Diagnostic approach to CD30⁺ T-cell lymphoma. Cohesive growth of large cells including hallmark cells, with strong and homogeneous expression of CD30 at the membrane and in the cytoplasm with a paranuclear “Golgi-like” pattern, suggests anaplastic large cell lymphoma (ALCL). Demonstration of T-cell surface markers or expression of cytotoxic molecules is required to show T-cell lineage and distinguish from potential mimics, such as metastatic melanoma or carcinoma, or a variety of other hematologic neoplasms that may be CD30⁺, notably classic Hodgkin lymphoma. Clonality studies may be necessary or useful in some instances to show monoclonal TR gene rearrangements because immunohistochemistry results may not accurately represent cell lineages, and some cases of ALCL may be completely negative for T-cell markers (“null” phenotype). EBV testing is recommended in cases of presumed ALCL or CD30⁺ PTCLs, and HTLV-1 serology may be helpful in selected instances because EBV-associated NK- or T-cell lymphomas (extranodal NK/T-cell lymphoma, nasal type [ENKTCL]; primary nodal EBV⁺T/NK-cell lymphoma or aggressive NK-cell leukemia) and ATLL can present as tumors with anaplastic morphology and CD30 expression,^50-52 and EBV is by definition negative in ALCL. Immunohistochemistry is the routinely used method to detect ectopic ALK expression reflecting ALK rearrangement. In selected cases, FISH analysis or other genetic assays may be useful to confirm an ALK rearrangement or specific ALK fusion transcripts. In the small cell and the lymphohistiocytic variants of ALK⁺ ALCL, the neoplastic cells tend to be smaller with less numerous hallmark cells and show more heterogeneous CD30 staining, therefore ALK testing should be generously applied to other PTCLs with various levels of CD30 expression, especially in pediatric cases where ALK⁺ ALCL is most prevalent. Differentiating ALK⁻ ALCL from CD30⁺ peripheral T-cell lymphoma, NOS (PTCL, NOS), may be difficult or subjective, and there is a number of cases whose classification remains uncertain.^53-55 In addition, other lymphomas such as enteropathy-associated T-cell lymphoma (EATL), or transformed mycosis fungoides (MF), may resemble ALCL and involve lymph nodes.⁵¹ Therefore, clinical history, topography of the lesion, and staging need to be integrated into the diagnosis. Only cases with strong CD30⁺ expression can eventually be considered for ALK⁻ ALCL, which may present in various sites. With extremely rare exceptions, those in the vicinity of a breast implant presenting as a periprosthetic effusion or a capsular mass in principle correspond to breast implant-associated (BIA) ALCL. Cutaneous presentation can reflect primary cutaneous (pc) ALCL or cutaneous presentation of a systemic disease, and likewise nodal ALK⁻ ALCL may represent systemic disease or nodal dissemination from a primary cutaneous or breast implant–associated ALCL.⁵⁶ Staging is essential to the correct diagnosis because there is no single phenotypic or genetic mark that reliably allows their distinction. In (systemic) ALK⁻ ALCL, FISH testing for DUSP22 rearrangement (recommended by the ICC and optional in WHO5) enables the identification of DUSP22-rearranged cases, which represent a biologically distinct subgroup.⁵⁷ FISH, fluorescent in situ hybridization.