Clinical, Laboratory, and Genetic Features of Erdheim-Chester Disease Patients from Two Reference Centers in a Developing Country

INTRODUCTION: Erdheim-Chester Disease (ECD) is a rare histiocytic neoplasm with a heterogenous clinical course with asymptomatic localized course or systemic compromise involving multiples organs causing significant morbidity and mortality. There are few cohorts published however mainly from North America and Europe. Given the scarcity of data on ECD in Latin America, we have established a local registry in the city of São Paulo to collect clinical and biological material of ECD patients.

METHODS: We retrospectively collected clinical data on biopsy-proven ECD patients diagnosed and treated at two reference centers for histiocytic disorders (Hospital das Clínicas da Universidade de São Paulo e Hospital Sírio-Libanês, Brazil) from January 2006 to February 2020.

RESULTS: Sixteen patients with confirmed diagnosis of ECD were included with median age of 53 years. 75% were males and a median follow-up time of 50 months (7-163). Median time from onset of symptoms to diagnosis was 13 months (0.1-142). Immunohistochemistry (IHC) findings showed positivity for CD68 in 15/16 (94%) and for S100 in 3/16 (19%) patients, no case had CD1a positivity. The most frequent organs involved were: bone (75%), skin (44%), central nervous system (CNS) (44%), lymph nodes (31%), lung (13%), liver (6%), spleen (6%), and gastrointestinal tract (6%) of cases. CNS lesions involvement occurred mostly in the pituitary gland (86%). Twelve of 16 (75%) patients presented disease in more than one organ. Xanthelasma and xanthoma were the most common skin lesions (44%). The most frequent histiocytosis-related clinical manifestations were bone pain (44%) and diabetes insipidus (38%). The most frequent radiologic findings were osteosclerosis in 12/16 (75%) patients, retroperitoneal fibrosis around the kidneys in 6/16 (38%), the coated aorta sign and orbital infiltration were found in 4/16 (25%) of cases. 18FDG/PET-CT was performed in all patients, of whom 13 (81%) had hypermetabolic lesions. BRAF status at diagnosis was available in 13/16 patients using the technique of Sanger in 5/13, pyrosequencing in 3/13, IHC in 3/13 and polymerase chain reaction (PCR) in 2/13. Mutations were detected in only 3/16 (19%) cases. All patients received treatment due to symptomatic disease with a median of two lines of therapy (1-7). Median time between diagnosis and the first treatment was one month. First-line treatments were interferon in 12/16 patients, steroids in 5/16, and each one of thalidomide, vemurafenib and tumoral resection in one patient. Beyond first-line therapy, the most conventional chemotherapy regimens used were cladribine (4/16 patients) and LCH-like etoposide-containing vinblastine, methotrexate and mercaptopurine (2/16 patients). Other treatments included radiotherapy (4/16 patients) and a single patient used cobimetinib, imatinib and infliximab. Median progression free survival (PFS) after the first line treatment was 7.5 months (95% CI 5-10), and median overall survival (OS) was not reached to this date. Time to next treatment was 9 months in patients who did not achieved at least partial response after first line, and 15 months in those who attained it. PFS at 2 years was 45% (95% CI 0.17-0.71), and OS at 2 years was 100%. One patient died due to infection complication after the first cycle of cladribine after 50 months of follow-up.

CONCLUSION: To our knowledge, despite the low number of patients, this is the largest Latin American cohort of patients with ECD reported to date. Our findings resemble demographic characteristics, sites of involvement and treatment choices reported by other groups. However, it is noteworthy that the proportion of ECD patients bearing a BRAF mutation (18.8%) was pretty lower than previously reported (approximately 50%). This needs to be taken cautiously due to the small number of subjects and due to technical issues, since all samples analyzed by PCR or Sanger were negative for BRAF mutation. A national registry of histiocytosis is needed to confirm these preliminary data.