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

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.

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.

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.

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.