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Prognostic factors of ECD
nosed at autopsy or after death, and the median and mean time from onset to diagnosis was 12 (range: 1–89) and 20.7 months (Online Supplementary Figure S1). No significant difference between interval from onset to diagnosis and presence of organ involvement, age, year of diagnosis, and any other clinical features were detected.
Table 1. Clinical characteristics of ECD patients Characteristics
Sex (male–female)
Median age at onset, y (range) Median age at diagnosis, y (range) Mean time for diagnosis, m (range) Year of diagnosis, no. (%)
Before 2000 2000–2004 2005–2009 2010 and later
Coexistence of LCH, no. (%)
Median number of involved organs (range) Skeletal involvement, no. (%)
Bone pain
CNS involvement, no. (%)
Parenchymal brain mass Exophthalmos
Meningeal involvement
Without any radiological findings
Cardiovascular involvement, no. (%) Cardiac involvement
Aortitis
Retroperitoneal involvement, no. (%)
Hydronephrosis
Hairy kidney
Endocrine involvement, no. (%)
Diabetes insipidus
Pituitary tumor without diabetes insipidus Hypothyroidism
Cutaneous involvement, no. (%)
Xanthelasma
Other
Pulmonary involvement, no. (%)
Pleural thickening
Fibrosis
Interlobular septal thickening Centrilobular shadow
Digestive involvement, no. (%)
Pancreas
Liver Gastrointestinal Gallbladder
CRP at onset (mg/dL), median (range)
All patients (n = 44)
28–16
51 (23–76) 53 (23–77) 20.7 (1–89)
5 (11.4) 8 (18.2) 9 (20.5) 22 (50.0) 4 (9.1)
4 (1–11) 38 (86.4) 22
22 (50.0) 12
6
4
2
23 (52.3) 19
11
22 (50.0) 10
8
18 (40.9) 15
2
1
18 (40.9) 11
7
15 (34.1)
5
3
2
1
6 (13.6)
3
2
2
1
2.61 (0.1–14.1)
15 (34.1) 25 (56.8) 5 (11.4) 5 (11.4) 4 (9.1) 1 (2.3) 2 (4.5) 1 (2.3) 1 (2.3) 1 (2.3) 1 (2.3) 10 (22.7 1 (2.3)
Fifteen patients (33.3%) were treated with interferon a (IFN-a) or pegylated IFN. Twenty-five patients (57.8%) were administered with corticosteroid. Patients who were diagnosed after 2005 were more frequently administered IFN than those diagnosed before 2005 (43.8% vs. 7.7%, P=0.034). No patient was administered with vemurafenib or other BRAF inhibitors.
The median number of involved organs per patient was four (range: 1–11). The lesions were mainly found in the bone (86.4%), the CNS (50.0%), the cardiovascular sys- tem (52.3%), the kidney and retroperitoneal organs (50.0%), the endocrine organs (40.9%), the skin (40.9%), the lungs (34.1%), and the digestive organs (13.6%). Oropharyngeal lesions in three patients (6.8%), lym- phadenopathy in three patients (6.8%), splenomegaly in two patients (4.5%), and breast lesions in two patients (4.5%) were also detected. In one patient, the testes, prostate, bladder, spinal cord, glottis, and bone marrow were also affected. These unusually affected organs were exclusively observed in patients with multiple (three or more) lesions and, in many cases, who were diagnosed at autopsy. Thirty-eight patients had skeletal lesions, of which 22 had bone pain. Four patients (9.1%) had simul- taneous or heterochronic LCH lesions. No patient was diagnosed as having immunoglobulin (Ig)G4-related dis- ease as the clinical and pathological findings did not corre- spond to the disease, although specific examinations such as serum IgG-4 levels and immunohistochemistry for IgG4 were not carried out on the majority of patients. Among the 18 patients with endocrine involvement, 15 had diabetes insipidus (DI), two had pituitary tumors without obvious DI and one had hypothyroidism. Twenty-three patients had cardiovascular involvement including 19 with cardiac involvement and 11 with aortitis (seven had both). Among the 22 patients with CNS involvement, six had exophthalmos, 12 had parenchymal brain mass and four had meningeal involvement. Two patients had no radiological finding of CNS but their neu- rological symptoms (delirium and cerebellar ataxia) were considered to be symptoms of ECD.
In addition, one patient had low-risk myelodysplastic syndrome (MDS) prior to ECD. He did not receive any treatment for MDS and one year later, after the detection of an abnormal pulmonary shadow, ECD was diagnosed through partial pneumonectomy. The shadow shrank after cyclosporine and prednisolone therapy, but he died of pneumonia 4.5 years after the ECD diagnosis.
Survival
The median follow-up period of survivors was 5.17 (range: 1.0–21.1) years. Eighteen out of 44 patients died during the clinical course of their illness, and the cause of death was associated with ECD in 13 patients (72.2%, Online Supplementary Table S2). Moreover, two other patients died from infection, possibly due to the use of corticosteroid therapy as a treatment for ECD.
The median survival from the initial onset, which was determined using the Kaplan–Meier method, was 10.42 years (Figure 1A). The log-rank test results revealed that
Treatments, no. (%)
IFN a or PEG-IFN Corticosteroid Irradiation Imatinib mesylate Cyclophosphamide Cladribine Etoposide Cyclosporine Prostaglandin I2 CHOP
JLSG-02 Bisphosphonate Lung transplantation
ECD: Erdheim–Chester disease; LCH: Langerhans cell histiocytosis; CNS: central nerv- ous system; CRP: C-reactive protein; IFN-a: interferon a; PEG: pegylated; CHOP: cyclophosphamide, adriamycin, vincristine, and prednisolone; JLSG-02: a regime protocol for LCH consisting of cytarabine, vincristine, and prednisolone.
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