T-cell lymphomas are a rare subset of non-Hodgkin lymphomas (NHLs) that originate from mature T-cells. NHLs that arise from natural killer (NK) cells are related to T-cell lymphomas, but have distinct features. T-cell and NK-cell lymphomas are generally classified on the basis of characteristics such as location, cell morphology, and immunophenotype. The classifications are further separated into four disease types: nodal, extranodal, cutaneous, and leukemic. The most common classifications of nodal T-cell lymphomas include peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS); angioimmunoblastic T-cell lymphoma (AITL); follicular T-cell lymphoma (FTCL); and anaplastic large-cell lymphoma (ALCL). Extranodal T-cell lymphomas include extranodal NK/T-cell lymphoma (nasal type), hepatosplenic T-cell lymphoma, and intestinal T-cell lymphoma. Cutaneous T-cell lymphomas include mycosis fungoides (MF) and Sézary syndrome, which is related to MF but includes a leukemic component. The diagnostic approach to T-cell and NK- cell lymphomas varies by the classification of disease suspected, but generally involves biopsy and phenotyping by flow cytometry and/or immunohistochemistry. Additional laboratory testing may include genetic evaluation.
Quick Answers for Clinicians
A comprehensive patient history and physical exam, including a full skin examination and attention to node-bearing areas, is recommended for the initial workup of T-cell lymphomas. Initial laboratory testing should include a CBC with differential, lactate dehydrogenase (LDH) testing, a comprehensive metabolic panel, and uric acid testing. Additionally, a bone marrow biopsy with aspirate, a positron emission tomography (PET)/computed tomography (CT) scan and/or chest/abdominal/pelvic CT scan, and an echocardiogram may be informative. Additional testing may be indicated based on the suspected classification. Molecular studies (T-cell clonality testing) may be helpful when the differential diagnosis includes a T-cell lymphoma versus a benign/reactive process (chronic inflammatory infiltrate).
Human T-lymphotropic virus-1 (HTLV-1) is known to cause adult T-cell leukemia/lymphoma (ATLL). Diagnosis of ATLL requires HTLV-1 testing. Generally, serology testing is recommended to determine the patient’s HTLV-1 infection history. However, in some cases, confirmatory Western blot or polymerase chain reaction (PCR) testing may be warranted. HTLV-1 positivity differentiates between ATLL and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and leads to alternate medical management. Epstein-Barr virus (EBV) is associated with extranodal NK/T-cell lymphomas and systemic EBV-positive T-cell lymphoma. EBV testing is recommended in certain circumstances to guide diagnosis and proper treatment. Finally, laboratory testing for HIV may be useful in selected cases.
The National Comprehensive Cancer Network (NCCN) T-Cell Lymphomas and Primary Cutaneous Lymphomas guidelines provide detailed recommendations for specific T-cell and NK-cell lymphomas, such as adult T-cell leukemia/lymphoma (ATLL), extranodal NK/T-cell lymphoma, mycosis fungoides (MF), and Sézary syndrome. The World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC) have provided detailed information about the classification of various T-cell and NK-cell lymphomas.
Several published indices are available to assess prognosis for the various T-cell or NK-cell lymphomas. Proper classification is also important for appropriate treatment and prognostication, given that many of these lymphomas have different biologic behavior and outcomes. Prognostic indices include the international prognostic index (IPI) and the age-adjusted IPI, the Prognostic Index for PTCL unspecified (PIT), and the modified PIT. These prognostic indices include factors such as age, extranodal involvement, lactate dehydrogenase (LDH) concentration, and bone marrow involvement to predict prognostic risk. Genetic risk factors should also be considered when determining prognostic risk. For example, prognosis in anaplastic large-cell lymphoma (ALCL) is related to translocations of the ALK and IRF4/DUSP22 genes.
The World Health Organization (WHO) has proposed a classification for T-cell lymphomas that integrates morphologic, immunophenotypic, genetic, and clinical features. These classifications are generally separated into four disease types: nodal, extranodal, cutaneous, and leukemic. The table below details the current WHO classifications for T-cell lymphomas and their disease types.
Nodal PTCL with TFH phenotypea
Indolent T-LPD of the GI tracta
Breast implant-associated ALCLa
Subcutaneous panniculitis-like TCL
Primary cutaneous CD30-positive TCL
Primary cutaneous ALCL
Hydroa vacciniforme-like LPD
Primary cutaneous gamma-delta TCL
Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphomaa
Primary cutaneous acral CD8-positive TCLa
Primary cutaneous CD4-positive small/medium T-cell LPDa
T-cell prolymphocytic leukemia
T-cell large granular lymphocytic leukemia
Aggressive NK-cell leukemia
Systemic EBV-positive TCL
Chronic LPD of NK cellsa
aIndicates provisional classifications.
ALK, anaplastic lymphoma kinase; ATLL, adult T-cell leukemia/lymphoma; EATL, enteropathy-associated T-cell lymphoma; EBV, Epstein-Barr virus; ENKTL, extranodal natural killer/T-cell lymphoma; GI, gastrointestinal; LPD, lymphoproliferative disorder; MEITL, monomorphic epitheliotropic intestinal T-cell lymphoma; T-LPD, T-cell lymphoproliferative disorder TCL, T-cell lymphoma; TFH, T-follicular helper phenotype; T-LPD, T-cell lymphoproliferative disorder.
Indications for Testing
Presentation of T-cell and NK-cell lymphomas varies widely between patients but may involve lymphadenopathy, hypergammaglobulinemia, hepatosplenomegaly, eosinophilia, skin rash, leukemic manifestations, extranodal masses, or elevated white blood cell (WBC) count. Phenotyping is necessary in most situations, and genetic studies may also be recommended. Specific diagnosis is important to determine proper medical management.
Phenotyping by flow cytometry can identify surface antigens on cells that can indicate the cell of origin and any immunophenotypic aberrancies. Flow cytometry is generally performed on peripheral blood, bone marrow, or tissue samples. NCCN recommends investigation of the following markers for the initial evaluation of PTCL: CD45, CD3, CD5, CD19, CD10, CD20, CD30, CD4, CD8, CD7, CD2, TCRαβ, and TCRγd. Investigation of additional markers may be useful to characterize specific classifications.
Immunohistochemical staining may also be utilized for lymphoma phenotyping. NCCN recommends the following markers for the initial IHC analysis: CD20, CD3, CD10, BCL6, Ki-67, CD5, CD30, CD2, CD4, CD8, CD7, CD56, CD21, CD23, EBER-ISH, TCRβ, TCRδ, PD1/CD279, and ALK. Additional IHC markers may be useful to characterize specific classifications. For more information, refer to ARUP’s Immunohistochemistry Stain Offerings.
T-Cell Clonality Screening
Polyclonal TCR gene rearrangements are characteristic of benign or reactive disease, whereas monoclonal rearrangements may indicate a lymphoma, although they are not entirely specific and can also be seen with infections, autoimmune diseases, and other sources of chronic inflammation. Conversely, a negative result does not exclude a lymphoma diagnosis. As such, TCR gene testing can be helpful but should be supported by cytologic and immunophenotypic testing to detect abnormal T-cell populations. NCCN recommends T-cell clonality testing to support a diagnosis of T-cell lymphoma because this testing often provides essential information and increased diagnostic precision.
Genetic tests to detect somatic mutations or structural abnormalities are often informative and, in some cases, are essential for accurate and precise diagnosis and prognostic assessment of T-cell and NK-cell lymphomas.
ALK Gene Rearrangement
In a subset of CD30-positive ALCLs, ALK gene translocations are present that affect the expression of the ALK protein. The WHO includes two separate classifications of ALCLs, ALK positive and ALK negative. Because prognosis and management differ greatly for these two classifications, determination of ALK gene rearrangements and/or ALK protein expression is essential to differentiate between them.
IRF4/DUSP22 Gene Rearrangement
IRF4/DUSP22 gene rearrangements are associated with a subset of ALK-negative ALCLs and are also seen in lymphomatoid papulosis. Testing for IRF4/DUSP22 rearrangements should be considered if CD30-positive, ALK-negative ALCL is diagnosed because these rearrangements are associated with a significantly better prognosis. Testing may also be useful under certain circumstances for the diagnosis of primary cutaneous CD30+ T-cell LPDs.
IDH1 and IDH2 Mutational Analysis
Somatic mutations in IDH1 and IDH2 have been identified in some AITLs. Mutational analysis of these genes may be helpful to distinguish AITLs from other T-cell lymphomas.
Additional Genetic Markers
ARUP Laboratory Tests
For additional immunohistochemical tests that may be useful in the diagnosis or differential diagnosis of PTCL, refer to ARUP’s Immunohistochemistry Stain Offerings.
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.
Marchi E, O'Connor OA. The rapidly changing landscape in mature T-cell lymphoma (MTCL) biology and management. CA Cancer J Clin. 2020;70(1):47-70.
Willemze R, Cerroni L, Kempf W, et al. The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas. Blood. 2019;133(16):1703-1714.
International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. N Engl J Med. 1993;329(14):987-994.
Lee Y, Uhm JE, Lee HY, et al. Clinical features and prognostic factors of patients with "peripheral T cell lymphoma, unspecified". Ann Hematol. 2009;88(2):111-119.
Gallamini A, Stelitano C, Calvi R, et al. Peripheral T-cell lymphoma unspecified (PTCL-U): a new prognostic model from a retrospective multicentric clinical study. Blood. 2004;103(7):2474-2479.
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(Suppl 1):S71-S87.