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PTCL Subtypes
The Importance of Accurate Diagnosis of PTCL Subtypes

Released: October 14, 2019

Francine Foss
Francine Foss, MD
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Peripheral T‑cell lymphomas (PTCL) comprise a heterogeneous group of diseases. Overall, aggressive T‑cell lymphomas total approximately 9000 cases per year in the United States. The WHO classification for T‑cell lymphoma divides the diseases into 4 groups based on their clinical manifestations: nodal, extranodal, leukemic, and cutaneous. Most patients fall into the nodal T‑cell lymphoma group. This group has its own subgroups, with the 3 most common comprising more than 60% of all T-cell lymphomas: PTCL not otherwise specified (PTCL-NOS) (26%), angioimmunoblastic T‑cell lymphoma (AITL) (18%), and anaplastic large‑cell lymphoma (ALCL) (12%), followed by natural killer (NK) T‑cell lymphoma and adult T‑cell lymphoma associated with HTLV1, both with an incidence of approximately 10%. Each of these subtypes has specific characteristics that are important not only for diagnosis but also for prognostic and treatment implications.

Subtype Characteristics

PTCL-NOS
PTCL-NOS is a basket category for T-cell lymphomas that do not fit other categories. It is characterized by mature T-cells, usually alpha/beta CD4‑positive T-cells. There are a number of different prognostic groups within PTCL-NOS, often characterized by molecular markers and expression of different pathway genes, such as the GATA3 gene. In addition, many patients with PTCL-NOS have CD30 expression and other markers, such as CCR4, which is of particular importance because targeted therapies have been developed specifically for these markers (brentuximab vedotin for CD30 and mogamulizumab for CCR4).

Angioimmunoblastic
AITL is a disease of follicular helper T-cells, characterized by expression of the CXCL13 chemokine and the PD-1 receptor. Patients with AITL can have unique molecular characteristics and often have mutations in epigenetic genes and pathways. This makes AITL particularly sensitive to specific therapies such as the histone deacetylase inhibitors.

Anaplastic Large Cell
ALCL is divided into ALK‑positive and ALK‑negative groups. ALK‑positive ALCL has an excellent prognosis and often these patients are cured with conventional multiagent chemotherapy approaches, whereas ALK‑negative ALCL has an outcome similar to other subtypes of nodal T‑cell lymphoma, usually needing consolidation therapy with autologous stem cell transplant (ASCT). Both ALK‑positive and ALK‑negative ALCL express CD30, which is of added importance now that we have targeted therapy with the antibody–drug conjugate brentuximab vedotin. Brentuximab vedotin is approved for relapsed/refractory ALCL based on earlier clinical trials, and recently, it was approved in combination with cyclophosphamide, doxorubicin, and prednisone (CHP) in the frontline setting in patients with CD30-expressing ALCL and other T-cell lymphomas, based on results from the ECHELON-2 trial that showed superior OS compared with standard CHOP chemotherapy.

Natural Killer
NK T‑cell lymphoma is characterized by expression of Epstein-Barr virus in the tumor cells, and typically presents with involvement of the upper aerodigestive tract, particularly the sinuses or the oropharynx. In those cases, patients can be treated effectively with chemotherapy and involved‑field radiotherapy. However, NK T‑cell lymphoma can be metastatic, and when patients present with stage IV disease, it has a significant impact on their survival.

Other T-Cell Lymphomas
Very rare subtypes of T-cell lymphomas also exist. Patients with hepatosplenic T‑cell lymphoma often present with fevers and pancytopenia and can be very difficult to diagnose, with involvement of the liver, spleen, and bone marrow. Enteropathy T‑cell lymphoma can be associated with celiac sprue and is characterized by involvement of the small bowel. Panniculitic-type T‑cell lymphomas and primary cutaneous gamma/delta T‑cell lymphoma of the skin can be confused in that they can have similar clinical manifestations, with nodularity of the skin and skin ulcerations. Patients with panniculitic T‑cell lymphoma of the alpha/beta type generally have a more benign and indolent disease, whereas those with gamma/delta T‑cell lymphoma of the skin have a more aggressive clinical course.

Prognosis
OS for patients with aggressive T‑cell lymphomas is generally inferior to that of patients with aggressive B‑cell lymphomas. Retrospective studies such as the International T‑Cell Lymphoma Project and the Swedish Lymphoma Registry of more than 700 patients with PTCL have shown that patients with ALK‑positive ALCL with CD30 expression have better outcomes, with a 5‑year OS of approximately 70% and a clear plateau on their survival curve. In comparison, for other subtypes of aggressive T‑cell lymphoma, including patients with ALK‑negative ALCL, AITL, and PTCL-NOS, the median survival is approximately 2‑3 years with a 5-year OS of approximately 34% for all PTCL. However, a study in patients from the Nordic Lymphoma Study Group who received upfront ASCT in first remission show that there may be some improvement in outcome for these patients.

Patients with primary cutaneous ALCL with only skin involvement, without evidence of lymph node or other visceral involvement, have excellent outcomes, with a 5‑year OS of approximately 80%; most of these patients are cured with conservative therapies.

New prognostic factors have been identified for ALK‑negative ALCL, including the DUSP22 and the TP63 genes, which have been shown to have prognostic significance for OS, with patients who are DUSP22 positive having superior OS vs those who are DUSP22 negative. Patients who have TP63 mutation tend to have an inferior outcome.

Treatment Approaches
Overall, for aggressive T‑cell lymphomas AITL, PTCL-NOS, and ALCL, most patients receive anthracycline‑containing chemotherapy such as CHOP and now with the data from ECHELON-2, the combination of brentuximab vedotin and CHP in patients who are CD30 positive, particularly with ALCL.

For patients with AITL, PTCL, or ALK‑negative ALCL, if they have a CR with frontline chemotherapy, guidelines suggest that ASCT in first remission can be considered for patients who are transplant eligible. However, there are no randomized trials that would suggest that ASCT in first remission is better than either maintenance therapy, which has not been studied in PTCL, or observation. One important biologic feature of NK T‑cell lymphoma that has been recognized is the sensitivity of these cells to L‑asparaginase. The newer treatment regimens for NK T‑cell lymphoma all include L‑asparaginase as part of the regimen and those regimens, including the SMILE regimen, AspMetDex, and GELOX regimen, all of which are effective both in frontline as well as relapsed NK T-cell lymphomas.

In conclusion, peripheral T-cell lymphomas are a heterogenous and challenging group of diseases, but with proper diagnosis and identification of targetable markers, clinicians are able to offer their patients a greater opportunity for improved outcomes.

Your Thoughts?
What are your most pressing questions regarding PTCL subtypes? Join the conversation by leaving a question or comment below.

For more information on the latest data on the management of patients with newly diagnosed PTCL and a brief summary resource, click here.

Register here to attend a free CCO Friday Satellite Symposium on PTCL, “New Directions in Treating Peripheral T-Cell Lymphomas: Expert Guidance and Case Discussions,” preceding the 61st ASH Annual Meeting & Exposition in Orlando, Florida, on December 6, 2019!

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