1. GENERAL INFORMATION
Peripheral T-cell lymphomas constitute an apparently heterogeneous group of malignancies previously classified as T-zone, lymphoepithelioid cell, pleomorphic, or T-immunoblastic lymphomas according to the Kiel classification (Banks 1992; Lennert 1978). This corresponds mostly to diffuse small-cleaved cell, diffuse mixed small and large cells or large-cell immunoblastic lymphomas in the Working Formulation. This is a group of lymphomas uncommon in Western countries, whose classification is very difficult because the lack of reliable immunophenotypic markers of T-cell malignancies. Some distinct clinical syndromes with recognizable morphologic features of T-cell malignancies have been described, and they should be considered separately. Peripheral T-cells in various stages of transformation have been postulated as the normal-cell counterparts for peripheral T-cell lymphomas.
Peripheral T-cell lymphomas constitute less than 15% of all NHLs in the United States and Europe but are more common in other parts of the world. According to the REAL classification, the most common subtypes of peripheral T-cell lymphomas are the unspecified peripheral T-cell lymphoma (54% of cases), anaplastic large cell lymphoma (17%), angioimmunoblastic (13%), angiocentric (9%), intestinal T-cell lymphoma (7%), and hepatosplenic g/d T-cell lymphoma (0.5%) (Lopez-Guillermo 1998). In the present article, only data regarding unspecified peripheral T-cell lymphoma are reported.
1.3 Risk factors
No risk factors have been clearly identified in peripheral T-cell lymphomas (PTCL). The frequent positivity of Epstein-Barr virus suggests, as is the case for B-cell neoplasms, a role for this virus in pathogenesis of PTCL. No particular correlation between PTCL and inherited immunological deficiency disease, or other immunological disorders has been reported. There are no convincing data regarding the role of chronic antigenic stimulation in the genesis of PTCL. However, the inflammatory background and the follicular dendritic cell proliferation observed in these malignancies suggest a pathogenesis mediated by different chemokines. Several chemical substances such as solvents, pesticides and fertilizers as well as dusts and particles, hair, smoking and diet have been suggested as possible aetiological factors in NHL (Weisenburger 1985). Among other pesticides, 2,4-D (Zahm 1990) and organophosphate insecticides (Woods 1987) and phenoxy herbicides (La Vecchia 1989) have been suggested as aetiological agents. Although the highest risk is related to the occurrence of large-cell lymphomas, all histotypes of NHL occur in people whose work involves application of pesticides (Scherr 1992; Weisenburger 1990).
2. PATHOLOGY AND BIOLOGY
Peripheral T-cell lymphomas of unspecified types show a diffuse or occasionally interfollicular proliferation that gives rise to cells ranging from small to medium-sized or large cells. Most cases contain a mixed population of small and large cells, and even those with a predominance of medium-sized or large cells often contain a broad spectrum of cell sizes (Suchi 1987; Weiss 1985). Admixed eosinophils or epithelioid histiocytes may be numerous (Patsouris 1988). The neoplastic cells often have irregular nuclei and vary considerably in size and shape, with occasional large, hyperchromatic cells that may resemble Reed-Sternberg cells. True Reed-Sternberg cells are rare or absent. Stratification according to the number of large/medium cells, defining the categories as medium-sized cell, mixed medium and large cell, and large cell types has been proposed (Harris 1994).
The cells of peripheral T-cell lymphomas variably express the T-cell-associated antigens (CD3+/-, CD2+/-, CD5+/-, CD7-/+), CD4 > CD8, may be CD4-CD8-. These cells do not express the B-cell-associated antigens, but rare cases of CD20+ have been reported (Borowitz 1986 ; Hastrup 1989; Strickler 1987).
2.3 Genetic features
Cytogenetic data on peripheral T-cell lymphomas are still limited because of the rarity of these malignancies in Western countries and the use of different histological classifications. TCR genes are usually but not always rearranged; Ig genes are germline (Weiss 1985; Weiss 1988). Some types of T-cell lymphomas show specific chromosome abnormalities, that is t(2;5)(p23;q35) associated with anaplastic large T-cell lymphoma and isochromosome 7q in hepatosplenic g/d T-cell lymphoma. High-grade peripheral T-cell lymphomas, predominantly pleomorphic medium- and large-cell lymphomas differ significantly from low-grade peripheral T-cell lymphomas (AILD, lymphoepithelioid T-cell, T-zone, and cutaneous T-cell lymphomas) with regard to the presence of normal metaphases, aberrant clones, polyploidy, and complexity of the clones (Campo 1998). Deletions of 6q, total or partial trisomies of 7q and monosomy 13 or changes 13q14 are significantly more common in high-grade than in low-grade lymphomas (Schlegelberger 1994). Chromosomally abnormal clones were identified in 71% of PTCL cases, 1p36 breakpoints in half of them (Inwards 1990). Chromosome abnormalities previously attributed to B-cell malignancies are infrequent.
3.1 Clinical presentations
Usually, unspecified peripheral T-cell lymphomas occur in adults, with a median age of 55-60 years old, similar to that reported for B-cell lymphomas (Campo 1998). These lymphomas arise in older patients by comparison with other T-cell lymphomas such as angiocentric, anaplastic large cell or intestinal forms (Lopez-Guillermo 1998). A higher prevalence among males with respect to B cell lymphomas has been reported (Campo 1998). This clinically heterogeneous group of malignancies presents more often as disseminated disease (stage III or IV disease), occasionally with eosinophilia, pruritis or hemophagocytic syndromes (Falini 1990). Generalized lymphadenopathies, cutaneous or subcutaneous lesions (12%), hepatic (13%), marrow (41%), splenic and visceral involvements (extranodal sites in 65% of cases) constitute the most frequent clinical presentations (Chott 1992; Gonzalez-Clemente 1991; Lopez-Guillermo 1998). B-symptoms are present in more than 50% of cases, high serum LDH level in 53%, high serum b2-microglobulin in 62% of cases (Lopez-Guillermo 1998). By contrast with angiocentric lymphoma, involvement of gastrointestinal tract is rare, while CNS is infiltrated in less than 5% of cases (Lopez-Guillermo 1998), and contrasting with anaplastic large cell lymphoma, only one quarter of patients with unspecified peripheral T-cell lymphoma shows a low-risk according to the International Prognostic Index. On the basis of the predominant mode of presentation, peripheral T-cell lymphomas can be grouped as predominant leukemic or disseminated, nodal or extranodal malignancies (Chan 1997).
3.2 Diagnostic criteria
Usually, unspecified peripheral T-cell lymphomas occur in adults, with a median age of 55-60 years. These lymphomas arise in older patients compared with other T-cell lymphomas such as angiocentric, anaplastic large cell or intestinal forms (Lopez-Guillermo 1998). A higher prevalence of B cell lymphomas among males has been reported (Campo 1998). This clinically heterogeneous group of malignancies presents more often as disseminated disease (stage III or IV disease), occasionally with eosinophilia, pruritis or hemophagocytic syndromes (Falini 1990), generalized lymphadenopathies, cutaneous or subcutaneous lesions (12%), and hepatic (13%), marrow (41%), splenic and visceral involvement (extranodal sites in 65% of cases) (Chott 1992; Gonzalez-Clemente 1991; Lopez-Guillermo 1998). B-symptoms are present in more than 50% of cases, high serum LDH level in 53%, high serum 2-microglobulin in 62% of cases (Lopez-Guillermo 1998). From a morphological point of view, peripheral T-cell lymphomas of unspecified type show a diffuse or occasionally interfollicular proliferation that produces cells ranging in size from small to medium-sized or large cells. Most cases contain a mixed population of small and large cells, and even those with a predominance of medium-sized or large cells often contain a broad spectrum of cell sizes (Suchi 1987; Weiss 1985). Admixed eosinophils or epithelioid histiocytes may be numerous (Patsouris 1988). The neoplastic cells often have irregular nuclei and vary considerably in size and shape, with occasional large, hyperchromatic cells that may resemble Reed-Sternberg cells. True Reed-Sternberg cells are rare or absent. Stratification according to the number of medium/large cell, defining the categories as medium-sized cell, mixed medium and large cell, and large cell types has been proposed (Harris 1994). Immunophenotyping is extremely useful in diagnosis of peripheral T-cell lymphoma. The tumor cells variably express the T-cell-associated antigens (CD3+/-, CD2+/-, CD5+/-, CD7-/+), CD4 > CD8, may be CD4-CD8-. They do not express the B-cell-associated antigens, but rare cases of CD20+ have been reported (Borowitz 1986; Hastrup 1989; Strickler 1987). Cytogenetic studies can show TCR genes rearrangement, while Ig genes are germline (Weiss 1988; Weiss 1985). Some types of T-cell lymphomas show specific chromosome abnormalities, that is t(2;5)(p23;q35) associated with anaplastic large T-cell lymphoma and isochromosome 7q in hepatosplenic T-cell lymphoma. High-grade peripheral T-cell lymphomas differ significantly from low-grade peripheral T-cell lymphomas with regard to the presence of normal metaphases, aberrant clones, polyploidy, and complexity of the clones (Campo 1998). Deletions of 6q, total or partial trisomies of 7q and monosomy 13 or changes 13q14 are significantly more common in high-grade than in low-grade lymphomas (Schlegelberger 1994).
3.3 Additional useful tests
No reliable molecular markers are available for monitoring of minimal residual disease in unspecified peripheral T-cell lymphoma.
4.1 Staging procedures
Complete staging work-up for unspecified peripheral T-cell lymphoma is the same that used routinely for nodal NHL. It includes an accurate physical examination, complete haematological and biochemical exams, total-body computerized tomography, gastrointestinal tract examination, and bone marrow aspirate and biopsy. Lymphangiography has been completely replaced by abdominal computerized tomography considering the higher sensitivity of tomography to detect mesenteric nodes and its capacity to show a true estimation of node sizes, which usually are underestimated with lymphangiography. Since the clinical relevance of marrow involvement and general statements for all NHL , marrow biopsy should be bilateral. Laparoscopy with multiple liver biopsies should be carried out only when there is a strong suspicion of liver involvement in a patient who would otherwise be diagnosed as having stage I-II disease. Staging laparotomy and splenectomy should never be performed in ordinary clinical practice as a routine staging procedures. Although laparotomy-related mortality is lower than 1%, morbidity has been reported in up to 40% of patients (Herman 1977). The major factor that accounts for the limited need for laparotomy is the high yield of information from less morbid procedures and the recognition that precise definition of involvement probably has limited importance in treatment planning for most patients.
4.2 Staging system
The standard staging system used for unspecified peripheral T-cell lymphomas is the same as that proposed for Hodgkin’s disease at the Ann Arbor Conference in 1971 (Carbone 1971). This system is currently used for all non-Hodgkin’s lymphomas, even if other staging systems are used in some extranodal lymphomas which display particular biological behaviour. The Ann Arbor staging system reflects both the number of sites of involvement and the presence of disease above or below the diaphragm. This staging system considers four stage of disease: Stage I: involvement of a single lymph node region (I) or a single extranodal site (IE). Stage II: involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic site (IIE). Stage III: involvement of lymph node regions on both sides of the diaphragm (III) or localized involvement of an extralymphatic site (IIIE) or spleen (IIIs) or both (IIIEs). Stage IV: diffuse or disseminated involvement of one or more extralymphatic organs with or without associated lymph node involvement. Localized involvement of liver or bone marrow is also considered stage IV. Patients are divided in two subsets according to the presence (A) or absence (B) of systemic symptoms. Fever of no evident cause, night sweats and weight loss of more than 10% of body weight are considered systemic symptoms. Even though it is a frequently accompanying symptom, itch should not be considered as a systemic symptom. The presence of bulky mass, such as a lesion of 10 cm or more in the longest diameter is signaled as “X”, while the extranodal involvement should be identified by a symbol (O: bone, L: lung, D: skin, etc.).
4.3 Molecular analysis
No reliable molecular markers are available for monitoring of minimal residual disease in unspecified peripheral T-cell lymphoma.
4.4 Restaging procedures
Restaging should include all the diagnostic procedures which were positive at time of diagnosis and initial staging.
5.1 Natural history
Peripheral T-cell lymphomas represent a heterogeneous group of malignancies, including several subtypes with some unique clinical and prognostic features. With the exception of the anaplastic large cell subtype, these malignancies usually present with unfavorable features, respond poorly to treatment and have short survival (Campo 1998). The overall complete response rate is lower than 50% – in comparison with almost 70% reported for anaplastic large cell lymphoma- with a risk of relapse at four years of 50% and a median survival shorter than 2 years (65 months for anaplastic large cell lymphoma) (Lopez-Guillermo 1998; Pittaluga 1996). Median survival of patients with unspecified peripheral T-cell lymphoma is similar to that reported for angiocentric and angioimmunoblastic lymphomas, while it is significantly longer than that reported for patients affected by intestinal T-cell lymphomas (Lopez-Guillermo 1998). Overall, no plateau has been observed in relapse and survival curves suggesting that cure is a very rare event in these patients, even among the many low-risk patients (Gisselbrecht 1998; Melnyk 1997).
5.2 Prognostic factors
Specific prognostic indicators for each subtype of peripheral T-cell lymphomas have not been definitively identified. However, the prognosis and indicators of peripheral T-cell lymphomas should be differentiated from those of anaplastic large cell lymphoma, as this lymphoma subtype shows a significantly better prognosis than the rest of the other peripheral T-cell lymphomas. The main survival indicators for peripheral T-cell lymphomas, excluding the anaplastic large cell subtype, are performance status, advanced stage, extranodal involvement, serum 2-microglobulin level, and International Prognostic Index (Pittaluga 1996). To date, the last of these factors is the unique significant prognostic indicator described for unspecified peripheral T-cell lymphoma (Campo 1998). Several studies have addressed the prognosis of patients with peripheral T-cell lymphomas (PTCL), in comparison with B-cell lymphomas, but the reports are conflicting. PTCL patients were found to have the same (Cheng 1989; Kwak 1991) or poorer (Lippman 1988; Melnyk 1997) prognoses than B-cell lymphomas patients. Although T-cell phenotype seems to be an independent and significant prognostic factor in NHLs, it is not possible to demonstrate a statistically significant effect on overall survival among the different lymphoma subtypes (Kwak 1991).
6.1 Treatment of limited disease Melnyk (Stage I-II)
Only 20% of patients with unspecified peripheral T-cell lymphoma have a stage I-II disease at presentation. Since this clinical presentation is so rare, a standard treatment has not been established. As for limited stage B-cell lymphomas with aggressive clinical behaviour, combined treatment with primary systemic conventional-dose polychemotherapy followed by radiation therapy is suitable for individual clinical use on a type R basis (Lopez-Guillermo 1998).
6.2 Treatment of advanced disease (Stage III-IV)
The standard therapeutic option for patients with stage III-IV disease is conventional-dose systemic anthracycline-containing chemotherapy. With this treatment, an overall response rate of more than 60% has been reported, with a complete remission rate of 47% (Lopez-Guillermo 1998). The median duration of complete remission is 47 months, and the median survival of 22 months. No significant difference in term of survival was observed comparing CHOP or CHOP-like regimens and third-generation ones. The role of high-dose chemotherapy supported by autologous or allogeneic bone marrow transplantation is still investigational. Presently, the worldwide experience is very limited. A very interesting study of paediatric patients has been reported (Gordon 1992). Nine patients with relapsed or high-risk peripheral T-cell lymphoma have been transplanted using thiotepa, total body irradiation and escalating doses of VP16. Eight patients were disease-free after a median follow-up of 25 months, with an estimated 2-year relapse-free survival of 89%. Toxicity was significant but manageable. Bone marrow transplantation has been used in an anecdotal series of older patients (median age 17 years) with disappointing results (Gordon 1992).
6.3 Treatment of relapsed or refractory diesease
The standard therapeutic option for patients with relapsed disease has not been established. High-dose chemotherapy supported by bone marrow transplantation should be considered in these patients, given the aggressive behaviour of relapsed T-cell lymphomas and the lack of valid therapeutic alternatives. However, since the worldwide experience is limited, it remains an investigational option.
6.4 New active drugs and therapeutic options
The use of gemcitabine is suitable for individual clinical use on a type 3 level of evidence. Gemcitabine (1200 mg/m2, days 1, 8 and 15 of a 28-day schedule) has been used in 13 relapsed patients with different T-cell lymphomas, achieving one complete remission and 8 partial remissions with a median duration of 11 months (Zinzani 1998). This treatment has been extremely well tolerated.
Ansell SM, Habermann TM, Kurtin PJ, Witzig TE, Chen MG, Li CY, et al. Predictive capacity of the International Prognostic Factor Index in patients with peripheral T-cell lymphoma. J Clin Oncol 1997; 15: 2296-2301 [Medline]
Arai E, Katayama I. Role of apoptosis in spontaneous regression of peripheral T-cell lymphoma arising in the skin or subcutis. Hum Pathol 1997; 28: 472-477 [Medline]
Ascani S, Zinzani PL, Gherlinzoni F, Sabattini E, Briskomatis A, de Vivo A, et al. Peripheral T-cell lymphomas. Clinico-pathologic study of 168 cases diagnosed according to the R.E.A.L. Classification. Ann Oncol 1997; 8: 583-592 [Medline]
Banks PM. Incorporation of immunostaining data in anatomic pathology reports. Am J Surg Pathol 1992; 16: 808 [Medline]
Borowitz MJ, Reichert TA, Brynes RK, Cousar JB, Whitcomb CC, Collins RD, et al. The phenotypic diversity of peripheral T-cell lymphomas: the Southeastern Cancer Study Group experience. Hum Pathol 1986; 17: 567-574 [Medline]
Campo E, Gaulard P, Zucca E, Jaffe ES, Harris NL, Diebold J, et al. Report of the European Task Force on Lymphomas: workshop on peripheral T-cell lymphomas. Ann Oncol 1998; 9: 835-843 [Medline]
Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res 1971; 31: 1860-1861 [Medline]
Chan AC, Ho JW, Chiang AK, Srivastava G. Phenotypic and cytotoxic characteristics of peripheral T-cell and NK- cell lymphomas in relation to Epstein-Barr virus association. Histopathology 1999; 34: 16-24 [Medline]
Chan JK, Sin VC, Wong KF, Ng CS, Tsang WY, Chan CH, et al. Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm. Blood 1997; 89: 4501-4513 [Medline]
Cheng AL, Chen YC, Wang CH, Su IJ, Hsieh HC, Chang JY, et al. Direct comparisons of peripheral T-cell lymphoma with diffuse B-cell lymphoma of comparable histological grades–should peripheral T-cell lymphoma be considered separately? J Clin Oncol 1989; 7: 725-731 [Medline]
Chott A, Dragosics B, Radaszkiewicz T. Peripheral T-cell lymphomas of the intestine. Am J Pathol 1992; 141: 1361-1371 [Medline]
Falini B, Pileri S, De Solas I, Martelli MF, Mason DY, Delsol G, et al. Peripheral T-cell lymphoma associated with hemophagocytic syndrome. Blood 1990; 75: 434-444 [Medline]
Gisselbrecht C, Gaulard P, Lepage E, Coiffier B, Briere J, Haioun C, et al. Prognostic significance of T-cell phenotype in aggressive non-Hodgkin’s lymphomas. Groupe d’Etudes des Lymphomes de l’Adulte (GELA). Blood 1998; 92: 76-82 [Medline]
Gonzalez-Clemente JM, Ribera JM, Campo E, Bosch X, Montserrat E, Grau JM. Ki-1+ anaplastic large-cell lymphoma of T-cell origin in an HIV- infected patient. AIDS 1991; 5: 751-755 [Medline]
Gordon BG, Warkentin PI, Weisenburger DD, Vose JM, Sanger WG, Strandjord SE, et al. Bone marrow transplantation for peripheral T-cell lymphoma in children and adolescents. Blood 1992; 80: 2938-2942 [Medline]
Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84: 1361-1392 [Medline]
Hastrup N, Ralfkiaer E, Pallesen G. Aberrant phenotypes in peripheral T cell lymphomas. J Clin Pathol 1989; 42: 398-402 [Medline]
Herman TS, Jones SE. Systematic re-staging in the management of non-Hodgkin’s lymphomas. Cancer Treat Rep 1977; 61: 1009-1015 [Medline]
Inwards DJ, Habermann TM, Banks PM, Colgan JP, Dewald GW. Cytogenetic findings in 21 cases of peripheral T-cell lymphoma. Am J Hematol 1990; 35: 88-95 [Medline]
Jaffe ES, Krenacs L, Kumar S, Kingma DW, Raffeld M. Extranodal peripheral T-cell and NK-cell neoplasms. Am J Clin Pathol 1999; 111: S46-S55 [Medline]
Jaffe ES, Krenacs L, Raffeld M. Classification of T-cell and NK-cell neoplasms based on the REAL classification. Ann Oncol 1997; 8 Suppl 2:17-24: 17-24 [Medline]
Kinney MC. The role of morphologic features, phenotype, genotype, and anatomic site in defining extranodal T-cell or NK-cell neoplasms. Am J Clin Pathol 1999; 111: S104-S118 [Medline]
Kwak LW, Wilson M, Weiss LM, Doggett R, Dorfman RF, Warnke RA, et al. Similar outcome of treatment of B-cell and T-cell diffuse large-cell lymphomas: the Stanford experience. J Clin Oncol 1991; 9: 1426-1431 [Medline]
La Vecchia C, Negri E, D’Avanzo B, Franceschi S. Occupation and lymphoid neoplasms. Br J Cancer 1989; 60: 385-388 [Medline]
Lennert K. Malignant lymphomas: other than Hodgkin’s disease: histology, cytology, ultrastructure, immunology. Berlin: Springer-Verlag. book 1978 [Medline]
Lippman SM, Miller TP, Spier CM, Slymen DJ, Grogan TM. The prognostic significance of the immunotype in diffuse large-cell lymphoma: a comparative study of the T-cell and B-cell phenotype. Blood 1988; 72: 436-441 [Medline]
Lopez-Guillermo A, Cid J, Salar A, Lopez A, Montalban C, Castrillo JM, et al. Peripheral T-cell lymphomas: initial features, natural history, and prognostic factors in a series of 174 patients diagnosed according to the R.E.A.L. Classification. Ann Oncol 1998; 9: 849-855 [Medline]
Melnyk A, Rodriguez A, Pugh WC, Cabannillas F. Evaluation of the Revised European-American Lymphoma classification confirms the clinical relevance of immunophenotype in 560 cases of aggressive non-Hodgkin’s lymphoma. Blood 1997; 89: 4514-4520 [Medline]
Patsouris E, Noel H, Lennert K. Histological and immunohistological findings in lymphoepithelioid cell lymphoma (Lennert’s lymphoma). Am J Surg Pathol 1988; 12: 341-350 [Medline]
Pileri SA, Ascani S, Sabattini E, Falini B. Peripheral T-cell lymphoma: a developing concept. Ann Oncol 1998; 9: 797-801 [Medline]
Pittaluga S, Verhoef G, Criel A, Wlodarska I, Dierlamm J, Mecucci C, et al. “Small” B-cell non-Hodgkin’s lymphomas with splenomegaly at presentation are either mantle cell lymphoma or marginal zone cell lymphoma. A study based on histology, cytology, immunohistochemistry, and cytogenetic analysis. Am J Surg Pathol 1996; 20: 211-223 [Medline]
Sakashita, Kobayashi H, Satake N, Maseki N, Sakurai M, Izumo T, et al. Amplification of the TCL1 flanking region at 14q32.1 with no TCL1 gene transcription in a patient with peripheral T cell lymphoma. Leukemia 1998; 12: 970-971 [Medline]
Scherr PA, Hutchison GB, Neiman RS. Non-Hodgkin’s lymphoma and occupational exposure. Cancer Res 1992; 52: 5503s-5509s [Medline]
Schlegelberger B, Weber-Matthiesen K, Sterry W, Bartels H, Sonnen R, Maschmeyer G, et al. Combined immunophenotyping and karyotyping in peripheral T cell lymphomas demonstrating different clonal and nonclonal chromosome aberrations in T helper cells. Leuk Lymphoma 1994; 15: 113-125 [Medline]
Strickler JG, Weiss LM, Copenhaver CM, Bindl J, McDaid R, Buck D, et al. Monoclonal antibodies reactive in routinely processed tissue sections of malignant lymphoma, with emphasis on T-cell lymphomas. Hum Pathol 1987; 18: 808-814 [Medline]
Suchi T, Lennert K, Tu LY, Kikuchi M, Sato E, Stansfeld AG, et al. Histopathology and immunohistochemistry of peripheral T cell lymphomas: a proposal for their classification. J Clin Pathol 1987; 40: 995-1015 [Medline]
Weisenburger DD. Environmental epidemiology of non-Hodgkin’s lymphoma in eastern Nebraska. Am J Ind Med 1990; 18: 303-305 [Medline]
Weisenburger DD. Lymphoid malignancies in Nebraska: a hypothesis. Nebr Med J 1985; 70: 300-305 [Medline]
Weiss LM, Crabtree GS, Rouse RV, Warnke RA. Morphologic and immunologic characterization of 50 peripheral T-cell lymphomas. Am J Pathol 1985; 118: 316-324 [Medline]
Weiss LM, Picker LJ, Grogan TM, Warnke RA, Sklar J. Absence of clonal beta and gamma T-cell receptor gene rearrangements in a subset of peripheral T-cell lymphomas. Am J Pathol 1988; 130: 436-442 [Medline]
Woods JS, Polissar L, Severson RK, Heuser LS, Kulander BG. Soft tissue sarcoma and non-Hodgkin’s lymphoma in relation to phenoxyherbicide and chlorinated phenol exposure in western Washington. J Natl Cancer Inst 1987; 78: 899-910 [Medline]
Yamashita Y, Yatabe Y, Tsuzuki T, Nakayama A, Hasegawa Y, Kojima H, et al. Perforin and granzyme expression in cytotoxic T-cell lymphomas. Mod Pathol 1998; 11: 313-323 [Medline]
Zahm SH, Weisenburger DD, Babbitt PA, Saal RC, Vaught JB, Cantor KP, et al. A case-control study of non-Hodgkin’s lymphoma and the herbicide 2,4- dichlorophenoxyacetic acid (2,4-D) in eastern Nebraska. Epidemiology 1990; 1: 349-356 [Medline]
Zaja F, Russo D, Silvestri F, Fanin R, Damiani D, Infanti L, et al. Retrospective analysis of 23 cases with peripheral T-cell lymphoma, unspecified: clinical characteristics and outcome. Haematologica 1997; 82: 171-177 [Medline]
Zinzani PL, Magagnoli M, Bendandi M, Orcioni GF, Gherlinzoni F, Albertini P, et al. Therapy with gemcitabine in pretreated peripheral T-cell lymphoma patients. Ann Oncol 1998; 9: 1351-1353 [Medline]
Dr. Andrés Ferreri (Associate Editor)
San Raffaele Scientific Institute – Milan, Italy
Dr. Emilio Montserrat (Reviewer)
Hospital Clinic, Hemato-Oncology Institute – Barcelona, Spain
Dr. Carlo Tondini (Editor)
START Clinical Editor – Ospedali Riuniti – Bergamo, Italy