Histologic Transformation in Marginal Zone Lymphomas

Information concerning histologic transformation (HT) of marginal zone lymphomas (MZL) into aggressive entities is scant. We retrospectively analyzed the clinical variables at diagnosis and outcome, with special reference to HT, in a population of consecutive patients (pts) with confirmed diagnosis of MZL, including extranodal MZL (MALT lymphoma), splenic MZL (SMZL) and nodal MZL (NMZL).

The database of the Oncology Institute of Southern Switzerland (IOSI, Bellinzona) and of the Hematology Division of the Amedeo Avogadro University of Eastern Piedmont (Novara) includes 373 cases of MZL diagnosed and treated since 1979 to 2012: 186 MALT lymphomas (50%), 88 SMZL (23%), 36 NMZL (10%). Sixty-three patients (17%) could not be properly classified (uMZL): they presented with bone marrow infiltration with or without detectable involvement of peripheral blood but without splenomegaly and with apparently no other extranodal or nodal involved site.

Incidence was not significantly different according to sex (male: 47; female: 53%), median age at diagnosis was 68 years (20–94 years); 244 pts (65%) had stage III-IV disease. LDH was elevated in 45/212 (21%) tested pts, beta2-microglobulin in 108/205 (53%) tested pts. B symptoms were reported in 27/368 pts (7%). Five percent of pts had an ECOG performance status higher than 1. Serologic evidence of hepatitis C virus (HCV) infection was reported in 45/243 (19%) pts for whom the data was available. Among the 186 MALT lymphomas, 91 pts (49%) had a gastric localization, and 54 (29%) had multiple extranodal sites of disease involvement.

Median overall survival (OS) and progression-free survival of the whole population were 15 years and 8 years, respectively. After a median follow-up of 5 years, HT was observed in 14 cases (4%, 95%CI:2%-6%). A diagnosis of diffuse large B cell lymphoma was documented in 12 pts (85.7% of patients undergoing HT), while in two cases the diagnosis was of classical Hodgkin lymphoma and mantle cell lymphoma, respectively. HT occurred after a median interval of 3 years (range: 1–12 years) after diagnosis. With respect to MZL type, HT occurred in 6% SMZL, 4% MALT lymphomas, 3% NMZL, and 2% uMZL (P=0.635). Risk of HT was 4% (95%CI, 2–8%) at 5 years, 6% (95%CI:3%-11%) at 10 years and 9% (95%CI, 5–16%) at 15 years; the rate of transformation tended to plateau from that point onward. At the time of HT, most pts had high LDH serum levels (8/11, 73%) and presence of B symptoms (6/10, 60%). After transformation, nine pts received anthracycline-containing regimens, and four pts were treated with high dose cytarabine regimens; in a single patient only supportive measures were adopted. In four pts, autologous stem cell transplantation was performed after induction. At a median follow-up of 12 months after HT, five of 14 pts died, all for lymphoma-related causes, with a 2-year post-transformation survival rate of 38% (95%CI:5%-74%). There was no significant association between the risk of HT and any of the clinical variables at diagnosis or frontline treatment strategies.

This large retrospective series documents that the risk of HT is low across all MZL types. The incidence of HT in MZL is apparently lower than that of other indolent B cell malignancies, namely follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). As also observed in FL and CLL, HT in MZL occurs relatively early during the clinical course, pointing to putative biological differences at diagnosis in MZL patients destined to transform.

Off Label Use: Trial partially supported by a research grant by Celgene. Lenalidomide was provided free by Celgene. The use of Lenalidomide is off-label in untreated DLBCL. Bertoni:OncoEthix SA: Research Funding.