The first reported case of Erdheim–Chester disease (ECD) was by two pathologists Jacob Erdheim and William Chester [7], in 1930, who called it lipoid granulomatosis, and the term ECD was coined only in the 1970s. In the meantime, from symptoms onset to diagnosis is reportedly a protracted 2.7 years, ranging from a couple of months to 25 years, mainly due to mislabelling and treatment as a different pathology before correct diagnosis [1]. In our case, the duration for correct diagnosis was of nearly 5 years since the onset of symptoms and 4.5 years since the first visit to the hospital.
Due to the systemic nature of the disease and multisystem involvement, a thorough multisite evaluation by CT, MRI, nuclear imaging is useful to ascertain the exact extent of the disease. Skeletal involvement is seen in up to 96% of cases and presents with bone pain, particularly involving the long bones of the appendicular skeleton [4]. On plain radiography, there is typical symmetrical bilateral cortical sclerosis affecting meta-diaphysis and involvement of medulla, leading to complete loss of cortico-medullary differentiation with continued progression. Sclerotic changes in axial skeleton and epiphysis and also lytic lesion are seen in a minority of cases [3, 4]. In the present case, the involvement of the long bones was giving a “bone within bone” appearance, which has not been previously described with ECD. The skeletal lesions show FDG avidity on PET-CT, which has much better resolution than Technetium 99 m scintigraphy and also provides information about extra-skeletal involvement. Differentials for a skeletal appearance on radiographs include other osteosclerotic conditions, while symmetrical radiotracer uptake on PET is a key point in favour of ECD.
ECD tends to affect the CNS in nearly 50% of cases and is an independent predictor of death, which has been reported in almost one-third of cases [7]. The lesions are mostly extra-axial and intra-axial involvement, as is a rare presentation. The extra-axial disease process involves the pituitary gland and infundibulum presenting with central Diabetes insipidus. It may diffusely infiltrate the dural and meningeal layers leading to the formation of enhancing masses which nay mimic meningioma. Osteosclerosis of calvarial bones may also be seen. Perivascular involvement by the infiltrates can lead to stroke [8]. The intra-axial involvement is rare and can be seen as an area of altered signal intensity, usually in the posterior fossa structures with symmetrical involvement of the cerebellum and occasionally middle cerebellar peduncles and pons [9]. This neurodegenerative presentation is due to demyelination and is associated with cognitive deterioration and also cerebellar or brainstem syndromes with symptoms like ataxia, chorea and loss of balance, as seen in our case. The disease can also present as space-occupying lesions due to focal parenchymal deposits usually seen in the posterior fossa [4]. The neuroimaging differentials of ECD include Langerhans cell histiocytosis (LCH), sarcoidosis and meningiomas and a key differentiator is the concurrent orbital masses and osteosclerotic lesions of bones [4].
The deposition of ferromagnetic substances in the basal ganglia, red nucleus, substantia nigra and dentate nuclei along with striatal and cerebellar atrophy has been reported in the ECD with clinical presentation of choreoathetosis and ataxia [10, 11]. Miron et al. [11] suggested the possibility of the disruption of motor pathway circuits due to basal ganglia lesions as a cause for these symptoms. However, the basal ganglia involvement is a very non-specific feature and more common in the Langerhans cell histiocytosis (LCH), which also presents with chorea, tremor and cognitive decline. The supra- and infratentorial involvement with the presence of ferromagnetic substances deposition presenting with choreoathetoid movements seen in the present case of ECD is extremely rare.
The involvement of vasculature is a poor prognostic sign as the disease process culminated in fibrosis and consequent persistent and progressive ischemic manifestations. The vasculature associated with the aorta is most frequently involved, and the disease course involves the formation of soft tissue infiltrates in a circumferential or non-circumferential pattern of segmental involvement. On CT, as was seen in our case, hypodense plaque-like tissue infiltrates circumferentially involving the aorta (coated aorta sign) are seen. This needs to be differentiated from Takayasu’s arteritis, which also involves the vasculature. However, the involvement of the vessel wall is transmural in nature in Takayasu’s while it is only adventitial in ECD, and vessels wall MR imaging would be useful in such cases [12, 13].
Retroperitoneum is a common site in ECD after bones and is characterized by the involvement of kidneys seen as perirenal soft tissue infiltrates extending into the posterior pararenal spaces. This extrinsic development of soft tissue causes a compressive mass effect on the kidney. The spiculated appearance of these infiltrates on close inspection begets the use of the term “hairy kidney sign”. These infiltrates may involve bilateral adrenal glands without any adrenal insufficiency. This has to be differentiated from retroperitoneal fibrosis. The initiation of the disease from aortic bifurcation with the involvement of distal ureters and sparing the perirenal space are features of retroperitoneal fibrosis. The ECD is centred at the level of the renal hilum and tends to involve the proximal ureters. Typically, the disease does not involve solid visceral organs, but when it does, the prognosis is very poor [3, 4, 14].
The last decade saw considerable breakthroughs in understanding the molecular pathways of histiocytic disorders, with the discovery of BRAF-V600E mutation in 2010, followed by deep insights into the kinase mutations and the role of RAS–RAF–MEK–ERK pathways. This culminated in reassigning Langerhans cell histiocytosis (LCH) and ECD to the “L” group of revised 2016 histiocytosis classification [1, 15, 16]. As per WHO, the histiocytic disorders are to be classified either as class 1, with LCH or class 2, encompassing all non-LCH conditions like ECD, juvenile xanthogranuloma and Rosai–Dorfman disease or as class 3 which includes malignant histiocytic disorders. While ECD and LCH overlap in a certain minority of cases, IHC for S-100 protein and electron microscopic assessment of Birbeck granules are key differentiators. BRAF mutation is usually positive in over half of all cases of ECD [3]. However, Parks et al. [9] found that BRAFV600E mutation status was not associated with an increased risk of radiographic CNS involvement.
Our index case highlights the typical dilemma inpatient of ECD, right from protracted diagnostic time to initiation of therapy. The biggest contributory factor is the low disease incidence and a varied presentation both clinically and radiologically. To diagnose ECD, one must have it as a differential, especially in all those patients who presented with symmetric meta-diaphyseal involvement of bones or diffuse involvement of regions of cerebellar peduncles and dentate nucleus. A detailed multimodality and multiorgan evaluation have to be performed in these cases, including thoracic and abdominal CT, MRI brain and radiographs of the long bones. The role of PET-CT cannot be overstated as the regions of involvement show FDG uptake and thus help in collaborating the diagnosis. Arnaud et al. [17] reported the specificity of PET-CT at initial and follow-up scans for diagnosis of CNS disease as 92.3% and 100%, respectively. PET-CT also allows for monitoring of the number of lesions based on SUVmax of the lesions, which correlates with the metabolic activity. PET scanning is useful in assessing CNS involvement in the disease, which is a major prognostic factor in ECD. PET scans have a moderate sensitivity but a decent specificity for the evaluation of large vessel involvement when compared to CT scans. The sensitivity of PET scans to detect involvement of the orbit, paranasal sinuses and retroperitoneum is very low [17].
There are only limited cases in the literature showcasing multiple typical ECD features on the initial PET scan. Our case had FDG avid regions in CNS–midbrain, pons, pituitary; mediastinum—along the left subclavian artery, descending aorta (coating of the aorta); abdomen—along with bilateral renal sinuses (hairy kidney sign), both adrenal glands, abdominal aorta at the level of origin of renal arteries and even paraaortic nodes; and musculoskeletal multiple ribs.
The extent of extra-osseous involvement affects the prognosis in ECD similar to in LCH. The affliction of certain organ systems like the central nervous and cardiovascular are particularly associated with a poor response to chemotherapy. While the morbidity because of ECD has significantly decreased as a result of therapeutic advances, the mortality is still significant, with a 5-year survival of only 68% [4].