Investigators report a case of a man, aged 55 years, with an extensive and prolonged course of an unexplained multi-systemic disease, and also review common clinical manifestations, mutations, diagnoses, and targeted therapies for Erdheim-Chester disease.
Erdheim-Chester disease (ECD) is a rare type of non-Langerhans cell histiocytosis. However, its prevalence has increased significantly the past few years due to increased awareness about the disorder, and 1500 cases have been reported worldwide. It is often a multisystemic disease with skeletal, cardiovascular, urologic, renal, retroperitoneal, pulmonary, endocrine, cutaneous, and neurologic involvement. MAPK pathway mutations, such as BRAF activating and MAP2K1 mutations, play a key role in its pathogenesis. In addition to the characteristic clinical, radiological, and histopathological findings, identifying underlying mutations helps diagnose and treat patients with highly effective targeted therapies such as BRAF and MEK inhibitors. We report a case of a man, aged 55 years, with an extensive and prolonged course of an unexplained multisystemic disease, later diagnosed with BRAF V600E–negative and MAP2K1-positive ECD on cell-free DNA testing. Additionally, we review common clinical manifestations, mutations, diagnoses, and targeted therapies for ECD.
Oncology (Williston Park). 2023;37(7):298-302.
Erdheim-Chester disease (ECD) is a rare type of non-Langerhans cell histiocytosis (LCH).1 It was first described as “lipoid granulomatosis” by Jakob Erdheim and William Chester in 1930 and was later named after its discoverers.2 It is a rare disease, but its prevalence has increased substantially in the past few years due to increased awareness about the disorder, and 1500 cases have been reported worldwide.1
Infiltration of tissues with foamy CD68+, CD1a– histiocytes is one of the characteristic features of ECD.3 It is most commonly a multisystemic disease with skeletal, cardiovascular, urologic, renal, retroperitoneal, pulmonary, endocrine, cutaneous, and neurologic involvement, and clinical manifestations vary depending upon the system(s) involved.2 Pathogenesis of ECD involves mutations in the MAPK pathway, such as BRAF V600E and MAP2K1 mutations.2 ECD’s diagnostic criteria are based on clinical, radiological, histopathological, and molecular findings.2 The ability to find the underlying mutations has significantly helped treat patients with highly efficacious and robust targeted therapies, including BRAF and MEK inhibitors.1
We report a case of a man, aged 55 years, with an extensive and prolonged course of an unexplained multisystemic disease, later diagnosed with BRAF V600E–negative and MAP2K1-positive ECD on cell-free DNA testing. Additionally, we review common clinical manifestations, mutations, diagnoses, and targeted therapies for ECD.
A man, aged 55 years, presented with the chief complaint of bilateral leg swelling. On the physical exam, he was found to have bilateral lower extremity edema, ascites, and hepatomegaly. CT of the abdomen revealed retroperitoneal fibrosis. An exploratory laparotomy with a biopsy of the retroperitoneal area confirmed fibrosis. Multiple studies to determine the cause of fibrosis were unsuccessful, and he was started on steroids for idiopathic retroperitoneal fibrosis. Subsequent CT scans showed pleural thickening and mediastinal fibrosis in addition to the unchanged retroperitoneal fibrosis encasing both kidneys and the aorta. Because of the diffuse multifocal involvement, he was thought to have systemic fibrosclerosis. It was further complicated by testicular insufficiency secondary to bilateral testicular fibrosis, and he eventually required bilateral orchiectomies. Further, he developed right and left heart failure symptoms, and the thoracic CT scan showed thickening of the pericardium with no significant fluid in the pericardial cavity. Subsequently, he needed a pericardiectomy for constrictive pericarditis.
Progression of the disease continued with the development of paranasal sinus symptoms. A CT scan revealed opacification of bilateral maxillary sinuses, and sinus biopsy was remarkable for fibrosis. Concurrently, he also had resistant hypertension secondary to stenoses of renal arteries; renal artery stent placement was necessary to control hypertension. Furthermore, he had other vascular occlusions, including of the internal carotids, superior mesenteric artery, celiac artery, and bilateral iliac arteries. Even the coronary arteries were not spared; he presented with acute coronary syndrome, for which he underwent percutaneous coronary intervention of multiple coronary arteries. Later, he developed dyspnea on exertion, and pulmonary function tests were consistent with restrictive lung disease. A CT of the chest revealed centrilobular nodules, pleural thickening, and interlobular septal thickening (Figure 1D). This constellation of clinical and radiological findings raised suspicion of ECD.
Further work-up included bone scintigraphy to assess skeletal involvement; repeat imaging to confirm pulmonary, abdominal, and vascular findings of ECD; and then tissue and liquid biopsy to detect histopathological and molecular findings of ECD. Bone scintigraphy showed abnormal uptake in the bilateral tibia, bilateral maxillary bones, and shoulder regions consistent with ECD (Figure 1A). In addition, a CT scan showed diffuse circumferential wall thickening and calcification throughout the thoracic and abdominal aorta and its major branches (Figure 1B), conditions associated with ascending thoracic aortic ectasia and type V thoracoabdominal aortic aneurysm. It is important to note that the aorta was coated circumferentially (Figure 1C), pointing toward ECD as the diagnosis. The posterior wall of the aorta is rarely affected in idiopathic retroperitoneal fibrosis.4
A CT scan of the abdomen showed the “hairy kidney” sign with irregular, symmetric infiltration of the bilateral perirenal and posterior pararenal spaces (Figure 1E). Right-sided tibial biopsy showed extensive fibrosis and calcification, but foamy histiocytes were not present; this was not inconsistent with ECD but was also not diagnostic due to the scant cellularity of the specimen (Figure 2A). Immunohistochemical staining of the spindle and ovoid cell population was negative for CD1a and S100 (Figure 2B and 2C). However, the oval cells that were morphologically suggestive of histiocytes and a component of the spindle cells were CD68+, which confirmed the histiocytic nature of the cells (Figure 2D). Based on the immunohistochemistry, molecular testing was not ordered because of insufficient representative cellularity.
Subsequently, the patient underwent bronchoscopy with endobronchial ultrasound and fine-needle aspiration of a 5-cm subcarinal lymph node that showed blood, respiratory cells, and benign cartilage. However, the tissue sample was inadequate, with no lymphoid tissue. Later, an incisional pleural biopsy was performed that revealed dense fibrous tissue with rare chronic inflammatory cells; unfortunately, the tissue sample was insufficient for further testing. Finally, a liquid biopsy was obtained to look for mutations for targeted therapy; it came back negative for BRAF V600E mutation but positive for MAP2K1 (MEK1) K57N mutation with a variant allele frequency of 1.2%, confirming the diagnosis of ECD. The time between symptom onset and the diagnosis was around 22 years.
There are 3 different functional classes of MEK1 mutations, and MEK1 K57N is a class II mutant that is sensitive to currently available MEK inhibitors like trametinib.5 Therefore, the patient was started on targeted therapy with trametinib, an inhibitor of MEK1 and MEK2. However, within 2 weeks of starting the medication, the patient started experiencing intolerable adverse effects (AEs) including nausea, vomiting, diarrhea, fever with chills, body aches, mouth sores, fatigue, and headache. Trametinib was held for a few days and the plan was to resume it later at a lower dose. However, the patient refused further treatment due to intolerable AEs. Posttreatment imaging studies could not be obtained as the patient was on treatment only for about 2 weeks. Unfortunately, the patient died 3 months later from complications of the disease.
ECD is a rare histiocytic disorder with variable clinical presentation ranging from mild localized disease to life-threatening multisystemic illness.3 It is 70% to 75% more common in men than women and in the United States, it is most frequently diagnosed in middle-aged adults (mean age at diagnosis, 46 years).3 BRAF V600E mutation is seen in 57% to 70% of cases, followed by MAP2K1 mutation in about 20% of cases.2 The discovery of underlying mutations in ECD, such as activating kinase mutations and fusions involving MAPK and P13K/AKT pathways, helped establish ECD as a clonal neoplastic disorder; it is classified among the “L” (Langerhans) group of the 2016 revised histiocytosis classification of the Histiocyte Society.6 In addition, these mutation discoveries transformed the diagnostic and management approaches for ECD.3
ECD is most commonly a multisystemic disease and can affect almost any organ.3 In this review, we will discuss the most common manifestations of ECD.
The most frequent manifestation of ECD is long-bone osteosclerosis, which is observed in 80% to 95% of cases.7,8 It is usually asymptomatic but may present with mild leg bone pain.7 Although radiological imaging such as x-rays, CT scans, and MRIs can detect osteosclerosis, bone scintigraphy and PET scans are more sensitive modalities. Bone scans show increased radiotracer uptake, and PET scans show 18F-fluorodeoxyglucose uptake most commonly in bilateral femurs and tibia.7
Cardiovascular involvement is seen on CT angiography in the form of aortic sheathing (“coated aorta”), secondary to periaortic infiltration. Extension into the main branches of the aorta may or may not be present, and periaortic infiltration is usually asymptomatic.1 In addition, fibrosis in ECD tends to encircle the aorta without sparing any wall; in contrast, idiopathic retroperitoneal fibrosis rarely affects the posterior wall of the aorta.4 Other cardiac manifestations include right atrium pseudotumor, coronary artery stenosis, and myocardial infarction due to infiltration of coronary arteries; pericardial involvement may be in the form of pericarditis, pericardial effusion, or cardiac tamponade. Dedicated cardiac MRI is the preferred type of imaging to detect cardiac involvement in ECD.1
Pulmonary involvement is seen in 30% to 50% of cases.1 It is generally asymptomatic, but some patients may present with dyspnea on exertion. Thoracic CT scans may reveal pleural involvement as pleural thickening due to infiltration of the pleura or pleural effusions.9 In addition, interstitial lung disease–like patterns—including interlobular septal thickening or, rarely, small centrilobular nodular opacities, ground-glass opacities, and interlobar fissure thickening—can be seen due to infiltration of the lung parenchyma.2,7,9 Pulmonary function tests show a restrictive pattern in 30% of cases.7
Retroperitoneal involvement is not uncommon.1 Perirenal fat infiltration and encasement of the kidneys (“hairy kidneys”) can be seen on an abdominal CT scan.1 Retroperitoneal fibrosis can cause renal artery stenoses, which require renal artery stents to control hypertension. It can also cause hydronephrosis due to ureteral obstruction, which may require ureteral stent placement.7,8
ECD can affect any endocrine organ.1 Diabetes insipidus is usually the first and most common endocrine manifestation in ECD, observed in 33% of cases.10 Anterior pituitary involvement is not uncommon and can manifest as growth hormone deficiency (53.1%), hyperprolactinemia (44.1%), gonadotrophic hormone (luteinizing hormone and follicle-stimulating hormone) deficiencies (22.2%), thyrotropin deficiency (9.5%), or adrenocorticotropic hormone deficiency (3.1%).10 Testicular deficiency is seen in 53.1% of men with ECD and is associated with sonographic evidence of bilateral testicular infiltration in 29% of the cases.10 MRI pituitary reveals infiltration of the pituitary and its stalk in some cases.10 Although adrenal insufficiency is rare, adrenal infiltration is a common finding on an abdominal CT, present in 39.1% of patients.10
Neurological, orbital, and facial manifestations
ECD is known for numerous and diverse neurological manifestations. Cerebellar and pyramidal syndromes are the most frequent signs (41% and 45% of cases, respectively).11 Also reported are such other manifestations as seizures (12%), cognitive symptoms like dementia and amnesia (21%), neuropsychiatric symptoms (5%), headaches (5%), cranial nerve paralysis, sensory disturbances, and asymptomatic lesions.11 A cerebral MRI reveals either infiltrative lesions or meningeal lesions.11 Infiltrative lesions are seen in the form of nodules or intracerebral masses.11 Meningeal lesions can be either solitary or multiple meningioma-like tumors or diffuse thickening of pachymeninges.11 Infiltration of retro-orbital soft tissues that leads to exophthalmos, often bilateral, is seen in one-fourth of patients.2 Infiltration of sinuses is also common in ECD and more frequently involves maxillary and sphenoid sinuses (47%) than ethmoid and frontal sinuses (17%).1,12
Skin involvement in ECD is most frequently seen as xanthelasma-like lesions in 25% to 30% of patients; upper eyelids are the most common location.13 Other cutaneous manifestations of ECD include nonspecific patches or papulonodular lesions affecting the legs, trunk, and/or back.13,14
Diagnosing ECD can be challenging because it requires the interpretation of characteristic histopathologic findings in conjunction with clinical, radiological, and molecular disease findings.3,15 A biopsy is needed to make the diagnosis of ECD. Histopathology of the affected tissues shows infiltration by foamy or lipid-laden histiocytes surrounded by fibrosis with or without the presence of Touton giant cells.3,15 On immunohistochemical staining, histiocytes in ECD are positive for CD68, CD163, and factor XIIIa and negative for CD1a and CD207.3,15 All patients must be tested for BRAF V600E mutation.3 In BRAF V600E mutation–negative cases, alterations in other genes of the MAPK/ ERK pathway and P13K/AKT pathways should be tested using targeted-capture next-generation sequencing with a commercially available assay.3 Cell-free DNA testing can be used as a reasonable alternative in cases where the tissue specimen is insufficient for molecular analysis.3
Due to the rarity of this disease and the relative lack of sample size, no clinical treatment trials have been designed solely for ECD.1 However, approximately 60% of patients with ECD have BRAF-activating mutations, making BRAF inhibitors an appealing therapeutic choice.1 In 2012, 3 patients with ECD and a BRAF V600E mutation were treated with and responded to vemurafenib, a BRAF inhibitor.2 Responses were similar in the phase 2 VE-BASKET trial (NCT01524978) at Memorial Sloan Kettering Cancer Center.16,17 As for long-term outcomes, the LOVE study (NCT02089724) showed that relapses after 6 months occurred in 75% of patients who stopped vemurafenib.18 Treatment was restarted in 10 patients, leading to eventual remission.18 AEs reported with BRAF inhibitors include arthralgia, skin complications (such as keratosis pilaris, spinocellular carcinoma, photosensitivity, and melanoma), DRESS syndrome, pancreatitis, and QT prolongation.1,18 Tolerance to the treatment varies, as demonstrated by the VE-BASKET trial.19
Before the discovery of BRAF inhibitors, interferon alfa was the best initial choice of treatment for ECD, and it still is a possibility for those with BRAF V600E mutation–negative disease.20 In one report of a series of 8 patients who were treated with interferon alfa for a median duration of 23 months, the treatment was said to be well tolerated. However, response to treatment varied from partial regression to complete failure.21 Reported AEs include severe depression and fatigue.1,2
Other possible treatment options include MEK inhibitors like cobimetinib and trametinib. As more evidence emerged that other MAPK/ERK pathway mutations, like MAP2K1 mutations, exist among BRAF V600E mutation–negative patients with ECD, downstream blockade of this pathway was successfully explored in patients with refractory ECD, resulting in robust responses to either cobimetinib or trametinib.3 The efficacy of cobimetinib as monotherapy has been reported in 3 patients with BRAF V600E mutation–negative ECD who were refractory to conventional therapy. All 3 patients showed a sustained metabolic response; they experienced minimal AEs, including vomiting and acneiform rash, but no cardiac or ocular complications.22
In a case study of a patient with a MAP2K1 gene mutation who lacked a complete response to the original treatment of interferon alfa, the regimen was changed to cobimetinib. After 8 months of treatment with cobimetinib, the patient had a normal PET/CT indicative of remission.23 Another case report revealed a novel “dropped head syndrome,” in which a patient with ECD was treated with cobimetinib but developed neck pain and reduced mobility, with no discernible etiology. Symptoms improved upon cessation of the drug, and the patient was then eventually able to tolerate a decreased dosage, which led to the eventual resolution of the disease as evidenced by no new lesions and reduction of old lesions on PET/CT.24 Another patient with ECD with MAP2K1 Q56P–mutant disease who was refractory to 4 lines of prior therapy, responded to cobimetinib within a month of treatment; there was resolution of PET-avid disease in renal, aortic, and maxillary sinus infiltrations.25
The literature review revealed that trametinib is effective in treating LCH, and we also found a few case reports demonstrating trametinib’s efficacy in treating patients with ECD. A case report of a patient with multisystem, multifocal LCH showed that low doses and even intermittent use of trametinib were associated with rapid improvement in most of the disease manifestations.26 In another case report, a patient with multisystem LCH harboring MEK1 mutation responded to targeted therapy with trametinib, with complete remission of skin lesions and significant improvement in the symptoms of LCH-induced diabetes insipidus.27 Moreover, the efficacy of trametinib has also been reported in a patient with ECD who had progressive disease after treatment with both interferon alfa and anakinra and was symptomatic due to inflammatory ascites and renal failure. The patient was then treated with trametinib after MAP2K1 K57N mutation was detected in perirenal lesions, which resulted in complete resolution of ascites and renal failure.25 Another patient with ECD was treated with trametinib after dabrafenib failure and had alleviation of symptomatology from the syndrome as well as decreasing C-reactive protein levels, indicating reduction of the disease.28 A case report of a patient with ECD who received combination therapy of trametinib with dabrafenib reported an AE of a rash, which required dose adjustments and eventually resolved. With this treatment regimen, the patient had a reduction in lesions in the liver, bone, and brain.29
Ankita Aggarwal, MD1; Mackenzie Taychert, DO1; MHD Louay Hasanin, MD2; Donald Doll, MD3; Mira Gabrielle Basuino, BS1; Hassan Hasanein, MD3
1University of Missouri, Columbia, MO
2Al-Baath University, Homs, Syria
3Division of Hematology and Medical Oncology, University of Missouri, Columbia, MO
Ankita Aggarwal, MD
Address: 3601 West Broadway
Columbia, MO, 65203