Erdheim-Chester Disease Patients Research Articles

Erdheim-Chester disease initially discovered at extraskeletal locations: a clinicopathological analysis of four cases

Objective: To investigate the clinicopathological features of Erdheim-Chester disease (ECD) initially diagnosed at extraskeletal locations. Methods: Clinical and pathological data of four cases of ECD diagnosed initially in extraskeletal locations were collected at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, from January 2013 to June 2023. BRAF V600E gene was detected by reverse transcription polymerase chain reaction (RT-PCR). Pertinent literatures were reviewed. Results: Four ECD patients included two males and two females ranging in ages from 2 years 11 months to 69 years. The lesions located in the lung (two cases), central nervous system (one case), and the testicle (one case) were collected in the study. One patient had occasional fever at night, one had nausea and vomiting, and two were asymptomatic. Radiologically, the two pulmonary ECD showed diffuse ground-glass nodules in both lungs, and the lesions in central nervous system and testicle both showed solid masses. Microscopically, there were infiltration of foamy histiocyte-like cells and multinucleated giant cells in a fibrotic background, accompanied by varying amounts of lymphocytes and plasma cells. The infiltration of tumor cells in pulmonary ECD was mainly seen in the subpleural area, interlobular septa, and perivascular and peribronchiolar areas. The fibrosis was more pronounced in the pleura and interlobular septa, and less pronounced in the alveolar septa. Immunohistochemical staining showed that all tumor cells expressed CD68, CD163 and F􀃼a; one case showed S-100 expression; three cases were positive for BRAF V600E; all were negative for CD1α and Langerin. RT-PCR in all four cases showed BRAF V600E gene mutation. Conclusions: Extraskeletal ECD is often rare and occult, and could be easily misdiagnosed, requiring biopsy confirmation. The radiologic findings of pulmonary ECD is significantly different from other types of ECD, and the histopathological features of pronounced infiltration in the subpleura area, interlobular septa, perivascular and peribronchiolar areas can be helpful in the differential diagnosis from other pulmonary diseases. Detection of BRAF V600E gene mutation by RT-PCR and its expression by immunohistochemical staining are also helpful in the diagnosis.

Erdheim-Chester Disease With Eyelid and Orbital Involvement: A Review of Treatment Modalities at One Institution From 2014 to 2022.

To review all cases of Erdheim-Chester disease (ECD) with orbital involvement treated at Bascom Palmer Eye Institute in Miami, Florida from 2014 to 2022 and compare presentations, treatment modalities, and outcomes. A retrospective chart review of all patients diagnosed with ECD who presented to Bascom Palmer Eye Institute from 2014 to 2022 was performed. Data collected included demographics, pretreatment history and ophthalmic examination, pathology report, treatment, subsequent examination, and relevant laboratory results. Histopathology, treatments, and outcomes were reviewed and compared between patients. Four cases were included. Primary treatments included vemurafenib (n = 2), cobimetinib (n = 1), and prednisone (n = 1). All patients demonstrated improvement of ophthalmic symptoms. Vemurafenib was the only medical treatment that was tolerated well and resulted in significant improvement in proptosis despite some reported dry eye; all other medications were discontinued due to intolerable side effects. BRAF inhibitors such as vemurafenib have been used as novel therapy in the treatment of ECD. Vemurafenib demonstrated its utility in reducing proptosis in ECD patients at one ophthalmic institution. Vemurafenib may be a favorable treatment option for BRAF-positive ECD patients presenting with orbital disease.

Dabrafenib and steroids for the treatment of Erdheim-Chester disease with extensive CNS involvement: a case report.

Erdheim-Chester disease (ECD) is an exceedingly rare non-Langerhans cell CD68+ CD1a- S100- histiocytic multi-organ disease. Diagnosis of ECD is often delayed due to non-specific radiographic findings and heterogeneous lesional tissue. Increasingly, the role of genomic alterations is being recognized for both diagnosis and treatment of ECD. More than half of ECD patients harbor the BRAFV600E mutation. Evaluation for this mutation be can falsely negative on immunohistochemical staining and confirmation with molecular analyses is recommended. We present a case of the 44year-old male with BRAFV600E-positive ECD treated successfully with steroids followed by single-agent dabrafenib.

Deciphering the Epigenetic Landscape in Histiocytic Neoplasms

Background: Histiocytic neoplasms are driven by mutations activating the MAPK/ERK pathway; however, their epigenetic landscape remains poorly understood. MicroRNAs (miRNAs) are epigenetic regulators implicated in cancer development. Moreover, DNA methylation of miRNAs affects hematological malignancies development. Our previous study identified a unique miRNA expression signature in Erdheim-Chester Disease (ECD) patients. To further understand the biological mechanisms of ECD, we investigated the involvement of miRNAs, genes, and their methylation status in ECD, Langerhans cell histiocytosis (LCH), and Rosai-Dorfman disease (RDD). Methods: Methylation profiles of 14 LCH, 6 ECD, and 10 RDD patients were determined from histyocitic infiltrated tissues (Illumina EPIC-methylation array). These were compared to controls, suture granulomas (n=4), localized inflammatory reactions characterized by non-neoplastic histiocytic infiltrates. miRNAome data was identified by NanoString analysis and qRT-PCR. Results: We identified significant alterations in 23,322 methylation sites (FDR<0.05, |Δß|≧20%) between controls and the histiocytosis group, indicating differential epigenetic regulation. ECD and LCH exhibited a shared methylation signature distinct from RDD. Pathway analyses revealed that the differentially methylated genes (DMGs) were involved in inflammatory response, RAS, TNF, and PI3K-mTOR signaling pathways, linked to histiocytic neoplasms. Specifically, we found DMG involvement in regulation and generation of non-coding RNAs. Notably, we observed significant downregulation of the let7-miRNA family, particularly let7b, in ECD and LCH patients. Subsequent analysis revealed hypermethylation of specific CpG islands in the let7b DNA sequence, potentially silencing let7b expression in these diseases. Given the let7-miRNA family's role in regulating the MAPK pathway, this suggests a novel mechanism in the pathogenesis of these neoplasms. Conclusions: We provide valuable insights into differential methylation patterns in histiocytosis neoplasms, highlighting the involvement of epigenetic modifications in their development and progression. This enhances our understanding of histiocytosis development and may contribute to the identification of novel diagnostic and therapeutic approaches for these patients.

High Prevalence of Vulvar and Hepatic Manifestations in a Series of 18 Histiocytosis with Brafdel Mutations

Introduction L-group histiocytosis (Erdheim-Chester disease (ECD) and Langerhans-cell histiocytosis (LCH)) are multi-system diseases characterized by histiocyte infiltration in several organs. These histiocytes frequently harbor activating somatic mutations of the MAP Kinase pathway. Many of these mutations are frequently associated with a specific phenotype: BRAF V600Emutated ECD patients have more frequently cardiac and vascular involvements, MAP2K1 mutated ECD patients may exhibit overt Rosai-Dorfman Disease (RDD) component, and ALK-mutated patients have a high prevalence of neurological involvement. Our objective was to describe characteristics of patients with histiocytosis and a particular BRAF-deletion mutation. Methods We performed a retrospective multi-center study. Patients were identified through the Histiocytosis national referral center pathology laboratory in Ambroise-Paré Hospital (Boulogne-Billancourt) in which all suspected diagnosis of histiocytosis samples are sent for proofreading and sequencing. Samples are sequenced with a specific panel next generation sequencing. We identified patients with BRAFdel mutations and contacted the centers for clinical, morphological, and biological datas. Results Twenty-four patients with a BRAFdel mutation were identified. Data were available for 18 of them. Most patients (n=17) had LCH (one with an ECD component) and one had an ECD. Median age at diagnosis was 50 years (IQR 35-78). The most frequent manifestations were hepatic (n=8, 44%) and vulvar (8/10 female gender patients, 80%). Other manifestations were cystic interstitial lung disease (n=6), lytic bone lesions (n=7), diabetes insipidus (n=6), panhypopituitarism (n=3), pachymeningitis (n=2), long bone osteosclerosis (n=1), perirenal infiltration (n=1), salivary gland infiltration (n=1) and digestive track infiltration (n=1). Hepatic manifestation was sclerosing cholangitis in all patients, and 5/6 patients had histiocytic infiltration in liver biopsy. All patients with sclerosing cholangitis had biological cholestasis, elevated aminotransferases, and hyperbilirubinemia. No patient had cirrhosis. Hepatic MRI, when performed, always showed cholangitis (5/5). PET-scan showed liver abnormalities in 4/6 patients (heterogenous liver uptake or uptake in biliary ducts). First line treatments included vinblastine (n=5), aracytine (n=1), methotrexate (n=1), cladribine (n=1) and cobimetinib (n=1). Nine patients did not receive any treatment. Two patients received cobimetinib, that resulted in partial remission and stable disease at 6 months. After a median follow-up of 43 (IQR 11-315 months), one patient had died from unknown cause. Conclusion BRAF-deletion mutations in histiocytoses are associated with a specific LCH pattern with high prevalence of hepatic and vulvar involvements. These manifestations should be carefully screened in these patients.

The clinical spectrum and prognostic factors of Erdheim-Chester disease and mixed Langerhans cell histiocytosis and Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a rare and probably fatal multisystemic non-Langerhans cell histiocytosis (LCH). To comprehensively investigate the clinical features, genomic analysis, treatments, and prognostic factors of ECD, we retrospectively analyzed the clinical data of 75 ECD patients and 10 mixed LCH and ECD patients in our center. The median age at diagnosis was 46years (range, 5-70). ECD patients were older at diagnosis (p = 0.006) and had more cardiac involvement (p = 0.011) as well as vascular (p = 0.031) involvement compared to mixed LCH and ECD patients. 64.8% of ECD patients and 87.5% of mixed LCH and ECD patients carried BRAFV600E mutation. The BRAFV600E mutation correlated with a greater number of affected organs (p = 0.030) and was associated with lung involvement (p = 0.033) as well as pleural involvement (p = 0.002). The median follow-up time was 38months (range, 1-174). The estimated 5-year progression-free survival (PFS) and overall survival (OS) were 48.9% and 84.7%, respectively. In a multivariate analysis, right atrial pseudotumor (p = 0.013) and pancreatic involvement (p = 0.005) predicted worse OS, while pleural (p = 0.042) and central nervous system (CNS) involvement (p = 0.043) predicted worse PFS. Our study described the clinical spectrum of ECD and mixed LCH and ECD, while also revealed the prognostic value of right atrial pseudotumor and pancreatic, pleural, and CNS involvement for worse survival.

Cerebrospinal Fluid Metabolomic Pattern of Different Pituitary Stalk Lesions.

To describe the cerebrospinal fluid (CSF) metabolomic pattern of pituitary stalk lesions. CSF was collected from patients with different pituitary stalk lesions treated at Peking Union Medical College Hospital: germ cell tumor (GCT, n = 27); hypophysitis (n = 10); and Langerhans cell histiocytosis (LCH) or Erdheim-Chester disease (ECD) (LCH + ECD, n = 10). The CSF metabolome profiles were characterized by liquid chromatography-mass spectrometry (LC-MS). There were 44 metabolites that significantly differed between patients with GCT and those with hypophysitis (P < .05). Between patients with GCT with CSF level of beta subunit of human chorionic gonadotrophin (β-hCG) < 5 mIU/mL and those with hypophysitis, there were 15 differential metabolites (P < .05, fold change > 1.5 or < 1/1.5). All of the metabolites had an area under the curve (AUC) above 0.7. There were 9 metabolites that significantly differed between patients with GCT and those with LCH + ECD (P < .05) and 7 metabolites had significant differences between GCT (CSF β-hCG < 5 mIU/mL) and LCH + ECD (P < .05, fold change > 1.5 or < 1/1.5). We found 6 metabolites that were significantly different between patients with hypophysitis and those with LCH + ECD (P < .05) and 5 of these had fold change more than 1.5 or less than 1/1.5. Three metabolites, 5-deoxydiplosporin, cloversaponin I, and phytosphingosine, showed excellent capabilities to differentiate the 3 disease categories. Furthermore, we identified 67 metabolites associated with clinical test results (ρ > 0.2, P < .05) and 29 metabolites showed strong correlation (ρ > 0.4, P < .05). Our study is the first to systematically investigate the metabolomics of CSF in different pituitary stalk lesions. CSF metabolomics is a useful strategy for biomarker discovery.

Performance of 68Ga-Labeled Fibroblast Activation Protein Inhibitor PET/CT in Evaluation of Erdheim-Chester Disease: A Comparison with 18F-FDG PET/CT.

Erdheim-Chester disease (ECD) involves multiple organs and tissues and has diverse manifestations, which makes it difficult to distinguish lesions caused by ECD from those caused by other diseases. Variable degrees of fibrosis are present in ECD. Therefore, we conducted a prospective cohort study to explore the ability of 68Ga fibroblast activation protein inhibitor (68Ga-FAPI) PET/CT to detect lesions in ECD patients. Methods: Fourteen patients diagnosed with ECD, as confirmed by histology, were included in this study. For every patient, 68Ga-FAPI PET/CT and 18F-FDG PET/CT were conducted within 1 wk. The positive rate and SUVmax of the lesions in the involved organs were compared between the examinations. Results: The most commonly involved organs were bone (100%), heart (57.1%), lung (57.1%), kidney (42.9%), and peritoneum or omentum (35.7%); other common manifestations were intracranial infiltration (50%) and cutaneous infiltration (35.7%). 68Ga-FAPI PET/CT detected 64 of 67 lesions in 14 patients, whereas 18F-FDG PET/CT detected 51 of 67 lesions (P = 0.004). The SUVmax for 68Ga-FAPI PET/CT was significantly higher than the SUVmax for 18F-FDG PET/CT of the heart (4.9 ± 2.4 vs. 2.8 ± 1.2, respectively; P = 0.050), lung or pleura (6.8 ± 4.9 vs. 3.1 ± 1.3, respectively; P = 0.025), peritoneum or omentum (5.7 ± 3.6 vs. 2.8 ± 1.7, respectively; P = 0.032), and kidney or perinephric infiltration (4.9 ± 1.2 vs. 2.9 ± 1.1, respectively; P = 0.009). Conclusion: The detectivity of 68Ga-FAPI PET/CT is superior to that of 18F-FDG PET/CT. Moreover, 68Ga-FAPI PET/CT has a better image contrast and higher SUVmax for lesions in multiple organs including the heart, lungs, peritoneum, and kidneys. 68Ga-FAPI PET/CT is a promising tool to assess pathologic features and disease extent in ECD patients.

Longitudinal assessment of cardiac involvement in Erdheim-Chester disease using cardiac magnetic resonance imaging.

7067 Background: Erdheim-Chester disease (ECD) is a rare multi-systemic non-Langerhans cell histiocytosis that affects the heart in nearly half of patients. Atrial infiltration and pericardial effusion are the hallmarks of cardiac involvement and can lead to clinical complications (conduction disorders, coronary artery stenosis, tamponade, constrictive pericarditis). Evolution under treatment is poorly studied. We aimed to investigate the evolution of cardiac involvement in ECD using cardiac magnetic resonance (CMR) imaging. Methods: All ECD patients with a CMR imaging disclosing a cardiac involvement and who underwent at least one follow-up CMR imaging between 2005 and 2020 at a French tertiary center were retrospectively included. First and last CMR imaging were compared. Multivariable analysis was performed to search for independent predictors of cardiac involvement resolution. Variables were included in the model if their P-value was &lt; 0.1 on univariable analysis. Results: Overall, 46 patients were included. Median age at first imaging was 63 years [53-69]. Median delay between the first and the last imaging was 4 years [2-7]. BRAFV600E mutation was present in 43 patients (94%). Patients received a median of 2 [1-3] treatments. All patients (100%) had cardiac involvement at baseline. Right atrio-ventricular sulcus (RAVS) was infiltrated in 38 patients (83%) and was the main cardiac feature.Overall, complete regression was observed in 6 patients (13%), partial regression in 26 patients (56%), stable imaging in 12 patients (26%), and worsening in 2 patients (5%). In patients with RAVS infiltration, complete regression was observed in 5 patients (16%) and partial regression was seen 22 patients (58%) regression. On univariable analysis, patients with regression of their infiltration had a lower rate of death (16% versus 64%, P= 0.002), a higher rate of atrial infiltration late gadolinium enhancement (LGE) (97% versus 71%, P= 0.01), a higher rate of hydronephrosis (50% versus 14%, P= 0.03) and a lower rate of interferon prescription (69% versus 100%, P= 0.02). A similar rate of vemurafenib use was observed in both groups (69% versus 54%, P= 0.3). On multivariable analysis, death remained significantly associated with follow-up imaging status (ß = -2.3 P= 0.01), while atrial infiltration LGE (ß = 2.7, P= 0.06), hydronephrosis (ß = 1.6, P= 0.1) and treatment with interferon (ß = -16, P= 1) were no longer significantly associated with imaging status. Conclusions: Partial or complete resolution of cardiac involvement was observed in 69% of patients with ECD and was significantly associated with a lower rate of death on multivariable analysis.

Histiocytic Lesion Masquerading as Interstitial Lung Disease—A Case Report

Erdheim Chester Disease (ECD) is a rare histiocytic neoplasm with heterogeneous features. It can frequently be misdiagnosed if proper clinical and radiological details are not available. Biopsy with confirmatory immunohistochemistry (IHC) for BRAFV600E or molecular analysis for the gene forms the mainstay of diagnosis. Most ECD patients require treatment and the choice of therapy must be individualized based on clinical characteristics. Herein is reported one such case of ECD in a 45-year-old male who remains disease-free after six months of follow-up.

Comparison of neuroimaging features of histiocytic neoplasms with central nervous system involvement: a retrospective study of 121 adult patients

ObjectivesTo compare neuroimaging characteristics of three types of histiocytoses, namely Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and Rosai-Dorfman disease (RDD), with central nervous system (CNS) involvement.MethodsA total of 121 adult patients with histiocytoses (77 LCH, 37 ECD, and 7 RDD) and CNS involvement were retrospectively included. Histiocytoses were diagnosed based on histopathological findings combined with suggestive clinical and imaging features. Brain and dedicated pituitary MRIs were systematically analyzed for tumorous, vascular, degenerative lesions, sinus, and orbital involvement and for hypothalamic pituitary axis involvement.ResultsEndocrine disorders, including diabetes insipidus and central hypogonadism, were more common in LCH patients than in ECD and RDD patients (p < 0.001). In LCH, tumorous lesions were mostly solitary (85.7%), located in the hypothalamic pituitary region (92.9%), and without peritumoral edema (92.9%), while in ECD and RDD, tumorous lesions were often multiple (ECD: 81.3%, RDD: 85.7%), their distribution was more widespread with meninges mostly involved (ECD: 75%, RDD: 71.4%), and they most likely presented with peritumoral edema (ECD: 50%, RDD: 57.1%; all p ≤ 0.020). Vascular involvement was an exclusive imaging characteristic of ECD (17.2%), which was not observed in LCH or RDD; this was also associated with a higher risk of death (p = 0.013, hazard ratio = 11.09).ConclusionThe typical characteristic of adult CNS-LCH was endocrine disorders with radiological findings limited to the hypothalamic pituitary axis. The pattern of multiple tumorous lesions with predominant involvement of meninges was the main manifestation of CNS-ECD and CNS-RDD, while vascular involvement was pathognomonic for ECD and associated with poor prognosis.Clinical relevance statementInvolvement of the hypothalamic-pituitary axis is the typical imaging characteristic of Langerhans cell histiocytosis. Multiple tumorous lesions, predominantly involving but not limited to meninges, occur in most Erdheim-Chester disease and Rosai-Dorfman disease patients. Vascular involvement occurs only in Erdheim-Chester disease patients.Key Points• The different distribution patterns of brain tumorous lesions can help differentiate among LCH, ECD, and RDD.• Vascular involvement was an exclusive imaging finding of ECD and was associated with high mortality.• Some cases with atypical imaging manifestations were reported to further expand the knowledge on these diseases.

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.

Prevalence, patterns and outcomes of cardiac involvement in Erdheim-Chester disease.

Cardiac involvement of Erdheim-Chester disease (ECD), a rare L group histiocytosis, has been reported to be associated with poor outcomes, but systematic studies are lacking. The present study aimed to investigate the prevalence, clinical features, imaging features, and prognosis of cardiac involvement in ECD in a large series. All patients with ECD who underwent cardiac magnetic resonance (CMR) imaging between 2003 and 2019 at a French tertiary center were retrospectively included. Primary outcome was all-cause mortality. Secondary outcomes were pericarditis, cardiac tamponade, conduction disorders, device implantation and coronary artery disease (CAD). A total of 200 patients were included [63 (54-71) years, 30% female, 58% BRAFV600E mutated]. Median follow-up was 5.5 years (3.3-9 years). On CMR, right atrioventricular sulcus infiltration was observed in 37% of patients, and pericardial effusion was seen in 24% of patients. In total, 8 patients (4%) had pericarditis (7 acute, 1 constrictive), 10 patients (5%) had cardiac tamponade, 5 patients (2.5%) had ECD-related high-degree conduction disorders, and 45 patients (23%) had CAD. Overall, cardiac involvement was present in 96 patients (48%) and was associated with BRAFV600E mutation [Odds ratio (OR) = 7.4, 95% confidence interval (CI) (3.5-16.8), P < 0.001] and ECD-related clinical events [OR = 5, 95%CI (1.5-21.2), P = 0.004] but not with lower survival in multivariate analysis [adjusted hazard ratio (HR) = 1.4, 95% CI (0.8-2.5), P = 0.2]. Cardiac involvement is present in nearly half of ECD patients and is associated with BRAFV600E mutation and complications (pericarditis, cardiac tamponade, and conduction disorders) but not with lower survival.

RAF-Independent MEK Mutations Drive Histiocytic Neoplasms In Vivo and Are Sensitive to Single-Agent ERK Inhibition in Patients

Histiocytic neoplasms are clonal disorders of the monocyte/macrophage lineage that include Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD). Histiocytoses are defined by recurrent, mutually exclusive mutations activating MAP kinase signaling, including BRAFV600E mutations in ~50% of LCH and ECD patients, which confer robust lasting clinical responses to BRAF inhibition. Mutations in MEK1/2, ARAF, and a diverse array of other kinases are present in BRAF wild-type histiocytoses patients and are broadly responsive to the allosteric MEK1/2 inhibitor cobimetinib. Following genomic analysis of ~300 pediatric and adult patients with diverse histiocytoses, the single most common genomic alteration following BRAFV600E mutations are MEK1 E102_I103 in-frame deletions. In contrast to BRAFV600E, the biological impact of activating mutations in MEK1/2 kinases are unknown, and no cancer associated MEK1/2 mutation has ever been modeled in vivo. MEK1/2 mutations are recurrent across a wide variety of human cancers and RASopathies and are now often found at resistance to emerging KRAS-mutant selective inhibitors. These findings motivated us to generate Map2k1E102_I103del conditional knock-in mice within the endogenous locus of Map2k1 (encoding MEK1 kinase), which represent the first genetically engineered mouse model of MEK1/2 mutations. We first crossed Map2k1E102_I103del mice to inducible Mx1-cre driver mice. Interestingly, Mx1-cre Map2k1E102_I103del knock-in mice developed a 100% penetrant lethal myelomonocytic disorder by 5-6 weeks of age while their cre-negative Map2k1E102_I103del littermates did not develop disease (Figure A). Notably, recombination of the Map2k1E102_I103del alleleoccurred spontaneously without pIpC administration and resulted in strong activation of phosphorylated ERK1/2 in bone marrow and spleen mononuclear cells. Mx1-cre Map2k1E102_I103del mice developed a myelomonocytic neoplasm with suppression of B-lymphopoiesis and expansion of classical and non-classical monocyte subsets, macrophages, and Cd11b+ conventional dendritic cells. Monocyte, macrophage, and dendritic cells infiltrated hematopoietic organs (bone marrow, spleen, and peripheral blood), as well as liver and skin, each of which are common sites of LCH and ECD disease involvement. The Mx1-cre Map2k1E102_I103del disease was hematopoietic cell autonomous and could be propagated by serial hematopoietic reconstitution in irradiated recipient mice, as well as using Vav1-cre Map2k1E102_I103del knock-in mice (where Cre is expressed only in hematopoietic cells from earliest hematopoietic development). Finally, restricting MEK1 mutant expression to monocyte and dendritic cell precursors using CD11c-cre resulted in similar lethal expansions of monocyte, macrophage, and dendritic cells as seen in the Mx1-cre and Vav1-cre models. Prior in vitro work has demonstrated that MEK1 p.E102_I103del activates MEK and ERK without requiring activated GTP-bound RAS and is associated with resistance to allosteric MEK inhibitors. Consistent with this, we identified nine histiocytosis patients with this specific MEK1 mutation, three of which had de novo resistance to cobimetinib. These three patients and one treatment-naïve patient were treated with an oral ERK1/2 inhibitor ulixertinib under the FDA single-patient compassionate use program. Three of 4 patients had a clinical or radiological partial or complete response to ulixertinib (Figure B). Overall, these data identify the impact of oncogenic MEK kinase mutations in vivo as found in children and adults with histiocytoses and RASopathies. Expression of a RAF-independent MEK1 mutation in vivo gave rise to disease reminiscent of human systemic histiocytic neoplasms. Importantly, this molecular entity is resistant to MEK inhibition in some patients, a phenomenon previously undocumented, but responsive to ERK inhibition, which may be a promising therapeutic approach to histiocytic neoplasms unresponsive to allosteric MEK inhibition. The clinical observation of efficacy of ERK inhibition in MEK inhibitor resistant histiocytoses patients has resulted in a soon-to-be initiated focused phase 2 clinical trial of ulixertinib in adults with histiocytoses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Erdheim-Chester Disease with Isolated CNS Involvement: A Systematic Review of the Literature.

Erdheim–Chester disease (ECD) is a rare, sporadic, non-Langerhans cell histiocytosis that can have various presentations and higher mortality in patients presenting with neurological symptoms. We performed a systematic review to investigate and chronicle the frequency of neurological manifestations, imaging findings, treatments, and outcomes in published ECD patients presenting with neurological symptoms. A PubMed literature search was conducted for articles (published between January 1980 and June 2021) on ECD cases presenting with neurological manifestations. We analyzed the data of 40 patients, including our patient. Cranial neuropathies and ataxia were the most frequent clinical manifestations. A total of 50% of the symptomatic ECD CNS lesions were intraparenchymal and nearly 33% of patients died due to the disease itself or complications. CNS involvement may be the only manifestation of ECD and sometimes may require a repeat biopsy with IHC testing for excellent treatment outcomes.

Serum vascular endothelial growth factor is associated with cardiovascular involvement and response to therapy in Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a rare histiocytosis, considered to be an inflammatory myeloid neoplasm. Tropism for specific involvements of the disease remains unexplained. Vascular endothelial growth factor-A (VEGF) is implicated in cancer pathophysiology and mutations of the RAS oncogene have been shown to induce upregulation of VEGF gene expression. We therefore hypothesized that VEGF might play a particular role in ECD pathophysiology. We conducted a retrospective, single-center study to assess serum VEGF (sVEGF) concentrations and determine whether they were associated with the characteristics of ECD patients, and to determine whether VEGF was expressed by histiocytes. We evaluated 247 ECD patients, 53.4% of whom had sVEGF levels above the normal range (>500 pg/mL). Patients with high sVEGF levels more frequently had cardiac and vascular involvement (58.3% vs. 41.4%, P=0.008 and 70.5% vs. 48.3%, P=0.0004, respectively). In treatment-naïve patients (n=135), the association of C-reactive protein >5 mg/L and sVEGF >500 pg/mL was strongly associated with vascular involvement (odds ratio=5.54 [95% confidence interval: 2.39-13.62], P<0.001), and independently associated with cardiac involvement (odds ratio=3.18 [95% confidence interval: 1.34-7.83], P=0.010) after adjustment for the presence of the BRAF V600E mutation. Changes in sVEGF concentration on treatment were associated with a response of cardiac involvement on consecutive cardiac magnetic resonance images. All histological samples analyzed (n=24) displayed histiocytes with intracytoplasmic expression of VEGF, which was moderate to high in more than 90% of cases. Our study suggests a role for VEGF in cardiac and vascular involvement in ECD.

Ophthalmologic Involvement in Adults with Histiocytic Disorders: Clinical Presentation and Treatment Outcomes

To evaluate the clinical presentation, treatment, and outcomes in adult patients with histiocytic disorders with ocular, orbital, optic nerve, or cavernous sinus involvement. Observational, retrospective chart review. Adult patients (age ≥ 18 years) at Mayo Clinic from January 1, 1996, to July 1, 2021, with histiocytic disorders. Inclusion criteria were (1) histiocytic disorder by biopsy and appropriate clinical phenotype; (2) available medical records; and (3) ocular, orbital, optic nerve, or cavernous sinus involvement. Retrospective chart review. Response to therapy, measured in clinical and radiographic impact. Thirty-two patients were identified: 7 with Langerhans cell histiocytosis (LCH); 15 with Erdheim-Chester disease (ECD); 1 with mixed LCH/ECD phenotype; 8 with Rosai-Dorfman disease (RDD); and 1 with mixed RDD/ECD phenotype. Ophthalmologic involvement was part of the initial presentation in 69% of patients (22/32). Eyelid edema (13/32, 41%) and proptosis (12/32, 38%) were the most frequent presentations. Isolated orbital or cavernous sinus involvement was present in 3 of 7 patients with LCH and 1 of 8 patients with RDD. Optic nerve sheath involvement was present in 2 of 7 LCH patients, 14 of 15 ECD patients, and 1 RDD/ECD patient. Diffuse (> 75%) orbital involvement was seen in 12 of 15 ECD patients and 1 of 7 LCH patients. Ocular involvement was seen in 1 of 15 ECD patients, 6 of 8 RDD patients, and 1 of 1 mixed RDD/ECD patient. The cavernous sinuses were involved in 1 of 7 LCH patients, 5 of 15 ECD patients, and both mixed phenotype patients. Visual acuity was affected in 14 patients (14/24, 58%) with a median logarithm of the minimum angle of resolution visual acuity of 0.1 (range, -0.12 to 3). BRAF V600E mutations were found in 75% (3/4) of LCH patients and 91% (10/11) of ECD patients. Patients received a variety of treatment, and response was variable across disease types. Orbital involvement was more commonly seen in LCH and ECD, whereas ocular involvement was more common in RDD. Visual acuity may be impacted from ocular involvement or compression of the optic nerve with diffuse orbital involvement.

Erdheim–Chester disease and vemurafenib: a review of ophthalmic presentations and clinical outcomes

ABSTRACT Purpose To provide a comprehensive review of ocular and orbital manifestations of Erdheim–Chester Disease (ECD) and compare clinical outcomes with vemurafenib (INN) to historical treatments (HT). Primary outcomes are ophthalmic findings on presentation, changes in visual acuity, and mortality rate. Secondary outcomes include the progression of ocular findings, systemic involvements, and treatment modalities. Methods All published literature from January 1983 to March 2021 was searched for ophthalmic manifestations of ECD. Clinical outcomes following HT were collected and compared with INN. Results Forty-seven patients with ECD and ophthalmic presentations were identified. The mean age was 49.6 years (SD = 15.0). Proptosis (65.6%) and extraocular muscle restrictions (42.5%) were the most common presenting signs. Of 41 (87.2%) patients with orbital masses on radiologic examination, 90.2% were bilateral, and 53.7% were located in the intraconal space. Ophthalmic examination was significant for xanthelasma (27.2%), optic disc edema (34.0%), and subretinal changes (21.3%). Common treatments were systemic steroids (76.6%), interferon-α (17.0%), and cyclophosphamide (14.9%). INN was less commonly used (12.8%). The mean change in logMAR visual acuity declined with HT (29.9%) but improved with INN (79.1%) (p > 0.05). The proportion of eyes with complete vision loss increased after HT (p < 0.05). The overall mortality rate was 27.7% and notably higher in the HT group (29.3%) when compared to the INN group (16.7%) (p > 0.05). Conclusion ECD presents with many ophthalmic manifestations. Although the intraocular treatments remain controversial, INN should be highly considered in treating orbital ECD patients with BRAF-V600E mutations to prevent and reverse vision loss.

Novel Recurrent Mutations in Eldheim-Chester Disease Patients Identified By Whole Exome Sequencing and Whole Genome Sequencing

▪Background: Erdheim-Chester disease (ECD) is a type of systemic, non-Langerhans histiocytic disorder characterized by diffuse organ damage with infiltration of CD68-positive, CD163-positive, and CD1a-negative histiocytes. Although most patients have mutations associated with the hyperactivation of the MAPK pathway, including BRAF, MAP2K1, and NRAS, the remaining have no known driver mutations. So far, there is no specific target of treatment for them. To elucidate novel driver mutations and establish new treatment strategies in these patients, we performed whole-exome sequencing (WES) and whole-genome sequencing (WGS) using patient samples with ECD. In addition, we performed WES with multi-organ lesions in a patient with ECD to reveal the mutational profiles of each organ lesion.Methods: We performed a nationwide survey and collected clinical samples of ECD in Japan. We collected 22 samples of ECD lesions from 15 adult patients. All cases were pathologically proved. Twenty of 22 samples were formalin-fixed and paraffin-embedded tissue (FFPE) and were examined by WES. For WGS, DNA was extracted from 2 raw samples of ECD lesions. In addition, we collected multi-organ lesions in 3 patients. One patient developed myelodysplastic syndrome (MDS) and subsequent acute myeloid leukemia (AML). Therefore, we also performed WES with each bone marrow (BM) sample to reveal the relationship between ECD and these myeloid malignancies. We used 6 samples of peripheral blood, 1 BM sample, 1 skin sample, and 1 oral mucosa sample as normal controls.Result: We detected known driver mutations in seven of 15 cases (47%). Among them, BRAF V600E was detected in 5 cases (8 samples), MAP2K1 C121S in 1 case (1 sample), and NRAS Q61R in 1 case (2 samples) by WES and WGS. A mean of 69 nonsynonymous mutations per patient was identified in normal-tumor analysis (range, 2-491) and 188 in tumor-only analysis (range, 17-3598) of WES, and 3134 in normal-tumor analysis (range, 2588-3680) of WGS. The median variant allele frequency (VAF) for the 11 samples with known activating kinase mutations identified by WES and WGS was 14.4% (range, 6.3-34.7). We could not detect known driver mutations in the other 8 cases (53%). Therefore, to reveal novel driver mutations, we focused on these 8 cases. Notably, EPHA2 P786L, MYBPC3 D798N, TDRD5 P115L, and TCEAL4 F17L mutations are recurrently found in 2 out of the 8 cases, suggesting new driver mutations are contained in these. The VAFs of EPHA2 P786L were 9.1% and 9.3%, MYBPC3 D798N 5.5% and 11.9%, TDRD5 P115L 10.2% and 18.7%, and TCEAL4 F17L 7.5% and 9.0% in each case. We also analyzed multiple organ samples of a case with BRAF V600E mutation (5 samples of ECD lesions, BM with MDS, BM with AML, and skin as normal control). Interestingly, BRAF V600E mutation was identified in 3 samples (bone lesion, heart, and intestine) but was not in other samples (kidney lesion, dura matter, BM tumor, BM with MDS, and BM with AML), suggesting mutational profiles are different depending on the organ of the lesion.Conclusion: Our nation-wide analysis revealed that no well-known driver mutations were found in more than half of the ECD cases. We identified EPHA2 P786L, MYBPC3 D798N, TDRD5 P115L, and TCEAL4 F17L mutations as candidates of novel driver mutations in ECD. To elucidate the role of these mutations in pathogenesis of ECD, further functional analyses are warranted. In addition, we revealed heterogeneity of mutational profile of multi lesions in an ECD patient with BRAF V600E mutation. It is noteworthy that mutational profiles might be different depending on the organ of the lesion. DisclosuresHonda: Chugai Pharmaceutical: Other: Lecture fee; Ono Pharmaceutical: Other: Lecture fee; Nippon Shinyaku: Other: Lecture fee; Takeda Pharmaceutical: Other: Lecture fee; Otsuka Pharmaceutical: Other: Lecture fee; Jansen Pharmaceutical: Other: Lecture fee. Matsuda: Kyowa Kirin: Other: Lecture fee; Ono Pharmaceutical: Other: Lecture fee. Taoka: ONO PHARMACEUTICAL CO., LTD.: Other; Chugai Pharmaceutical Company: Other. Kurokawa: Teijin Limited: Research Funding, Speakers Bureau; Chugai Pharmaceutical Company: Research Funding, Speakers Bureau; Takeda Pharmaceutical Company Limited.: Research Funding, Speakers Bureau; ONO PHARMACEUTICAL CO., LTD.: Research Funding, Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; MSD K.K.: Research Funding, Speakers Bureau; Nippon Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Daiichi Sankyo Company.: Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding, Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Research Funding, Speakers Bureau; AbbVie GK: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau.

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.