The Challenge of Unexplained Splenomegalies: Preliminary Data of the French Prospective Multi-Center Splenomegaly Study (SMS)

Introduction: The most prevalent etiologies of splenomegaly (SM) easily detected by routine clinical practice are hematological malignancies, portal hypertensions (PH), and hemolytic anemias. However, after these first line diagnoses are ruled out, many cases of SM can remain unexplained. At this point, diagnosis becomes challenging due to the fact that many signs and symptoms can be non-specific, and SM could also be associated to rarer etiologies, such as lysosomal storage diseases (LSD) (e.g. Gaucher disease, acid sphingomyelinase deficiency (Niemann Pick Diseases)). The SplenoMegaly Study (SMS) is a prospective, observational, multi-center, and longitudinal study ongoing in France, which aims to estimate the prevalence of the different etiologies of unexplained SM. We present here preliminary descriptive data on the patients' characteristics and their established diagnosis at follow-up.

Methods: Since 2015, all patients aged ≥15 years and referred to the hematology or internal medicine department in 117 French hospitals, with an unexplained SM diagnosis (confirmed by echography or CT-scan with a craniocaudal length ≥13 cm) have been invited to participate. Unexplained cause of SM was defined as a first negative clinical workup based on patient's interview and physical examination, and biological routine tests (including complete blood and reticulocytes count, clotting test, liver enzymes, bilirubin, protein electrophoresis, ESR and CRP). A total of 500 patients will be enrolled. For each patient, last visit takes place at the moment an etiology is identified or up to 12 months after the inclusion. All exams and tests conducted for diagnostic purposes are under each physician's responsibility. Since there is no clinical gold standard for the precise definition of SM, Splenocalc application, adjusting for gender and patient height [Chow and al., 2016], is used to confirm the SM.

Results: As of May 2018, 190 consecutive patients (58% male) have been included with a median age of 53 years (16-94 years), a median spleen length of 15 cm (range: 13-30 cm), and 88.6% showed an homogeneous spleen structure. Three patients presented with an obvious diagnosis following the initial workup (n=2, chronic lymphocytic leukemia with lymphocytosis; n=1, sarcoidosis with adenopathies) should not have been included. A total of 129 patients (68%) were considered to have completed the study. Of them, 72 patients (56%) had an established diagnosis. Five categories were identified: lymphoproliferative malignancies (n=20; 27.8%; median age: 66); autoimmune disorders (n=15; 20.8%; median age: 48); myeloproliferative malignancies (n=10; 13.9%; median age: 72); PH (n=10; 13.9%; median age: 62) and other diagnoses, including LSDs (n=17; 23.6%; median age: 40). PH was mainly of nonalcoholic origin. Patients with an established diagnosis were significantly older (median age: 61.5 years vs. 45.0 years; p=0.002) and the SM was significantly greater (mean length: 16.7±3.2 vs. 15.6±2.3 cm; p=0.05) than those with no diagnosis. Hematological malignancies were more common in the oldest patients compared to other diagnostic categories (median age: 66.5; p=<0.001). Baseline height data were available in 179 patients, which allowed us to confirm their SM by using Splenocalc application. After height-gender adjustment, 157 patients (87.7%) had their SM confirmed; 14 patients (9.5%) had uninterpretable results and 8 patients (4.5%) had no SM confirmation. However, within these 8 patients with no SM after adjustments, 2 (1.1%) had already an established diagnosis (lymphoma and tuberculosis).

Conclusions: Patients who finally have an established diagnosis were older and had a significantly larger spleen than those with no diagnosis. The spleen length cut-off of 13 cm or more seems reliable since almost 9 out 10 cases were confirmed by Splenocalc application. Furthermore, after 12 months of regular medical evaluations, 44% of patients remained with an unexplained SM. This proportion seems to be higher than percentages reported in the literature, but our 12-month follow up period might be too short. The final analysis planned on a total population of 500 patients will estimate the prevalence of each etiology of unexplained SM as well as the exams and tests conducted for diagnosis purpose.