Introduction
Erdheim-Chester Disease (ECD) is a systemic histiocytosis, recognized as a type of non-Langerhans cell histiocytosis (LCH) and inflammatory myeloid neoplasm.1–3 Among various histiocytic disorders, ECD is currently assigned to the L-group in the revised classification of histiocytoses, alongside LCH and extracutaneous or disseminated juvenile xanthogranuloma.4 It is known to harbor MAPK pathway mutations, such as BRAF V600E. These gene mutations result in the constitutive activation of the MAPK pathway providing oncogenic characteristics in these histiocytoses.5
ECD occurs mostly in adults, with a median age of 46 years (range 25–76) and an M/F ratio of 1.6.6 It rarely develops in children. The clinical features of ECD are multifaceted, including fever, weight loss, fatigue, and various organ diseases. Involved organs (frequencies) include the bones (95%) with bilateral symmetrical diffuse osteosclerotic lesions in the lower and upper extremities; kidneys (65%), with hypodense fibrotic tissue deposition in the perirenal fat and hilum (“hairy kidneys”) and retroperitoneal fibrosis; hypogonadism (65%); cardiovascular systems (62%), with periaortic encasement (“coated aorta” appearance on computed tomography (CT) findings); lungs (52%); and central nervous system (CNS), with central diabetes insipidus (CDI; 47%) and CNS disease (38%). Additionally, the heart (37%), with right atrial pseudotumor or pericardial effusion; xanthelasma palpebrarum (XP; 33%); and xanthoma can be noted. The combination of involved organs varies from case to case.
Histopathology of ECD shows clusters of lipid-laden foamy histiocytes with a phenotype of CD68+/CD1a-/S100+/−.7 In terms of the prognosis of ECD, one retrospective analysis revealed that 22 of 59 patients died with a mean follow-up of 32 months.8 More recently, a better outcome is expected with the use of anti-BRAF targeted therapy.5 We report here a case of a young Japanese man with ECD, whose symptoms included CDI, symmetrical involvement of the long bones in the upper and lower extremities, and facial xanthoma/XP lesions. He was initially treated with conventional regimens followed by targeted therapy successfully. We have also discussed the various problems in the use of targeted therapy.
Case report
A 39-year-old Japanese male presented with complaints of polyuria/polydipsia, and weight loss (minus 5 kg over the past five months). The patient also complained of bone pain in the bilateral tibia extensor. He was afebrile, with blood pressure 147/103 mmHg, heart rate 127/min, and laboratory data showing white blood cell 9,700/µL, hemoglobin 14.1g/dL, and platelet count 731K/µL, associated with a high serum C-reactive protein (CRP) of 6.11mg/dL (reference; < 0.29). The liver and renal function were within normal ranges. The patient, 170 cm tall and weighing 60 kg, was neither anemic nor icteric and had bilateral XP at the inner eyelids and xanthoma lesions at the right temple on his face (Fig. 1a, b). He had no lymphadenopathy or hepatosplenomegaly. Brain magnetic resonance imaging (MRI; T1W1) revealed a thickened pituitary stalk associated with the loss of high signal in the posterior pituitary lobe (Fig. 2a), consistent with clinical symptoms of CDI. Computed tomography (CT) of the lower extremities showed thickened bone cortex and intramedullary sclerotic changes in the proximal tibia and distal femur (Fig. 2b). Technetium-99m (99mTc-) bone scintigraphy confirmed abnormal changes in the bilateral lower long bones (Fig. 2c). Additionally, 18F-fluorodeoxyglucose positron emission tomography (PET)/CT confirmed these changes as fuorodeoxyglucose-avid signals in the diaphyses of the humerus and radius, the distal femur and the entire tibia (Fig. 2d). Although these findings strongly suggested a clinical diagnosis of ECD, no other vascular, cardiac or renal abnormalities, such as pericardial effusion, “coated aorta” or “hairy kidneys” were noted. Hormonal studies showed reduced serum anti-diuretic hormone (0.7pg/mL; reference; < 4.2). However, no anterior pituitary lobe hormone deficiency was noted.
Histopathological diagnosis of ECD was confirmed by biopsies of the bone (including bone marrow) at the left tibial tuberosity and the xanthoma lesion at the right temple. Touch preparation of the bone marrow specimen showed aggregates of foamy histiocytes (Fig. 3a), and immunostaining of the paraffin-embedded tissue showed ECD-compatible histology with CD68-positive, S100 partially positive, and CD1a-negative markers (Fig. 3b-e). The biopsied skin lesion was diagnosed as xanthoma (Fig. 1c). Both fresh tissues were BRAF V600E mutation-positive using the droplet digital polymerase chain reaction procedure,9 with bone marrow 9.2% positive (reference; 0%) and xanthoma 1.9% positive (reference; 0%). Peripheral blood (PB) BRAF V600E was also positive (PB mononuclear cells 0.029% and plasma 0.7%). PB BRAF was employed in the follow-up of disease activity as shown in Table 1. As initial treatment, we chose not to use interferon-α but a CD regimen consisting of 2-chlorodeoxyadenosine (cladribine; one cycle 0.1mg/kg, intravenous infusion, day 1–5, q4w for 5 cycles) along with intravenous dexamethasone (3.8 mg x 2, day 1–5, q4w for 5 cycles).10,11 CDI was controlled with desmopressin.
Table 1Response of ECD activity for various treatment regimens
| Treatment regimens | Time after treatment (months) | Serum CRP (< 0.27 mg/dL)* | Serum sIL-2R (< 496 U/L)* | BRAF Mutation in PBMNC(ND)*/Plasma (ND)* | ECD activity¶
|
|---|
| Bone | XP | TPS |
|---|
| Before treatment | 0 | 6.11 | 1,305 | 0.029/0.7 | +++ | ++ | +++ |
| CD; X 5 courses | No AEs |
| Post-CD | 6 | 1.07 | 598 | 0.0/0.0 | + | + | +/− |
| VCP; X 6 courses | No AEs |
| Post-VCP | 10 | 1.07 | 487 | 0.0/0.0 | +/− | +/− | +/− |
| Infliximab for 9 months | No AEs (XP exacerbated) |
| Post-Infliximab | 20 | 0.43 | 485 | 0.0/0.0 | +/− | +++ | +/− |
| Special C for 9 months | No AEs |
| Post-Special C | 30 | 0.18 | 438 | NT/NT | +/− | +++ | +/− |
| trametinib for 7 months | AEs (grade 1/2) |
| Post- Trametinib | 39 | 0.41 | 641 | NT/NT | +/− | ++ | +/− |
| Off therapy | (after Trametinib, off-therapy for 6 months) |
| dabrafenib/trametinib for 1 month | No AEs |
| Post-Dab/Tra | 46+ | 0.08 | 219 | NT/NT | +/− | + | +/− |
For a comprehensive evaluation of disease activity in response to various treatments, imaging studies such as brain MRI, PET/CT, physical findings, and markers such as PB-BRAF, serum CRP, and soluble IL-2 receptor (sIL-2R) were employed and summarized in Table 1. Treatment with five courses of the CD regimen achieved a good response. The patient no longer complained of bone pain, with significantly reduced CRP (from 6.11mg/dL to 1.07 mg/dL), nearly normalized sIL-2R levels, and no detectable PB-BRAF gene mutation. The thickened pituitary stalk improved, and XP markedly resolved (Table 1). Following this, because no targeted therapy was available, conventional treatment was continued with six courses of a VCP regimen, a combination of vinblastine (8mg/dose, day 1), cytosine arabinoside (120mg/dose, day 15), and oral prednisolone (60mg/day, days 1–4) every four weeks. After 24 weeks of the VCP regimen, he was in stable disease. We then switched to infliximab (5mg/kg/dose)- a total of seven doses over nine months, as its effectiveness in ECD had been previously confirmed.12,13 During this period, an exacerbation of XP occurred (Fig. 4a). Therefore, the Special C regimen, effective for LCH,14 was employed for nine months, but the XP lesions did not respond (Fig. 4b). No adverse events were noted in the above four conventional regimens. As summarized in Table 1, despite a nearly complete resolution of the bone lesions, negative PB-BRAF gene mutation, and no recurrence of the thickened pituitary stalk on MRI, the worsening of XP remained an uncomfortable and annoying problem for the patient. We discussed the necessity of targeted therapy to improve this complication. After ethics committee approval (Uji-Tokushukai No.2022-26), the patient was given oral trametinib (a MEK inhibitor) alone (starting from 0.5mg/day up to 2.0mg/day) as off-label usage for 6 months on self-pay treatment. This was partially effective in improving XP (Fig. 4c), but with adverse events (grade 1/2 acneiform rash and hepatic dysfunction), necessitating interruptions of the drug and modifications with oral glucocorticoid. We started the new targeted therapy after a six-month interval of off-therapy, during which a combination of dabrafenib (a BRAF inhibitor) and trametinib was approved for ECD in Japan. One month after starting this treatment, his XP markedly improved (Fig. 4d). At this writing (46 months from initial treatment of ECD), he does not complain of XP discomfort and maintains a stable response. Fortunately, up to now, the patient did not develop cardiovascular involvementor progressive CNS disease of ECD.15,16
Discussion
In 2015, Ogura conducted a retrospective epidemiological study of ECD in Japan,6 collecting 71 cases through a multi-institutional survey over 15 years (April 2000 to March 2014). This study estimated the incidence of ECD at approximately 4.7 cases per year, about 1/15 of the incidence of LCH in Japan.17 A significant finding was that only 13/71 (18%) of ECD cases first visited hematology clinics, while the majority did various non-hematology clinics. To diagnose ECD without delay, physicians in both hematology and non-hematology clinics must be aware of the disease. It is also crucial to remember that clinical symptoms/signs in ECD overlap with those of LCH, and mixed-type (ECD/LCH) histiocytosis can also be diagnosed.18
The updated 2020 guidelines for ECD provide detailed consensus recommendations on diagnosis, treatment, and response assessment/monitoring.5 Regarding molecular diagnosis, nearly 50% of ECD cases are driven by activating mutations in BRAF V600E, and another 25% by activating mutations in MAP2K1. Mutations in ARAF, NRAS, KRAS, and PIK3CA are less frequently noted.5 Previously, interferon-α, anakinra, and infliximab were used for ECD treatment, with interferon-α once considered the best option.10 More recently, targeted therapy has been recommended as the first choice in the guidelines for ECD.5 When we started treating this case, targeted therapy was not yet approved in Japan. Therefore, considering the neoplastic nature of histiocytic diseases and better drug transfer through the blood-brain barrier to CNS lesions, we chose cladribine due to its effectiveness for CNS-LCH/ECD as previously confirmed.11,19 Although the CD (cladribine/dexamethasone) regimen was initially effective in our case, other conventional regimens following the CD regimen were insufficient, and exacerbated XP became a problem for the patient.
XP can be triggered by hyperlipidemia or non-hyperlipidemic diseases and is noted in one-third of ECD cases.20 Other xanthomatous skin lesions are considered part of the ECD constellation.21 In this case, the xanthoma at the right temple (Fig. 1b) biopsied revealed a BRAF gene mutation, indicating it was part of ECD. These lesions were not associated with hyperlipidemia. It was unclear whether the worsening of XP during infliximab therapy was incidental or related to the administration of infliximab. Regardless, the exacerbated XP was very troublesome for the patient. Managing XP is generally problematic.22 However, in ECD, targeted drugs such as BRAF inhibitors (e.g. vemurafenib) have been effective for orbital ECD patients with BRAF V600E mutations,23 though some opinions suggest reserving targeted therapy for the most severe symptoms in ECD.24 We decided to start with an off-label MEK inhibitor for six months. After the approval of targeted therapy for ECD in Japan, the patient was treated with a combination of dabrafenib and trametinib, which rapidly improved the condition.
Regarding useful biomarkers reflecting disease activity and predicting the outcome of ECD, Toya et al., in a nationwide survey of 44 Japanese cases, reported that serum CRP levels > 3.0 mg/dL at onset were associated with worse outcomes.25 According to this definition, our case may belong to a poor outcome group. Serum sIL-2R was also useful as a biomarker in this case. More recently, a droplet digital polymerase chain reaction procedure detecting PB-BRAF gene mutation and PET/CT have been available to monitor ECD activity. Thus, the treatment response in our case was evaluated using multiple measures as shown in Table 1. The fact that serum CRP remained above normal level (< 0.29mg/dL) even when PB-BRAF gene mutation became undetectable indicates that CRP is sensitive enough to assess ECD activity.
The limitation of this report is that it discusses a single case; however, through its management, we learned about the effectiveness and adverse events of conventional and targeted regimens. Targeted therapy, considered the most effective for ECD, is now available for ECD patients However, there are concerns regarding this type of therapy. The optimal doses and duration of these drugs for ECD treatment remain unknown, and recurrence of ECD lesions may occur whenever the administration of targeted drugs is interrupted. However, the response could be obtained again when the drugs are restarted.26 Care must be taken when deciding to stop targeted therapy in this patient. In addition, if a suboptimal response is obtained from targeted therapy, alternate therapeutic options such as conventional therapy are required.5
Conclusions
The optimal application of effective treatment promises a better prognosis for ECD patients. Before the availability of targeted therapy (anti-BRAF and MEK inhibitors), various conventional therapy has been attempted. Currently, targeted therapy is considered the best regimen for histiocytic disorders like LCH/ECD. We hope that incorporating such targeted drugs early in the treatment could resolve XP as well as ECD-related life-threatening cardiovascular involvements and progressive CNS disease. However, therapy with targeted drugs must be carefully undertaken in each case by assessing optimal dosing, treatment response, and treatment duration.
Declarations
Acknowledgement
The authors thank all staff members who took care of the patient.
Ethical statement
The study was performed in accordance with the ethical standards of the institutions to which we are affiliated and with the Declaration of Helsinki (as revised in 2013). Written informed consent was obtained from the patient for reporting the case and accompanying images.
Funding
None.
Conflict of interest
The authors declare no conflicts of interest.
Authors’ contributions
Manuscript drafting (MK, YS, SI), treating the patient (MK, YK, NA, SI), and BRAF gene mutation analysis (KK). All authors have made a significant contribution to this study and have approved the final manuscript.