Discussion:
First described in 1930 by William Chester and Jakob Erdheim (3), ECD is
now considered a clonal hematopoietic disorder (4). It makes part of the
“L” group along with Langerhans histiocytosis according to the
Histiocyte Society classification (5), both sharing genetic mutations
and they may even coexist (6). The molecular alterations underpinning
the disease such as recurrent mutations activating kinases of the
mitogen-activated protein kinase (MAPK) are now more understood (7).
Histological diagnosis requires the presence of xanthogranulomatous
lesions typically characterized by foamy histiocytes in a background of
inflammatory stroma with an immunochemical characteristic of CD68
positivity and CD1a negativity. The multisystem infiltrate makes
variable histological aspects depending on the organ (4).
The clinical presentation of ERD is variable. Bone lesions are the most
common affecting up to 95% of patients (1). Usually symptomatic of bone
pain most frequently in the knees. It can reveal the disease, such is
the case of our patient. Meta-diaphyseal osteosclerosis around the knees
is pathognomonic (8). Plain radiographs may show cortical osteosclerotic
lesions but the Technetium-99 bone scintigraphy is more sensitive
revealing the increased radiotracer uptake in the distal metaphysis and
diaphysis of femur, tibia and fibula. Pelvic bones involvement like in
the case of our patient is less common as well as axial skeleton, skull,
and ribs lesions.
Retroperitoneal fibrosis can be found in one third of ECD patients (9)
with typically a perirenal infiltrate described as “ hairy kidney”,
including encasement of renal pedicules and ureter that can, sometimes,
be complicated of high blood pressure, hydronephrosis and renal failure.
Retroperitoneal fibrosis is a common site of biopsy. Histologically it
is characterized by abundant fibrosis with inflammatory infiltrate often
mimicking IgG4-related disease (4). Our patient had retroperitoneal
fibrosis with bilateral ureteral dilation with normal renal function.
Pan et al reported hepatomegaly as an unusual manifestation of ECD (10).
Similarly, our patient had hepatomegaly among multisystem involvement
and pathologic proof of ECD therefore other diagnosis such as lymphoma
didn’t seem quite probable since she also had a very good general state.
Villatoro-Villar et al reported tissue thickening sheathing the thoracic
and abdominal aorta and its branches usually described on CT imaging as
“coated aorta” in approximately 50% of patients (11). Arterial
involvement includes as well aneurysms, ectasia and stenosis.
Periarterial encasement of the aortic arch branch vessels has also been
described with the left carotid being the most involved (11). In this
case supra-aortic branches were infiltrated by atherosclerosis rather
than soft tissular encasement causing thus the ischemic cerebral stroke.
In the case of our patient the perivascular infiltrate included the
inferior vena cava which is rarely described (9).
Cardiac involvement in ECD include pericardial disease which is frequent
(9), right atrium pseudotumor and myocardial infarction complicating
coronary arteries stenosis (12). Our patient had pericardial effusion
but no signs of coronary disease.
Pulmonary disease includes parenchymal and pleural involvement. When
systematically screened by chest computed tomography parenchymal
abnormalities reach up to 90% of patients and pleural involvement 63%
(13) in some studies and 53% and 41%, respectively, in others (14).
Interstitial lung disease including frequently septal thickening,
solitary or multiple nodules, ground glass opacities and less commonly
cysts (13). When systematically performed in patients with CT lesions,
pulmonary function tests are usually abnormal with mostly diffusing-
capacity defects (13). Mixed ventilation disorders such in our patient’s
case has been reported in 13% of patients in Wang et al study (13).
Cutaneous lesions in ECD are typically periorbital xanthelasma reported
in around one third of patients in many series (9).
Breast involvement in ECD is rare and has been mentioned in few case
reports (15) including breast lumps with axillary expansion sometimes,
with variable mammographic findings and infiltration of the breast
tissue and skin thickening on CT scans. Our patient had an erythematous
and macular plaque on the left breast skin with no nodules and normal
mammography but the scan revealed bilateral infiltrative lesions.
Treatment of ECD has drastically evolved since the better understanding
of the molecular aspects of the disease. Various treatment regimens have
been tried with some conventional therapies and recently targeted
therapies. Goyal et al (8) summarized the different treatment protocols
based on case reports, series and clinical trials. First line
conventional therapy include Interferon alpha (IFN- α) and pegylated
IFN-α with large series (16) demonstrating the favorable clinical
efficacy and better survival rates even in severe cases. Cladribine and
Anakinra efficacy have been cited in case reports and series with
moderate responses (17) (18) . The use of second line conventional
therapy demonstrated variable results and were particularly an
interesting solution in case of no access to targeted therapies and
low-burden disease. This latter, including , but not only, Tocilizumab
(IL-6 receptor antagonist), Infliximab (anti TNF-α inhibitor) which
results are controversial (19). Methotrexate that has a low clinical and
radiologic response (20) however its use seems interesting in reducing
infliximab immunogenicity. Due to the lack of targeted and conventional
first line therapy in our country, narrowing down the treatment options,
the management of our patient’s disease was challenging. Considering the
risk of progression and the altered quality of life we opted for a
combined protocol including second line agents.
Targeted therapies like BRAF inhibitors (Vemurafenib, Dabrafenib) and
MEK inhibitors (Cobimetinib, Trametinib) have promising results yet
considerable risks and side effects.
More clinical trials, series and experience sharing are needed to
improve the management of ECD patients and to provide consensus
guidance.
Clinical response in our case is assessed by anamnesis and physical
examination during follow-up and a PET-CT is intended to assess the
radiological response after six months of treatment.