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Prognostic factors of ECD
The CRP level was elevated in many patients with ECD, and declined after IFN or vemurafenib treatment,8,22 simi- lar to the finding in our cohort. In this study, we firstly revealed that the CRP level at onset as well as the drop in CRP levels after initial therapy predict the patient out- come. We have to interpret this result with caution because initial treatments in our cohort were quite hetero- geneous and most of them were not standard therapy. Recently, ECD has been considered as an inflammatory myeloid neoplasm. Although the MAPK pathway and other mutations, such as PIK3CA, tend to attract attention to the neoplastic aspect of the disease, the association between CRP levels and poor prognosis evokes the neces- sity of vigorous research on the inflammatory characteris- tic of Janus-faced ECD because these mutations them- selves do not necessarily induce elevated CRP. Some inflammatory markers, such as interleukin (IL)-1, IL-6 and tumor necrosis factor, have also been reported as activa- tion markers of ECD.25-28 However, CRP levels are relative- ly easy to measure compared with inflammatory cytokines and might be suitable as a convenient marker to detect patients at risk.
Interestingly, low-risk MDS and ECD coexisted in one patient in our cohort. Papo et al. reported that adult histi- ocytic neoplasms frequently co-occur with other myeloid neoplasms (9.5%), and MAPK pathway-associated muta-
tions (BRAF, NRAS, and other mutations) could coexist with MDS-associated mutations (IDH1/2, ASXL1, and TET2 mutations) in the hematopoietic stem/progenitor cells of ECD patients.29 Unfortunately, we were unable to acquire a sample from the patient, and the genetic infor- mation was unavailable.
Due to the retrospective nature of our study, we could not analyze some of the most important clinical informa- tion of many of the patients, such as osteosclerosis of the sinuses and BRAF or other mutations.30 It is now mandato- ry to systematically collect clinical findings, radiological and laboratory data, and above all histological samples for patients with ECD. A more sophisticated method of detec- tion for the BRAF mutation is also warranted. Sanger sequencing is a classic method and still plays an important role in detecting ECD, partially owing to its low cost and convenience. However, immunohistochemistry for the BRAF V600E protein and hypersensitive methods, such as droplet digital PCR and/or targeted sequencing techniques, are becoming crucial because only a small fraction of cells in an ECD lesion actually harbor the BRAF mutation, and some studies have reported that a BRAF mutation in the peripheral blood could only be detected with ultrasensitive techniques as opposed to Sanger sequencing.15
In summary, our nationwide survey revealed the clinical characteristics of patients with ECD, and clarified the
Table 5. CNS involvement and clinical factors. Characteristics
Sex (male–female)
Median age at onset, y (range)
Diagnosed after 2005, no. (%)
Coexistence of LCH, no. (%)
Median number of involved organs (range) Skeletal involvement, no. (%) Cardiovascular involvement, no. (%) Retroperitoneal involvement, no. (%) Endocrine involvement, no. (%) Cutaneous involvement, no. (%) Pulmonary involvement, no. (%)
Digestive involvement, no. (%)
CRP at onset (mg/dL), median (range)
CNS (−) (n=22)
13–9
45 (25–70) 16 (72.7)
2 (9.1)
3 (1–8)
21 (95.5)
7 (31.8)
8 (36.4)
6 (27.3)
11 (50.0)
5 (22.7)
2 (9.1) 1.37 (0.10–14.1)
5 (22.7) 8 (36.4) 4 (18.2) 2 (9.1) 3 (13.6) 0 (0)
0 (0)
0 (0)
1 (4.5)
0(0)
0 (0)
1 (4.5)
CNS (+) (n=22) P 15–7 0.75
62 (23–76)
15 (68.2) 1
0.033 2 (9.1) 1
5 (2–11)
17 (77.3) 0.19
16 (72.7)
14 (63.6) 0.13 12 (54.5) 0.12
7 (31.8) 0.36 10 (45.5) 0.20 4 (18.2) 0.66 3.64 (0.12–12.6) 0.34
10 (45.5) 0.20
0.0042
0.015
Treatments, no. (%)
IFN a or PEG-IFN
Steroid
Radiation
Imatinib mesylate
Cyclophosphamide
Cladribine
Etoposide
Cyclosporine
Prostaglandin I2
CHOP
JLSG-02
Lung transplantation
0.014
17 (77.3)
1 (4.5) 0.34
3 (13.6) 1 1 (4.5) 0.61 1 (4.5) – 2 (9.1) – 1 (4.5) –
0 (0) – 1(4.5) – 1 (4.5) –
LCH: Langerhans cell histiocytosis; CNS: central nervous system; CRP: C-reactive protein; IFN-a: interferon a; PEG: pegylated; CHOP: cyclophosphamide, adriamycin, vincristine, and prednisolone. JLSG-02: a regimen protocol for LCH consisting of cytarabine, vincristine, and prednisolone
0 (0) –
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