomas, pulmonary angiocentric lymphomas of T or NK phenotype, and anaplastic large-cell lymphomas are cytotoxic T-or NK-cell neoplasms.     

Usefulness of flow cytometry for differential diagnosis of precursor and peripheral T-cell and NK-cell lymphomas: analysis of 490 cases

Although various CD markers have been analyzed in T-cell and natural killer (NK)-cell lymphomas, the sensitivity and specificity of these phenotypic features have not been satisfactorily characterized. Flow cytometry (FCM) was used to determine the phenotypic pattern of 490 T/NK-cell lymphomas with the aid of a set of surface antigens (CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11c, CD16, CD19, CD20, CD25, CD30, CD34, and CD56). In data obtained from 319 patients, CD10 expression was detected in 57% of angioimmunoblastic T-cell lymphomas, CD30 in 93% of anaplastic large cell lymphomas, CD34 in 50% of lymphoblastic lymphomas, and CD56 in 100% of extranodal NK/T-cell lymphomas nasal type. A total of 92% of adult T-cell leukemia/lymphomas (ATLL) had expression of CD25 and downregulation of CD7. Of special interest is that 92 ATLL (50%) were CD4⁺CD7^-CD25⁺ phenotype while only four peripheral T-cell lymphoma unspecified (9%) and one (9%) cutaneous T-cell lymphoma had this phenotype. Phenotypic analysis using FCM was thus found to be useful for differential diagnosis of T-cell and NK-cell lymphomas.     

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.     

Nasal T-cell lymphoma: a clinicopathological and immunophenotypic analysis of 13 cases

Thirteen cases of nasal lymphomas with T-cell or natural killer (NK)-cell phenotype were studied, with attention to clinical presentation and follow-up, the presence of Epstein-Barr virus (EBV) using in situ hybridization (EBER), the immunophenotype, and the presence of cytotoxic granules. All but two patients presented with stage I disease. In three cases local progression resulted in involvement of the central nervous system. When dissemination occurred, this was predominantly to extranodal localizations, in two cases to the skin. Response to therapy was highly variable, but patients treated with radiotherapy with or without additional chemotherapy had a better prognosis than patients treated with initial chemotherapy alone. All lymphomas were associated with EBV, and most cases howed cytotoxic features, ten of which were CD56 positive. In eight cases a T-cell origin was proven, but in five ases a possible NK-cell origin could not be excluded, No clinical differences were seen between true T-cell lymphomas and possible NK-cell neoplasms. Nasal T-cell lymphomas should be considered as a distinct clinicopathological entity, strongly associated with EBV, and with cytotoxic features in most cases. No prognostic parameters were detected to predict dissemination and response to therapy.     

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.     

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 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     

EBV-associated, extranodal NK-cell lymphoma, nasal type of the breast, after heart transplantation.

Post-transplantation lymphoproliferative disorders (PTLDs) are predominantly Epstein-Barr virus (EBV)-associated B-cell lymphoproliferations. PTLDs of T-cell lineage are rare, mostly reported after renal transplantation and show less frequent association with EBV. NK-cell lymphomas after transplantation (NK-cell PTLDs) are very rare; only five cases are reported so far in the English literature, all developed after renal transplantation. We describe a case of EBV-associated, extranodal NK-cell lymphoma of nasal type, involving the breast in a cardiac allograft recipient 5 years after transplantation. The neoplastic cells are positive for CD2, cytoplasmic CD3, CD7, CD43, CD56, TIA-1 and p53; and negative for surface CD3 and CD57. Analysis of T-cell receptor beta and gamma genes fails to show clonal rearrangement. EBV studies show clonal episomal integration of EBV and latency II pattern (EBER-1+, LMP-1+, EBNA-1+, EBNA-2-). In conclusion, NK-cell PTLDs are rare complications that arise relatively late after solid organ transplantation, show strong association with EBV, and can follow an aggressive clinical course. To the best of our knowledge, we present the first reported case of NK-cell PTLD after cardiac transplantation and the unifying clinical and diagnostic features of NK-cell PTLDs occurring after solid organ transplantation.     

Phenotypic analysis of peripheral T/NK cell lymphoma: study of 408 Japanese cases with special reference to their anatomical sites

The World Health Organization (WHO) classification of malignant lymphoma presented a list of disease entities well defined by clinical, immunological and genetic features. Therefore, the current diagnosis of peripheral T/NK-cell lymphomas (PTNKLs) essentially requires the inclusion of anatomical sites of disease and phenotypical features. We analyzed 408 Japanese cases of PTNKLs in order to clarify the relationship between anatomical sites of disease and phenotypical features and to translate the functional subsets of T and NK cells into their diagnoses for further understanding lymphomatic biology. The T/NK-cell lymphoma entities were allocated into three categories: (i) cytotoxic memory T-cell and/or NK-cell lymphoma (n = 151) consisting of extranodal NK/T-cell tumors other than mycosis fungoides (MF); (ii) non-cytotoxic memory T-cell lymphoma (n = 142) consisting of nodal and cutaneous tumors such as angioimmunoblastic T-cell lymphoma, adult T-cell lymphoma/leukemia and MF; and (iii) anaplastic lymphoma kinase positive anaplastic large cell lymphoma (n = 110) that has unique features and might be regarded as cytotoxic 'naive' T-cell lymphoma. Overall, these three categories were significantly correlated with age of onset, anatomical sites, the level of expression of cytotoxic molecules and CD45RO, and association with Epstein-Barr virus. This concept might provide a new insight enabling further understanding of the interrelationships among WHO T/NK-cell disease entities.     

Epstein - Barr virus positive T and NK-cell lymphoproliferations: Morphological features and differential diagnosis

The spectrum of Epstein-Barr virus (EBV)-positive T and NK-cell lymphoproliferations is broad and ranges from reactive self-limited disorders to neoplastic processes with a fulminant clinical course. EBV plays an important role promoting lymphomagenesis, although the precise mechanisms remain elusive. EBV-positive lymphoproliferative disorders (LPD) are more common in East Asia (China, Japan, Korea and Taiwan), and Latin America suggesting a strong genetic predisposition. The revised 2016 World Health Organization (WHO) lymphoma classification recognizes the following malignant NK- and T-cell lymphomas; extranodal NK/T-cell lymphoma, nasal type (ENKTCL), aggressive NK-cell leukemia (ANKL), and the provisional entity within the group of peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) “primary EBV-positive nodal T or NK cell lymphoma”. Disorders presenting mainly in children and young adults include chronic active EBV infection (CAEBV) - systemic and cutaneous forms – which are not considered malignant disorders but were included in the WHO classification for the first time because of the differential diagnosis with other T- or NK-cell lymphomas. CAEBV, cutaneous form, includes hydroa vacciniforme-like LPD (HV-LPD) and severe mosquito bite allergy (SMBA). Finally, systemic EBV-positive T-cell lymphoma of childhood was recognized as lymphoma because of its fulminant clinical course. Given the shared pathogenesis of these disorders, overlapping features are common demanding a close clinical, morphological and molecular correlation for an accurate diagnosis. This review summarizes the clinical, histopathological and molecular features of EBV-associated T and NK-cell LPD, highlighting the main features that might aid in the differential diagnosis.     

The pathology of NK-cell lymphomas and leukemias

Natural killer (NK) cell lymphomas and leukemias are a rare but clinically important group of neoplasms. Most of these tumors are aggressive, with a high rate of mortality. They include extranodal NK/T-cell lymphomas of nasal type and aggressive NK-cell leukemias. Both are Epstein-Barr virus (EBV) associated and show similar epidemiologic features. A closely related entity seen mainly in children is hydroa vacciniforme-like lymphoma, which also is EBV positive. EBV influences the pathophysiology of these tumors, through the induction of cytokines and chemokines. The differential diagnosis of NK-cell malignancies includes fulminant EBV-associated T-cell lymphoproliferative disorder, a condition referred to in the past as fatal infectious mononucleosis. Benign proliferations of NK cells can be seen in association with viral infection. The disease formerly referred to as blastic NK-cell lymphoma is now considered to be a malignancy derived from a dendritic cell precursor.     

Histopathologic and molecular aspects of CD56+ natural killer/ T-cell lymphoma of the testis

Primary nasal-type natural killer/T-cell lymphoma of the testis is a rare malignancy. Although dissemination to the testis from other sites occurs somewhat more frequently than a primary presentation, even secondary testicular involvement is uncommon. In this article, the authors report on the comprehensive histopathologic, immunohistochemical, and molecular analysis of a case of primary testicular nasal-type natural killer/T-cell lymphoma, and review the features of 16 previously reported patients. The investigation carried out in this study indicates that the testicular nasal-type natural killer/T-cell lymphomas occur at a younger age than their B-cell counterparts, express cytoplasmic CD3 and surface CD56, and consistently show an infection by Epstein-Barr virus. These tumors have variable expression of T-cell antigens other than cytoplasmic CD3 and may show monoclonal rearrangement of T-cell receptor genes. Testicular natural killer/T-cell lymphomas of nasal type invariably follow an aggressive clinical course.     

Natural killer-cell lymphoma involving the gynecologic tract

Non-Hodgkin lymphomas (NHL) can involve the gynecologic tract, most often as a manifestation of systemic involvement, and most cases reported have been of B-cell lineage. We describe 2 women with natural killer (NK)-cell lymphoma involving the gynecologic tract that initially presented with vaginal bleeding. In case 1, the patient had a stage IE nasal-type NK-cell lymphoma involving the cervix. The tumor was composed of medium-sized, irregular lymphoid cells with angioinvasion and necrosis. In case 2, the patient had a stage IV blastoid NK-cell lymphoma/leukemia infiltrating all organs in a hysterectomy and bilateral salpingo-oophorectomy specimen. Subsequent biopsy specimens revealed that the bone marrow and lymph nodes were also involved. The neoplasm was composed of small to medium lymphoid cells with fine nuclear chromatin. Case 1 was assessed immunohistochemically and the neoplastic cells were positive for CD3, CD56, and TIA-1. Case 2 was analyzed using both immunohistochemical and flow cytometry methods. The neoplastic cells were positive for cytoplasmic CD3, CD4, CD7, CD43, CD45, and CD56 and were negative for surface CD3. Both cases were negative for Epstein-Barr virus (EBV) ribonucleic acid (RNA) and molecular studies showed no evidence of T-cell receptor gamma chain gene rearrangements. The immunophenotype and absence of T-cell receptor gene rearrangements support NK-cell origin. We report these cases to illustrate that NK-cell lymphomas can involve, and rarely arise in, the gynecologic tract.