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T-cell and natural killer (NK)-cell lymphomas are a rare subset of non-Hodgkin lymphomas (NHLs) that originate from T cells and NK cells. T-cell and NK-cell lymphomas are classified based on characteristics such as site of presentation (i.e., hematolymphoid, cutaneous, gastrointestinal tract, liver, or spleen), morphology, immunophenotype, and cytogenetic and molecular features. , The diagnostic approach to T-cell and NK-cell lymphomas varies depending on the suspected diagnosis but generally involves morphologic evaluation of a biopsy, preferably excisional or incisional, and immunophenotyping by flow cytometry and/or immunohistochemistry (IHC). Additional laboratory testing may include genetic and molecular studies such as karyotyping, fluorescence in situ hybridization (FISH), next generation sequencing (NGS), and others.
Quick Answers for Clinicians
The initial workup will vary depending on the specific T-cell or natural killer (NK)-cell lymphoma suspected. Generally, a comprehensive history and physical exam—including a full skin examination and close evaluation of node-bearing areas, liver and spleen size, and presence of B symptoms (e.g., fever, night sweats, and unintentional weight loss)—are recommended for the initial workup. Initial laboratory testing should include a tissue biopsy for diagnostic purposes, a CBC with differential, a lactate dehydrogenase (LDH) test, a comprehensive metabolic panel (CMP), and uric acid testing. Additionally, a bone marrow biopsy with aspirate, a positron emission tomography (PET)/computed tomography (CT) scan, a chest/abdominal/pelvic CT scan, and an echocardiogram are often needed. Further testing, such as an infectious workup, skin biopsy, CT scans, ultrasounds, magnetic resonance imaging (MRI), serologic markers for autoimmune diseases, human leukocyte antigen (HLA) typing, C-reactive protein (CRP), soluble interleukin-2 receptor, T-cell clonality testing, and other tests, may be indicated in certain patients depending on the suspected diagnosis or possible treatment options.
Human T-lymphotropic virus-1 (HTLV-1) is known to cause adult T-cell leukemia/lymphoma (ATLL). To diagnose and distinguish ATLL from other lymphomas such as peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) and cutaneous T-cell lymphomas, positive HTLV-1 serology is needed. , It may be important to screen for HTLV-1/2 by serology or other methods in certain patients with peripheral T-cell lymphomas, T-cell large granular lymphocytic lymphoma, and other T-cell lymphomas, as the results may impact therapy. Generally, serology testing consists of an enzyme-linked immunoassay (ELISA) with reflux to Western blot for confirmation if positive. If the Western blot is indeterminate, polymerase chain reaction (PCR) testing may be performed. Epstein-Barr virus (EBV) is associated with nodal T- and natural killer (NK)-cell lymphomas, extranodal NK-/T-cell lymphomas, angioimmunoblastic T-cell lymphoma (AITL), and T- and NK-cell lymphoid proliferations and lymphomas of childhood. , EBV testing is recommended in certain circumstances to guide diagnosis, treatment, and monitoring. Laboratory testing for HIV, hepatitis B and C (HBV and HCV), and cytomegalovirus (CMV) may be useful in select cases.
The National Comprehensive Cancer Network (NCCN) guidelines on T-cell lymphomas and primary cutaneous lymphomas provide detailed recommendations for the most common subtypes, including peripheral T-cell lymphomas (PTCLs), breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), T-cell large granular lymphocytic leukemia (TPLL), adult T-cell prolymphocytic leukemia (ATLL), hepatosplenic T-cell lymphoma (HSTCL), extranodal natural killer (NK)-cell/T-cell lymphomas (ENKLs), mycosis fungoides (MF), Sézary syndrome (SS), and primary cutaneous CD30+ T-cell lymphoproliferative disorders (PCTLDs). For more information regarding diagnostic criteria, refer to the Classification section.
Several published indices are available to assess prognosis for the various T-cell and natural killer (NK)-cell lymphomas. Proper classification is important for appropriate treatment and prognostication, as many of these lymphomas have different biologic behavior and outcomes. Prognostic indices for peripheral T-cell lymphomas include the International Prognostic Index (IPI), the age-adjusted IPI, the prognostic index for peripheral T-cell lymphoma, unspecified (PTCL-U) (PIT), the modified PIT, and the T-cell score. Other indices include the prognostic index of natural killer lymphoma (PINK), the prognostic index of natural killer-cell lymphoma with Epstein-Barr virus (EBV) DNA (PINK-E), the prognostic index for acute- and lymphoma-type adult T-cell leukemia/lymphoma (ATL-PI), and the modified ATL-PI. These prognostic indices include factors such as age, extranodal involvement, lactate dehydrogenase (LDH) concentration, Eastern Cooperative Oncology Group (ECOG) performance status, stage of disease, Ki-67 proliferation index, serum albumin, absolute neutrophil count, 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 rearrangements of the ALK, IRF4/DUSP22, and TP63 genes.
Classification
The World Health Organization (WHO) and the International Consensus Classification (ICC) have classification systems for T-cell and NK-cell lymphomas that integrate the site of presentation (i.e., hematolymphoid, cutaneous, gastrointestinal tract, liver, or spleen) with morphologic, immunophenotypic, genetic, and clinical features. ,
Indications for Testing
The presentation of T-cell and NK-cell lymphomas varies widely among patients and depends on the site and extent of involvement. Signs and symptoms may include lymphadenopathy, hepatosplenomegaly, cutaneous manifestations (i.e., rash, nodules, etc.), B symptoms (e.g., fever, night sweats, unintentional weight loss), effusions, malabsorption, epigastric pain, cytopenias, leukocytosis, hyper-/hypogammaglobulinemia, and hemophagocytic lymphohistiocytosis.
Laboratory Testing
Tissue Biopsy
Excisional or incisional biopsy is preferred for definitive diagnosis and histologic grading. Fine needle aspiration (FNA) is insufficient for the initial diagnosis of lymphoma, and histologic grading cannot be performed on an FNA specimen. Core needle biopsies are an appropriate alternative when excisional or incisional biopsy cannot be performed and may be used in conjunction with FNA and ancillary testing to make a diagnosis.
Lymphoma Phenotyping
Adequate immunophenotyping by flow cytometry and/or IHC is essential for the diagnosis of various subtypes of T-cell and NK-cell lymphomas, as it allows for the identification of surface antigens, which can indicate the cell of origin and any immunophenotypic aberrancies. Flow cytometry is generally performed on peripheral blood, body fluid, and/or tissue biopsy specimens. If a bone marrow biopsy is performed, flow cytometry is usually performed on that specimen as well. The National Comprehensive Cancer Network (NCCN) recommends using morphology and clinical presentation to guide the selection of markers. Commonly ordered markers involved in the initial evaluation of T-cell and NK-cell lymphomas include CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD21, CD23, CD30, CD56, BCL6, ALK, PD1/CD279, granzyme B, perforin, TIA1, CD1a, CXCL13, TdT, TCRβ, TCRẟ, and Ki-67. The NCCN also has specific recommendations regarding additional markers and the workup for T-cell lymphomas.
T-Cell Clonality Screening
The NCCN recommends T-cell clonality testing (polymerase chain reaction [PCR] with capillary or gel electrophoresis, high-throughput sequencing (HTS)/NGS, or flow cytometry) to detect TCR gene rearrangements, which are indicative of clonal T-cell expansion, to support a diagnosis of T-cell lymphoma. Clonal TCR gene rearrangements must be interpreted in the context of morphologic and immunophenotypic findings to detect abnormal T-cell populations, as these rearrangements are not unique to T-cell lymphomas and may also occur in infections, autoimmune diseases, and other sources of chronic inflammation. Conversely, a negative result does not exclude a diagnosis of lymphoma.
Molecular Genetics
Genetic tests to detect somatic mutations or structural abnormalities are often informative and, in some cases, essential for diagnosis, prognostic assessment, and/or detection of minimal residual disease (MRD) of T-cell and NK-cell lymphomas. , Genetic testing may include FISH, karyotyping, HTS/NGS, and/or array-based comparative genomic hybridization (CGH).
MRD testing in lymphoma may be used to monitor treatment and detect molecular relapses during periods of clinical remission. The methodologies used to detect MRD are highly sensitive and specific to the lymphoma subtype and include FISH, real-time quantitative PCR, digital droplet PCR, multicolor flow cytometry, and NGS.
ALK Gene Rearrangement
In a subset of CD30-positive anaplastic large-cell lymphomas (ALCLs), some ALK gene translocations are present that affect the expression of the ALK protein. The WHO and the ICC recognize ALK-positive and ALK-negative ALCLs as separate entities. , Because prognosis and management differ greatly for these two classifications, determination of ALK gene rearrangements by FISH or targeted messenger RNA sequencing and/or ALK protein expression by IHC is essential to differentiate between the two. ,
IRF4/DUSP22 Gene Rearrangement
IRF4/DUSP22 gene rearrangements are associated with a subset of CD30-positive, ALK-negative ALCLs and primary cutaneous CD30-positive T-cell lymphoproliferative disorders. , Testing for IRF4/DUSP22 rearrangements should be considered in cases of CD30-positive, ALK-negative ALCLs because some studies have shown a more favorable prognosis, similar to that of ALK-positive ALCL, allowing the treatment algorithm for ALK-positive ALCL to be considered. Testing may also be useful in certain cases of primary cutaneous ALCL or lymphomatoid papulosis.
Other Genetic Markers
TP63 rearrangements are associated with a subset of ALK-negative ALCLs. It is important to identify these cases as they often have an aggressive course. TCL1 and TRA translocations are associated with T-cell prolymphocytic leukemia (T-PLL). Testing for mutations in TET2, IDH2, RHOA, DNMT3A, STAT3, and/or STAT5B may be indicated in certain circumstances, depending on the possible diagnoses.
ARUP Laboratory Tests
Flow Cytometry
Capillary Electrophoresis/Polymerase Chain Reaction (PCR)
Fluorescence in situ Hybridization (FISH)
References
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NCCN - T-cell lymphomas v1.2025
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: T-cell lymphomas. Version 1.2025. Updated Nov 2024; accessed May 2025.
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T-cell and NK-cell lymphoid proliferations and lymphomas
Lim M, German O, Ferry JA, et al. T-cell and NK-cell lymphoid proliferations and lymphomas. In: WHO Classification of Tumours Editorial Board. WHO Classification of Haematolymphoid Tumours. 5th ed. International Agency for Research on Cancer; 2024. Accessed May 2025.
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NCCN - Primary cutaneous lymphomas v2.2025
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: primary cutaneous lymphomas. Version 2.2025. Updated Apr 2025; accessed May 2025.
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Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of mature lymphoid neoplasms: a report from the Clinical Advisory Committee. Blood. 2022;140(11):1229-1253.
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Zhang S, Wang X, Yang Z, et al. Minimal residual disease detection in lymphoma: methods, procedures and clinical significance. Front Immunol. 2024;15:1430070.
For additional immunohistochemical tests that may be useful in the diagnosis or differential diagnosis of PTCL, refer to ARUP’s Immunohistochemistry Stain Offerings.