Gamma-delta T-cell Lymphoma Research Articles

Hepatosplenic and Other γΔ T-Cell Lymphomas

The 2005 Society for Hematopathology/European Association for Haematopathology Workshop session 11 was dedicated to hepatosplenic T-cell lymphoma (HSTCL). HSTCL is a rare aggressive type of extranodal lymphoma characterized by hepatosplenomegaly, bone marrow involvement, and peripheral blood cytopenias. HSTCL exhibits a distinctive pattern of infiltration; tumor cells preferentially infiltrate the sinusoids of the splenic red pulp, liver, and bone marrow. The tumor cells have a nonactivated cytotoxic T-cell immunophenotype and frequently carry a recurrent cytogenetic abnormality, isochromosome 7q. Most cases express the gammadelta T-cell receptor, but cases can have an alphabeta phenotype and are considered to be a variant of the disease. Although HSTCL is the prototype peripheral T-cell lymphoma expressing the gammadelta T-cell receptor, non-HSTCL proliferations of gammadelta T cells can involve other extranodal sites, mainly skin and mucosa. These gammadelta T-cell lymphomas display marked heterogeneity in clinical and histologic features. In contrast with HSTCL, non-HSTCL gammadelta T-cell lymphomas frequently have an activated cytotoxic phenotype and most likely are not a single disease entity.

Lymphome T gamma delta avec atteinte méningée exclusive révélé par une dermatomyosite

Introduction Peripheral T cell lymphomas are a heterogeneous group of post-thymic, mature lymphoid malignancies, accounting for approximately 10–15% of all non-Hodgkin's lymphomas. A rare entity within this group is represented by hepatosplenic T cell lymphoma, characterized by primary extranodal disease with infiltration of the liver and the spleen and by expression of the T cell receptor gamma delta chain. Exegesis A 64-year old man with dermatomyositis developed rapid-onset paraparesia and deafness. Cerebrospinal fluid analysis revealed large granular lymphomatous cells with CD3+ CD4– CD8– CD7+ CD16– CD56– surface antigens, expressing the gamma delta T-cell receptor. There was no evidence of skin or bone marrow infiltration by lymphoma or any other involvement. This is the first report of dermatomyositis associated with a gamma delta T-cell lymphoma (GDTL). Moreover, primitive and isolated meningeal involvement of such lymphomas has never been described before. Conclusion GDTL should be added to the differential list of neoplasia associated with dermatomyositis. Physiopathological mechanisms implicated in the neurological involvement of such lymphomas need to be elucidated.

LARGE GRANULAR LYMPHOCYTIC LEUKEMIA VERSUS GAMMA DELTA T-CELL LYMPHOMA: A CLINICAL CHALLENGE.

Background We are describing an interesting case that challenged our interpretation between large granular lymphocytic leukemia (LGL) and gamma delta T-cell lymphoma. LGL is a rare leukemia with a median age onset at 55 years having characteristic morphology, multiple autoimmune disorders, and an indolent clinical course in females, whereas gamma delta positive T-cell lymphoma is an uncommon aggressive non-Hodgkin9s lymphoma variant found in young males. Case Presentation A 53-year-old female with a 3-year history of pancytopenia, recurrent upper respiratory infections, and lupus presented with worsening cytopenia. CT scan of the chest, abdomen, and pelvis showed diffuse hepatosplenomegaly with minimal lymphadenopathy. Peripheral blood smear showed pancytopenia with a minor population of large granular lymphocytes (WBC 1.1 L, RBC 3.2 L, Hb 11 L, platelets 86 L, neurophil 0.1 L, lymph 80 H). Bone marrow biopsy revealed 40 to 50% cellularity with involvement by T-cell lymphoproliferative disorder of TCR-gamma/delta immunophenotype; positive for CD2, CD3, CD5 dim, and CD7dim and negative for CD4, CD8, CD16, CD25, and CD56, with variable CD57 expression. Molecular studies for T-cell receptor gene rearrangement showed no evidence of T-cell clonal population. The cytogenetics were normal diploid. Since the patient had features of both LGL and T-cell gamma delta lymphoma, the case was referred to M.D. Anderson Cancer Center for a second opinion, where LGL was the final diagnosis. Patient was treated with cyclosporine and she responded well to it, resolving her pancytopenia. Discussion In view of the characteristics of these rare disorders our patient was CD8 negative and CD3 positve. CD8 negativity is not consistent with LGL, yet she had systemic signs and symptoms, including fatigue, sweats, recurrent infections, and arthritis, which are main clinical features of T-cell LGL. In addition, CT scan findings of mild hepatosplenomegaly, which is observed in 20%, and IgM and IgG monoclonal gammopathy, which is present in 8% of patients, supported the diagnosis of LGL. A female patient with an indolent clinical course and 72% lymphocytes in the peripheral blood also argues against the features of T-cell gamma delta lymphoma. This case highlights the clinical spectrum of LGL proliferations and T-cell gamma delta lymphoma and how immunophenotypic and genotypic studies can help establish the diagnosis and modify the treatment.

The First Infant Case With Hepatosplenic γδ T-cell Lymphoma After Acute Disseminated Encephalomyelitis (ADEM)-like Exacerbation

We report the first infant case with hepatosplenic gammadelta T-cell lymphoma after recurrent acute disseminated encephalomyelitis-like, which were rapidly resolved with steroid pulse therapy. The patient had a history of recurrent bronchitis, intractable diarrhea, and failure to thrive since 4 months of age. Immunologic analysis revealed higher percentage of circulating gammadelta T-cells with markedly reduced numbers of CD3TCRalphabetaCD8 T-cells. The patient developed gammadelta T-cell lymphoma at the age of 15 months. Clinical course of the patient suggests the importance of immunological background for the development of hepatosplenic gammadelta T-cell lymphoma.

Hepatosplenic γδ T‐cell lymphoma following seven malaria infections

Hepatosplenic gammadelta T-cell lymphoma (HSTL) is a clinicopathological entity associated with an immunocompromised status in approximately 25% of patients. Herein is described a case of HSTL in a 53-year-old Brazilian man with seven previous malaria infections, initially misdiagnosed as a hyperreactive splenomegaly due to chronic malaria. A characteristic lymphoid infiltrate was observed in spleen, liver and bone marrow sinusoids/sinuses. Neoplastic cells had a CD45RO+, CD2+, CD7+, CD3+, CD5-, CD8+, CD56+, perforin+, FasL-negative, T-cell receptor (TCR)alphabeta-negative, TCRgammadelta+ profile. Analyses of gamma and delta TCR rearrangements confirmed diagnosis of gammadelta T-cell lymphoma by detecting VgammaI/Vdelta1-Jdelta1 clonal rearrangements. Sensitive polymerase chain reaction (PCR) for Plasmodium falciparum, Epstein-Barr virus and herpesvirus-8 failed to demonstrate infection. The disease progressed to a fatal outcome following cutaneous infiltration and leukemic proliferation. The authors also comment on the association of lymphoma and infection, focusing on PCR diagnosis of TCRgamma and delta clonal rearrangements and the presumed pathogenic events leading to HSTL in the context of chronic malaria infection. Initial lymphomagenic stages might not be direct consequences of antigenic stimulation of Vdelta1 T-cells, but might depend on interactions between gammadelta T and B cells during cooperative or regulatory responses to Plasmodium sp.

Hepatosplenic γδ T-cell lymphoma with ring chromosome 7, an isochromosome 7q equivalent clonal chromosomal aberration

Hepatosplenic T-cell lymphoma is a rare, clinically aggressive lymphoma. Most cases represent a neoplasm of mature non-activated gammadelta T cells. Isochromosome 7q i(7)(q10) is thought to be the primary cytogenetic abnormality of this disease. In this paper, we describe a hepatosplenic gammadelta T-cell lymphoma case, with clonal ring chromosome 7 exemplifying an isochromosome 7q equivalent clonal aberration. A 62-year-old female patient presented with thrombocytopenia, isolated hepatosplenomegaly, and extremely high levels of LDH. Bone marrow work-up demonstrated a sinusoidal cytotoxic T-cell infiltrate with blastic features, while molecular studies verified monoclonal rearrangement for both TCR gamma and TCR delta genes. Cytogenetics revealed clonal abnormalities including ring chromosome 7, trisomy 8, and der(19), while FISH analysis detected 7q amplification with partial deletion of 7p in ring chromosome 7. To the best of our knowledge, this is the first reported T-cell lymphoma case with ring chromosome 7.

A case of hepatosplenic γ–δ T‐cell lymphoma with a transient response to Fludarabine and Alemtuzumab

Hepatosplenic gamma-delta T-cell lymphoma is a rare, usually fatal lymphoma and available literature on management is sparse. Allografting is probably the only curative option. We describe a further case with a dramatic, though transient response to Fludarabine and Alemtuzumab combination, following a failure of conventional chemotherapy. Given the dreadful prognosis with conventional chemotherapy, it is a regimen worth pursuing as a disease reduction strategy prior to allograft where appropriate.

Flow cytometric immunophenotypic profiles of mature gamma delta T‐cell malignancies involving peripheral blood and bone marrow

In this study we compared clinical findings with flow cytometric immunophenotypic results in a series of patients with aggressive and indolent gamma delta T-cell malignancies with peripheral blood and/or bone marrow involvement. Gamma delta T-cell malignancies were detected based on flow cytometric demonstration of an abnormal T-cell population staining positive with T-cell receptor gamma delta and confirmed by morphologic and clinical reviews. Clinical data were obtained through chart review and discussion with the patients' physicians. Blood or bone marrow involvement was present in all patients. Hepatosplenic and cutaneous gamma delta T-cell lymphomas had an aggressive clinical course, whereas the gamma delta T-cell large granular lymphocyte (LGL) leukemias had an indolent course. Expressions of CD5, CD8, CD16, and CD57 differed in gamma delta T-cell LGL leukemia compared with hepatosplenic and cutaneous gamma delta T-cell lymphomas. Gamma delta T-cell malignancies have a poor prognosis with the exception of gamma delta T-cell LGL leukemia (indolent process). Because CD57 expression is specific for gamma delta T-cell LGL leukemias, expression of this antigen may be associated with a more indolent clinical course. Because cutaneous gamma delta T-cell lymphoma can present with peripheral blood involvement, flow cytometric evaluation of peripheral blood is important in staging these patients.

Autopsy case of CD4–/CD8– cutaneous T‐cell lymphoma presenting disseminated pagetoid reticulosis with aggressive granulomatous invasion to the lungs and pancreas

Pagetoid reticulosis is a rare cutaneous T-cell lymphoma with striking epidermotropism similar to that present in Paget's disease. There are two forms of pagetoid reticulosis: localized and disseminated. Reported herein is an autopsy case of disseminated pagetoid reticulosis with CD4(-)/CD8(-) phenotype T cells and massive invasion of the lungs and pancreas. The abnormal cells in the epidermis expressed a protein derived from a rearranged T-cell receptor beta gene, and this feature was used to confirm the monoclonality of these cells by polymerase chain reaction. At present, the World Health Organization (WHO) classification system considers pagetoid reticulosis to be an indolent form of primary cutaneous T-cell lymphoma and a variant of mycosis fungoides/Sezary syndrome with prominent epidermotropism. Some differences have been observed between pagetoid reticulosis and mycosis fungoides in terms of clinical course, tumor cell phenotype, and genetic findings; and these differences are highlighted in the present case. The relation between disseminated pagetoid reticulosis, CD4(-)/CD8(-) cutaneous T-cell lymphoma, and gammadelta T-cell lymphoma, including whether pagetoid reticulosis is a variant of mycosis fungoides, remains unclear.

Hepatosplenic γδ T-cell lymphoma

To investigate the clinicopathologic characteristics, immunophenotype and TCR gene rearrangements of hepatosplenic T-cell lymphoma in eight Chinese patients. Eight Chinese patients with hepatosplenic gammadelta T-cell lymphomas were studied. Hematoxylin-eosin-stained slides and clinical histories were reviewed. We also carried out immunohistochemical staining for CD3, CD4, CD8, CD20, CD43, CD56, CD79a, UCHL-1, and TCR gammadelta. Rearrangements of TCR gamma and delta chain genes were also studied. The spleens were enlarged and the cut surfaces were homogeneous and red-purple in color without identifiable gross lesions or enlarged hilar lymph nodes. Histologically, lymphoma cells infiltrated the cords of Billroth and often packed the sinuses. Liver biopsy showed lymphoma cell infiltrations in the sinusoids, and three cases showed involvements of the portal tracts. Immunohistochemically lymphoma cells were positive for CD3, CD43, and CD56 in all cases. Four of eight cases were positive for CD8, and all cases were negative for CD4 (6/6). Monoclonal rearrangements of TCR gamma gene were demonstrated by PCR analysis in five out of the eight cases. TCR delta gene rearrangements were detected in six out of the eight cases, which demonstrated single bands on PAGE gel, and the amplification products in two cases were confirmed by sequencing. The clinicopathology of hepatosplenic gammadelta T-cell lymphoma in Chinese patients is similar to what was previously reported except that the splenomegaly is not so massive, and CD8 is positive.

Mature T-Cell and NK-Cell Lymphomas in the Pediatric Age Group

Despite the overall rarity of T-cell and natural killer (NK)-cell neoplasms, these tumors are not uncommon in children. Anaplastic lymphoma kinase (ALK)+ anaplastic large cell lymphoma is the most common pediatric mature T-cell malignancy, usually having a good prognosis. Some cases with unusual clinical manifestations, such as a leukemic phase or central nervous system involvement, are more aggressive. ALK+ large B-cell lymphomas are rare in children and most commonly exhibit translocations involving ALK and clathrin. Notably, other malignant neoplasms encountered in the pediatric age group usually are derived from cytotoxic T cells or NK cells. These tumors are derived from cells of the innate immune system, comprising a more primitive type of immune response. Cases presented at the Society for Hematopathology and the European Association for Haematopathology workshop included examples of hepatosplenic gammadelta T-cell lymphoma, aggressive NK-cell leukemia, and fulminant Epstein-Barr virus-positive T-cell lymphoproliferative disease. This early component of the immune system might be targeted more often in pediatric hematologic malignant neoplasms, whereas tumors of the more mature adaptive immune system are more rare in children.

Gamma/Delta T-cell Lymphoma as a Recurrent Complication after Transplantation

We present a case of gamma-delta (γδ) T-cell lymphoma as a recurrent event in a pediatric liver transplant recipient. Liver transplantation was performed during infancy in an 18-month-old black girl because of cryptogenic cirrhosis. The patient received immunosuppression with cyclosporine and prednisone. Five years after transplantation, the patient was found to have a γδ T-cell lymphoma located in retroperitoneal nodes. She received chemotherapy and did well, remaining disease-free for 6 years. She remained only on prednisone for prevention of graft rejection, but was noted to have a non-tender skin nodule that upon biopsy proved to be again a γδ T-cell lymphoma. However, comparison of tissue from both tumors revealed that the second occurrence of this malignancy was a de novo event, differing from the first by immunophenotypic and immunohistochemical characteristics, and TCR rearrangement. The patient continues to do well, without evidence of disease recurrence, after being treated again with chemotherapy. A summary of the literature is presented and comparison of our case is made.

Primary Omental Gamma/Delta T-Cell Lymphoma Involving the Central Nervous System

Gamma/delta T-cell lymphoma (GDTL) is an uncommon lymphoma that was initially reported to involve only the liver and spleen. GDTL other than the hepatosplenic type is extremely rare. Frequent primary sites include skin and subcutaneous tissue, intestine, or nasal region. We report a case of GDTL of the omentum in a 54 year-old-man. The tumor cells are CD2-, CD3+, CD4-, CD5-, CD8+, CD56+, TIA-1+, granzyme B+/-. They expressed the identical phenotype of intestinal GDTL. The patient was treated with 2 courses of CHOP which comprised cyclophosphamide, doxorubicin, vincristine and prednisolone, and 3 courses of EPOCH which comprised etoposide, prednisolone, vincristine, cyclophosphamide and doxorubicin. However, he failed to obtain remission. During the fourth course of EPOCH, muscle weakness of the lower extremities developed and intracranial masses were observed by computed tomographic scan of the brain. Dissemination of lymphoma to the central nervous system was considered and it may be attributable to the expression of CD56 in this case. High dose methotrexate (HD-MTX) chemotherapy successfully eliminated the omental tumor and reduced the size of the intracranial masses, thus HD-MTX appears to be an effective treatment against GDTL.

Chronic Clonal Proliferative Disease of Gamma-Delta (γδ) T-cells in a Patient with Rheumatoid Arthritis and Neutropenia: Lack of the Morphology and the Immunophenotype of Large Granular Lymphocytes

Normal gammadelta T-lymphocytes have the morphology of large granular lymphocytes (LGL) and, as the LGL of alphabeta T-cells, they express pan-T antigens, NK-associated antigens and the cytotoxic molecules, perforin and granzime B. In this report we describe an unusual patient with rheumatoid arthritis and neutropenia who has a chronic gammadelta T-cell proliferation with a chronic, indolent clinical course and atypical lymphocytes, lacking the classical LGL morphology, not expressing NK-associated antigens, and not expressing perforin or granzyme B. In spite of the atypical morphological features of the clonal cells, which were suggestive of a more malignant process, the patient has been followed for 4 years without aggressive therapy. It is important to recognize this entity and to distinguish it from other gammadelta T proliferations such as the hepatosplenic gammadelta T-cell lymphoma.

Gamma/Delta T-Cell Lymphoma of Duodenal BulbA Case Report

Gamma/delta T-cells represent a minor subset of T lymphocytes in the peripheral blood of limited diversity and a tissue restricted distribution. 1 Groh V Porcelli S Fabbi M Lanier LL Picker LJ Anderson T et al. Human lymphocytes bearing T cell receptor gamma/delta are phenotypically diverse and evenly distributed throughout the lymphoid system. J Exp Med. 1989; 169: 1277-1294 Crossref PubMed Scopus (437) Google Scholar , 2 Falini B Flenghi L Pileri S Pelicci P Fagioli M Martelli MF et al. Distribution of T cells bearing different forms of the T cell receptor gamma/delta in normal and pathological human tissues. J Immunol. 1989; 143: 2480-2488 PubMed Google Scholar These T-cells have a predilection for the red pulp of the spleen and the GI tract. 1 Groh V Porcelli S Fabbi M Lanier LL Picker LJ Anderson T et al. Human lymphocytes bearing T cell receptor gamma/delta are phenotypically diverse and evenly distributed throughout the lymphoid system. J Exp Med. 1989; 169: 1277-1294 Crossref PubMed Scopus (437) Google Scholar , 2 Falini B Flenghi L Pileri S Pelicci P Fagioli M Martelli MF et al. Distribution of T cells bearing different forms of the T cell receptor gamma/delta in normal and pathological human tissues. J Immunol. 1989; 143: 2480-2488 PubMed Google Scholar , 3 Bordessoule D Gaulard P Mason DY Preferential localisation of human lymphocytes bearing gamma delta T cell receptors to the red pulp of the spleen. J Clin Pathol. 1990; 43: 461-464 Crossref PubMed Scopus (72) Google Scholar Most neoplasms arising from the gamma/delta T-cell subpopulation are hepatosplenic gamma/delta T-cell lymphomas, a distinctive clinicopathologic entity. 4 Wong KF Chan JK Matutes E McCarthy K Ng CS Chan CH et al. Hepatosplenic gamma delta T-cell lymphoma. A distinctive aggressive lymphoma type. Am J Surg Pathol. 1995; 19: 718-726 Crossref PubMed Scopus (96) Google Scholar , 5 Cooke CB Krenacs L Stetler-Stevenson M Greiner TC Raffeld M Kingma DW et al. Hepatosplenic T-cell lymphoma: a distinct clinicopathologic entity of cytotoxic gamma delta T-cell origin. Blood. 1996; 88: 4265-4274 PubMed Google Scholar Several cases have been reported of non-hepatosplenic gamma/delta T-cell lymphoma in specific sites such as cutaneous tissue, 6 Fujita M Miyachi Y Furukawa F Toichi E Furukawa I Nakajima N Imamura S A case of cutaneous T-cell lymphoma expressing gamma delta T-cell receptors. J Am Acad Dermatol. 1993; 28: 355-360 Abstract Full Text PDF PubMed Scopus (26) Google Scholar , 7 Arnulf B Copie-Bergman C Delfau-Larue MH Lavergne-Slove A Bosq J Wechsler J et al. Nonhepatosplenic gammadelta T-cell lymphoma: a subset of cytotoxic lymphomas with mucosal or skin localization. Blood. 1998; 91: 1723-1731 PubMed Google Scholar the nasopharyngeal region, 7 Arnulf B Copie-Bergman C Delfau-Larue MH Lavergne-Slove A Bosq J Wechsler J et al. Nonhepatosplenic gammadelta T-cell lymphoma: a subset of cytotoxic lymphomas with mucosal or skin localization. Blood. 1998; 91: 1723-1731 PubMed Google Scholar , 8 Kanavaros P Lescs MC Briere J Divine M Galateau F Joab I et al. Nasal T-cell lymphoma: a clinicopathologic entity associated with peculiar phenotype and with Epstein-Barr virus. Blood. 1993; 81: 2688-2695 PubMed Google Scholar the GI tract, 7 Arnulf B Copie-Bergman C Delfau-Larue MH Lavergne-Slove A Bosq J Wechsler J et al. Nonhepatosplenic gammadelta T-cell lymphoma: a subset of cytotoxic lymphomas with mucosal or skin localization. Blood. 1998; 91: 1723-1731 PubMed Google Scholar , 9 Lavergne A Brocheriou I Delfau MH Copie-Bergman C Houdart R Gaulard PH Primary intestinal gamma-delta T-cell lymphoma with evidence of Epstein-Barr virus. Histopathology. 1998; 32: 271-276 Crossref PubMed Scopus (23) Google Scholar , 10 Tsujikawa T Itoh A Bamba M Andoh A Hodohara K Inoue H et al. Aggressive jejunal gamma delta T-cell lymphoma derived from intraepithelial lymphocytes: an autopsy case report. J Gastroenterol. 1998; 33: 280-284 Crossref PubMed Scopus (6) Google Scholar , 11 Katoh A Ohshima K Kanda M Haraoka S Sugihara M Suzumiya J et al. Gastrointestinal T cell lymphoma: predominant cytotoxic phenotypes, including alpha/beta, gamma/delta T cell and natural killer cells. Leuk Lymphoma. 2000; 39: 97-111 Crossref PubMed Scopus (57) Google Scholar and a single case involving the thyroid gland. 12 Yamaguchi M Ohno T Kita K gamma/delta T-cell lymphoma of the thyroid gland. N Engl J Med. 1997; 336: 1391-1392 Crossref PubMed Scopus (38) Google Scholar Reported here is the first case of gamma/delta T-cell lymphoma of the duodenal bulb. Expression of gamma/delta T-cell receptor (TCR) was confirmed by both genetic analysis of the TCR gamma and the delta chain by using the polymerase chain reaction (PCR) method, and immunostaining of TCR gamma. Systemic examination by CT and gallium scintigraphy incidentally revealed metastasis to the right lobe of the thyroid gland. The patient was treated with combination chemotherapy and was disease free at one year follow-up.

Gamma-delta T-cell phenotype is associated with significantly decreased survival in cutaneous T-cell lymphoma

The importance of alpha beta versus gamma delta T-cell subset antigen expression in the classification of peripheral T-cell lymphomas is still unclear. The objective of this study was to investigate the prognostic value of T-cell receptor-delta 1 (TCR delta 1) expression in primary cutaneous T-cell lymphomas. TCR delta 1 cellular expression was assessed in skin biopsy specimens of 104 individuals with cutaneous T-cell lymphoma by immunohistochemistry. Both univariate (Kaplan-Meier) and multivariate (Cox regression) analyses were conducted to determine which variables (T-cell subtype, hemophagocytosis, histologic profile, age, sex, and adenopathy) were significantly associated with survival. Univariate analysis indicated that there was a statistically significant difference in survival between the patients with alpha beta cutaneous T-cell lymphoma and patients with gamma delta cutaneous T-cell lymphoma (P <.0001). There was also a statistically significant decrease in survival among patients who had subcutaneous involvement compared with patients who had epidermotropic and/or dermal involvement (P <.0001). Cox model analysis indicated that TCR delta 1 expression was the factor that was most closely associated with decreased survival (P <.0001). Among those patients with cutaneous gamma delta T-cell lymphoma (n = 33), there was a trend for decreased survival for patients who had histologic evidence of subcutaneous fat involvement in comparison with patients who had epidermotropic or dermal patterns of infiltration (P =.067). No other prognostic factors were identified as having a notable association with outcome in this subgroup. TCR delta 1 expression in primary cutaneous lymphomas is an independent prognostic factor associated with decreased survival.

Preferential Expansion of Vγ9-JγP/Vδ2-Jδ3 γδ T Cells in Nasal T-Cell Lymphoma and Chronic Active Epstein-Barr Virus Infection

We recently established an Epstein-Barr virus (EBV)-positive gammadelta T-cell line from a nasal T/natural killer (NK)-cell lymphoma (Nagata H, Konno A, Kimura N, Zhang Y, Kimura M, Demachi A, Sekine T, Yamamoto K, Shimizu N: Characterization of novel natural killer (NK)-cell and gammadelta T-cell lines established from primary lesions of nasal T/NK-cell lymphomas associated with the Epstein-Barr virus. Blood 2001, 97:708-713). Subsequently, we established two novel EBV-positive gammadelta T-cell lines from the peripheral blood of patients with chronic active EBV infection. Analysis of the terminal repeat of EBV showed that the three cell lines consisted of monoclonal populations, and flow cytometry showed that they had a common phenotype of gammadelta T cells: CD3(+) CD4(-) CD8(-) CD16(-) CD19(-) CD56(+) CD57(-) HLA-DR(+) T-cell receptor (TCR) alphabeta(-) TCR gammadelta(+). Analysis for the expression of TCR by flow cytometry showed that all three cell lines were Vgamma9(+)/Vdelta2(+), but negative for VgammaI, Vdelta1, or Vdelta3 TCR. Southern blot analysis for TCR genes showed that the three cell lines had a common rearrangement of Vgamma9-JgammaP and Jdelta3 genes. Polymerase chain reaction and sequence analysis of the junction between Vdelta and Jdelta genes revealed that the Jdelta3 genes were rearranged with the Vdelta2 genes. In contrast, none of the EBV-negative gammadelta T-cell lines, Molt-14, Peer, or Loucy, which were analyzed for controls, had Vgamma9 or Vdelta2 TCR, or a rearrangement of Jdelta3 genes. These results indicated that Vgamma9-JgammaP/Vdelta2-Jdelta3(+) gammadelta T cells were preferentially affected by EBV and expanded in patients with nasal gammadelta T-cell lymphoma and chronic active EBV infection. Jdelta3(+) gammadelta T cells are known to be a very minor population in gammadelta T cells of peripheral blood, whereas Vgamma9-JgammaP/Vdelta2-Jdelta1(+) cells are the major population. The close association of EBV with this particular gammadelta T-cell population may provide a key to the etiology of EBV-positive lymphoproliferative diseases.

A Type of Rat Hepatosplenic Gamma-delta (γδ) T-cell Lymphoma Developed after Injections with Hepatocyte Growth Factor (HGF) Oligonucleotides, which was Rejected by Surviving Syngeneic Spleen Graft

The transduction of exogenous hepatocyte growth factor (HGF) genes to spleen T lymphocytes and the immune effects of syngeneic spleen graft on spleen lymphoma cells were studied in LEW/Sea rats. Three different systems were designed. (1) Six female rats and six male rats received irradiated spleen graft and were followed for 7 months. (2) Five female rats and six male rats received intra-peritoneal (ip) injections of the Lewis red cells incorporated 20-bp HGF genes and anti-interleukin-6 (IL-6) antibody (Ab) with spleen graft and were followed for 5.5 months. (3) Four females and five males received ip injections of the Lewis red cells incorporated 20-bp HGF genes and anti-IL-6 Ab without spleen graft and were followed for 5.5 months. Hemato-pathological analyses, flow cytometer analyses of gamma-delta (γ δ ) T-cell receptor (TCR)-positive lymphocytes and reverse-transcription-polymerase chain reaction (RT-PCR) of TCR γ gene, TCRV α 3 gene and apoptotic genes were performed. Results showed that one of the six females received irradiated spleen graft developed nodal gamma-delta (γ δ ) T-cell pre-lymphoma with 100% of γ δ TCR + lymphocytes in the mesenteric lymph nodes. One female injected with the HGF genes and anti-IL-6 Ab and grafted spleen died of advanced hepatosplenic γ δ T-cell lymphoma at 3.5 month observation. All the five males injected with the HGF genes and anti-IL-6 Ab without spleen graft developed early hepatosplenic γ δ T-cell lymphoma at 5.5 month observation. In two rats with spleen graft and the two rats without spleen graft, which were injected with the HGF genes and anti-IL-6 Ab, the lymphoma was suspected uncertainly with activated TCRV α 3 mRNA. The ip injections of HGF genes, which were incorporated in the red blood cells, triggered hapatosplenic γ δ T-cell lymphoma. Surviving spleen graft rejected the lymphoma cells, but not in rats rejected the graft. Spleen graft was a good organ transplantation to expect graft versus lymphoma effects.

Bone marrow involvement in lymphomas with hemophagocytic syndrome at presentation: a clinicopathologic study of 11 patients in a Western institution.

Hemophagocytic syndrome (HPS) is a clinicopathologic syndrome that can reveal a non-Hodgkin's lymphoma. The pathologic features of lymphoma associated with HPS remain ill defined. We studied 11 lymphomas associated with HPS on initial bone marrow biopsies, consecutively diagnosed during a 6-year period in a Western institution. There were seven diffuse large B-cell lymphomas (DLBCLs), three T-cell lymphomas (one peripheral T-cell lymphoma unspecified, two hepatosplenic gammadelta T-cell lymphomas [HS gammadeltaTLs]), and one aggressive NK-cell lymphoma/leukemia (NKL). These lymphomas shared common clinicopathologic features with a systemic presentation, a poor outcome (nine patients died within 2 years), and a mild interstitial lymphoid infiltrate of the bone marrow at presentation in nine patients. This equivocal lymphoma infiltrate was blending with normal hematopoietic cells, and CD20 and CD3 immunolabelings were essential for its detection. A high number of reactive T (CD3+) cells, most often with a predominant cytotoxic (CD8+ TiA1+) phenotype, was present in all DLBCLs. By in situ hybridization, Epstein-Barr virus was detected in neoplastic cells of three cases (one DLBCL, one HS gammadeltaTL, and one NKL), which also showed serum viral DNA. Polymerase chain reaction studies disclosed HHV6 DNA sequences in tumor tissues of two DLBCLs, whereas HHV8 DNA was not detected. Because tumor mass indicative of lymphoma was not striking in most patients, bone marrow biopsy appears to be of great value for the diagnosis of an HPS-associated lymphoma, which may be, in Western patients, of B- as well as T- or NK-cell type. Immunostaining for CD3 and CD20 is essential to identify the common subtle lymphoma involvement. Together with a better understanding of the pathogenic processes, an early diagnosis may improve the prognosis of HPS-associated lymphoma.

Expression of CD94/NKG2A and killer immunoglobulin-like receptors in NK cells and a subset of extranodal cytotoxic T-cell lymphomas

Thirty-two natural killer (NK) and cytotoxic T-cell lymphomas and 14 noncytotoxic nodal T-cell lymphoma controls were immunostained with the use of monoclonal antibodies reactive against NK-cell receptor (NKR) molecules (CD94, NKG2A, p58.2, p58.1, p140, p70, p50.3). All NK-cell lymphomas (4 nasal/oral and 1 intestinal) expressed at least 1 NKR, the CD94/NKG2A complex. Two were positive for 1 or more killer immunoglobulin-like receptors. Of 15 extranodal cytotoxic T-cell lymphomas, 3 expressed CD94, including 2 intestinal and 1 hepatosplenic gammadelta T-cell lymphomas. In contrast, none of the nodal lymphomas were positive. Detection of NKRs may provide a useful tool to confirm the diagnosis of NK-cell lymphomas and to delineate a subgroup of cytotoxic T-cell lymphomas. Expression of NKRs only in extranodal cytotoxic T-cell lymphomas might reflect differences in the homing capabilities of cytotoxic T cells expressing NKRs in normal individuals and might be influenced in part by localized chronic immune reactions.