Diagnosis Of Erdheim-Chester Disease Research Articles

Erdheim-Chester disease and nuclear medicine imaging. A case report and brief review.

Erdheim-Chester disease (ECD) is a rare clonal myeloid neoplasm typically affecting adults over 50years old, with bone lesions in almost all patients. The prognosis is poor in most cases if left untreated. Clinical manifestations are not specific, which hinders early diagnosis. The disease has distinct radiological features. However, three-phase bone scintigraphy exhibits the most typical pattern of all imaging modalities, which is the prominent strikingly symmetrical radiotracer uptake in the distal ends of the femurs and proximal and distal ends of the tibiae, sparing the epiphyses. We report a case of a 54-year-old female patient, presenting with atypical persistent knee joint pain. After an MRI scan, she underwent a three-phase bone scan, revealing the characteristic pattern, thus indicating a possible ECD diagnosis, which was eventually confirmed in biopsy material. Novel aspects of the pathophysiology and treatment of the disease, as well as a differential diagnosis from the perspective of an MSK radiologist and nuclear medicine physician, are also discussed.

Erdheim-Chester disease as complex clinical presentation and diagnosis: A case report and concise review of literature.

Erdheim-Chester disease (ECD) is a rare multisystemic disease characterized by the infiltration of multiple organs by foamy CD68 + CD1a-histiocytes. The genetic background consists of gain-of-function somatic mutations in the mitogen-activated protein kinase pathway. The purpose of the present paper is to make a contribution to the scientific literature on ECD by reporting our experience with a complex clinical case report, along with a concise review of the literature. We discussed the unusual clinical presentation, the complex diagnostic process and the comparison with other published cases. A 70-year-old man presented with arthralgia due to multiple bone areas of sclerosis, first diagnosed with metastases of a prostatic neoplasm. Sequential thorax-abdomen, femoral and homer contrast-enhanced computed tomography (CT) showed pericardial effusion, pulmonary fibrosis, and perirenal fibrous tissue as "hairy kidneys." He underwent. Three bone biopsies were unsuccessful to reach diagnosis. A xanthelasma biopsy showed histopathological signs compatible with ECD; genetic analysis showed the mutation BRAFV600E. The patient underwent targeted therapy with vemurafenib (BRAF-inhibitor), discontinued 2 weeks later due to the onset of a diffuse erythematous papular rash on the trunk and limbs. At the 1-year follow-up, there was only progression of chronic kidney disease (CKD). The present case report describes how ECD diagnosis could represent a challenge for clinicians, owing to its heterogeneous clinical presentation. Early diagnosis followed by prompt therapy is essential for modifying the natural history of the disease.

Cardiovascular Morbidity in Erdheim-Chester Disease (ECD) Patients with and without Cardiac Involvement

Purpose: The understanding of cardiac-involved ECD (ECD-CV) and how this affects outcomes and pre-existing diseases remains limited. We aimed to determine the association, burden, and severity of pre-existing and de novo cardiovascular (CV) comorbidities with ECD-CV compared to patients (pts) without cardiac-involved ECD (ECD-noCV). Methods: Records of pts with ECD diagnosed from Jan-1990 to Dec-2021, consecutively seen at Mayo Clinic, AZ, FL, and MN were reviewed. Cardiac involvement was diagnosed by imaging. CV comorbidities were captured before and after ECD diagnosis. CTCAE v3.0 based grading system was used to assess CV comorbidities which graded the conditions as mild (grade 1), moderate (grade 2), severe (grade 3), and life-threatening or disabling (grade 4). Chi-square test was used to determine if having ECD-CV worsens pre-existing CV comorbidities in pts with ECD. As per the established methods, the cumulative CV disease burden was defined after considering 8 CV morbidities that are known to have direct structural and functional implications on the heart, including hypertension (HTN), coronary artery disease (CAD), myocardial infarction (MI), congestive heart failure (CHF), atrial fibrillation (afib), pericardial effusion, valvular disease, and conduction disorders. A composite CV morbidity grade was assigned based on the highest grade in one of the 8 CV comorbidities (Oeffinger, NEJM, 2006). Lastly, a multivariant analysis was conducted using the presence of BRAFV600E mutation, smoking, age ≥ 60 years (yr), conventional vs targeted therapy, and ECD-CV in pts with a composite grade of 4. Results: Among 106 ECD pts, 38% (n=40) had cardiac involvement. The median age at diagnosis of ECD was 57 yr (range: 49-67); 61% were males. The median follow-up was 5 yr (95% CI: 3.5-6.1), and 4.1 yr (95% CI: 3.2-6.5) for ECD-CV and ECD-noCV pts, respectively p=0.92. The median time of CV diagnoses for the entire cohort before and after ECD diagnosis was 4.8 yr (range: 0.06-42.5) and 3.4 yr (range: 0.05-18.7), respectively. BRAFV600E mutation was present in 65% (n=26) of ECD-CV vs 42% (n=28) of ECD-noCV, p=0.02. Eight pts with ECD-CV died; one from sudden cardiac death, while 9 ECD-noCV pts died, p=0.39. Smoking was present in 43% (n=18) of ECD-CV pts compared to 24% with ECD-noCV (n=16), p=0.05. In comparison to ECD-noCV pts, increased prevalence of pre-existing HTN [59% (n=23) vs 35% (n=23), p=0.016] and MI [10% (n=4) vs 2% (n=1), p=0.046] was seen in ECD-CV. There was no difference in hyperlipidemia, diabetes mellitus, CAD, CHF, valvular disease, afib, and conduction disorders among the two cohorts. After ECD diagnosis, de novo diagnosis of hyperlipidemia [67% (n=26) vs 38% (n=25); p=0.004] and CHF [35% (n=14) vs 7% (n=5); p=<0.001] was seen more frequently in ECD-CV pts compared to ECD-noCV. Following the diagnosis of ECD, the severity of pre-existing conditions did not change in pts with or without ECD-CV. ECD-CV pts had a greater cumulative CV disease burden as the total number of CV morbidities was greater in ECD-CV pts both before and after ECD diagnosis (Table 1). Additionally, pts with ECD-CV had greater severity of CV morbidity (composite grade ≥4) than ECD-noCV before (35% v 3%; p=<0.001) and after (42.5% vs 7.6%; p=<0.001) ECD diagnosis. The composite grade of 4 before ECD diagnosis was most attributable to pericardial effusion (42% in pts with ECD-CV vs 0% in pts with ECD-noCV) and CAD (50% in pts with ECD-CV vs 100% in pts with ECD-noCV); after ECD diagnosis pericardial effusion (42% in pts with ECD-CV vs 0% in pts with ECD-noCV) and CAD (41% in pts with ECD-CV vs 100% in pts with ECD-noCV). After considering BRAFV600E mutation, age ≥60, smoking, ECD-CV, and first-line therapy (conventional vs targeted therapy), ECD-CV was the only factor independently associated with a composite grade of ≥4, before (OR 25.6, 95% CI: 4.8-137) and after (OR 9.7, 95% CI: 3.0-30.8) ECD diagnosis. Nonetheless, smoking, age >60, and ECD-CV were independent factors associated when considered a composite grade of ≥3, before and after ECD diagnosis. Conclusion: ECD-CV did not prognosticate pts and did not worsen the pre-existing CV conditions compared to pts with ECD-noCV. However, ECD-CV pts had a higher cumulative CV disease burden and a higher grade of pre-existing and de novo CV morbidities compared to ECD-noCV. The presence of cardiac involvement in ECD was independently associated with a severe cumulative CV disease burden grade.

Erdheim-Chester disease; a 31-year-old woman presented with bone pain and ophthalmologic involvement: a case report

Erdheim-Chester disease (ECD) is a rare non-Langerhans histiocytic disorder with no actual known incidence rate. It primarily affects multiple organs via increased expression of proinflammatory cytokines, eventually leading to histiocyte activation and infiltration at multiple sites. A 31-year-old virgin female presented with progressive generalized bone pain and blurred vision. She underwent a comprehensive clinical and paraclinical evaluation. Based on the final results, the diagnosis of ECD was established. We started treatment mainly using Interferon-α and corticosteroids, estrogen, levothyroxine, and desmopressin acetate. In adults with a mysterious chronic disease affecting multiple organs, we should always consider ECD as a differential diagnosis. Although ECD is still rare, the detection rate of this disease has increased significantly in recent decades. A comprehensive clinical and paraclinical evaluation is necessary to make a definitive diagnosis and determine the extent of the disease.

99mTc-MDP bone scan in the diagnosis of Erdheim-Chester disease

nil

Neurological Erdheim-Chester Disease Manifesting with Subacute or Progressive Cerebellar Ataxia: Novel Case Series and Review of the Literature.

Neurological involvement is relatively common in Erdheim-Chester disease (ECD), a rare clonal disorder of histiocytic myeloid precursors characterized by multisystem involvement. In ECD patients, neurological symptoms can occur either at onset or during the disease course and may lead to various degrees of neurological disability or affect patients' life expectancy. The clinical neurological presentation of ECD often consists of cerebellar symptoms, showing either a subacute or progressive course. In this latter case, patients manifest with a slowly progressive cerebellar ataxia, variably associated with other non-specific neurological signs, infratentorial leukoencephalopathy, and cerebellar atrophy, possibly mimicking either adult-onset degenerative or immune-mediated ataxia. In such cases, diagnosis of ECD may be particularly challenging, yet some peculiar features are helpful to address it. Here, we retrospectively describe four novel ECD patients, all manifesting cerebellar symptoms at onset. In two cases, slow disease progression and associated brain MRI features simulated a degenerative cerebellar ataxia. Three patients received a definite diagnosis of histiocytosis, whereas one case lacked histology confirmation, although clinical diagnostic features were strongly suggestive. Our findings regarding existing literature data focused on neurological ECD will be also discussed to highlight those diagnostic clues helpful to address diagnosis.

Efficacy of MEK Inhibitors in Erdheim Chester Disease

Background Erdheim Chester disease (ECD) is a rare histiocytosis with variable clinical behavior known to be driven by recurrent activating mutations in the MAP kinase pathway. BRAF inhibitors were the first targeted therapy used in this neoplastic disorder given the presence of the BRAFV600E mutation in 50-60% of patients. Increased understanding of additional driver mutations within this pathway resulted in a study of MEK inhibitors (MEKi) in cases not harboring this mutation, ultimately leading to the FDA breakthrough designation of cobimetinib for BRAFV600E negative histiocytic neoplasms. Herein, we present data from our institution on MEKi treatment of ECD, the largest cohort to date. Methods We included all patients with ECD consecutively seen at Mayo Clinic and treated with one of the 3 available MEKi (cobimetinib, trametinib, or binimetinib) between 2019-2021. Tumor MAPK pathway mutation status was determined with next-generation sequencing (NGS) via the Tempus-xT® assay (Chicago, IL). If NGS data was unavailable, immunohistochemistry (IHC) or allele-specific PCR was used to determine BRAF-specific mutation status. Time-to-event analyses were calculated from the time of MEKi initiation to progression, therapy discontinuation due to intolerant side effects, or initiation of systemic non-MEKi therapies. Response assessment was done based on the established positron emission radiography (PET)-response criteria used for clinical trials of targeted therapies in histiocytosis. Adverse events (AEs) were graded using the National Cancer Institute Common Toxicity Criteria v5.0 Results A total of 22 patients with ECD underwent treatment with a MEKi and were included. Median follow up was 19 months (95% CI 10 - 28 months) and 55% (n=12) were female. Median age at diagnosis of ECD was 54 years (IQR 36.8 - 70.8 years). Most common system involvement included osseous (68%), retroperitoneal soft tissue (46%), central nervous system (41%), and cardiovascular (41%). Mutational assessment studies included NGS in 82% (n=18). The four remaining patients had assessment of BRAFV600E by IHC or PCR. Tumor genomic profile included non-BRAFV600E mutations in 15 patients (68%). BRAFV600E was identified by IHC in one patient. All other patients did not have successful NGS (n=2) or had no pathogenic variants identified (n=3). Additional details presented in Table 1. Median time on a MEKi was 6.5 months (IQR 3 - 15 months). It was used as first-line therapy in 72.7% (n=16) of cases. Within the 22 patients, 28 instances of MEKi initiation were observed in our cohort, as 5 patients (23%) received 2 different MEKi throughout follow up and one patient had cobimetinib rechallenge after first progression. MEKi used included: cobimetinib (n=23, 82%), trametinib (n=3, 11%), and binimetinib (n=2, 7%). Response assessment after initiation of first MEKi was not available in 1 patient. In the remaining 21 cases, overall response rate was 81% including complete or near-complete response (CR/nCR) in 5 (24%), partial response (PR) in 12 (57%), stable disease (SD) in 2 (10%), and progressive disease (PD) in 2 (10%). Median EFS was 36 months (95%CI 9 - not reached), respectively. Intolerable AEs with MEKi included G3/4 diarrhea (n=2), G3 lower extremity edema (n=2), G3 acneiform rash (n=1), G2 pericardial effusion (n=1), and "dropped-head syndrome” (n=1). Of the 6 patients who were treated with a second MEKi (Figure 1), five had data for response assessment and had CR/nCR (n=2) or a PR (n=3) as best responses. At time of last follow-up, 21 patients (96%) were alive and one died due to progression of ECD. Of the 22 patients, 10 patients (46%) remained on MEKi at the time of last follow-up. Reasons for therapy discontinuation included intolerable side effects (n=4), drug holiday after response achievement (n=4), disease progression on therapy (n=3), and change to other kinase inhibitors (n=1). Additional details regarding patient follow-up are presented in Figure 1. Conclusion Our study suggests that MEK inhibitors are a highly efficacious treatment in patients with ECD. Main limitation of our study includes its retrospective nature and sample size. While treatment discontinuation due to severe toxicities / intolerance was common, this did not preclude from maintenance of tumor response for extended periods of time. Not all patients will respond to MEKi and further research to guide individualized therapies is required. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

PMON110 Panhypopituitarism as a Rare Presentation of Erdheim – Chester disease (ECD) in an Adolescent Patient

Abstract Background Erdheim-Chester disease (ECD) is a rare multisystemic histiocytic disorder. Only a dozen pediatric cases are reported. Here, we present a case of ECD in a pediatric patient who presented with short stature and delayed puberty. Clinical Case A 14-year-old male with history of autism and ADHD presented with short stature and pubertal delay. He grew along the 40th percentile until age 7 years when growth velocity declined. On exam, his height was 145.6 cm (0.98%ile, z-score -2.34), weight was 55.6 kg (63.19%ile, z-score 0.34), and testicular size was 5-6 mL. He had increased thirst and episodes of bedwetting since age 7. Bone age was delayed at 11 years 6 months. Further workup was recommended, but family was lost to follow up. At 16, he returned with continued poor growth, polydipsia, and nocturia. Height was 153 cm (0.26%ile, z-score -2.80), weight 61.1 kg (40%ile, z-score -0.25). Labs revealed IGF-BP3 2.8mcg/mL(3.1-8.9), IGF-1 35ng/mL(245-522), LH 1.2mIU/mL(0.29-4.77), and total testosterone <7.0 ng/dL(250-1100). Prolactin, cortisol, thyroid, and karyotype were normal. Growth hormone (GH) stimulation test confirmed GH deficiency. He was referred to oncology clinic when a brain MRI revealed a nodular enhancing suprasellar mass extending from the third ventricular floor to the dorsum sella along the pituitary stalk and rounded sclerotic lesion in the frontal bone. Biopsy of the suprasellar lesion was remarkable for foamy histiocytes positive for CD68, negative for S100 and CD1a, an eosinophilic cell background highlighted by S100 and synaptophysin, SALL4 negative. A diagnosis of xanthomatous hypophysitis was made. Additionally, lab studies confirmed diabetes insipidus (DI), treated with DDAVP. Growth hormone was trialed for 2 weeks, but he developed acute pancreatitis, so it was discontinued. He subsequently developed recurrent pancreatitis of unclear etiology requiring frequent hospitalization with development of insulin-dependent diabetes mellitus due to pancreatic damage. He was lost to follow up for 12 months after leaving home at age 18. He returned to our institution after incidental findings of 7th right rib expansile lytic bony lesions on abdominal CT during a pancreatitis admission. Biopsy of the rib lesion was positive for a BRAF-V600E mutation. Skeletal survey revealed new multiple small lytic skull lesions. Repeat brain MRI demonstrated new calvarial lesions, increased suprasellar mass. Chest CT scan showed a micronodular pattern with mediastinal lymph node enlargement. PET confirmed widespread multifocal FDG hypermetabolic lesions. Final diagnosis of ECD was made; he was started on targeted therapy with Vemurafenib, a BRAF inhibitor. Conclusion Erdheim-Chester disease (ECD) is a non-Langerhans cell histiocytosis, which rarely affects pediatric patients who present with bone pain and DI; however, here we present a case of ECD in an adolescent with short stature and multiple pituitary deficiencies to highlight the varied presentation of the disorder. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

S2212 A Rare Systemic Illness Presenting With Fever and Abdomen Pain

Introduction: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytic disease. ECD can practically involve any organ system in the body with common organs involved being skeletal system, cardiovascular system and the central nervous system. Rarely, other organs like breast, liver, spleen, kidney, testis and thyroid glands were reported to be involved. Case Description/Methods: A 51-year-old female presented to our emergency with fever and left upper quadrant pain abdomen of 10 days. Historically, she was symptomatic for last 3 years with complaints of intermittent fever, knee joints pain, polyuria, nocturia and polydipsia. Contrast enhanced computer tomography (CECT) chest and abdomen showed bilateral pleural and pericardial effusion, thrombosis in splenic vein and right portal vein, splenic infarct, bilateral urothelial thickening with perinephric fat stranding, soft tissue thickening around the aorta and asymmetrical bulky adrenals. PET-CT revealed Flouro-deoxyglucose (FDG) avid ill-defined lesion in the pericardium which was extending into the inter-atrial and atrioventricular septum and FDG avid asymmetrical mural thickening of aorta extending from ascending thoracic aorta up to the infrarenal abdominal aorta. There was presence of bulky tail of pancreas, bulky left adrenal, lytic lesions involving left femoral head, right sacrum and mandible, FDG avid lesions involving meninges, sella and cranial venous sinuses. Tc-99m bone scan showed increased tracer uptake in maxilla, mandible, bilateral forearm bones, bilateral femurs and bilateral tibia. PET guided biopsy from the lytic bone lesion in the right sacrum showed presence of cluster of atypical histiocytes with occasional multinucleated Touton type giant cells. The cells also showed granular cytoplasmic positivity for BRAFV600E, confirming the diagnosis of Erdheim Chester disease (ECD). She was initiated on oral vemurafenib, BRAF inhibitor, at a dose of 240mg twice a day. Discussion: ECD presenting with splenic infarct has not been described previously. A thorough evaluation and targeted biopsy confirmed the diagnosis. BRAFV600E is the most common mutation noted in these patients, seen in nearly 60% of the patients and the patients with BRAF mutations respond well to vemurafenib, a kinase domain inhibitor of mutant BRAF. Here in, we report a patient of ECD who presented with multisite venous thrombosis and splenic infarct, a rare manifestation of ECD, who was treated successfully with vemurafenib.

S2996 Erdheim-Chester Disease Associated With Aggressive Sclerosing Cholangitis

Introduction: Erdheim-Chester disease (ECD) is a rare histiocytosis recently recognized as a neoplasm due to discovery of MAPK pathway mutations. ECD can involve multiple systems, but hepatic involvement is exceedingly rare. Case Description/Methods: A 64-year-old male presented with fatigue, pruritis, 15-pound weight loss, bilirubin 1.8 mg/dL (0.3-1), and alkaline phosphatase (ALP) 1671 IU/L (44-147). MRCP showed multifocal, short segment dilation of intrahepatic ducts only. Liver biopsy showed periportal and focal bridging fibrosis suggesting primary sclerosing cholangitis (PSC). Anti-smooth muscle, anti-mitochondrial, antineutrophil cytoplasmic antibodies (ANCA) were negative, IgG subclasses normal. A month later he developed emesis, weakness, and leukocytosis. CT scan showed perinephric and periaortic soft tissue stranding suggestive of ECD. 18FDG PET/CT showed a 2.1x2.9 cm highly FDG avid mediastinal mass, follicular lymphoma on biopsy. He improved with antibiotics but returned after a few days with emesis, leukocytosis, and bilirubin 10.7 mg/dL, ALP 1277 IU/L. CT scan showed progressive perinephric and periaortic soft-tissue encasement (Figure1A). Endoscopic retrograde cholangiopancreatography showed a common bile duct (CBD) stricture and non-filling right hepatic duct. Despite CBD stenting bilirubin continued to rise. He now had molluscum like skin lesions which on biopsy revealed dermal proliferation of CD68+, Factor XIIIa+, CD1a- histiocytes and multiple giant cells characteristic of ECD (Figure1B). Targeted therapy with BRAF or MEK pathway inhibitors was considered though there was concern that he may be too sick to receive these. Patient and family opted for comfort care. Discussion: Despite symptoms, cholestatic liver function and biopsy suggestive of PSC, several factors make us question this diagnosis; such as lack of inflammatory bowel disease or positive ANCA which are seen in 60-80% patients with PSC. PSC is usually indolent, time from diagnosis to death or liver transplant generally being 10-12 years. This patient was transitioned to hospice within 6 months. This makes us suspect hepatic involvement with ECD or an overlap syndrome, or that PSC associated with ECD runs a much more aggressive course. Though liver and CBD biopsies did not show ECD, it is not unusual for biopsy findings in ECD to be obscured by non-specific fibrosis. We want to highlight that a negative biopsy should not delay diagnosis of ECD if imaging is indicative, especially as effective therapy is now available.Figure 1.: 1A: CT abdomen showing perinephric soft tissue stranding and encasement. B: extensive histiocytic infiltration (majority of cells) seen on skin biopsy.

Erdheim-Chester disease: Cytomorphologic clues for a rare histiocytic neoplasm including a distinct tigroid background pattern on smears

We present the cytomorphologic features of Erdheim-Chester disease (ECD) from 7 patients who have a confirmed diagnosis of ECD, including correlation with the histology on the needle core biopsies. ECD is a rare multi-organ neoplastic histiocytic disorder. The most common locations of involvement are long bones, retroperitoneum, and vasculature. Cytologic preparations often show scant cellularity. Even when neoplastic histiocytes are present on smears, they may be readily overlooked as they are not typically monomorphic, and instead exhibit a variety of morphologies from epithelioid to spindled, with multinucleated giant cells variably present. To our knowledge, ours is the first description of a distinct reticular or tigroid background on smears that is variably present due to rupture of the foamy neoplastic cells. Typically, smears from a targeted mass lesion from any site showing scant polymorphous histiocytes would be regarded as non-diagnostic. A diagnosis of ECD in all cases was based on the needle core biopsy with corresponding immunohistochemical (IHC) stains and BRAF mutational analysis, except for one case in which molecular analysis was not able to be performed. We present these cases to alert practicing cytopathologists to the pitfalls related to the highly variable location, smear cellularity, and cytomorphology of ECD, which should prompt the request of dedicated tissue cores at the time of rapid on-site evaluation and trigger careful clinical-radiologic correlation, as well as consultation with hematopathology colleagues.

A Case of Erdheim-Chester Disease with Omental Caking Initially Mistaken for a Malignancy

Introduction: Erdheim-Chester disease (ECD) is an uncommon non-Langerhans cell histiocytosis. Bilateral symmetric sclerosis of the long bones and possible multiorgan involvement are the main presentations of this disease. Histologically, lipid-laden foamy histiocytes are positive immunochemically for CD68 (occasionally for PS100) and negative for S100 and CD1a in ECD. Case Presentation: We describe the case of a 35-year-old man diagnosed with ECD with peritoneal and retroperitoneal infiltrations and bone involvement. The diagnosis of ECD was only confirmed after two years of non-specific abdominal pain, nausea, and weight loss. Primarily, the patient’s clinical symptoms and abdominal computed tomography (CT) findings, which indicated omental caking, peritoneal thickening, and perinephric soft tissue density, suggested an intra-abdominal malignancy. Finally, a peritoneal biopsy was carried out, which demonstrated xanthogranulomatous infiltrations from ECD. Further radiographic skeletal survey based on histopathological results showed symmetric osteosclerosis of the long bones. Conclusion: Although ECD, associated with peritoneal and retroperitoneal infiltrations, is an uncommon finding, it should be included in the differential diagnosis of patients with non-specific gastrointestinal manifestations, along with multiorgan involvement and typical radiological findings.

Erdheim-Chester Disease in a 48-Year-Old Woman With “an Unknown Tumor of the Heart”: An Autopsy Report

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis. Erdheim-Chester disease is considered a potentially severe multisystemic disease with life-threatening manifestations due to the compression of normal structures. Recently, mutation of the proto-oncogene BRAF (BRAFV600E) has been found in 100% of cases. The common sites of involvement are the skeleton, central nervous system, cardiovascular system, lungs, retroperitoneum, and skin. We present the autopsy case of a 48-year-old White woman with an unknown tumor of the heart, where finally autopsy revealed the diagnosis of ECD. The clinical, radiological, and pathological manifestations associated with ECD are highlighted.

Mimics of Erdheim–Chester disease

Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm with frequent multiorgan involvement. An accurate diagnosis of ECD requires the correlation of clinical features, histopathologic and radiologic findings. We describe a case series of patients with a referral diagnosis of ECD, whereby the diagnosis was changed to non-histiocytic diseases after comprehensive review at a tertiary care center. This accurate revision of the referral diagnosis of ECD enabled initiation of proper disease-directed therapy in a timely manner for these patients and avoided unnecessary exposure to systemic cytotoxic chemotherapy or targeted agents. Our study highlights the value of a multidisciplinary team of histiocytosis experts in confirming the diagnosis of ECD and also brings attention to other conditions to consider that can mimic ECD, including osteopoikilosis, tenosynovial giant cell tumour, IgG4-related disease, fibrous dysplasia and chronic recurrent multifocal osteomyelitis.

Classical and Non-Classical Phenotypes of Erdheim-Chester Disease: Correlating Clinical, Radiographic, and Genotypic Findings

▪Background: Erdheim-Chester disease (ECD) is characterized by multi-organ infiltration of clonal histiocytes bearing activating mutations predominantly in the MAPK pathway. The diagnosis of ECD is clinico-pathologic; histopathologic findings alone are often non-specific. Characteristic pathognomonic finding of ECD is the symmetric osteosclerosis of the distal femur and proximal tibia/fibula, seen in >90% of cases, and referred to herein as classic ECD (C-ECD). There is a paucity of data on the phenotypic and mutational differences between C-ECD and non-classic ECD (NC-ECD). Determining phenotypic patterns may allow for earlier suspicion and diagnosis.Methods: Patients who met the revised ECD criteria proposed by Haroche J et al (Blood 2020;135:1311-1318) and had full body imaging that included the lower legs (18-FDG-PET/CT or CT/bone scan) were included. ECD diagnosis was made when >1 major criteria plus >1 minor criteria were present. Major criteria: 1) symmetric meta-diaphyseal osteosclerosis in legs; 2) “hairy kidneys”; “coated aorta”, right atrial pseudotumor, xanthelasma, exophthalmos; or osteosclerosis of paranasal sinuses. Minor criteria: 1) histologic finding of typical foamy histiocytes (CD68+/CD163+/CD1a-) associated with fibrosis; 2) mutation/gene fusion of BRAF, CSF1R, or MAPK/PI3K pathways. We compared the organ involvement and BRAF V600E mutational status between C-ECD and NC-ECD.Results: A total of 105 patients were included. The median age at diagnosis was 57 years (range, 38-81) and most were males (62%). Majority had 18-FDG-PET/CT (83%) and BRAF V600E testing (65%). The main organ systems involved were skeletal (83%), renal (64%), adrenal (44%), and pulmonary (42%). Central diabetes insipidus (DI), “hairy kidneys”, and “coated aorta” were present in 27 (26%), 54 (51%), and 44 (42%) patients, respectively. Among those tested, BRAF V600E mutation was found in 48/67 (72%) by immunohistochemistry. In our cohort, most patients (n=87. 83%) had C-ECD. NC-ECD had significantly lower number of organs/systems involved compared with C-ECD (median 3 vs 6, p=0.002). C-ECD had significantly higher rates of involvement of paranasal sinuses (51%/7%, p=0.002), DI (26%/0%, p=0.02), and similar rates of lung (44%/43%), cardiac (34%/14%), and skin (14%14%) involvement when compared to NC-ECD. BRAF V600E was significantly more common in C-ECD (88%/30%, p=0.004). Thirty-nine (37%) patients underwent next generation sequencing, of whom 33 (31%) had successful testing. In C-ECD, 3 patients had mutations other than BRAF V600E, these included: NRAS, MAP2K1, and MEF2C-FLT3 fusion. In NC-ECD, 5 patients had mutations other than BRAF V600E, these included: MAP2K1, KRAS, and NF1.Conclusions: Our study suggests distinct differences in clinical presentation and molecular findings exist between C-ECD and NC-ECD. C-ECD has a higher degree of organ involvement and harbor BRAF V600E more frequently than NC-ECD. Further analysis of histopathologic findings and outcomes in this cohort may provide insights into these ECD subsets that can optimize future management of this disease.Figure 1: Sites of involvement of classical Erdheim-Chester Disease (C-ECD) versus non-classical Erdheim-Chester Disease (NC-ECD) [Display omitted] DisclosuresVassallo: Bristol-Myers-Squibb: Research Funding; Sun Pharma.: Research Funding; Pfizer: Research Funding. Tobin: Mayo Clinic Center for MS and Autoimmune Neurology: Research Funding; Mallinckrodt Pharmaceuticals: Research Funding; National Institutes of Health: Research Funding. Bennani: Verastem: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Vividion: Consultancy, Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board.

Skin Involvement by Erdheim-Chester Disease; A Case Report

Abstract Introduction/Objective Erdheim-Chester Disease (ECD) is considered one of the rare forms of non-Langerhans cell histiocytosis. It is caused by infiltration of different organs with lipid-laden histiocytes with foamy cytoplasm. Clinically, it can present as an indolent localized disease or a fatal disease with multi-organ failure. Methods/Case Report Here we report a case of fifty year-old female with a history of Erdheim Chester disease involvement of the left parietal lobe presented to the dermatology clinic with purpuric, tender maculopapular rash on bilateral cheeks, trunk, and bilateral upper extremities. Biopsy of the lesion on central chest revealed acute and chronic superficial dermal inflammation and skin crusting. The dermis is also infiltrated by many foamy lipid-laden macrophages. These macrophages stained with CD68 and CD163 and were S-100 and CD1a negative. BRAF V600E mutation was detected. Based on the immunophenotypic characteristics, as well as the molecular testing results and the clinical history of the patient, diagnosis of cutaneous involvement by Erdheim- Chester disease was made. Results (if a Case Study enter NA) NA Conclusion In summary, despite the fact that skin involvement by Erdheim- Chester disease is rare, it is imperative to consider it in the differential diagnosis of histiocytic diseases affecting the skin and differentiate it from its histologic mimickers. Molecular testing is a helpful tool in the diagnosis of Erdheim-Chester disease. Accurate diagnosis is crucial for guiding treatment plans.

ERDHEIM-CHESTER DISEASE (ECD): A RARE ETIOLOGY OF OBSTRUCTIVE ACUTE ABDOMEN IN A YOUNG PATIENT

Erdheim-Chester disease (ECD) is a rare multisystemic disorder, classified as non-Langerhans histiocytosis according to WHO-2016. It is a malignant neoplasm derived from myeloid progenitor cells, particularly from monocytic/dendritic origin. Its actual incidence is unknown, and fewer than a thousand cases have been reported to date in the medical literature. Recurrent somatic mutations involving the BRAF gene (BRAF V600E) and other components of the MAPK signaling pathway play a central role in its oncogenesis. Although rare, cases in patients under 40 years-old are reported. Frequently the median age of ECD patients is around 50-60 years-old, with a predominance of males (3:1). The disease may have a polymorphic clinical presentation, usually involving bones, central nervous system (CNS), pituitary and peri-aortic or retroperitoneal fibrosis with ureteral stenosis. Several therapeutic options can be used to control the disease, including corticosteroids, radiotherapy, interferon-α, purine analogues (2Cda or DCF), mono/polychemotherapy, and targeted drugs such as vemurafenib and dabrafenib. To report one case of atypical presentation of ECD, manifested as acute obstructive abdomen in a patient under 20 years-old. An 18-year-old woman, with no previous comorbidities, sought medical service at the HC-FMUSP due to abdominal pain, abdominal distension, and stopping of the elimination of gases and feces. Abdominal ultrasound showed an extensive mass with a cystic/solid aspect in the pelvic region. Exploratory laparotomy revealed a large solid mass adhered to the wall of the small intestine and the lateral wall of the rectum. A 15-cm enterectomy, ileo-bowel anastomosis, protective distal colostomy and insertion of a double-J catheter into the urinary tract were performed. Histopathological examination revealed atypical cell proliferation with staining for CD68+, CD163+, Ki67+ (20-30%) on immunohistochemistry study. Molecular test in a sample fixed in formalin and embedded in paraffin (FFPE) revealed the presence of BRAF V600E mutation, confirming the diagnosis of ECD. She started therapy with cladribine (2-Cda) 5 mg/m 2 , I.V., D1-D5, 30/30 days, for six cycles. After the end of chemotherapy, 18-FDG-PETCT was performed, compatible with complete metabolic response. She is currently asymptomatic and with an excellent quality of life. ECD is a rare disorder that can present with atypical extra-osseous symptoms. We describe here an unusual case of a patient outside the usual age range for this disease, with intra-abdominal manifestation and a case of bowel occlusion, requiring exploratory laparotomy and extensive surgical resection. As this is a classically relapsing disease, it is known that isolated surgical resection is often ineffective. Although it has a mutation that works as a target for specific therapeutic intervention (BRAF inhibitors), these drugs are unavailable in the context of the Brazilian Public Health System. Thus, our patient underwent conventional cytotoxic treatment, with manageable toxicity and excellent therapeutic response.

Perirenal infiltration: Key point in Erdheim-Chester disease diagnosis

Perirenal infiltration: Key point in Erdheim-Chester disease diagnosis

Clonal Hematopoiesis in Erdheim-Chester Disease

Rationale: In patients with Erdheim-Chester disease (ECD), accumulation of foamy histiocytes leads to multi-systemic disease with various organs involvement. During the past few years, we showed that Langerhans-cell histiocytosis (LCH) and other hemopathies were frequently associated with ECD. These findings, as well as the fact that BRAFV600Emutation is found in as much as 70% of ECD tissues, led to the reclassification of ECD as a myeloid neoplasm.Methods: We conducted a systematic next-generation sequencing (NGS) using bone marrow samples obtained from 69 patients with ECD (49 males, median age at the time of NGS 62.68 years SD 13.33, median time of evolution since ECD diagnosis 4.2 years). We performed molecular analysis using high-throughput sequencing focused on 36 genes recurrently mutated in myeloid malignancies. Libraries were prepared using the Ampliseq System according to the manufacter's instructions and run on Ion Proton (Thermofisher). Raw data were analyzed with both Torrent Browser (Thermofisher) and SeqNext (JSI Medical System).Results: Overall, 75 somatic mutations other than BRAFV600E in myeloid cancer candidate genes were present in 29 patients (42%), in a limited number of genes. Seventeen of these 29 patients (59%) had multiple mutations (range: 2-7 mutations). The most frequently mutated genes were TET2 , ASXL1 , DNMT3A and NRAS (in 16, 7, 5 and 4 patients respectively). CBL , KRAS , JAK2 and SRSF2 were mutated in 3 patients each. These genes accounted for 77% of all mutation-positive patients. Both the presence and the number of mutations per patients positively correlated with age (p=0.0055 and p=0.0069 respectively). Some patients harbored multiple mutations in the same genes, including TET2 , ASXL1 and NRAS . Six out of 41 patients (15%) carried karyotypic abnormalities. Twelve patients (17%) had a definite myeloproliferative neoplasm other than ECD (mainly CMML in 7 patients). Additionally, BRAFV600E was present in tissues histiocytes of 40/61 patients (not determined in 8 others) and in 13/60 patients in bone marrow (not determined in 9), some of the latter being treated with BRAF inhibitors. Two patients had a BRAFV600E mutation detectable in bone marrow but not in tissues. The presence of at least one TET2 mutation was associated with the presence of the BRAFV600E mutation in tissues (p=0.04). Among the 40 patients with the absence of somatic mutation in the panel of myeloid genes, only 17 were BRAFV600E Wild-Type and therefore showed no evidence of clonal hematopoiesis. These patients were characterized by less associated LCH (0 versus 23%; p=0.03), less vascular (41 versus 73%; p=0.02) and less cardiac (29 versus 69%; p=0.005) involvements.Conclusions: A subset of genes that are mutated in patients with myeloid neoplams is frequently mutated in ECD. These mutations may represent early events in the development of hematologic malignancies. DisclosuresEmile:Merck Serono: Honoraria.

A rare case of erdheim-chester disease with braf mutation – a case report

Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm with multisystemic involvement, commonly involving the bones, cardiovascular organs and retroperitoneal region. We report a 68-year-old female who was admitted due to a fall following an episode of dizziness, and was noted to have a retroperitoneal soft tissue mass involving the bilateral perinephric spaces and bowel mesentery, which extended superiorly into the thoracic cavity, causing encasement of the ureters, adrenal glands and major vessels. A biopsy revealed a histiocytic infiltrate with foamy cytoplasm, which was positive for CD163, fascin and factor XIIIa on immunohistochemical staining, but was negative for CD1a, S100, AE1/3 and HMB45. Molecular testing for BRAF was positive. The overall clinical, imaging and histology findings were supportive of a diagnosis of ECD. Awareness of this entity and exclusion of its differential diagnoses is important to ensure correct diagnosis for subsequent targeted therapy. 1.Brousse N, Pileri SA, Haroche J, et al. Erdheim Chester disease. In: Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue. Revised 4th ed. Lyon: IARC, 2017; 481–2.2.Goyal G, Heaney ML, Collin M, et al. Erdheim-Chester disease: consensus recommendations for evaluation, diagnosis, and treatment in the molecular era. Blood 2020; 135: 1929–45.3.Aubart FC, Emile JF, Carrat F, et al. Targeted therapies in 54 patients with Erdheim-Chester disease, including follow-up after interruption (the LOVE study). Blood 2017; 130: 1377–80.