PAX5-NEGATIVE HODGKIN-LIKE LYMPHOMAS: A DIAGNOSTIC CHALLANGE

Hodgkin lymphoma (HL) is a lymphoma that originates from peripheral B lymphocytes. However, the neoplastic Hodgkin and Reed-Sternberg cells typically lack most B-cell markers, including CD20, CD79a, CD19, Oct2, and BOB1, and retain only the transcription factor regulating B-cell differentiation, BSAP, encoded by the PAX5 gene. This antigen is generally expressed at a weaker intensity compared to that observed in small reactive B lymphocytes, which serve as internal controls ensuring adequate staining. Moreover, not all neoplastic cells show positivity for PAX5. For this reason, PAX5 immunoreactivity represents the only phenotypic clue to the B-cell origin of classical Hodgkin lymphomas. The diagnosis of HL is relatively straightforward when this phenotype is present and coexists with other immunomorphological features such as CD30 and CD15 positivity and negativity for B- and T-cell lineage markers, cytotoxic markers, and EMA. Morphologically similar Hodgkin and Reed-Sternberg-like cells can also be observed in other lymphoid proliferations, including anaplastic large cell lymphoma (ALCL), a lymphoma that also shares with HL a strong expression of CD30.³ ALCL originates from T lymphocytes but, similarly to HL, is highly defective in lineage-specific marker expression, often lacking T-cell markers or expressing only a subset of them. As a cytotoxic T-cell lymphoma, it frequently expresses perforin and typically shows aberrant expression of an epithelial antigen (EMA). Two genetic variants of ALCL exist: one carrying a translocation involving the ALK gene, detectable in tissue by immunohistochemistry, and the ALK-negative variant, which is considerably more challenging to diagnose. Further contributing to diagnostic complexity, ALCL may exhibit architectural patterns and morphology resembling those of HL, to the extent that the WHO classification recognizes a morphological "Hodgkin-like" subtype within ALK-positive ALCL. In diagnostic practice, rare cases are encountered that morphologically resemble classical HL but are PAX5-negative; these cases may coexpress T-cell markers such as CD3 or CD8, cytotoxic markers (e.g., perforin), and EMA and/or show clonal rearrangement of T-cell receptor genes.⁵ Some reported cases have subsequently developed a true T-cell lymphoma and/or exhibited more frequent relapses, resembling HL cases with poorer prognosis. In some of these cases, rearrangement of the JAK2 gene has been described, a genetic alteration more typically associated with ALCL. Given the potential immunomorphological overlap between PAX5-negative HL and ALK-negative ALCL, we aim to collect these rare cases to assess whether a recurring pattern of morphological, phenotypic, and genetic features can be identified, based on the data used to establish the diagnosis. The study is observational, multicenter, international, prospective and retrospective