BACKGROUND: Nodular, lymphocyte-predominant Hodgkin lymphoma (NLPHL) represents a rare entity. METHODS: A clinical registry was launched from 1973 to 2003 in France. To determine the histologic transformation (HT) rate to diffuse large B-cell lymphoma (DLBCL) and long-term outcomes, 164 patients were selected after histologic review. RESULTS: The median follow-up was 9.5 years. The high biopsy rate (85%) at each recurrence enabled the analysis of HT. The median patient age was 30 years (range, 6-69 years), 80% of patients were men, 83% had Ann Arbor stage I/II disease, 65% had supradiaphragmatic-disease; 27% received radiotherapy, 9% received chemotherapy, 29% received combined-modality therapy, and 35% were followed with a watch-and-wait strategy. All 106 treated patients achieved complete remission and 66 patients developed disease recurrence at a median of 3.3 years (range, 0.4-18.3 years after diagnosis). The majority of recurrences were NLPHL, but 19 patients progressed to DLBCL at a median of 4.7 years (range, 0.4-18 years after diagnosis). The 10-year cumulative HT rate was 12% and was found to be associated significantly with a poor prognosis. The 10-year overall survival rate was 91%. Fourteen patients died (7 died of progressive disease, 3 died of secondary cancers, and 4 died from other causes). HT was diagnosed at a median of 4.7 years (range, 0.4-18 years after diagnosis). The 19 patients who had HT were treated with curative intent: Nine patients received high-dose therapy with subsequent autologous stem cell transplantation (ASCT), and 10 patients received different chemotherapy regimens. The overall survival rate after HT did not differ between patients who underwent ASCT and the others. CONCLUSIONS: This long-term follow-up study confirmed that NLPHL is a separate entity that has a favorable clinical presentation and outcome despite frequent recurrences. The current findings also emphasize the importance of biopsies at the time patients develop recurrent disease to evaluate HT. Cancer 2010;116:631-9. (C) 2009 American Cancer Society.