Peripheral T cell lymphoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

The peripheral T-cell lymphomas (PTCLs) consists of a heterogeneous group of aggressive diseases that constitutes ~10%-15% of non Hodgkin lymphoma. The incidence has been estimated to be <1 case per 100,000 of ppl in United states. [1]The most common type is Peripheral T cell lymphoma, not otherwise specified (PTCL, NOS), followed by Anaplastic large cell lymphoma, primary systemic type (ALCL) , Angioimmunoblastic T cell lymphoma (AITL) and Extranodal NK/T cell lymphoma, nasal type (PTCLs ), which is the rarest type. Although each type presents differently and has special histological features, they all have similar treatment . In addition, all the types have been associated with poor prognosis. [2] The most common presentation is generalized lymphadenopathy with or without extra nodal manifestations. [3]

Classification

In 2008, WHO classified peripheral T cell lymphoma in 4 groups ( cutaneous, nodal, extra nodal and leukemic) based on their clinical manifestations .[2]

In which the majority of aggressive T-cell lymphomas have been included in the nodal, extranodal, and leukemic groups.

The nodal lymphoma consists of 3 entities which include :PTCL, not otherwise specified (NOS) which is the most common subtype accounting for 25.9% of cases, [4] anaplastic large cell lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma (AITL).

Anaplastic large cell lymphoma (ALCS) has two recognized sub groups: ALK+ and ALK- lymphomas. Both subtypes are morphologially and immunophenotypically similar to each other however they are different molecularly. [5]They have similar incidences (6.6% and 5.5% respectively) [6]

Angioimmunoblastic T-cell lymphoma (AITL) comprises 18.5% of cases .[7] One of its variants ,lymphoepithelioid cell variant is consists of CD8 T cells with epithelioid cells in the background which is different than other variants. [8]

Less common entities have been described in extra nodal groups. Tissue tropism has been the characterized distinguishing factor.

First subtype which comprises around 1.4% of PTCL cases [9]and almost always is reported in children and young adults [10]is Hepatosplenic γδ T-cell lymphoma. In this tumor, immature or nonactivated γδ T cells infiltrate bone marrow sinusoides and spleen and Isochromosome 7q chromosomal abnormality is present.

In second subgroup, which is hepatosplenic T-cell lymphoma has often poor prognoses with median survival of below 2 years. Patients usually present with B-symptoms and decreased cell counts. The cells express CD2, CD3 and CD7 markers and lack CD4, CD5 . while CD8 and natural killer cell markers expression are variable .

The third sub-type , Enteropathy-associated T-cell lymphoma (EATL) is more common in populations with high incidence of celiac disease and accounts for 4.7% of cases of T-cell lymphoma. Pain, weight loss, and bowel perforation are the usual clinical presentations. Two morphological variants have been recognized ; pleomorphic and monomorphic. The former group is associated with celiac disease the cells usually express CD3 and CD7 and lack CD56 expression [11]. Conversely, The latter group is often not associated with the celiac disease and express CD56. Gains at chromosome 9q33-q34 has been reported in up to 70% of cases[12].

Furthermore, the intestinal T- and NK-cell lymphomas are part of the nasal-type NK-/T-cell lymphoma[13] which have been reported in Asian countries and are associated with Epstein-Barr virus (EBV) infection .

In addition, The mucocutaneous γδ T-cell lymphomas[14],the nasal type NK-/T-cell lymphomas, and even ALCLs all can present as an intestinal lymphoma[15].

Panniculitis-like T-cell lymphomas constitute only 0.9% of PTCLs which is more common in males. The characteristic clinical presentation is subcutaneous nodules that can become necrotic .The cells express CD3 and CD8 and are CD4- .[16]

The last group,leukemia has 4 subtypes including adult T-cell lymphoma (ATL) associated with human T-lymphotropic virus type I (HTLV-1), T-cell chronic large granular lymphocytic (LGL) leukemia associated with neutropenia , aggressive NK-cell leukemia, and T-cell prolymphocytic leukemia. . NK-cell leukemia and ATL often have a poor outcome.

Other types which have been included in WHO classifications include: hydroa vacciniforme-like lymphoma, NK-cell lymphoma and systemic EBV-positive T-cell lymphoproliferative disease of childhood.

Pathophysiology

Recently three key mechanisms of peripheral T cell transformation have been demonstrated in different studies, including" (a) the deregulation of signaling pathways controlling T cell development, differentiation, and maturation; (b) the remodeling of the peritumor microenvironment; and (c) the virus-mediated rewiring of T cell biology."[17]

Clinical Features

Depending on the subtypes, clinical manifestations may vary however, the majority of patients present with generalized lymphadenopathy with or without extranodal disease [18]. Having nodal disease alone is seen in around 38% of patients, 49% present with both nodal and extranodal disease, while around 13% only present with extranodal disease [19]. Hepatomegaly is seen in 17% and splenomegaly in 24% of patients. The bone marrow involvement is seen in 20%. Some patients present with eosinophilia, pruritus[20]]. In 1/4 of cases, thrombocytopenia and anemia are seen. [21]

Extranodal sites involved are mainly skin and gastrointestinal tract [22]. Fever, night sweats and weight loss which are typical systemic B symptoms ,are reported in 35% of cases [23]. 50% of patients have increased LDH level and 14% of cases are associated with hypergammaglobulinemia.

The distinction between subtypes of Peripheral T cell Lymphoma and with other diseases

  • ·        AITL tumor cells have typical morphological characteristics which are absent in PTCL, NOS . AITL, tumor cells express CD10, BCL6, PD1, or CXCL13 as well as mutations in DNMT3A, TET2, IDH2, and RHOG which is not the case in PTCL, NOS[24] [25], Differential diagnosis of peripheral T cell lymphoma are other T cell lymphomas and B cell lymphomas that share common morphologic and/or immunophenotypic characteristics, and disorders such as hypersensitivity reactions and prolonged or robust immune responses to viral infections which can cause hyperplasia of nodal paracortical T cell zones.

Epidemiology and Demographics

  • The incidence of PTCL is < 1 case per 100 000 people in the United States.[26] The most common subtypes are the nodal T-cell lymphomas, with PTCL-NOS (25.9%) followed by AITLs (18.5%) and the ALCLs (12%). NK-/T-cell lymphomas (10.4%), while enteropathy-associated T-cell lymphomas (4.7%), hepatosplenic T-cell lymphomas (1.4%), and panniculitis-like T-cell lymphomas (0.9%) .

Gender and age

  • NK-cell nasal and nasal-type lymphomas is more common in males than in females.[27] individuals older than 60 years are commonly affected although it can happen at any age during adulthood.

Race

  • PTCL-NOS is more common in North America and less common in the European and Asian countries; AITL is more common in Europe than in Asia or North America; ALK+ ALCL is more common in North America; ALK− ALCL is slightly more common in Europe; and the NK-/T-cell lymphomas and ATL are more common in Asia.[28] The EBV-associated lymphoproliferative, T-cell, and NK-cell neoplasms are seen mainly in Japan, Korea, and Northern China, but also in Native American populations from Central and South America. NK-cell nasal and nasal-type lymphomas is more commonly reported in Asia and Latin America[29]

Diagnosis

Diagnostic Criteria

  • The diagnosis made based upon the results of a tissue biopsy (usually lymph node biopsy) that demonstrates evidence of a T cell lymphoma in addition to immunophenotyping with markers mentioned in the classification section[30]. File:PTCL NOS.jpg

Laboratory Findings

  • Complete blood count with differential (CBC), chemistry with liver and renal function and electrolytes, lactate dehydrogenase (LDH), hepatitis B, HIV, and uric acid.

Imaging Findings

  • A contrast-enhanced computed tomography (CT) scan of the chest, abdomen, and pelvis which would aid in staging . Echocardiogram or MUGA should be performed if anthracyclines are planned to be used.

Other Diagnostic Studies

  • Unilateral bone marrow aspiration and biopsy.

Treatment

Medical Therapy

The combination of chemotherapy drugs used most often is CHOP:

  • cyclophosphamide (Cytoxan, Procytox)
  • doxorubicin (Adriamycin)
  • vincristine (Oncovin)
  • prednisone[31]

Sometimes the following chemotherapy drugs may be used alone:

  • fludarabine (Fludara)
  • cladribine (Leustatin)
  • pentostatin (deoxycoformycin, Nipent)
  • gemcitabine (Gemzar)

Based on stage of disease, evidence based treatment has been proposed.[32]

Early-stage with localized disease:chemotherapy followed by radiotherapy

All patients except for those with low IPI (International Prognostic Index ) be consolidated with ASCT.

Among all subtypes, ALK+ ALCL is shown to have an excellent outcome. However ALK+ patients with high IPI are the exclusions.

Nodal T-cell lymphomas : CHOP-based therapy.

Extranodal regimens differ according to subtypes as following:

Panniculitis-like T-cell lymphoma, αβ type: single-agent therapies or combination chemotherapy and have shown to have an excellent outcome.

γδ type: should be treated with aggressive chemotherapy followed by transplantation as they do poorly.

In addition,hepatosplenic and intestinal T-cell lymphomas have a poor outcome.

NK-/T-cell lymphoma patients have also do not respond well to CHOP-based regimens, and alternative regimens should be considered.

Radiation therapy

External beam radiation therapy is often used addition to chemotherapy. It is given to affected lymph node areas at early stages of disease,

Targeted therapy

If there is recurrence of disease or other aforementioned agents are ineffective, targeted therapy may be used.

Including:

  • alemtuzumab (Campath)
  • romidepsin (Istodax)[33]

Stem cell transplant

Stem cell transplant is offered in case of recurrence of disease or in patients who are in remission after chemotherapy..

Prognosis

Most peripheral T cell lymphoma subtypes have a worse prognosis than that seen in typical cases of diffuse large B-cell lymphoma[34].The median overall survival for most subtypes is on average 1–3 years, with a 5-year overall survival rate of only about 30%. However patients with anaplastic large cell lymphomas that are positive for anaplastic lymphoma kinase (ALK), have a 5-year survival rate of approximately 70% with CHOP regimen.

The most popular prognostic scoring system is the prognostic index for PTCL, unspecified (PIT) : One point for each of the factors

●Age >60 years

●Increased serum lactate dehydrogenase

●Eastern Cooperative Oncology Group (ECOG) performance status ≥2

●Bone marrow involvement

A retrospective study showed patients with zero, one, two, or three to four of these adverse prognostic factors had five-year overall survival rates of 63, 53, 33, and 18 percent, respectively. [35]

References

  1. ↑ Morton, L. M. (2006). "Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001". Blood. 107 (1): 265–276. doi:10.1182/blood-2005-06-2508. ISSN 0006-4971.
  2. ↑ Moskowitz, A. J.; Lunning, M. A.; Horwitz, S. M. (2014). "How I treat the peripheral T-cell lymphomas". Blood. 123 (17): 2636–2644. doi:10.1182/blood-2013-12-516245. ISSN 0006-4971.
  3. ↑ . doi:10.1182/blood-2010-09-310342. Check |doi= value (help). Missing or empty |title= (help)
  4. ↑ "International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study: Pathology Findings and Clinical Outcomes". Journal of Clinical Oncology. 26 (25): 4124–4130. 2008. doi:10.1200/JCO.2008.16.4558. ISSN 0732-183X.
  5. ↑ Salaverria, Itziar; Beà, Silvia; Lopez-Guillermo, Armando; Lespinet, Virginia; Pinyol, Magda; Burkhardt, Birgit; Lamant, Laurence; Zettl, Andreas; Horsman, Doug; Gascoyne, Randy; Ott, German; Siebert, Reiner; Delsol, Georges; Campo, Elias (2008). "Genomic profiling reveals different genetic aberrations in systemic ALK-positive and ALK-negative anaplastic large cell lymphomas". British Journal of Haematology. 140 (5): 516–526. doi:10.1111/j.1365-2141.2007.06924.x. ISSN 0007-1048.
  6. ↑ "International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study: Pathology Findings and Clinical Outcomes". Journal of Clinical Oncology. 26 (25): 4124–4130. 2008. doi:10.1200/JCO.2008.16.4558. ISSN 0732-183X.
  7. ↑ "International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study: Pathology Findings and Clinical Outcomes". Journal of Clinical Oncology. 26 (25): 4124–4130. 2008. doi:10.1200/JCO.2008.16.4558. ISSN 0732-183X.
  8. ↑ Geissinger, Eva; Odenwald, Tobias; Lee, Seung-Sook; Bonzheim, Irina; Roth, Sabine; Reimer, Peter; Wilhelm, Martin; M�ller-Hermelink, Hans Konrad; R�diger, Thomas (2004). "Nodal peripheral T-cell lymphomas and, in particular, their lymphoepithelioid (Lennert?s) variant are often derived from CD8+ cytotoxic T-cells". Virchows Archiv. 445 (4): 334–343. doi:10.1007/s00428-004-1077-2. ISSN 0945-6317. replacement character in |last8= at position 2 (help); replacement character in |last9= at position 2 (help)
  9. ↑ "International Peripheral T-Cell and Natural Killer/T-Cell Lymphoma Study: Pathology Findings and Clinical Outcomes". Journal of Clinical Oncology. 26 (25): 4124–4130. 2008. doi:10.1200/JCO.2008.16.4558. ISSN 0732-183X.
  10. ↑ Charton-Bain MC, Brousset P, Bouabdallah R, Gaulard P, Merlio JP, Dubus P; et al. (2000). "Variation in the histological pattern of nodal involvement by gamma/delta T-cell lymphoma". Histopathology. 36 (3): 233–9. PMID 10692026.
  11. ↑ Zettl, Andreas; deLeeuw, Ron; Haralambieva, Eugenia; Mueller-Hermelink, Hans-Konrad (2007). "Enteropathy-Type T-Cell Lymphoma". American Journal of Clinical Pathology. 127 (5): 701–706. doi:10.1309/NW2BK1DXB0EQG55H. ISSN 0002-9173.
  12. ↑ Zettl, Andreas; Ott, German; Makulik, Angela; Katzenberger, Tiemo; Starostik, Petr; Eichler, Thorsten; Puppe, Bernhard; Bentz, Martin; Müller-Hermelink, Hans Konrad; Chott, Andreas (2002). "Chromosomal Gains at 9q Characterize Enteropathy-Type T-Cell Lymphoma". The American Journal of Pathology. 161 (5): 1635–1645. doi:10.1016/S0002-9440(10)64441-0. ISSN 0002-9440.
  13. ↑ Au, W.-y.; Weisenburger, D. D.; Intragumtornchai, T.; Nakamura, S.; Kim, W.-S.; Sng, I.; Vose, J.; Armitage, J. O.; Liang, R. (2008). "Clinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project". Blood. 113 (17): 3931–3937. doi:10.1182/blood-2008-10-185256. ISSN 0006-4971.
  14. ↑ Shapira, Michael Y.; Caspi, Ofer; Amir, Gail; Zlotogorski, Abraham; Naparstek, Yaakov (2009). "Gastric-Mucocutaneous γδ T Cell Lymphoma: Possible Association with Epstein-Barr Virus ?". Leukemia & Lymphoma. 35 (3–4): 397–401. doi:10.3109/10428199909145745. ISSN 1042-8194.
  15. ↑ Kanavaros, P.; Boulland, M. L.; Petit, B.; Arnulf, B. (2009). "Expression of Cytotoxic Proteins in Peripheral T-Cell and Natural Killer-Cell (NK) Lymphomas: Association with Extranodal Site, NK or Tγδ Phenotype, Anaplastic Morphology and CD30 Expression". Leukemia & Lymphoma. 38 (3–4): 317–326. doi:10.3109/10428190009087022. ISSN 1042-8194.
  16. ↑ Toro, J. R. (2003). "Gamma-delta T-cell phenotype is associated with significantly decreased survival in cutaneous T-cell lymphoma". Blood. 101 (9): 3407–3412. doi:10.1182/blood-2002-05-1597. ISSN 0006-4971.
  17. ↑ Pizzi, Marco; Margolskee, Elizabeth; Inghirami, Giorgio (2018). "Pathogenesis of Peripheral T Cell Lymphoma". Annual Review of Pathology: Mechanisms of Disease. 13 (1): 293–320. doi:10.1146/annurev-pathol-020117-043821. ISSN 1553-4006.
  18. ↑ Vose J, Armitage J, Weisenburger D, International T-Cell Lymphoma Project (2008). "International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes". J Clin Oncol. 26 (25): 4124–30. doi:10.1200/JCO.2008.16.4558. PMID 18626005.
  19. ↑ Weisenburger DD, Savage KJ, Harris NL, Gascoyne RD, Jaffe ES, MacLennan KA; et al. (2011). "Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project". Blood. 117 (12): 3402–8. doi:10.1182/blood-2010-09-310342. PMID 21270441.
  20. ↑ Falini B, Pileri S, De Solas I, Martelli MF, Mason DY, Delsol G; et al. (1990). "Peripheral T-cell lymphoma associated with hemophagocytic syndrome". Blood. 75 (2): 434–44. PMID 2153036.
  21. ↑ Weisenburger DD, Savage KJ, Harris NL, Gascoyne RD, Jaffe ES, MacLennan KA; et al. (2011). "Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project". Blood. 117 (12): 3402–8. doi:10.1182/blood-2010-09-310342. PMID 21270441.
  22. ↑ Chott A, Dragosics B, Radaszkiewicz T (1992). "Peripheral T-cell lymphomas of the intestine". Am J Pathol. 141 (6): 1361–71. PMC 1886751. PMID 1466400.
  23. ↑ Weisenburger DD, Savage KJ, Harris NL, Gascoyne RD, Jaffe ES, MacLennan KA; et al. (2011). "Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project". Blood. 117 (12): 3402–8. doi:10.1182/blood-2010-09-310342. PMID 21270441.
  24. ↑ Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R; et al. (2016). "The 2016 revision of the World Health Organization classification of lymphoid neoplasms". Blood. 127 (20): 2375–90. doi:10.1182/blood-2016-01-643569. PMC 4874220. PMID 26980727.
  25. ↑ Palomero T, Couronné L, Khiabanian H, Kim MY, Ambesi-Impiombato A, Perez-Garcia A; et al. (2014). "Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas". Nat Genet. 46 (2): 166–70. doi:10.1038/ng.2873. PMC 3963408. PMID 24413734.
  26. ↑ Morton, L. M. (2006). "Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001". Blood. 107 (1): 265–276. doi:10.1182/blood-2005-06-2508. ISSN 0006-4971.
  27. ↑ Foss, F. M.; Zinzani, P. L.; Vose, J. M.; Gascoyne, R. D.; Rosen, S. T.; Tobinai, K. (2011). "Peripheral T-cell lymphoma". Blood. 117 (25): 6756–6767. doi:10.1182/blood-2010-05-231548. ISSN 0006-4971.
  28. ↑ Savage, K. J.; Harris, N. L.; Vose, J. M.; Ullrich, F.; Jaffe, E. S.; Connors, J. M.; Rimsza, L.; Pileri, S. A.; Chhanabhai, M.; Gascoyne, R. D.; Armitage, J. O.; Weisenburger, D. D. (2008). "ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project". Blood. 111 (12): 5496–5504. doi:10.1182/blood-2008-01-134270. ISSN 0006-4971.
  29. ↑ Foss, F. M.; Zinzani, P. L.; Vose, J. M.; Gascoyne, R. D.; Rosen, S. T.; Tobinai, K. (2011). "Peripheral T-cell lymphoma". Blood. 117 (25): 6756–6767. doi:10.1182/blood-2010-05-231548. ISSN 0006-4971.
  30. ↑ Lage, Luis Alberto de Pádua Covas; Cabral, Tamara Carvalho dos Santos; Costa, Renata de Oliveira; Gonçalves, Marianne de Castro; Levy, Debora; Zerbini, Maria Cláudia Nogueira; Pereira, Juliana (2015). "Primary nodal peripheral T-cell lymphomas: diagnosis and therapeutic considerations". Revista Brasileira de Hematologia e Hemoterapia. 37 (4): 277–284. doi:10.1016/j.bjhh.2015.03.017. ISSN 1516-8484.
  31. ↑ Moskowitz, A. J.; Lunning, M. A.; Horwitz, S. M. (2014). "How I treat the peripheral T-cell lymphomas". Blood. 123 (17): 2636–2644. doi:10.1182/blood-2013-12-516245. ISSN 0006-4971.
  32. ↑ Foss, F. M.; Zinzani, P. L.; Vose, J. M.; Gascoyne, R. D.; Rosen, S. T.; Tobinai, K. (2011). "Peripheral T-cell lymphoma". Blood. 117 (25): 6756–6767. doi:10.1182/blood-2010-05-231548. ISSN 0006-4971.
  33. ↑ Foss, F. M.; Zinzani, P. L.; Vose, J. M.; Gascoyne, R. D.; Rosen, S. T.; Tobinai, K. (2011). "Peripheral T-cell lymphoma". Blood. 117 (25): 6756–6767. doi:10.1182/blood-2010-05-231548. ISSN 0006-4971.
  34. ↑ Foss, F. M.; Zinzani, P. L.; Vose, J. M.; Gascoyne, R. D.; Rosen, S. T.; Tobinai, K. (2011). "Peripheral T-cell lymphoma". Blood. 117 (25): 6756–6767. doi:10.1182/blood-2010-05-231548. ISSN 0006-4971.
  35. ↑ Gallamini A, Stelitano C, Calvi R, Bellei M, Mattei D, Vitolo U; et al. (2004). "Peripheral T-cell lymphoma unspecified (PTCL-U): a new prognostic model from a retrospective multicentric clinical study". Blood. 103 (7): 2474–9. doi:10.1182/blood-2003-09-3080. PMID 14645001.

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