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Peripheral T-cell Lymphoma

Peripheral T-cell lymphoma (PTCL) is a general term referring to a heterogeneous group of T-cell lymphomas. They arise from mature T-cells and develop as solid tumors at distinct nodal and extranodal sites. At the time of diagnosis, PTCL have often reached an advanced stage and trigger constitutional symptoms. Most types of PTCL follow an aggressive course and their response to current treatment regimens is poor.


Presentation

PTCL patients may present with solid tumors. They often develop in the lymph nodes but may also arise in the skin, liver, spleen, bone marrow, or any other organ [1]. Depending on the site of tumor growth, distinct signs of organ dysfunction may be triggered. Hepatomegaly and splenomegaly, for instance, may be palpated during the clinical examination. They may cause loss of appetite, early satiety, nausea, and vomiting, among others [2]. Furthermore, patients may describe constitutional symptoms such as fever, night sweat, and weight loss [3]. Additional symptoms may be attributed to a paraneoplastic syndrome. In this context, affected individuals may present with eosinophilia, pruritus, or hemophagocytic syndrome.

Plethora
  • The need to identify new active drugs for patients with PTCL has been addressed in part over the last several years, as 4 drugs have now been approved by the US Food and Drug Administration for patients with relapsed or refractory disease, and a plethora[ncbi.nlm.nih.gov]
  • While most new drugs are not licensed and not readily available, a plethora of other innovative drugs targeting (epi-)genetic abnormalities are in early development.[ncbi.nlm.nih.gov]
Fever of Unknown Origin
  • A 52-year-old man presented to our hospital for further workup of fever of unknown origin after an extensive workup at an outside hospital had failed to reveal a diagnosis.[ncbi.nlm.nih.gov]
Constitutional Symptom
  • Furthermore, patients may describe constitutional symptoms such as fever, night sweat, and weight loss. Additional symptoms may be attributed to a paraneoplastic syndrome.[symptoma.com]
Fishing
  • Here, we report a case of PTCL, not otherwise specified (NOS) with the karyotype 46,Y,add(X)(p22),t(6;14)(p25;q11) and FISH-proved breakpoints in the IRF4 and TCRAD loci, leading to juxtaposition of both genes.[ncbi.nlm.nih.gov]
Aspiration
  • Findings on imaging and fine-needle aspiration biopsy were inconclusive. Pathologic studies of excisional biopsy specimens ultimately revealed the diagnosis of PTCL-NOS.[ncbi.nlm.nih.gov]
Hemoptysis
  • We describe the case of a 66-year-old woman who was admitted to the hospital because of fever, hemoptysis, lymphadenopathy, and skin rash.[ncbi.nlm.nih.gov]
Subcutaneous Mass
  • We report an EBV   PTCL in a 9-year-old child with initial symptom of subcutaneous masses without lymph node involvement.[ncbi.nlm.nih.gov]
Ptosis
  • Three months later, she presented with generalized lymphadenopathy and sudden left-eye ptosis as a complication of CNS involvement and died after 20 months from the initial disease presentation.[ncbi.nlm.nih.gov]
Corneal Infiltrate
  • Development and persistence of corneal infiltration despite systemic chemotherapy may be a warning sign for resistance to treatment.[ncbi.nlm.nih.gov]
Neck Mass
  • We describe the case of a 68-year-old woman who presented with a 6-week history of an intermittently tender left-sided neck mass. Findings on imaging and fine-needle aspiration biopsy were inconclusive.[ncbi.nlm.nih.gov]
Testicular Swelling
  • A 40-year-old man presented with right testicular swelling for past three months. The swelling was painless, hard and rubbery. Testicular ultrasound showed diffuse increase in size of the testicle, with alteration in its echogenicity.[ncbi.nlm.nih.gov]
Vaginal Bleeding
  • We present a case of primary peripheral T-cell lymphoma, not otherwise specified, in the uterine cervix in a 49-year-old woman with a history of severe vaginal bleeding.[ncbi.nlm.nih.gov]

Workup

The diagnosis of PTCL is based on the assessment of tissue samples, so a biopsy of the affected organ has to be carried out. With regard to the histopathological examination, a common finding is the diffuse effacement of the nodal architecture by tumor cells. These cells have an atypical morphology and possibly contain pleomorphic, hyperchromatic, or vesicular nuclei with prominent nucleoli, which are surrounded by clear cytoplasm. Numerous mitotic figures may be noted. An inflammatory background with infiltration of eosinophils, plasma cells, and histiocytes is frequently seen and may complicate the identification of the tumor cell population [4].

Even though morphological features are often ambiguous, immunophenotyping and genetic characterization of the neoplasm usually allow for its identification as a particular type of PTCL. Standard panels comprising several T-cell markers (CD2, CD3, CD4, CD5, CD7, CD8, BCA1, PD1, and TCR-β), cytotoxic markers (TIA1, granzyme B, perforin), B-cell markers (CD20, CD79a, and PAX5), and non-specific immunomarkers (CD10, CD21, and CD30) are generally used for immunophenotyping [5]. It should be noted, though, that the downregulation of specific markers may hinder the identification of the tumor's origin. Loss of one of the pan T-cell antigens (CD2, CD3, CD5, or CD7) is seen in 75% of all cases [4]. The genetic landscape of PTCL is highly variable, with translocation t(2;5)(p23;q35) being the only recurrent chromosomal aberration. It is characteristic of anaplastic large-cell lymphoma, ALK-positive [6]. In any case, PTLC-NOS should be diagnosed only after the exclusion of other types of PTCL.

After the confirmation of PTCL, the patient should undergo a thorough staging procedure. Diagnostic imaging techniques are valuable tools to detect solid tumors in lymph nodes and extranodal sites. In this context, positron emission tomography with fluorodeoxyglucose is more sensitive than computed tomography [3].

Additionally, laboratory analyses of blood and bone marrow samples should be carried out. Although the peripheral blood may be involved, an overt leukemic presentation is uncommon. Circulating tumor cells are observed in about 10% of all cases [2]. The likelihood of bone marrow involvement depends on the type of PTCL and is highest in those suffering from hepatosplenic T-cell lymphoma [7].

Treatment

Patients diagnosed with localized extranodal disease should be considered for radiation treatment. By contrast, advanced-stage and nodal PTCL are often managed with anthracycline-based chemotherapy, namely with cyclophosphamide,
doxorubicin, vincristine, and prednisone (CHOP). The patient's response to chemotherapy largely depends on the particular type of PTCL, whereby no clear survival benefit could be demonstrated for the chemotherapeutic treatment of PTCL-NOS [2] [7]. Even in case of remission, a prompt relapse and subsequent progression remain likely [3]. Frontline consolidation with autologous stem cell transplantation has been proposed as an additional measure to extend the duration of remission and to achieve long-term control of the disease. The procedure may be realized after induction chemotherapy, and although response rates are far from optimum, it has been shown to improve the overall survival of PTCL-NOS patients [8]. Unfortunately, though, many patients are ineligible for autologous stem cell transplantation due to refractory disease and/or poor performance status, even after chemotherapy [9]. High-dose chemotherapeutic regimens could not be proven to more effectively prepare the patient for autologous stem cell transplantation than the standard approach [8] [9]. Evidence regarding the efficacy of allogeneic hematopoietic stem cell transplantation is scarce, and doesn't allow for reliable conclusions.

New therapeutic agents are urgently needed, but drug development is hindered by both the rarity and heterogeneity of PTCL. Still, some progress has been made, and pralatrexate, romidepsin, belinostat, and brentuximab vedotin have recently been approved for the treatment of relapsed and refractory PTCL [9]:

  • Pralatrexate is a T-cell-specific antifolate whose mechanism of action remains incompletely understood. In a phase-2 clinical trial, an overall response rate of 29% was obtained, and 12% of treated patients achieved complete remission. The mean duration of response exceeded 12 months. Leucovorin may be administered to reduce pralatrexate-associated mucositis.
  • Both romidepsin and belinostat are histone deacetylase inhibitors. The overall response rate, percentage of complete remission, and mean duration of response were reported to be 38%, 18%, and 9 months, and 26%, 11%, and 14 months for romidepsin and belinostat, respectively.
  • Brentuximab vedotin is an anti-CD30 antibody and a potent antimicrotubule agent, which induces G2-M cell-cycle arrest and apoptosis. The drug has only been approved for the treatment of relapsed, refractory systemic anaplastic large-cell lymphoma, where an overall response rate of 41% could be obtained. 24% of study participants achieved complete remission, but the mean duration of response was rather short.

Approvals of pralatrexate, romidepsin, belinostat, and brentuximab vedotin have been based on response rates alone because none of these drugs increased overall survival [3]. Further drugs have been tested regarding their safety and efficacy in PTCL, such as alisertib, bendamustine, crizotinib, sorafenib, duvelisib, plitidepsin, and mogamulizumab, but the results have been sobering. Some authors pin their hopes on combination therapies - future trials will show if their optimism is justified [9].

Prognosis

The tumor stage at the time of diagnosis is an important prognostic factor: The five-year-survival rate of patients found to suffer from stage 1 disease amounts to 64%, but the likelihood of survival is only 30% for those with stage 4 PTCL. Unfortunately, PTCL is often diagnosed during advanced stages [10].

Etiology

The incidence of PTCL increases with age, and genomic instability and immunosenescence are assumed to play key roles in the development of this type of lymphoid neoplasm. Some types of PTCL, however, are more frequently diagnosed during early and mid-adulthood. Anaplastic large-cell lymphoma is one of those entities, and senescence is out of the question as the cause of the disease. While the triggers of anaplastic large-cell lymphoma remain elusive, Epstein-
Barr virus has been related to extranodal NK/T-cell lymphoma, nasal type, to angioimmunoblastic T-cell lymphoma, and PTCL-NOS. Infections with human T-cell lymphotropic virus type 1 have been associated with the development of adult T-cell leukemia/lymphoma, and this type of PTCL is almost exclusively diagnosed in areas where the virus is endemic [1]. Beyond that, chronic antigenic stimulation has been proposed to be involved in the genesis of enteropathy-associated T-cell lymphoma and hepatosplenic T-cell lymphoma [10].

Epidemiology

In the United States, the overall incidence of PTCL has been estimated to be 6 per 1,000,000 inhabitants and year. Each about one-third of all cases correspond to anaplastic large-cell lymphoma and PTCL-NOS. Somewhat surprisingly, angioimmunoblastic T-cell lymphoma, a rather common type of PTCL in Europe, is rarely seen in North Americans. Blacks have been reported to be predisposed to hepatosplenic T-cell lymphoma, while Asians are more likely to develop extranodal NK/T-cell lymphoma, nasal type. With the exception of subcutaneous panniculitis-like T-cell lymphoma, PTLC affects males about twice as often as females. The majority of PTCL is diagnosed in the elderly, and the incidence of the disease increases with age [10].

Sex distribution
Age distribution

Pathophysiology

Diseases classified as PTCL-NOS show considerable phenotypic and cytological heterogeneity. For instance, considerable differences are to be expected between PTCL originating from the adaptive immune system and those arising from innate immune cells: The former tend to manifest as nodal neoplasms, are more frequently reported, and may induce the clonal proliferation of atypical B cells. As a general rule, PTCL originating from innate immune cells arise at mucosa-associated sites and are cytotoxic [4].

According to the results of gene expression profiling, PTCL tumor cells show global signatures similar to those displayed by activated T cells [11]. Clonal rearrangements of T cell receptor genes are common, but there are no specific abnormalities that would allow for a reliable cytogenetic or molecular biological diagnosis of PTCL. Chromosomal losses (7q, 8q, 17q, and 22q) and chromosomal gains (4q, 5q, 6q, 9p, 10q, 12q, and 13q) have repeatedly been observed.

Prevention

No recommendations can be given to prevent the development of PTCL.

Summary

According to the current classification of the World Health Organization, there are three major groups of lymphoma, namely Hodgkin lymphoma, B-cell lymphoma, and T-cell lymphoma [11] [12]. The latter term refers to about two dozen diseases, with the majority being at least partially characterized with regards to their etiology and pathogenesis. T-cell lymphomas may arise from precursors or mature cells, and because mature T-cells are found in the periphery, these neoplasms are also referred to as PTCL. There's no single category named PTCL, though. The majority of PTCL has been grouped according to their predominant site of organ involvement, so there are "extranodal NK/T-cell lymphoma, nasal type", "enteropathy-associated T-cell lymphoma", "hepatosplenic T-cell lymphoma", and "subcutaneous panniculitis-like T-cell lymphoma", among others. "Anaplastic large-cell lymphoma" and "angioimmunoblastic T-cell lymphoma" are other, rather common types of PTCL, but there's no predilection site for these entities. Finally, there's the category of "peripheral T-cell lymphoma, not otherwise specified" (PTCL-NOS).

In about 25% of cases, the clinical, immunophenotypic, and molecular biological features of the neoplasm don't allow for a classification more precise than PTCL-NOS [3]. Several entities are presumably combined in this category, and future modifications of the classification system are to be expected. Indeed, the assessment of the genomic signatures of about 120 specimens of PTCL-NOS led to the suggestion that neoplasms highly expressing GATA3 should be differentiated from those expressing TBX21. They may respond differently to distinct treatment regimens, which is assumed to affect the outcome [5].

Patient Information

Lymphocytes are key players in the immune system. If cancer arises from lymphocytes, it is called lymphoma. There are distinct types of lymphocytes, namely B cells and T cells, and B-cell lymphoma is distinguished from T-cell lymphoma. T cells originate from hematopoietic stem cells in the bone marrow and pass several developmental stages in the thymus before becoming mature, fully functional T-lymphocytes. Peripheral T-cell lymphoma (PTCL) is a type of T-cell lymphoma that derives from those mature T-cells, that populate tissues like lymph nodes, liver, and spleen, among others.

Due to the wide distribution of T cell throughout the human body, PTCL may manifest in many different ways. Some PTCL are easily palpated, especially if they develop in superficial lymph nodes or the skin. The involvement of the liver or spleen may be more difficult to note. Affected individuals may suffer the consequences of organ dysfunction, namely loss of appetite, early satiety, nausea, and vomiting, or present with constitutional symptoms such as fever, night sweat, and weight loss. They may also claim pruritus.

In order to diagnose PTCL, a tissue sample has to be obtained. Tumor cells have to be thoroughly characterized to identify the particular type of PTCL and to draw up a treatment plan according to the needs of the patient. While localized disease may eventually be treated with radiation therapy, chemotherapeutics are generally administered to those diagnosed during advanced stages of the disease. Unfortunately, most PTCL follow an aggressive course and their response to current treatment regimens is poor.

References

Article

  1. Rodriguez-Abreu D, Filho VB, Zucca E. Peripheral T-cell lymphomas, unspecified (or not otherwise specified): a review. Hematol Oncol. 2008; 26(1):8-20.
  2. Weisenburger DD, Savage KJ, Harris NL, et al. Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project. Blood. 2011; 117(12):3402-3408.
  3. Broccoli A, Zinzani PL. Peripheral T-cell lymphoma, not otherwise specified. Blood. 2017; 129(9):1103-1112.
  4. Jaffe ES, Nicolae A, Pittaluga S. Peripheral T-cell and NK-cell lymphomas in the WHO classification: pearls and pitfalls. Mod Pathol. 2013; 26 Suppl 1:S71-87.
  5. Iqbal J, Wright G, Wang C, et al. Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood. 2014; 123(19):2915-2923.
  6. Armitage JO. The aggressive peripheral T-cell lymphomas: 2017. Am J Hematol. 2017; 92(7):706-715.
  7. Vose J, Armitage J, Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008; 26(25):4124-4130.
  8. Wilhelm M, Smetak M, Reimer P, et al. First-line therapy of peripheral T-cell lymphoma: extension and long-term follow-up of a study investigating the role of autologous stem cell transplantation. Blood Cancer J. 2016; 6(7):e452.
  9. Marchi E, Raufi AG, O'Connor OA. Novel Agents in the Treatment of Relapsed or Refractory Peripheral T-Cell Lymphoma. Hematol Oncol Clin North Am. 2017; 31(2):359-375.
  10. Abouyabis AN, Shenoy PJ, Lechowicz MJ, Flowers CR. Incidence and outcomes of the peripheral T-cell lymphoma subtypes in the United States. Leuk Lymphoma. 2008; 49(11):2099-2107.
  11. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016; 127(20):2375-2390.
  12. Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011; 117(19):5019-5032.

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Last updated: 2019-07-11 20:26