T-Cell & NK-Cell Lymphomas

Overview and immunophenotype

Mature T and NK neoplasms. Post-thymic T-cell and NK-cell lymphomas are a minority of non-Hodgkin lymphomas in the West and more frequent in Asia, where HTLV-1 and EBV drive several of them. Most are aggressive (early mycosis fungoides is the indolent exception), and each is recognized by a signature clue: a virus, a fusion gene, or a favored organ.

Lineage markers. CD3, part of the T-cell receptor (TCR) complex, is the most lineage-specific T-cell marker. Neoplastic T cells often lose a pan-T antigen, classically CD7, whereas reactive T cells keep the full set; clonality is proven by TCR gene rearrangement.

Precursor versus mature. T-lymphoblastic leukemia/lymphoma (T-ALL) is TdT+ and often CD1a+ and CD34+; it classically affects adolescent boys as an anterior mediastinal (thymic) mass causing superior vena cava syndrome or airway compression. TdT, the DNA polymerase that adds random N-nucleotides during V(D)J recombination, marks only immature lymphoblasts, so mature T/NK lymphomas are TdT-negative.

Adult T-cell leukemia/lymphoma (HTLV-1)

Virus. HTLV-1 is a retrovirus endemic in southwestern Japan, the Caribbean, West Africa, and parts of South America, spread by breastfeeding, sex, and blood. It infects CD4+ T cells, and its Tax protein transactivates NF-κB targets, IL-2, and IL-2Rα (CD25), sustaining T-cell proliferation. Only a few percent of carriers develop ATLL, after decades of latency. The virus also causes HTLV-1-associated myelopathy/tropical spastic paraparesis, a slowly progressive spastic weakness of the legs.

Clinical picture. Acute ATLL brings lymphadenopathy, hepatosplenomegaly, skin infiltrates, and circulating CD4+ CD25+ cells with multilobed "flower" (cloverleaf) nuclei. Hypercalcemia with lytic bone lesions reflects tumor PTHrP plus RANKL-driven osteoclast activation, unlike the calcitriol-mediated hypercalcemia of Hodgkin lymphoma. Immunodeficiency invites Pneumocystis pneumonia and Strongyloides hyperinfection; acute and lymphoma forms carry a poor prognosis.

Mycosis fungoides and Sézary syndrome

Mycosis fungoides. The most common primary cutaneous lymphoma is a clonal proliferation of skin-homing CD4+ T cells that evolves over years from scaly patches (often on sun-protected buttocks and trunk) to indurated plaques to exophytic tumors, with late spread to nodes, blood, and viscera. The name reflects mushroom-like tumors, not a fungus. Biopsy shows atypical cells with convoluted, cerebriform nuclei invading the epidermis (epidermotropism) with little spongiosis; intraepidermal clusters are Pautrier microabscesses.

Pautrier microabscesses are malignant lymphocytes; neutrophilic Munro microabscesses in the stratum corneum mean psoriasis.

Sézary syndrome. The leukemic form combines generalized, intensely pruritic erythroderma, lymphadenopathy, and circulating clonal CD4+ Sézary cells with cerebriform nuclei, typically lacking CD7 and CD26 with a high CD4:CD8 ratio. It is far more aggressive than patch/plaque disease. Early mycosis fungoides receives skin-directed therapy (topical steroids, phototherapy, topical mechlorethamine); Sézary syndrome needs systemic treatment.

Anaplastic large cell lymphoma

Morphology. Large "hallmark" cells with eccentric horseshoe- or kidney-shaped nuclei are strongly CD30+ and often lose CD3; because Reed–Sternberg cells are also CD30+, ALCL can mimic Hodgkin lymphoma.

ALK-positive ALCL. Usually t(2;5)(p23;q35), fusing NPM1 (5q35) to ALK (2p23); NPM1-mediated dimerization makes the ALK tyrosine kinase constitutively active. It affects children and young adults and does better than ALK-negative ALCL of older adults; crizotinib (ALK inhibitor) and brentuximab vedotin (anti-CD30) exploit these targets. Contrast the B-cell translocations: t(14;18) BCL2 in follicular, t(11;14) cyclin D1 in mantle cell, and t(8;14) MYC in Burkitt lymphoma.

Breast implant-associated ALCL. An ALK-negative, CD30+ lymphoma in the fluid or capsule around textured implants, presenting as a delayed seroma or mass years after placement. Aspirated fluid is sent for CD30 staining; confined disease is usually cured by implant removal with total capsulectomy.

Other extranodal and nodal T/NK lymphomas

Enteropathy-associated T-cell lymphoma. EATL arises from intraepithelial T lymphocytes in long-standing or refractory celiac disease (HLA-DQ2/DQ8) and forms ulcerating jejunal masses; suspect it when pain, weight loss, obstruction, or perforation occur despite a strict gluten-free diet. Prognosis is poor. Gastric MALT lymphoma, by contrast, is an H. pylori-linked B-cell tumor.

Extranodal NK/T-cell lymphoma, nasal type. An EBV-driven (EBER+) angiocentric, angiodestructive infiltrate with necrosis ulcerates the nasal cavity and perforates the septum or palate; it is most common in East Asia and Latin America. Cells are CD56+ and cytoplasmic CD3ε+ but surface CD3-negative, with cytotoxic granules. The differential includes granulomatosis with polyangiitis (PR3-ANCA), cocaine use, mucormycosis in diabetic ketoacidosis, and nasopharyngeal carcinoma (EBV-linked but keratin-positive).

PTCL, not otherwise specified. The diagnosis of exclusion for mature T-cell lymphomas that fit no defined entity, and the most common PTCL subtype in Western countries: older adults with generalized lymphadenopathy and B symptoms, an aggressive course, CHOP-based therapy, and frequent relapse.