Diagnostic Impact of Integrated Molecular Testing in Nodal T-follicular Helper Cell Lymphoma Mimicking Castleman Disease and Classic Hodgkin Lymphoma: A Report of Two Cases

Nodal T-follicular helper cell lymphoma (nTFHL) has a broad morphologic spectrum and can closely mimic Castleman disease (CD) and classic Hodgkin lymphoma (CHL), particularly in limited biopsies and when flow cytometry is noncontributory.We report two diagnostically challenging cases in which the diagnosis was established by integrating histopathology, T-follicular helper (TFH) immunophenotyping, T-cell receptor (TCR) clonality testing, and targeted next-generation sequencing (NGS).Case 1 was a 64-year-old woman whose excisional lymph node biopsy showed regressed germinal centers, prominent high endothelial venules (HEVs), and hyalinized "lollipop" vessels resembling CD.Initial immunohistochemistry and flow cytometry were noncontributory.Clonal TCR gene rearrangement, NGS demonstrating DNMT3A R882H and two TET2 mutations (variant allele frequencies 26-33%), and subsequent TFH-marker staining established nTFHL with Castleman-like features.CD30 positivity (>20%) supported selection of brentuximab vedotinbased systemic therapy.Case 2 was an 82-year-old man with previously treated follicular lymphoma whose supraclavicular core biopsy contained CD30-positive Hodgkin/Reed-Sternberg (HRS)-like cells, initially suggesting CHL.Clonal TCR rearrangement, RHOA G17V, multiple TET2 variants (variant allele frequencies 36-44%), and a CTCF splice-site variant supported angioimmunoblastic-type nTFHL.Chromosomal microarray analysis (CMA), performed only in this case, showed complex genomic imbalances and was supportive rather than required for diagnosis.The patient completed six cycles of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone with a complete metabolic response and remains in remission on observation.These cases illustrate a practical stepwise approach: Castleman-like nodal architecture with focal atypia, or HRS-like cells in a T-cell-rich background, should prompt TFH immunophenotyping and TCR clonality testing.Targeted NGS can be added in selected inconclusive cases.TET2 and DNMT3A mutations and TCR clonality alone are not independently diagnostic.Comprehensive molecular testing is most useful when conventional evaluation is insufficient, rather than as a routine firstline approach.