Diagnostic utility and pitfalls of human T-lymphotropic virus serology in adult T-cell leukemia/lymphoma: evidence from a 25-year pathology-based nonendemic cohort.

Adult T-cell leukemia/lymphoma (ATLL) is a distinct type of peripheral T-cell lymphoma (PTCL) driven by human T-lymphotropic virus type I (HTLV-1)-infected T cells, but diagnosis can be confounded by histological overlap with non-ATLL PTCL. While molecular testing is the diagnostic gold standard in endemic areas, HTLV-1/2 serology is often used as a surrogate in nonendemic settings, yet its accuracy and limitations remain unclear. We retrospectively analyzed 881 PTCL cases over 25 years at two tertiary referral hospitals in Taiwan, where HTLV-1 is nonendemic. Serology was available in 48.2% of cases. Molecular confirmation was performed using HBZ in situ hybridization and tax quantitative polymerase chain reaction. Among the 44 seropositive PTCL patients with tissue available, 37 were diagnosed and molecularly confirmed as ATLL. Of the seven initially diagnosed as non-ATLL PTCL, three were reclassified as ATLL, while four showed no molecular evidence, including three likely false seropositives with borderline signal-to-cutoff (S/CO) values in serology assay and T follicular helper cell phenotype. In seropositive PTCL, clinicopathologic interpretation without molecular testing yielded 100% positive predictive value, 93% sensitivity, and 93% accuracy, compared with 91% positive predictive value by serology alone. In addition, retrospective molecular screening in 59 PTCL without prior serologic data revealed one case of ATLL that had initially been overlooked. In conclusion, our findings support routine HTLV-1/2 serologic testing in all newly diagnosed PTCLs. However, interpretation should be guided by clinicopathological correlation and serology index values. Borderline index results warrant molecular confirmation.