Abbreviation: ALT: Alanine transaminase; AST: Aspartate transaminase;
ALP: alkaline phosphatase; ESR: Erythrocyte sedimentation rate; FSH:
Folicullar stimulating hormone; HsTSH: High sensitivity thyroid
stimulating hormone; LH: Leutinizing hormone; Human immunodeficiency
virus; N/A: not available; PTH: Parathyroid hormone; PSA: Prostate
specific antigen; WBC: white blood cell
Diagnosis and differential diagnosis
With above evidence a diagnosis of multi-systemic Erdheim-Chester
Disease involving bone, retroperitoneum, lung, thyroid gland, and testis
was established.
ECD must be distinguished from other histiocytic disorders such LCH and
RDD. Both ECD and LCH involve multiple sites, most commonly bones.
Localization of sclerotic lesion to distal ends of limbs, absence of
birbeck granules and nuclear grooves along with CD68 reactivity makes
LCH unlikely. RDD is histologically distinguished from ECD because
macrophages have normal appearing lymphocyte residing in the macrophage
cytoplasm. The sclerotic lesions of bone in ECD should be distinguished
from variety of metabolic bone disorders such as Paget’s disease and
POEMS syndrome. However, radiographic, histologic, and immunophenotypic
findings makes this group of disorders unlikely in this patient.
RESULTS
He was treated with oral analgesic, levothyroxine 25 mcg po daily and
subsequently offered treatment with cladribine but he could not afford
it. Although we reached out to several foreign organizations, but
unfortunately, we couldn’t secure the support we hoped for. The fact
that we could not commence appropriate treatment after a decade of
agonizing pain and misdiagnosis is disheartening and frustrating both
for the patient and the clinicians. This case highlights the challenge
in diagnosis and management of such rare disease in a resource-limited
setting such as ours.
Discussion
Histiocytic neoplasms are rare neoplasms that arise from myeloid lineage
cells, namely mononuclear phagocytic cells (macrophage and dendritic
cells) or histiocytes. These conditions comprise Erdheim-Chester disease
(ECD), Langerhans cell histiocytosis (LCH), and Rosai-Dorfman disease
(RDD) [13].
ECD is a rare non-Langerhans histiocytic disorder. Around 1000 cases
have been reported [4-5]. Similar to our case, it predominantly
affects adult males between the fifth and seventh decades of life.
ECD is a clonal neoplastic disorder of unknown etiology. Somatic
activating mutations in BRAFV600E and other components of MAPK pathway
appears to derive [6-7]. This activating mutation is found in more
than 50% of cases [14]. Proinflammatory cytokine released by ECD
histiocytes cause chronic uncontrolled inflammation and fibrosis, which
are the primary mediators of organ dysfunction [15].
ECD has a wide range of presentations that varies from indolent,
localized asymptomatic disease to rapidly progressive life-threatening
multi-systemic disease. The clinical feature varies depending on the
organ involved, the most commonly affected tissue include the skeleton,
vascular, retroperitoneum, endocrine, cardiac, pulmonary, central
nervous system, and orbit.
Radiographic skeletal lesion is seen in 95% of cases, however only 50%
of patients experience bone pain as their initial symptom. ECD is
characterized by bilateral symmetric sclerosis of the metadiaphysis of
the long bones [11]. Long bones of lower extremities are most
commonly involved [16]. Sclerotic lesion of the long bone of upper
extremities and skull particularly facial bones has also been described
[16]. Unlike ECD which typically affect distal end of limbs, LCH
most commonly involve the skull, pelvis, proximal limb, and scapula
[17]. Our patient presented with a 13-year history of progressive
bilateral distal thigh pain coupled with a classic radiographic lesion
involving distal femur, proximal tibia, and distal humerus.
Cardiovascular involvement occurs in majority of patients and is a
substantial cause of morbidity and mortality. It’s usually discovered
incidentally on imaging [18-19]. The most common abnormality, known
as the “coated aorta,” is seen in two-thirds of patients and it’s
caused by circumferential soft-tissue thickening and encasement of the
thoracic and abdominal aorta and its branches [20-21]. In our case,
chest and abdominal CT scans revealed asymptomatic soft-tissue
encasement of the aortic arch, thoracic aorta, abdominal aorta, and
common iliac arteries.
Retroperitoneal infiltration by histiocytes is a frequent feature of
ECD, occurring in 30-50% of cases [22]. Most remain asymptomatic
for years. Symptoms may include flank or abdominal pain, dysuria, and
slowly progressive renal failure [23]. Diffuse bilateral
infiltration of perinephric tissue results in the so-called “hairy
kidney” and may cause hydronephrosis and ureteral obstruction [24].
In our patient, an abdominal CT scan revealed a bilateral hairy kidney
sign without hydronephrosis.
Pulmonary involvement is seen in 25-50% of ECD patients. It is usually
asymptomatic, but dyspnea and cough might occur on rare occasions
[23]. Findings on CT scan include interlobular septal thickening,
ground-glass opacities, centrilobular opacities, or lung cysts [25].
In our patient, chest CT revealed asymptomatic lung cysts as well as
ground glass opacities in right lower lung zone.
Endocrine manifestations are relatively common and any endocrine gland
can be involved. The Pituitary is the most commonly affected gland and
it commonly presents as diabetes insipidus [26-27]. ECD can also
infiltrate any peripheral endocrine gland. Testis is an unusual site of
involvement of ECD. Sonographic signs of testicular infiltration might
be seen, however this does not necessarily correspond with testosterone
levels or sperm count [26]. The patient may be asymptomatic or
present with infertility, erectile dysfunction, and decreased libido.
The laboratory tests point to hypergonadotropic hypogonadism. Our
patient had a history of decreased libido, impotence, and secondary
infertility. Low serum free testosterone combine with an elevated serum
LH level suggests hypergonadotropic hypogonadism. Thyroid gland
involvement is very rare [28]. It may manifest as a palpable nodule
or goiter. It may result in subclinical or primary hypothyroidism. In
our patient primary hypothyroidism was confirmed by thyroid function
test.
ECD is challenging to diagnose due to its rarity and wide range of
presentation. The diagnosis of ECD is based on identifying the
characteristic histologic features in an appropriate clinical and
radiologic context [23].
Histologic examination of the lesion typically demonstrates lipid-laden
or foamy histiocytes admixed with inflammation and fibrosis [12]. On
IHC staining, histiocytes are positive for CD68, CD163, and occasionally
S100 but negative for CD1a and langerin. Unlike ECD, LCH expresses CD1a
and langerin [12]. To guide therapy with BRAF inhibition, mutational
analysis for the BRAF V600E mutation should be performed in all patients
[9-10].
Due to the rarity of ECD, there is a scarcity of evidence from
randomized controlled trials and prospective therapeutic studies to
guide therapy. Patients with asymptomatic non-vital single organ or
minimally symptomatic (bone or cutaneous) disease can be monitored
without treatment. Treatment is reserved for patients with symptoms or
evidence of vital organ dysfunction or CNS involvement (including
asymptomatic cases) [10, 23]. Options of therapy include targeted
therapy such as BRAF inhibitors (vemurafenib, dabrafenib), MEK
inhibitors (Cobimetinib), mTOR inhibitors (sirolimus), other tyrosine
kinase inhibitors (imatinib, sorafenib); conventional therapy such as
interferon alpha (IFN-α) and pegylated interferon alpha (PEG-IFN-α);
anti-cytokine biologic agent (anakinra, infliximab, toclizumab), and
other systemic therapy (cladribine, glucocorticoids, methotrexate). In
patients with BRAF mutation, BRAF inhibitors such as vemurafenib or
dabrafenib is the recommended first line of treatment due to its
dramatic response in all disease sites [29-30]. In patient without
mutation or access to targeted therapy, IFN-α and PEG-IFN-α are the
preferred first-line agents. However, one of the drawbacks of treatment
with interferon or targeted agent is the possibility of recurrence after
stopping the medication, requiring a longer duration of therapy
[31]. Thus, in patients who are eligible to receive systemic
chemotherapy and/or are unable to access or tolerate targeted agents, a
short cycle of cladribine is recommended to achieve sustained response
[32].
ECD is incurable and has poor prognosis. Pulmonary fibrosis, renal
failure, secondary to retroperitoneal involvement, and heart failure are
the most common cause of death [33].
Our patient presented with classic features of ECD; chronic lower leg
pain along with classic bilateral symmetric metadiaphyseal
osteosclerosis of the femur and tibia on skeletal X-ray. The presence of
foamy histiocytes combined with fibrosis that are positive for CD68 and
negative for CD1a on histologic examination confirmed the diagnosis. The
presence of peri-aortic soft tissue encasement (coated aorta), and
perinephric soft tissue thickening (hairy kidney) on imaging further
support the diagnosis of ECD. Even though our patient has an indication
for treatment, therapy could not be instituted because of cost and lack
of access to the above-mentioned first-line medications. The
psychological impact of not being able to receive appropriate therapy
after a decade of agonizing pain without a definitive diagnosis is
immense.
This case highlights many of the diagnostic and therapeutic challenges a
clinician from resource-limited setting faces while caring for patients
with rare diseases such as ECD. Establishing the diagnosis is
challenging because of lack of expertise, lack of capacity to undertake
and evaluate biopsy with IHC staining, lack of ancillary investigations
such as mutational tests, and lack of advanced imaging modality.
Likewise, managing ECD is also challenging due to the lack of access to
first-line therapeutic drugs and the lack of academic medical centers
with expertise in treating ECD. International collaboration and
assistance by providing training for clinicians, building the capacity
of health facilities, and facilitating access to first-line medications
and inclusion in clinical trials are vital to improve the care and
outcome of ECD patients from resource-limited settings.
There were several limitations in the management of this case namely,
the absence of appropriate treatment, lack of brain imaging to rule out
asymptomatic CNS lesions, lack of mutational test, and lack of
testicular and thyroid biopsy to detect infiltration of these organs.
Conclusion
ECD is a rare histiocytic neoplasm with a wide range of clinical
manifestations, posing significant diagnostic and therapeutic
challenges. This case highlights the significance of entertaining ECD in
any patient presenting with bone pain and diffuse symmetric
osteosclerosis of long bones to allow for early diagnosis and treatment.
This case also emphasizes the importance of international collaboration
and assistance to improve the care and outcome of ECD patients in
resource-limited settings.