Breast Non Hodgkin’s Lymphoma (NHL): A Large Monocentric Study of Initial Characteristics, Natural History, and Prognostic Factors.
Authors: Arnaud Philippe , Asselain Bernard , Validire Patricia , Kirova Youlia , Plancher Corine , Vincent-Salomon Anne , Fourquet Alain , Sahli Rafika , Konopka Jessica , Decaudin Didier 
Published: October 2019

Abstract
Breast NHL represents less than 1% of all lymphomas and 2% of lymphomatous extranodal sites. We therefore reviewed all patients treated at the Institut Curie between 1986 and 2004 for a NHL having initial breast localization to define their initial characteristics, natural history and prognostic factors. Forty-six cases were selected for the study. Pathological review according to the WHO classification showed 2 patients with lymphocytic lymphoma, 3 cases of grade I follicular NHL, 1 case of MALT lymphoma, 1 case of grade III follicular NHL, 1 Burkitt’s lymphoma, and 38 diffuse large cell lymphomas [namely, 40 cases (87%) of high-grade NHL]. A complete analysis was performed on the 40 high-grade NHL patients. Initial characteristics were: median age 62 years (range: 22–86), B symptoms 17%, PS < 2 in 92%, stages III-IV 57%, nodal involvement 57% (47% axillary sites), 2 or more extra-nodal sites 32% (15% of bone marrow involvement and 2.5% of central nervous system (CNS) involvement), elevated LDH in 37%, and IPI score of 0–1/2/3/4–5 in 45%/12%/12% and 15%, respectively. Treatment consisted of chemotherapy in all cases (chlorambucil 3, anthracycline-based regimen with (30) or without (7) intrathecal prophylaxis), breast radiotherapy in 29 cases (72%), and rituximab in 4 patients. At the end of initial therapy, 36 patients (90%) achieved CR. With a median follow-up of 96 months (range: 14–188), nineteen patients (47%) relapsed. Relapses were localized in 8 cases and diffuse in 11 cases; breast localizations were observed in 10 cases (53%), one of which included contralateral involvement, axillary in 5 cases, and CNS site involvement in 3 cases. Among relapsed patients, 8 cases achieved second CR (47 %). Among the 10 patients with breast relapses, 8 received localized radiotherapy during first-line therapy. The 2- and 5-year disease-free survivals (DFS) were 65% (95% CI: 51 to 81%) and 54 % (95% CI: 40 to 72%), respectively; the 2- and 5-year overall survivals (OS) were 74% (95% CI: 62 to 89%) and 61% (95% CI: 47 to 78%), respectively. In univariate analysis, stage IV, 2 or more extranodal sites, elevated LDH level, high IPI score, and CNS involvement were prognostic for lower DFS; moreover, age greater than 60 years, PS > 1, ESR > 30, IPI score > 2, and 2 or more extranodal sites influence adversely OS. In multivariate analysis, the presence of 2 or more extranodal sites (p = 0.0008; RR 5.48; 95% CI: 2.01–14.9) was the only one factor that had a pejorative impact on DFS (Figure 1.A). PS > 1 (p = 0.02; RR 3.63; 95% CI: 1.18–11.07) and 2 or more extranodal sites (p = 0.05; RR 2.64; 95% CI: 1.0–6.96) were associated with poor OS (Figure 1.B). Finally, high-grade selected patients were compared to a historical series of 111 patients with aggressive lymphomas treated at the Institut Curie between 1982 and 1997 with an anthracycline-based regimen. Ann Arbor stage adjusted OS was significantly lower for patients with initial breast involvement (p < 0.0383). In conclusion, initial breast localization has a pejorative impact on the outcome of NHL patients, with an impressive adverse influence of additional extranodal sites on both DFS and OS. These results suggest a specific management of NHL with breast involvement in prospective clinical trials.