Incidence of Erdheim-Chester Disease in the United States

Background: Erdheim-Chester Disease (ECD) is an exceedingly rare inflammatory myeloid neoplasm characterized by infiltration and accumulation of clonal histiocytes within multiple organ systems. These histiocytes usually carry gain-of-function mutations that affect the MAPK-ERK or PI3K-AKT pathways. The most common mutation is BRAF^V600E, occurring in greater than 50% of patients, often with a low variant allele frequency (i.e. <5%). ECD presents as a spectrum of clinical manifestations that include symmetric osteosclerosis of the distal femora and proximal tibiae and/or fibulae (almost always present), ataxia from cerebellar/brainstem involvement, diabetes insipidus, periorbital xanthelasmas, pleuropulmonary disease, pseudotumor of the right atrioventricular groove, encasement of the (coated) aorta, and retroperitoneal involvement with ‘hairy’ kidneys. Patients may be asymptomatic or critically ill. Treatment options include targeted agents like BRAF or MEK inhibitors, as well as systemic agents such as interferon or chemotherapy. A recent combined report from France and Italy suggested incidence rates of 3.5 per 10 million adults (not age-adjusted). ECD was officially considered a hematopoietic malignancy by the World Health Organization in 2016 and a reportable cancer in the United States (US) beginning in 2021. For the first time, we report the incidence of ECD in the US.

Methods: We obtained ECD data in 2021, the only year available so far, from the Surveillance Epidemiology and End Results (SEER) program. The SEER program prospectively collects data from population-based cancer registries covering about 48% of the US population and is updated annually. Data elements include patient demographics, primary tumor site, tumor morphology and stage at diagnosis, first course of treatment, and follow-up for vital status. Twentytwo cancer registries (SEER 22) were included and screened for cases with the ECD International Classification of Diseases for Oncology (ICD-O) code 9749/3 for inclusion in this study. We used SEERstat version 8.4.3 to calculate the annual incidence. All incidence rates were age-adjusted to the 2000 US standard population. Confidence intervals (CI; 95%) were provided whenever available.

Results: In 2021, SEER documented 16 patients diagnosed with ECD. The median age at diagnosis was 52 years (range, 25-74). The most common age range at diagnosis was 55-59 years (31%). There was an even distribution of sexes (53% male), but greater proportion of minority patients (38% non-Hispanic White, 25% non-Hispanic Black, 25% Hispanic, 6% Asian/Pacific Islander, 6% unknown race/ethnicity). Most patients (94%) were diagnosed in large metropolitan areas. The overall incidence rate was 0.9 [CI: 0.2-5.2] per 10 million population. The incidence rates for various demographic subgroups were as follows (per 10 million): males (1.0 [0.4-1.9]), females (0.8 [0.4-1.7), non-Hispanic Blacks (1.9 [0.5-5.2]), Hispanic (1.1 [0.3-2.8]), non-Hispanic Whites (0.5 [0.2-1.2]), Asian/Pacific Islander (0.5 [0.0-3.4]), and ages 25-74 years (1.5 [0.8 – 2.5]). The most reported primary site was subcutaneous (25%), followed by bone (19%) and breast (19%). A greater number of cases had distant disease (56%; 31% localized, 13% unknown). Almost half of the patients received chemotherapy (44%) and few underwent radiation (13%) or surgery (13%).

Conclusion: We report the first estimate of ECD incidence in the US, highlighting the rarity of this entity. It should be noted that our reported incidence rates are likely underestimated. This could be due to the COVID-19 pandemic that resulted in social quarantine from 2020-2021. ECD is also a very challenging diagnosis to make. Future investigations of annual SEER updates and collective incidence data over several years will be required to strengthen our findings and further characterize the epidemiological features of ECD in the US.