Erdheim-Chester Disease Occult on Radiographs and CT but Visible on MRI and PET

Introduction

Erdheim-Chester disease (ECD) is a rare neoplastic disorder of CD68+/CD1a– histiocytes, which most commonly manifests as lesions in the long bones of the lower extremities but can affect almost any organ system, including, classically, the retroperitoneal/peri-renal soft tissues, the heart, and the retro-orbital space [1]. Since its initial description in 1930, approximately 1500 cases have been documented in the scientific literature [1]. Although ECD has historically been considered to be a non-Langerhans cell histiocytosis, a recent reclassification has grouped it under the moniker of L-group histiocytosis alongside Langerhans cell histiocytosis (LCH) owing to similarities in gene mutations and clinical overlap between the 2 entities [2].

ECD primarily affects adults, with a mean age at diagnosis of 55 years and a male-to-female ratio of 3: 1 [1]. Infiltration of the appendicular long bones is a classic finding in ECD, with an estimated 80–95% rate of involvement ranging [1]. While osseous lesions affect nearly all patients with ECD, bone pain is found in less than half of patients, and initial presenting symptoms vary [1,3,4]. Outside of the skeletal system, ECD commonly affects the neurologic, endocrine, cardiovascular, pulmonary, and renal systems [1,5]. Common extraosseous manifestations of ECD include diabetes insipidus, exophthalmos, periaortic or pericardial infiltration, interstitial lung disease, retroperitoneal fibrosis, and xanthelasma [1,3,5,6]. Such symptoms or imaging findings should prompt suspicion for the presence of ECD.

Patients may also experience generalized symptoms such as fever, weight loss, and weakness [6]. While a tissue biopsy for histopathological findings is required for a definitive diagnosis, a thorough radiological assessment also plays a key role in the diagnostic workup, especially in cases when classic ECD morphology is absent from the biopsy sample [7]. ECD lesions in the long bones have a distinct imaging appearance and typically can be visualized by plain radiography, bone scintigraphy, CT, 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) PET/CT, and MRI [8]. The distinct imaging findings of osseous ECD lesions are generally considered pathognomonic [9]. A subset of the typical imaging modalities used for ECD (ie, radiography, bone scintigraphy, and CT) rely on the sclerotic reparative changes in the bone around lesions to visualize them. The intrinsic advantage of either MRI or 18F-FDG PET is that they are both able to directly visualize marrow-based or marrow-replacing lesions that have not caused sclerosis to occur.

In this case report, we describe the clinical presentation and radiologic workup of a patient with ECD that was occult on multiple imaging modalities.

Case Report

A 60-year-old woman presented due to 4 months of aching pain in her left knee and calf. The pain was associated with intermittent lower-extremity swelling, as well as diffuse body aches, night sweats, and fatigue. She had no known history of inciting injury or trauma to the affected area, and had no history of known malignancy or underlying systemic inflammatory process. On physical exam, mild left lower-extremity swelling was noted, with full passive range of motion. MRI of the left knee showed innumerable marrow-replacing lesions throughout the distal femur, proximal tibia, and proximal fibula appearing as regions of low signal intensity on T1-weighted images (Figure 1A) and high signal intensity on a proton-density-weighted sequence (Figure 1B), raising concerns for multiple myeloma or metastatic disease.

Follow-up MRI of the pelvis showed additional enhancing lesions in the lumbosacral spine, pelvis, and proximal left femur, with the largest lesions located in the left ilium and femur (Figure 1C). However, these lesions were unable to be visualized on whole-body 99mTc-labeled methylene diphosphonate (MDP) bone scintigraphy (Figure 2), radiographic metastatic bone survey (Figure 3A, 3B), or CT scan of the chest, abdomen, and pelvis (Figure 4). PET/CT scans showed innumerable 18F-FDG-avid lesions throughout the axial and appendicular skeleton, including areas of nearly confluent lesions in the bilateral tibias, and additional foci in the left clavicle, sternum, lumbar spine, left ilium, and left femur (Figure 5). No areas of 18F-FDG-avidity were identified that were suggestive of extraosseous ECD; as such, some imaging tests that might be undertaken in the initial workup of a patient with ECD such as MRI of the heart and MRI of the orbits were not done. Biopsy of the left ilium showed almost complete replacement of the marrow space by a mixed inflammatory infiltrate predominantly consisting of sheets of foamy histiocytes with eosinophilic cytoplasm and immunohistochemical staining positive for CD68 and CD163 and negative for CD1a, consistent with a diagnosis of ECD [1].

Discussion

Bilateral and symmetric lesions of the long bones are considered a hallmark of ECD and are typically detected on radiography, 99mTc-MDP bone scintigraphy, MRI, CT, or 18F-FDG PET/ CT [3,4,10–12]. On skeletal radiographs, osseous ECD characteristically appears as bilateral symmetric osteosclerotic lesions of the diaphysis and metaphysis of the appendicular long bones, typically sparing the epiphysis and the axial skeleton [6,13]. Osteolytic or mixed sclerotic-lytic lesions are seen less commonly and may have an appearance similar to that of LCH [8,13]. Bone scintigraphy and 18F-FDG PET/CT often reveal a similar pattern of symmetric uptake, as well as preferential uptake near the distal ends of the long bones [6,9,13,14]. Typical MRI findings include replacement of fatty marrow by low-intensity-signal lesions on T1-weighted imaging, heterogeneous signal intensity on T2-weighted imaging, and patchy areas of gadolinium enhancement [14,15]. Involvement of osseous ECD in the axial skeleton is uncommon, but lesions in the pelvis and other regions of the axial skeleton have been reported [11,14]. In general, radiography, CT, and 99mTc-MDP bone scintigraphy are the most common modalities on which patients are likely to be identified, but the ability of 18F-FDG PET and MRI to see lesions in the marrow that have not yet caused a sclerotic reaction mean those modalities are useful problem-solving tools.

Although the ability to detect osseous ECD lesions depends on the imaging modality [11], the extensive lesions visualized on MRI and 18F-FDG PET/CT in this patient were unexpectedly absent on radiography, CT, and bone scintigraphy. Diagnostic criteria for ECD in the past have highlighted bone radiography or bone scintigraphy due to the distinct imaging appearance of skeletal involvement on these modalities [3,4,8]. In a study of 11 patients with histologically confirmed ECD, symmetric osteosclerotic lesions of the long bones detectable by both radiography and bone scintigraphy were shown to be nearly universal [4].

Recent studies have placed a greater emphasis on 18F-FDG PET/ CT, which has been shown to better evaluate global involvement of ECD, as well as histological findings [1,11,12]. 18F-FDG PET/CT has been identified as being useful in evaluating neurological and cardiovascular involvement of ECD in particular; however, it has also demonstrated lower sensitivity for osseous lesions compared to bone scintigraphy [12]. Imaging specialists and clinicians alike should be aware of the potential atypical imaging findings that may be associated with ECD. This case highlights the utility of 18F-FDG PET/CT in a multimodal, multidisciplinary approach for the diagnosis of radiographically occult ECD. Indeed, recent clinical practice guidelines have confirmed the role of 18F-FDG PET/CT in the whole-body evaluation of disease extent [16].

The genetics of ECD suggest that there is a limited number of genes that can drive development of the disease, including BRAF, KRAS, NRAS, PIK3CA, and MAP2K1 [17]. Those genes can dictate the distribution of disease and suggest that targeted therapies are likely to be effective in treating mutated ECD.

Although we do not have long-term follow-up results on this patient, it is typical for patients with BRAF-mutated ECD to be treated with the kinase-inhibitor vemurafenib [18], which can lead to complete resolution of visible disease [19].

Conclusions

Although there are described “classic” or “characteristic” findings of ECD on a variety of imaging modalities, in rare cases only the advanced imaging modalities that can interrogate the nature of the bone marrow may be positive for ECD findings. In that context, 18F-FDG PET/CT as a whole-body readout of disease activity and burden has an important place in the imaging of patients with ECD.