Marginal zone lymphoma (MZL) is an indolent B-cell malignancy with heterogeneous anatomical and clinical presentation. While MZLs are generally associated with long survival, some patients experience histological transformation to aggressive large B-cell lymphoma. Population-based long-term data on the transformation of MZL is limited. We conducted a nationwide population-based study to estimate the risk of transformation and relative survival in patients diagnosed with MZL in Finland from 1995–2018. We identified a total of 1454 patients with MZL from the Finnish Cancer Registry (FCR). The cumulative incidence of transformation was 4.7% (95% CI, 3.6−6.2) at 10 years. The highest incidence of transformation was observed in the patients with splenic MZL (14.0%; 95% CI, 8.6−22.7). The transformation was associated with a substantially increased risk of death (HR, 5.18; 95% CI, 3.58–7.50). Ten-year relative survival was 79% (95% CI, 73‒83%). Transformation, nodal MZL subtype, and older age at diagnosis were associated with increased excess mortality, whereas patients diagnosed at a later calendar period had a lower excess risk of death. We conclude that transformation resulted in a substantially increased mortality irrespective of MZL subtype compared with the patients without transformation. Our results also suggest a reduction in excess mortality in recent years.

Background Marginal zone lymphoma (MZL) is an indolent B-cell lymphoma with classical histopathological lesions and heterogeneous anatomical and clinical features. It is divided into three subtypes depending on the site of lymphoma involvement with extranodal MZL of mucosa-associated lymphoid tissue (MALT, ∼70%) being the most common, followed by splenic (SMZL, ∼20%) and nodal subtypes (NMZL, <10%). Although these subtypes differ with regard to biology and clinical presentation, MZLs are generally associated with long survival. However, a proportion of MZLs undergo transformation to large B-cell lymphoma characterized by aggressive clinical behavior and increased mortality. Population-based long-term data on transformation of MZL is lacking. Aims We estimated overall survival and the risk of transformation to large B-cell lymphoma in patients diagnosed with MZL in Finland in 1995−2018. We also compared mortality rates between the patients with or without transformation. Methods Patients diagnosed with incident MZL (ICD-O-3 morphology codes 9689/3 and 9699/3) and lymphoma not otherwise specified (NOS) (9590/3, 9591/3) in Finland between 1995 and 2018 were retrieved from the Finnish Cancer Registry (FCR). The Registry has an excellent coverage and provides accurate population-based nationwide data for all histologically verified cancers in Finland. The diagnosis of MZL and possible transformation were confirmed from the pathology reports. Transformation was defined as the diagnosis of morphologically verified large B-cell lymphoma at least 3 months after the primary diagnosis of MZL. For all patients with histologically verified MZL, we collected data on subtype, gender, date of birth, MZL diagnosis and last follow-up (f-up), vital status at the end of f-up, and date of transformation. F-up for overall survival (OS) was completed on December 31, 2018. The patients with missing information regarding MZL subtype or incorrect diagnostic were excluded. No patients were lost to f-up before the end of the study period, and none of the MZL diagnoses nor transformations were recorded by death certificate or autopsy only. The start of the f-up was defined as the date of MZL diagnosis. OS and the cumulative risk of transformation were estimated by the Kaplan-Meier method. Analysis of total mortality was performed using Cox regression. Risk factors included age at diagnosis, year of diagnosis, gender, and MZL subtype. Transformation was treated as a time-varying covariate. All statistical analyses were performed using R, version 4.0.4. Results We identified 1341 patients diagnosed with MZL after above mentioned exclusions. Baseline characteristics, as well as subtype-specific rates of transformation and death, are shown in the Table 1. Median age at diagnosis was 68 years (IQR, 58−76; range, 13−95 years), with a slight female predominance (59%). MALT subtype was the most frequent, followed by SMZL and NMZL. There were no clinically significant differences in age at diagnosis between males and females nor in the MZL subtypes. Median follow-up time was 5.5 years (IQR, 2.1−10.5; range 0−24 years). The majority of the NMLZ patients were diagnosed during more recent years. Transformation occurred in 47 patients during 9315 person-years of follow-up (crude transformation rate, 5.0 per 1000). The cumulative risk of transformation was 2.8% (95% CI, 1.7-3.8) at 5 years and 5.6% (95% CI, 3.8-7.3) at 10 years from diagnosis (Fig. 1), with no apparent plateau. Overall, 519 (39%) patients died during a total f-up of 9435 person-years (crude mortality rate, 55.0 per 1000). In comparison, the crude mortality rate following transformation was 233.4 per 1000. OS was 66.2% (95% CI, 73.8−78.7) at 5 years and 58.9% (95% CI, 55.8−62.2) at 10 years from diagnosis (Fig. 2). After adjusting for potential confounders (age at diagnosis, gender, year of diagnosis, and MZL subtype), transformation was associated with a substantial increase in mortality (HR, 5.13; 95% CI, 3.47−7.59; p < 0.001) (Table 2). Conclusions In this large nationwide population-based study, the risk of transformation to large B-cell lymphoma was 5.6% at 10 years, and transformation was associated with a substantially increased risk of death. Long-term OS and baseline characteristics were in accordance with previously published data for MZL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Gastrointestinal stromal tumour (GIST), the most common sarcoma of the gastrointestinal tract, can be treated effectively with tyrosine kinase inhibitors, such as imatinib. Cancer immune therapy has limited efficacy, and little is known about the immune suppressive factors in GISTs. Fibrinogen‐like protein 2 (FGL2) is expressed either as a membrane‐associated protein or as a secreted soluble protein that has immune suppressive functions. We found that GISTs expressed FGL2 mRNA highly compared to other types of cancer in a large human cancer transcriptome database. GIST expressed FGL2 frequently also when studied using immunohistochemistry in two large clinical series, where 333 (78%) out of the 425 GISTs were FGL2 positive. The interstitial cells of Cajal, from which GISTs may originate, expressed FGL2. FGL2 expression was associated with small GIST size, low mitotic counts and low tumour‐infiltrating lymphocyte (TIL) counts. Patients whose GIST expressed FGL2 had better recurrence‐free survival than patients whose GIST lacked expression. Imatinib upregulated FGL2 in GIST cell lines, and the patients with FGL2‐negative GIST appeared to benefit most from long duration of adjuvant imatinib. We conclude that GISTs express FGL2 frequently and that FGL2 expression is associated with low TIL counts and favourable survival outcomes.