Introduction
Erdheim–Chester disease (ECD) is a systemic non-Langerhans cell histiocytosis characterized
by multi-organ accumulation of foamy histiocytes. Owing to its rarity[1] and varied presentation, ECD presents diagnostic challenges to the clinician and
imageologist.
Radiography, CT, and MRI assist in the focused evaluation. 18F-FDG PET/CT plays a vital role in the diagnosis, detection of disease extent and
severity, assessment for an appropriate biopsy, and treatment response.[2]
[3]
[4]
[5]
We present a case of ECD with multi-system involvement with a discussion of the imaging
findings highlighting the importance of FDG-PET/CT.
Case History
A 73-year-old woman presented with a history of gradually progressive right proptosis
followed by the left with no diminution of vision.
MRI orbit demonstrated bilateral intra and extraconal soft tissue masses causing exophthalmos
with optic nerve encasement ([Figs. 1] and [2A–C]). Magnetic resonance imaging (MRI) of the brain showed no abnormality. Biopsy of
the orbital mass was suggestive of necrobiotic xanthogranuloma. Immunohistochemistry
(IHC), however, was not available. She was suspected to have ECD due to retro-orbital
involvement. A 99mTc-methylene diphosphonate bone scan was performed that revealed a characteristic
increase in the osteoblastic activity in the diametaphyses of the long bones of the
lower limb centered around the knees ([Fig. 3A] and [3B]) along with mandibular uptake.
Fig. 1 T2-weighted axial MRI (A) showing intraconal hypointense masses encasing the extraocular muscles (white arrow).
T1-weighted axial image (B) demonstrating the isointense nature of orbital masses (white arrow). Post-contrast
T1-weighted axial image (C) showing intense enhancement of the intraconal masses (white arrow) with encasement
of the optic nerves (yellow arrow). Non-contrast CT (D) demonstrating hypodense masses involving the intra- and extraconal compartments
with increased FDG uptake seen in corresponding regions on PET (E) and fusion PET/CT images (F). FDG, fluorodeoxyglucose; PET/CT, positron emission tomography-computed tomography;
MRI, magnetic resonance imaging.
Fig. 2 T2-weighted coronal MRI (A) showing hypointense intraconal masses (white arrows) encasing the optic nerve (yellow
arrows). T1-weighted coronal MRI (B) demonstrating orbital masses, which are isointense to the muscle (white arrow).
Post-contrast T1-weighted coronal MRI (C) showing avid enhancement of the intraconal masses (white arrow) with encasement
of the optic nerves (yellow arrow). TI-weighted sagittal image (D) demonstrating normal hyperintense signal of the neurohypophysis (thin white arrow).
MRI, magnetic resonance imaging.
Fig. 3 Anterior (A) and posterior (B) images of bone scan showing increased osteoblastic activity in the mandible (black
arrow), radius, ulna, shafts of tibia and femora. The MIP image of PET scan (C) showing FDG avidity in the mandible (black arrow) and lower limb long bones centered
on the knees—hot-knee pattern (bracket). Coronal CT; PET/CT Images (D and E) of the lower limbs (bone window) demonstrating metabolically active bilateral symmetrical
osteosclerosis of the diametaphyses of long bones with characteristic sparing of the
epiphysis (white arrow). MIP, maximum intensity projection; MRI, magnetic resonance
imaging; PET/CT, positron emission tomography-computed tomography.
She received interferon-α 2B and intravenous methylprednisolone. However, her symptoms
worsened with sudden diminution of vision and development of bone pains and hence
she was referred to our hospital for further evaluation.
An FDG-PET/CT scan was requested to assess for the extraosseous disease.
The PET/CT showed metabolically active enhancing retrobulbar soft tissue masses corresponding
to the MR findings with optic nerve compression and SUVmax of 13.2 ([Fig. 1E] and [1F]).
Widened metadiaphyses were observed in the appendicular bones with cortical thickening
and increased metabolic activity—SUVmax of 8.2. FDG avidity was also seen in the mandible ([Fig. 3C]–[3E]).
FDG avid soft tissue thickening was seen around the aorta and its branches, pericardium,
and bilateral posterior pararenal fascia, with SUVmax of 6.0 ([Figs. 4],[5],[6]).
Fig. 4 CECT of the upper chest (A) and PET/CT (B) showing circumferential hypodense, plaque-like hypermetabolic soft tissue encasing
the arch of the aorta and its branches (white arrows). Oblique–sagittal reformatted
image of the thoracic aorta (C and D) shows hypodense plaque-like soft tissue around the branches of the aortic arch (white
arrows) and encasing the descending thoracic aorta—coated aorta sign (yellow arrows).
CECT, contrast-enhanced computed tomography. PET/CT, positron emission tomography-computed
tomography.
Fig. 5 (A–F, clockwise) CECT (A) and PET/CT (B) showing smooth plaque-like hypermetabolic thickening mainly involving the right
side of the heart (thin white arrows), pericardial thickening with effusion (bold
white arrow), and bilateral pleural effusion (arrowheads). Coronal reformatted CECT
(C) and PET/CT (D) images showing plaque-like hypermetabolic soft tissue in relation to the right atrium
(white arrows). Axial (E) and coronal images (F) of the CT chest (lung window) demonstrating septal thickening in the lung bases
(bold yellow arrows). CECT, contrast-enhanced computed tomography; PET/CT, positron
emission tomography-computed tomography.
Fig. 6 Hairy kidney sign–CECT (A) demonstrating perirenal fat infiltration with a characteristic spiculated appearance
(thin white arrow) and enhancing pararenal soft tissue masses (bold white arrow).
PET/CT (B) demonstrating the hypermetabolic nature of perirenal and pararenal soft tissue thickening
(thin white arrows and bold white arrows, respectively). Coronal reformatted MIP image
of CECT abdomen (C) showing circumferential soft tissue encircling the mesenteric vessels; which is
also seen in images A and B (yellow arrows). Histology (D) showing sheets of foamy histiocytes. CECT, contrast-enhanced computed tomography;
MIP, maximum intensity projection.
The PET/CT findings supported the diagnoses of ECD and confirmed multi-organ involvement.
Metabolically active, easily accessible areas in the right pararenal region were selected
for CT-guided biopsy. A second biopsy was warranted to assess IHC and mutational status,
particularly with the worsening of symptoms as targeted therapy was being considered.
The biopsy showed sheets of foamy histiocytes ([Fig. 6D]), consistent with ECD. Immunohistochemistry showed the expression of CD 68 and CD
163 and was negative for S-100, CD1a, and Langerin. BRAF mutation was negative.
Owing to a negative BRAF mutation status, targeted therapy was not feasible. She was
treated with high-dose dexamethasone, cyclophosphamide, and vincristine to which there
was an initial response but the patient subsequently succumbed to the cardiac complications
of ECD.
Discussion
ECD is a subset of non-Langerhans cell histiocytosis, first described by William Chester
and Jakob Erdheim in 1930.[6]
The diagnosis is often delayed due to the rarity of the disease, multi-organ involvement,
and varied presentation.[7] Imaging including 18F-FDG PET/CT plays an important role in the diagnosis, assessing the extent and evaluating
the treatment response.[2]
[3]
[4]
[5]
[7]
Up to 96% of patients show skeletal involvement,[8]
[9] like our patient. The 99mTc-methylene diphosphonate bone scan and the FDG-PET showed intense, bilaterally symmetric
uptake at the end of long bones centered around the knees with sparing of the epiphysis—“hot-knee
pattern” ([Fig. 3]), which is characteristic of ECD.[7]
[10] The CT demonstrated corresponding symmetrical osteosclerosis of the diametaphyses
of the long bones with loss of corticomedullary differentiation, no periostitis, and
epiphyseal sparing[11] ([Fig. 3D] and [3E]). FDG-PET and bone scan uptake can precede radiographic abnormalities.[7]
[12]
Orbital involvement is present in up to 38%.[8]
[9]
[13] Exophthalmos was the initial presentation of our patient. The initial biopsy suggested
necrobiotic xanthogranuloma, which commonly presents as anterior orbital or ocular
adnexal lesions.[14] The retro-orbital involvement led to the suspicion of ECD. The MRI revealed classic
T1 and T2 hypointense multi-compartmental retro-orbital masses encasing the optic
nerve ([Figs. 1] and [2]). PET/CT showed corresponding increased metabolic activity ([Fig. 1]) with SUVmax of 13 similar to other studies.[7]
Imaging plays a vital role in surgical planning, particularly in the orbit. The exquisite
soft-tissue contrast of MRI helps planning for surgical decompression, particularly
if the optic nerve is at risk. Imaging including PET/CT, which identifies active tissue,
helps the ophthalmologist choose the best site for biopsy.
CNS involvement is seen in more than half of cases and is a leading cause of death.[8] The absence of a normal T1 hyperintense signal of the neurohypophysis, dural, and
meningeal involvement and symmetrical T2-hyperintensities of the dentate nucleus have
been described.[8]
[9]
The CNS involvement with increased FDG uptake has been linked to the BRAF gene mutation.[7] Our patient did not show CNS involvement and was BRAF gene-negative.
Cardiovascular involvement is seen in nearly three-fourths of cases and presents either
as circumferential infiltration of the adventitia of the blood vessels, commonly involving
the aortic arch or as pericardial infiltration or rarely as right-sided myocardial
involvement.[4]
[15]
[16]
[17]
PET/CT in our patient revealed hypermetabolic hypodense, plaque-like soft tissue circumferentially
encasing the aorta and its branches ([Fig. 4])—described as the “coated aorta sign.”[7]
[8] It also showed smooth plaque-like thickening involving the right side of the heart,
together with pericardial thickening and effusion ([Fig. 5A–D]).
Cardiovascular involvement indicates a poor prognosis and leads to death in ∼60% of
cases due to tamponade, arrhythmias, or infarction.[8]
[18] Our patient expired due to cardiovascular complications of ECD.
The lung and pleura are affected in ∼40 to 50% of cases[8] as smooth inter- and intralobular septal thickening[19] as was demonstrated in our patient ([Fig. 5E] and [5F]).
The retroperitoneum including the kidneys is involved in ∼68% of cases.[4]
[8] Our patient had FDG avid soft tissue masses in bilateral perirenal and posterior
pararenal spaces ([Fig. 6A] and [6B]). The hairy kidney sign refers to perirenal fat infiltration seen in ECD with a
characteristic spiculated appearance,[4]
[7]
[8] which was seen quite elegantly on the PET/CT ([Fig. 6A] and [6B]) with corresponding FDG uptake.
18F-FDG PET/CT assists in differentiating ECD from Langerhans histiocytosis (LCH), Rosai–Dorfman
Disease (RDD), IgG4-related disease, idiopathic retroperitoneal fibrosis, and sarcoidosis.[8]
Generally, LCH manifests earlier than ECD. The bony involvement in LCH is characteristically
osteolytic and involves the skull, spine, or long bones asymmetrically unlike the
symmetrical osteosclerosis seen in ECD, which involves the ends of the long bones.
Cardiac involvement is rare in LCH.[20]
RDD may show right heart involvement similar to ECD but bony involvement is characteristically
osteolytic.[20] Lymphadenopathy especially in more than one region with moderate to high 18F-FDG avidity is seen in RDD.
Specific FDG-PET/CT patterns have been described in IgG4-RD—diffusely increased 18F-FDG uptake in the pancreas and salivary glands, patchy lesions in the retroperitoneal
region and vascular wall, and multi-organ involvement.[21] Retroperitoneal fibrosis (RPF), retro-orbital involvement, and pachymeningitis are
common features between ECD and IgG4-RD. RPF associated with ECD generally affects
the perirenal areas with resultant proximal ureteric obstruction. RPF associated with
IgG4-related disease usually results in distal ureteric obstruction with medial deviation.[22]
Idiopathic RPF shows lower FDG uptake as compared with secondary RPF as seen in ECD.[23]
Sarcoidosis shows similarity with ECD as far as the CNS and pulmonary findings are
considered but the characteristic bony or vascular changes have not been described.[8] Sarcoidosis, in turn, is characterized by metabolically active lymphadenopathy.
Although the bone scan is a sensitive tool to assess skeletal involvement in ECD,[10] evaluation of the bone marrow is not possible. PET/CT not only evaluates skeletal
involvement but also occult visceral, vascular, and bone marrow involvement. FDG-PET
hence helps choose the best site for biopsy.
The Annual ECD Medical Symposium Consensus 2020 guidelines recommend multicore biopsies
from the most FDG-avid sites that are accessible and safe as histiocytic infiltration
may be heterogeneous.[24] The right posterior pararenal FDG avid soft tissue masses, which were easily and
safely accessible, were chosen for repeat biopsy in our patient.
These guidelines also recommend BRAF mutational status to initiate BRAF V 600E inhibitor therapy.[24] As the BRAF mutational status in our patient was negative, targeted therapy was not feasible.
If targeted therapies are unavailable or not indicated, treatment depends on the active
disease burden, wherein PET-CT plays an important role.[24]
Tissue fibrosis can occur in ECD and hence an evaluation of metabolic rather than
anatomic treatment response is essential with a follow-up PET-CT 3 to 6 months after
the initiation of therapy.[24]
Hence, 18F-FDG-PET/CT plays an important role in patients with ECD not only in the diagnoses
but also in the evaluation of disease extent as a guiding tool for targeted biopsies
and assessment for treatment response.
