Splenomegaly Study (SMS): Which Etiologies for Unexplained Splenomegalies?
Authors: Denis Guillaume , Terriou Louis , Séné Thomas , Costello Regis , Michaud Martin , Hellé Claudia , Lagadec Audrey , Bauduer Frédéric , Sanhes Laurence , Rose Christian , Urbanski Geoffrey , Berger Marc G. 
Published: November 2021

Abstract
The most prevalent etiologies of splenomegaly (SM) are easily detected in routine clinical practice. However, after these first-line diagnoses have been ruled out, many cases remain unexplained. Frequently, signs and symptoms are non-specific hiding rare etiologies such as Lysosomal Storage Diseases (LSD) (e.g., Gaucher disease (GD), Niemann-Pick disease type B). SplenoMegaly Study (SMS) aims to estimate the prevalence of different etiologies in unexplained SM and to describe their diagnostic work-up. We present here the final results of the study.
SMS is a prospective, observational, multi-center, longitudinal study performed in France. All patients with unexplained SM, aged ≥15 years, consulting to the French hematology or internal medicine departments were invited to take part of the study. SM was confirmed by echography or CT-scan with a craniocaudal length ≥13 cm; unexplained was defined as negative clinical and biological routine workup. All conducted exams and tests for diagnosis purpose were under each physician's responsibility. For each patient, last visit took place when an etiology was identified or up to 12 months after inclusion.
From Sept-2015 to Apr-2020, 505 patients were enrolled by 87 centers (secondary centers [71.3%] and tertiary centers [28.7%]). Physicians were mainly internists (52.9%) or hematologists (46.0%). Patients characteristics at inclusion were as follows: male gender, 61.2%; median age, 51.0 years old (16-94 years old); median spleen length, 15.0 cm (13-30 cm); heterogeneous spleen structure, 11.1%. A total of 501 patients completed the study. After a median duration of 6.6 months, 232 patients (46.3%) received a diagnosis. When compared to patients without diagnosis, patients with diagnosis were older (median age 59.5 vs 45.0; p&lt;0.001), had more often a massive SM (≥18 cm) (25.2% vs 10.7%; p&lt;0.001) and heterogeneous spleen structure (15.9% vs 6.6%; p=0.002). Their biological test results (hemoglobin, leucocytes, CRP, albumin) were also significantly altered and they showed more constitutional (48.3% vs 37.3%) and digestive symptoms (41.9% vs 28.4%) compared to patients without diagnosis. The proportion of diagnosed patients was higher in tertiary than secondary centers (55.2% vs 32.6%). Hematological (lymphoid and myeloid) malignancies represented only 38.7% (n=87) of established diagnoses (Figure 1). Non-malignant diseases, accounted for 61.3% of diagnosis, were: autoimmune disorders (20.0%, n=45), portal hypertension (12.0%, n=27), infectious diseases (11.6%, n=26), LSD (4.4% [n=10], including type 1 Gaucher Disease (GD1) [n=4]; Niemann-Pick disease type B [n=3] and type C [n=2]; and Fabry disease [n=1]), other disorders (13.3%, n=30) and non-specified (3%, n=7). Hematological malignancies were more common in elderly patients (median age 66.0, p&lt;0.001) with massive SM (p&lt;0.001). Compared to other diagnoses, a large proportion of patients diagnosed with portal hypertension were obese (51.9%) and had ongoing metabolism or nutrition disorders (40.7%). Patients with autoimmune disorders had higher CRP levels (median value, 11.5 mg/L) and showed more osteoarticular symptoms (34.8%). All 4 GD1 patients had thrombocytopenia (≤100G/L platelets). Among the tests contributing to diagnosis, biopsies were performed in 34.3% (n=172) of patients, mainly bone marrow trephine biopsy (BMTB) (20.8%, n=104). Half of patients with BMTB received a diagnosis. Splenectomy was performed in 19 patients (4.0%) and was conclusive in 14 of them. β-Glucocerebrosidase activity assay to test for GD was performed in 79.8% of patients. Among patients without diagnosis, 22.7% of them were not tested for GD.
In SMS, patients at inclusion had unexplained SM despite routine clinical and biologic analysis. The diagnostic yield improved after further medical evaluations reaching an etiologic diagnosis in 46% of patients. Patients with an established diagnosis were older, had a larger spleen and altered biological parameters compared to patients without diagnosis. Interestingly, non-malignant diseases accounted for 61.3% of diagnoses. It is noteworthy the diversity of LSD etiologies obtained: 10 patients (4%) were diagnosed with LSD, including 4 GD1 patients. This study provides useful new information to optimize the diagnostic strategy of splenomegaly poorly explained by routine workup. SMS is sponsored by Sanofi-Genzyme.
Figure 1 Figure 1.

Disclosures
Denis: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Terriou: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Séné: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Costello: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Michaud: Sanofi: Honoraria, Research Funding. Hellé: Sanofi: Current Employment. Lagadec: Sanofi: Current Employment. Bauduer: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sanhes: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Urbanski: Sanofi: Honoraria, Research Funding. Berger: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.