Hydroa vacciniforme lymphoproliferative disorder, a clinicopathologic and genetic analysis

Hydroa vacciniforme lymphoproliferative disorder (HV-LPD) is a rare Epstein-Barr virus (EBV)-associated disease and the systemic form shows a propensity to progress and some cases may eventually develop a disease simulating NK/T-cell lymphoma or even aggressive NK-cell leukemia. We report 12 patients with systemic HV-LPD of median age 15.8 years with dermatosis involving the face, trunk, extremities and serous membranes. Ten of 12 patients (83 %) had systemic symptoms including 9 with prominent facial edema and 2 with bone marrow involvement. All cases were positive for EBER and CD3 and lacked CD20. Additional positive markers included CD8 in 11 of 12 (91.6 %), CD56 in 1 of 12 (8.3 %), granzyme B in 6 of 7 (85.7 %), TIA1 in 2 of 2 (100 %) and CD30 in 1 of 3 (33.3 %). Two cases studied demonstrated monoclonal TCR-γ and one also had TCR-β rearrangements. Five cases were sequenced and showed recurrent mutations in ALMS1, ALPK2, BCORL1, KANK2, KMT2D, NCOR1, PTPRD, RHOA, TNIK, TP53 and ZFHX3, and single cases showed a variety of mutations including BCOR, CREBBP, DDX3X, DMXL2, IRF4, IRF8, KDM6A, MGA, NCOR2, PLCG1, PRDM1, RNF213, SMARCA4, STAT5B and TET2 mutation. Most patients were treated with immunomodulating therapy, two received methotrexate, three received multiagent chemotherapy and one underwent hematopoietic stem cell transplant. Follow-up was available in 10 patients of whom 6 died of disease and one was alive without disease. Our results showed that patients with persistent/progressive systemic HV-LPD have a poor prognosis and did not respond well to chemotherapy. The mutation spectrum bore some resemblance to extranodal NK/T lymphomas but also had notable differences.