Erdheim-Chester disease: a rare non-Langerhans histiocytosis

Abstract

A 3-year-old girl was admitted to our hospital with diabetes insipidus and a left eye proptosis. During investigation of diabetes insipidus, an extensive osteolytic mass, involving skull base and maxillo-facial bones, was revealed. Biopsy exhibited dense infiltrate of foamy histiocytes, which were positive for CD68 and CD163 and negative for CD1a and S100 confirming histopathological diagnosis of Erdheim-Chester disease. Treatment with dabrafenib was initiated, with good response and no side effects.

Background

Erdheim-Chester disease (ECD) is a rare non-Langerhans histiocytosis of unknown origin. It is predominantly seen in adults, between the fifth and seventh decades, being rare in children.¹

Bilateral symmetric sclerosis of the metaphyseal regions of long bones is usually present, but infiltration of other organs may also occur (kidney, lungs, heart, skin). Because of the variability of the distribution and severity of the lesions, clinical manifestations are diverse.² Bone involvement, diabetes insipidus and exophthalmos are the three classical findings. Skull base masses are rare.³

The diagnosis is based on typical histologic findings, with a xanthogranulomatous infiltration of foamy CD68+, CD163+, CD1a-, S100- histiocytes and occasional Touton giant cells.^{1 2} BRAF V600E mutation has been detected in some patients with ECD.² And because there is no standard treatment regimen for this disease, BRAF inhibitors, such as dabrafenib and vemurafenib, have shown promising results.^2–5 We report a case of paediatric ECD with diabetes insipidus and a skull base mass with intracranial extension, and its evolution with therapy with BRAF inhibitors.

Case presentation

A 3-year-old girl was referred to our hospital with a history of sudden polyuria and polydipsia for the last 2 weeks. Left eye proptosis was noticed in an ophthalmologic appointment 4 months earlier. She had no headaches or other symptoms, and physical examination, besides left eye proptosis, was unremarkable. Blood and urine analysis were done, with a low urinary density and osmolality and a high seric osmolality, favouring diabetes insipidus. Renal and hepatic function and hormonal measurements of the hypothalamic–pituitary axis were normal. A positive water deprivation test with desmopressin stimulation proof confirmed the diagnosis of diabetes insipidus. Treatment with desmopressin was initiated, with clinical and analytic improvement.

Investigations

The cranial X-ray showed an osteolytic lesion in the frontal skull (figure 1) and the MRI, an extensive osteolytic mass, involving skull base and maxillo-facial bones (left superior maxillary, left orbital pavement, right jaw, sphenoid bone), with intracranial extension (left orbit, pachymeninges, hypothalamus and pituitary stem) (figure 2).

Figure 1.

MRI showing extensive osteolytic parameningeal lesion on the left with involvement of the superior maxillary, orbital floor and sphenoid. Intracranial extension and invasion of the left cavernous sinus. Lesion in the right jaw (orange arrow).

Figure 2.

Osteolytic lesion in the frontal skull cap (arrow).

Langerhans cell histiocytosis (LCH) was the first clinical suspicion. The first biopsy performed at the left superior maxillary was not representative, and a second biopsy (at the right jaw) was done, exhibiting foamy histiocytes, which was positive for CD68 and CD163 and negative for CD1a and S100 confirming histopathological diagnosis of ECD (figure 3). No alterations were found in the chest X-ray or in the echocardiogram nor in abdominal, pelvic and renal ultrasound. Staging was completed with PET-CT that showed no other locations of disease.

Figure 3.

(A) Histiocytes with single nucleus and foamy cytoplasm; (B) histiocytes are CD68 positive.

Treatment

The initial treatment was with prednisolone (40 mg/m²) and because BRAF V600E mutation was positive in 20% of the cell, dabrafenib therapy was started at a dose of 3.75 mg/kg, once per day. Six months after starting dabrafenib, MRI showed no signs of disease and PET-CT confirmed complete remission (figure 4). Treatment with BRAF V600 inhibitor was maintained for 2 years, with no relevant side effects and a very good radiological evolution. Methotrexate 15 mg/m² once a week was introduced after stopping dabrafenib and was kept for 1 year.

Figure 4.

Post-treatment MRI images, with no lesion, showing response to treatment.

Outcome and follow-up

Currently, the patient is off treatment for 1 year and remains in complete remission.

Discussion

ECD is a rare non-Langerhans cell form of histiocytosis, with systemic involvement. It is rarer in children, with fewer than 20 known cases to date.⁵

Clinical presentation depends on distribution and severity of the lesions, ranging from asymptomatic bone lesions to life-threatening situations. Bone involvement is the most common clinical feature (95% of patients), with bilateral and symmetric sclerosis of long bones, predominating around the knee (lower femurs and upper tibiae).² Skull, rib, facial bones and vertebral involvement have also been described in children.³ Diabetes insipidus (due to neurohypophysitis) and proptosis are also common in ECD. Perinephric infiltration (‘hairy’ kidney), periaortitis (‘coated aorta’), xanthelasmas or xanthomas, brainstem, cerebellar or brain parenchymal lesions are other possible clinical manifestations present in ECD.²

The patient reported by the authors has all three clinical features that are usually present in this disease. It was the investigation of diabetes insipidus and proptosis that led the authors to diagnose ECD. Bone involvement was in a non-common location (skull and facial bones) and she had no other systemic involvement.

The differential diagnosis of ECD is mainly with LCH, and sometimes it can be difficult because both have similar clinical presentations, such as diabetes insipidus, exophthalmos and involvement of the bone.⁵ Most times, LCH is the first clinical hypothesis, like in our patient and in other cases reported in the literature.2 3 5 6 In some of them, treatment to LCH was initiated.^{2 5 6} LCH lesions are usually localised to the skull, which, in our case, made diagnosis more difficult. Biopsy is mandatory to confirm ECD diagnosis. Immunophenotypically, ECD histiocytic cells are positive for CD68 and CD163 and negative for S100 protein and CD1a. This helps differentiating ECD from LCH, in which histiocytes are positive for CD1a and S100.³ Investigation include also skeletal survey, CT scan of chest/abdomen/pelvis, whole body FDG-PET scan and MRI of the brain and heart.² BRAF V600E mutation has been described in 50%–60% of ECD cases.⁵ BRAF is a proto-oncogene involved in the mitogen-activated protein kinase signalling pathway. Its mutation causes uninhibited activation of this pathway leading to elevated levels of inflammatory cytokines including interferon-a (IFN-a), interleukin-12 and monocyte chemotactic protein-1, which are responsible for accumulation of histiocytes into ECD lesions.²

Corticosteroids are the traditional first-line treatment of ECD, but they usually have a temporary efficacy.³ Conventional therapies have been used over the years, with some good results, such as IFN-a and cytotoxic chemotherapy, such as cladribine and methotrexate, based on clinical experience in LCH and other haematologic neoplasms. Surgery and radiotherapy are not recommended because ECD is not a radiosensitive disease and could be multifocal.⁴

Recently, studies have shown promising results with the use of BRAF inhibitors, such as vemurafenib and dabrafenib.^2–5 In this case report, when the result of the BRAF V600E was known, dabrafenib was initiated, with improvement of the lesions. After 6 months of therapy, the patient was in complete remission. No recurrence was observed after dabrafenib therapy was suspended. Dabrafenib has already had success in a previous paediatric patient with intracranial ECD lesions.⁵ The optimal dose and duration of treatment with BRAF inhibitors have not been established. Future research is needed to answer these questions.

Learning points.

• Erdheim-Chester disease (ECD) is a rare disease that should be evoked in a patient with diabetes insipidus and bone lesions.

• Differential diagnosis between ECD and Langerhans cell histiocytosis can be difficult, with immunophenotyping being essential for establishing final diagnosis.

• Genetic testing for BRAF V600E mutation should be performed as it can influence treatment options, as BRAF inhibitors have shown promising results.

Ethics statements

Patient consent for publication

Parental/guardian consent obtained.