Cerebrospinal Fluid Metabolomic Pattern of Different Pituitary Stalk Lesions.

OBJECTIVE: To describe the cerebrospinal fluid (CSF) metabolomic pattern of pituitary stalk lesions. METHODS: 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). RESULTS: 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 (ß-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 ß-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). CONCLUSION: 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.

Erdheim-Chester Disease Due to a Novel Internal Duplication of NRAS: Response to Targeted Therapy with Cobimetinib.

Histiocytoses encompass a group of exceptionally rare disorders characterized by the abnormal infiltration of tissues by histocytes. Among these, Erdheim-Chester disease (ECD) stands out as a multisystem histiocytosis that typically affects bones and various other tissues. Historically, the treatment of ECD has been challenging. However, recent breakthroughs in our understanding, particularly the discovery of somatic mutations in the RAS-MAPK pathway, have opened new opportunities for targeted therapy in a significant subset of patients with ECD and other histiocytoses. In this report, we present the case of a patient with ECD harboring a previously unidentified microduplication in the NRAS gene in a small fraction of skin cells. This discovery played a pivotal role in tailoring an effective therapeutic approach involving kinase inhibitors downstream of NRAS. This case underscores the crucial role of deep sequencing of tissue samples in ECD, enabling the delivery of personalized targeted therapy to patients.

An effective treatment in Erdheim Chester disease: vemurafenib: a case report.

BACKGROUND: Erdheim Chester disease (ECD) is a rare disease with multisystemic involvement in the group of non-langerhans cell histiocytosis. Although nearly 100 years have passed since its definition, the number of cases reported all over the world is below 1000. In addition to the rarity of the disease, low awareness seems to play a role in this. CASE PRESENTATION: 47-year-old white caucasian women patient who presented to our clinic with symptoms of weakness-fatigue as well as increasing pain in the knees and ptosis in the left eye. Result of the patient's bone biopsy, ECD was considered pathologically and BRAF V600E mutation was shown molecularly. After presenting the clinical, laboratory and other examination results of the case, the dramatic response seen with targeted therapy will be discussed. CONCLUSIONS: BRAF V600E mutation is frequently seen in ECD. Vemurafenib plays an active role in targeted therapy.

An Unusual Case of Erdheim Chester Disease (ECD) with Knee Pain: A Case Report.

Background: Erdheim Chester disease (ECD) is a rare, non-Langerhans cell histiocytosis of unknown etiology that occurs in multiple organs. The clinical characteristics of ECD are unknown, making it difficult to diagnose. Case presentation: A 61-year-old woman presented with left knee pain and contracture. She had recent medical problems such as recurrent urinary tract infection, pericardial effusion, and pleural effusion. Simple radiography and magnetic resonance imaging of the knee revealed an osteosclerotic lesion. Under suspicion of malignancy, other radiologic modalities were performed, but there were no significant results showing malignancy. A bone biopsy of the knee lesion led to a final diagnosis of ECD. The patient was treated with systemic steroids and was ultimately tried on PEG-interferon. Conclusion: This report describes an unusual presentation of ECD involving the skeletal system and multiple extraskeletal organs. Owing to its non-specific nature, ECD was notably difficult to diagnose. Therefore, if a patient has knee pain and other multiorgan presentations without malignancy, clinicians should suspect ECD.

Erdheim-Chester Disease: A Case Report of BRAF V600E-Negative, MAP2K1-Positive ECD Diagnosed by Blood Next-Generation Sequencing Assay and a Brief Literature Review.

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.

Case report of a patient with Erdheim-Chester disease presenting with neuro-endocrine symptoms and negative for BRAF mutation.

RATIONALE: Erdheim-Chester disease (ECD) is a rare progressive disease affecting multiple systems. It has recently been recognized as a neoplastic disease following the discovery of activating mutations in the MAPK pathway. There are several striking signs of ECD, such as the long bone involvement, as well as the hairy kidney appearance on computed tomography scan. It is rare for ECD to manifest neurological symptoms. Central nervous system involvement is a strong prognostic factor and independent predictor of death. ECD is characterized by the overproduction and accumulation of foamy histiocytes and Touton's giant cells in various tissues and organs. ECD is a multisystem disorder in which any organ may be affected. PATIENT CONCERNS: This case report describes a 57-year-old woman with headaches and ataxia as the first clinical manifestation, without characteristic bone pain, but with delayed enuresis. In addition to the renal involvement, this patient had rarer splenic involvement. DIAGNOSES: The imaging presentation of this patient was similar to that of a "multiple meningiomas". A combination of clinical, imaging and pathology for the diagnosis of ECD. INTERVENTIONS: Patients were given INF-α therapy. OUTCOMES: Fortunately, the patient responded well to INF-α treatment. LESSONS: ECD patient with neuro-endocrine symptoms.

Targeting the BRAF pathway in haematological diseases.

Since the recognition of BRAF V600E mutations in the majority of cases of hairy cell leukaemia, Erdheim-Chester disease and Langerhans cell histiocytosis, the targeted oral kinase inhibitors dabrafenib and vemurafenib have been adapted for their treatment. Like other targeted agents, these drugs produce high response rates and predictable but unique side effects. Physician familiarity is essential for the effective use of these agents. We review the Australian experience of BRAF/MEK inhibitor therapy in these rare haematological cancers.

Treatment of Langerhans Cell Histiocytosis and Histiocytic Disorders: A Focus on MAPK Pathway Inhibitors.

Histiocytic disorders are rare diseases defined by the clonal accumulation of a macrophage or dendritic cell origin. These disorders include Langerhans cell histiocytosis, Erdheim-Chester disease, juvenile xanthogranuloma, malignant histiocytoses, and Rosai-Dorfman-Destombes disease. These histiocytic disorders are a diverse group of disorders with different presentations, management, and prognosis. This review focuses on these histiocytic disorders and the role of pathological ERK signaling due to somatic mutations in the mitogen--activated protein kinase (MAPK) pathway. Over the last decade, there has been growing awareness of the MAPK pathway being a key driver in many histiocytic disorders, which has led to successful treatment with targeted therapies, in particular, BRAF inhibitors and MEK inhibitors.

Rare cause of pericardial effusion: 'Erdheim-Chester disease'.

This report details the case of a woman in her 50s who presented with symptoms of congestive heart failure and raised inflammatory biochemical markers. Her investigations included an echocardiogram, which revealed a large pericardial effusion and a subsequent CT-thorax/abdomen/pelvis showing extensive retroperitoneal, pericardial and periaortic inflammation and soft-tissue infiltration. Genetic analysis of histopathological samples detected a V600E or V600Ec missense variant within codon 600 of the BRAF genewith BRAF variants, confirming the diagnosis of Erdheim-Chester disease (ECD).The patient's clinical management involved several treatments and interventions with input from a variety of clinical specialties. This included the cardiology team for pericardiocentesis, the cardiac surgical team for pericardiectomy due to recurrent pericardial effusions and finally the haematology team for further specialist treatment with pegylated interferon and consideration of BRAF inhibitor therapy. The patient became stable following treatment with significant improvement in her heart failure symptoms. She remains under regular joint cardiology and haematology team follow-up. The case highlighted the importance of using a multidisciplinary approach to best manage the multisystem involvement of ECD.

Successful treatment of non-Langerhans cell histiocytosis with the MEK inhibitor trametinib: a multicenter analysis.

Erdheim-Chester disease (ECD) and Rosai-Dorfman disease (RDD) are rare non-Langerhans cell histiocytoses (non-LCHs), for which therapeutic options are limited. MAPK pathway activation through BRAFV600E mutation or other genomic alterations is a histiocytosis hallmark and correlates with a favorable response to BRAF inhibitors and the MEK inhibitor cobimetinib. However, there has been no systematic evaluation of alternative MEK inhibitors. To assess the efficacy and safety of the MEK inhibitor trametinib, we retrospectively analyzed the outcomes of 26 adult patients (17 with ECD, 5 with ECD/RDD, 3 with RDD, and 1 with ECD/LCH) treated with orally administered trametinib at 4 major US care centers. The most common treatment-related toxicity was rash (27% of patients). In most patients, the disease was effectively managed at low doses (0.5-1.0 mg trametinib daily). The response rate of the 17 evaluable patients was 71% (73% [8/11] without a detectable BRAFV600E achieving response). At a median follow-up of 23 months, treatment effects were durable, with a median time-to-treatment failure of 37 months, whereas the median progression-free and overall survival were not reached (at 3 years, 90.1% of patients were alive). Most patients harbored mutations in BRAF (either classic BRAFV600E or other BRAF alterations) or alterations in other genes involved in the MAPK pathway, eg, MAP2K, NF1, GNAS, or RAS. Most patients required lower than standard doses of trametinib but were responsive to lower doses. Our data suggest that the MEK inhibitor trametinib is an effective treatment for ECD and RDD, including those without the BRAFV600E mutation.

Case Report of Erdheim-Chester Disease Successfully Treated with Pegylated Interferon: A Single-Center Experience.

Erdheim-Chester disease (ECD), also known as non-Langerhans cell histiocytosis, is a multi-systemic disease with unclear pathogenesis. Based on a small number of case studies, pegylated interferon-α (PEG-IFN-α) has been used as the front-line treatment option. However, there are limited data regarding administration of ropegylated-interferon α-2b (ROPEG-IFN-α 2b) for ECD patients. Herein, we report two cases of severe ECD treated with two types of PEG-IFN-α. One patient with heart and skeleton involvement and BRAF V600E mutation was treated with weekly PEG-IFN-α 2a. Another patient with bone involvement and no BRAF V600E mutation was administered monthly ROPEG-IFN-α 2b. The two types of PEG-IFN-α showed excellent disease control, excellent survival outcomes, and manageable toxicities in ECD patients. These results suggest that ROPEG-IFN-α 2b could be used equivalently to PEG-IFN-α 2a for management of advanced ECD.

Erdheim-Chester disease with Rosai-Dorfman-like lesions: treatment with methotrexate, anakinra and upadacitinib.

Erdheim-Chester disease (ECD) is a non-Langerhans cell histiocytosis characterised by clonal expansion of histiocytes in various organs. These induce an inflammatory environment, which leads to damage of the affected areas. Recently, a new disease entity was proposed encompassing key features of ECD but also of Rosai-Dorfman-Destombes disease, another histiocytosis. Mitogen-activated protein kinase kinase 1 (MAP2K1) mutations seem to present a specific genetic lesion for this subtype.Here, we describe a case of this new disease entity with clinical, radiological and genetic findings compatible with ECD but histological findings compatible with Rosai-Dorfman-Destombes disease. In particular, there were intraabdominal and retroperitoneal lesions, which tested positive for a (c.167A>C; p.Q56P) mutation of the MAP2K1 gene. On histological examination, S100-positive, giant histiocytes with focal emperipolesis of haematological cells in addition to infiltration by lymphocytes and granulocytes were seen.As described for this rare variant of ECD, there was also bilateral testicular infiltration. We also describe a manifestation of oligoarthritis in this patient with ECD.The patient was treated with methotrexate and prednisolone. While radiological response to this regime was excellent, arthritis persisted. We added anakinra, which induced a response of the arthritis for more than a year. Due to treatment failure therapy was switched to upadacitinib, which induced a remission of the arthritis as well.This case adds a rare phenotype to an already rare presentation of ECD. The patient responded to immunosuppressive therapy.

Ophthalmic histiocytic lesions (diseases of the L group): A multicenter clinicopathological study of 18 cases and review of literature.

INTRODUCTION: Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are rare histiocytic disorders in the L (Langerhans) group diseases. They range from self-limited benign diseases to lethal disseminated forms. METHODS: This retrospective study was conducted in 3 tertiary hospitals in Saudi Arabia and Brazil. Histopathological records were searched for all patients diagnosed with ocular and periocular histiocytic disorders from January 1993 to December 2018. Histopathological slides and medical files were reviewed for data collection and simple analysis of demographics, clinical manifestations, and management. The relevant literature is reviewed. RESULTS: Twenty-two eyes of 18 patients with biopsy-proven histiocytic disorders in the L group were included. Female-to-male ratio was 1.25:1. Average age at presentation was 14 years (range, 1-54). LCH was diagnosed in 14 eyes, while eight eyes had ECD. All LCH cases were unilateral and confined to the bone as cases of eosinophilic granuloma (EG), while patients with ECD were bilateral. Commonest presentations in EG and ECD were eyelid swelling (85.7%) and periocular xanthomas (75%), respectively. Orbit was involved in 100% of EG cases, with bony erosion in 54.5%. Relevant systemic involvement was found in 100% of ECD and 21% of EG cases. Surgical intervention was needed in 16 of the 22 eyes (72.7%). All EG and 25% of patients with ECD required surgical excision. CONCLUSIONS: Histiocytic disorders are a rare group of diseases, including the L group. Relevant systemic associations require specific and selective therapy. A high clinical index and multidisciplinary collaboration are essential for the proper evaluation and management of these patients.

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

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.

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

PURPOSE: To evaluate the clinical presentation, treatment, and outcomes in adult patients with histiocytic disorders with ocular, orbital, optic nerve, or cavernous sinus involvement. DESIGN: Observational, retrospective chart review. PARTICIPANTS: 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. METHODS: Retrospective chart review. MAIN OUTCOME MEASURES: Response to therapy, measured in clinical and radiographic impact. RESULTS: 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. CONCLUSIONS: 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.

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.