Anaplastic Large Cell Lymphoma (ALCL)

Anaplastic large cell lymphoma (ALCL) is a CD30-positive aggressive peripheral T-cell lymphoma comprising approximately 3-5% of all non-Hodgkin lymphomas and 10-15% of T-cell lymphomas. The 2017/2022 WHO classification recognizes four distinct entities: (1) ALK-positive systemic ALCL — defined by t(2;5)(p23;q35) NPM1-ALK translocation (75-85% of ALK+ cases) or variant ALK translocations (TPM3-ALK, TFG-ALK, ATIC-ALK), expressed as cytoplasmic and nuclear ALK staining, more common in children and young adults (median age 30-35 years), male predominance, favorable prognosis (5-year overall survival 70-80%); (2) ALK-negative systemic ALCL — older adults (median 55-60 years), characterized by DUSP22 (favorable prognosis) or TP63 (poor prognosis) rearrangements, intermediate outcomes (5-year survival 40-50%); (3) primary cutaneous ALCL — indolent course, excellent prognosis (>90% 5-year survival), part of CD30+ lymphoproliferative disorders spectrum with lymphomatoid papulosis; (4) breast implant-associated ALCL (BIA-ALCL) — distinct entity associated with textured breast implants, presents as late peri-implant seroma or mass, generally curable with implant removal and capsulectomy.

Epidemiology: incidence approximately 0.25 per 100,000 per year for systemic ALCL, bimodal age distribution (children/young adults for ALK+, older adults for ALK-), male-to-female ratio 1.5:1. Clinical presentation of systemic ALCL: B-symptoms (fever, night sweats, weight loss) in 60-75%, lymphadenopathy (90%), extranodal involvement (60%) including skin (20-25%), bone (10-15%), bone marrow (10-15%), liver (10%), gastrointestinal tract, lung; advanced stage disease at presentation (60-70%). Cutaneous ALCL presents as solitary or grouped papules/nodules/tumors, often ulcerated, on trunk and extremities, with self-regression in 40% but local recurrence common. BIA-ALCL presents 8-10 years post-implantation with delayed seroma (most common), capsular mass, breast pain, swelling, or skin rash.

Diagnosis requires excisional or incisional biopsy showing diffuse infiltration with large pleomorphic cells (hallmark cells with horseshoe/embryo-shaped eccentric nuclei, abundant cytoplasm with eosinophilic Golgi region), strong uniform CD30 expression (membrane and Golgi pattern), variable T-cell markers (CD2, CD3, CD4, CD5, CD43 — CD3 negative in 40%), cytotoxic markers (granzyme B, perforin, TIA1), EMA+, and ALK staining (positive in ALK+ subtype). Molecular testing: ALK FISH or IHC, NPM1-ALK fusion (most common), DUSP22 rearrangement, TP63 rearrangement, TCR clonality. Staging: PET-CT, CT chest/abdomen/pelvis, bone marrow biopsy, CSF analysis if neurologic symptoms. Treatment: systemic ALCL — first-line CHOP or CHP + brentuximab vedotin (BV-CHP regimen, ECHELON-2 study showed superior PFS over CHOP) for 6 cycles; pediatric protocols (BFM, ALCL99) for children; consolidation autologous stem cell transplantation considered for ALK-negative or high-risk disease; ALK inhibitors (crizotinib, alectinib, lorlatinib) for relapsed/refractory ALK+ disease; CAR-T cell therapy and other novel agents for refractory disease. Cutaneous ALCL: surgical excision, local radiation, low-dose methotrexate, brentuximab vedotin for multifocal/refractory. BIA-ALCL: complete capsulectomy and implant removal usually curative; chemotherapy for advanced disease.