[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 Fô€ƒ¼a; 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.

Typical Bone Scintigraphy Presentation of Erdheim-Chester Disease in a Patient Diagnosed With IgG4-Related Disease.

ABSTRACT: A 50-year-old woman presented a dry syndrome, joint pain, inflammatory syndrome, polyclonal hypergammaglobulinemia, and tubulointerstitial nephritis. Imaging studies (including FDG PET/CT) revealed infrarenal retroperitoneal fibrosis with periaortitis and hypermetabolic osteosclerotic lesions. Bone scintigraphy demonstrated intense uptake in the femoral, tibial, and radial regions, suggestive of non-Langerhans histiocytosis, specifically Erdheim-Chester disease. A bone biopsy confirmed the presence of IgG4-positive plasma cells but no histiocytes. The patient received corticosteroid therapy followed by rituximab, resulting in a complete response. This case suggests an atypical manifestation of bone lesions in IgG4-related disease, emphasizing the diagnostic challenge between IgG4-related disease and Erdheim-Chester disease.

Erdheim-Chester Disease Occult on Radiographs and CT but Visible on MRI and PET.

BACKGROUND Erdheim-Chester disease (ECD) is a rare neoplasm of histiocytes that is characterized by prominent involvement of the long bones. Approximately 1500 cases have been reported since the disease was first described in 1930. The imaging appearance of ECD can be highly variable given the numerous systems it can affect. In this case report we discuss a patient whose ECD was occult on multiple imaging modalities. CASE REPORT We report the case of a 60-year-old woman who presented with sub-acute left knee and calf pain that led to an MRI. She was found to have innumerable marrow-replacing lesions in the axial and appendicular skeleton visualized on the initial MRI, as well as on an ¹8F-FDG PET/CT scan. The patient did not have extraosseous abnormal uptake on the PET/CT. Subsequently, a lesion from the left iliac bone was histologically confirmed as ECD on the basis of positive staining for CD68 and CD163 and negative staining for CD1a. Osseous lesions in ECD have a distinct imaging appearance and are typically detected by radiography and bone scintigraphy, among other modalities; however, the lesions in this case were unexpectedly absent from those studies. CONCLUSIONS If there is a high degree of suspicion for ECD, 18F-FDG PET/CT and/or MRI may be necessary for adequate visualization of bone lesions, given that those lesions can have an infiltrative nature that may be difficult to image with other anatomic imaging modalities. Use of 18F-FDG PET/CT and/or MRI may also lead to adequate guidance of confirmatory biopsy.

[Xanthogranulomatous adrenalitis : A rare and difficult differential diagnosis of adrenal gland tumors]. / Xanthogranulomatöse Adrenalitis : Seltene und schwierige Differentialdiagnose von Nebennierentumoren.

A radiologically diagnosed tumor in a 29-year-old woman with a fever of around 39 °C was operated on under the suspicion of cholecystitis or a liver abscess. A solid tumor was found in the adrenal gland and resected. The frozen section findings did not reveal a clear diagnosis of entity and assignment. Histologically, the tumor was found to consist of densely clustered large histiocyte-like cells with expression of vimentin, CD68, and CD163 as well as negativity for keratin, langerin, and SMA. We diagnosed xanthogranulomatous adrenalitis and discussed the differential diagnoses (Langerhans cell histiocytosis, Rosai-Dorfman disease, malakoplakia, Erdheim-Chester disease).

Multisystem Erdheim-Chester disease presenting with pericardial effusion confirmed by the effusion cytology specimen.

Erdheim-Chester disease (ECD) is a rare histiocytosis characterized by the foamy CD68+CD1a- histiocytes infiltrating multiple organs and tissues. ECD might be asymptomatic or present with variable manifestations. The diagnosis of ECD requires characteristic radiological findings and pathological features. Herein, we described a 52-year-old female patient who was admitted to our hospital for recurrent pericardial effusion for two months. She has a medical history of papillary thyroid carcinoma (PTC) and underwent a total thyroidectomy two years before admission. The radiological findings suggested a potential diagnosis of ECD. Cytological analysis of the effusion cytology specimen revealed CD68+CD1a- histiocytes, confirming the ECD diagnosis. The BRAF V600E mutation was identified in the histiocytes, prompting the administration of vemurafenib, a BRAF inhibitor. After two months of standard-dose vemurafenib treatment, the disease was well controlled with pericardial effusion regression.

[Central nervous system disorders secondary to histiocytoses: neurodegeneration with potential for improvement].

Histiocytoses, including Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD), are inflammatory myeloid tumors in which monocyte lineage cells aggregate in various organs, causing tissue damage. Most of these tumors harbor oncogenic mutations in mitogen-activated protein kinase (MAPK) pathway genes, typified by BRAFV600E. Some patients with LCH develop bilateral symmetrical cerebellar lesions and brain atrophy several years after diagnosis when the initial symptoms disappear, leading to cerebellar ataxia and higher cerebral dysfunction. A similar neurological disorder has also been reported in ECD. This neurological disorder can be improved with MAPK inhibitors. When patients with this neurological disorder are identified among neurodegeneration of unknown etiology or histiocytosis patients and treated early with MAPK inhibitors, the disorder can be reversible.

Erdheim-Chester disease of brain parenchyma without any systemic involvement: A case report and review of literature.

Erdheim-Chester disease is a non-Langerhans cell histiocytosis syndrome characterised by histiocytic infiltration of different organs and systems in the body. Erdheim-Chester disease with isolated central nervous system (CNS) involvement causes diagnostic difficulties due to the absence of systemic findings and may result in misdiagnosis and inaccurate treatment choices. The case discussed in this report exemplifies how challenging it is to diagnose Erdheim-Chester disease with isolated CNS involvement. This case, which presented with progressive pyramidocerebellar syndrome, was clinically and radiologically resistant to all immunosuppressive and immunomodulatory treatments administered. The presence of false negative results in repeated histopathological investigations and the absence of evidence for systemic disease hindered the diagnosis and treatment work-up. In this study, we reviewed and discussed the prominent features of the presented case in light of the relevant literature.

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.

Genome-Wide Association Study Identifies the First Germline Genetic Variant Associated With Erdheim-Chester Disease.

OBJECTIVE: Erdheim-Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome-wide association study. METHODS: After quality controls, a cohort of 255 patients with ECD and 7,471 healthy donors was included in this study. Afterward, a logistic regression followed by in silico functional annotation was performed. RESULTS: A signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (P = 2.75 × 10-11 ; Odds Ratio = 2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease. CONCLUSION: Overall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role.

Erdheim-Chester Disease with Renal Mass Presentation: Report of the First Case From Palestine and a Review of the Literature.

BACKGROUND Erdheim-Chester disease (ECD), a form of non-Langerhans-cell histiocytosis, is extremely rare. The mean age of individuals with ECD is in their 50s. Histiocytic infiltration of vital organ systems is a potential cause of substantial morbidity, which is associated with the multisystemic form of ECD. This report presents the first case of ECD with renal abnormalities in Palestine. CASE REPORT A 54-year-old woman with no medical or surgical history presented with 6 months of bilateral flank pain with no radiation or fever. A physical examination revealed only bilateral flank pain. Urine tests showed microhematuria. Laboratory test results showed increased serum creatinine levels (1.21 mg/dL) and microcytic anemia. A CT scan revealed significant multi-organ abnormalities, including renal abnormalities with a hairy kidney sign, pericardial effusion, and an osteolytic lesion of the spine. The hairy kidney sign is pathognomonic for ECD, so the renal mass was biopsied to confirm the diagnosis. The biopsy showed foamy histiocytes, lymphocytes, and plasma cells. Foamy histiocytes were CD68-positive and negative for S100, CD1a, and HMB45. PAx5 and CD3 immunostaining showed T-predominant B-lymphocyte mixtures. CONCLUSIONS In the setting of systemic symptoms and imaging abnormalities such as presence of the hairy kidney sign, pericardial effusion, and osteolytic lesion of the spine, it is necessary to examine the possibility of ECD and proceed with a biopsy for confirmation. This is the first case in Palestine to be reported and the second case worldwide with a renal mass as an atypical presentation.

A new phenotype of myorhythmia: Oculofacial myorhythmia in a patient with Erdheim Chester disease.

Oculofacial myorhythmia (OFM) is a movement disorder characterized by slow, rhythmic, and repetitive movement that affects the periorbital and perioral muscles. This abnormal movement is classified as a tremor and is highly suggestive of brainstem lesions. Unlike the oculomasticastory myorhythmia, the oculofacial pattern has rarely been reported to date. We present a patient diagnosed with Erdheim Chester disease who two years after the diagnosis developed an oculofacial myorhythmia. We additionally provide a pathological framework based on evolutionary changes on neuroimaging which could explain the appearance of this very rare movement disorder. No cases of OFM have been described in patients with ECD to date. To our knowledge we are reporting the first case of oculofacial myorhythmia secondary to Erdheim Chester disease. To conclude, oculofacial myorhytmia could be a late-onset clinical manifestation of ECD with brainstem involvement.

[Combined histiocytosis of the Langerhans group (Langerhans cell histiocytosis and Erdheim-Chester disease) in a 64-year-old man with BRAF and NRAS mutations: a case report]. / Histiocitosis combinada de tipo Langerhans (Histiocitosis de células de Langerhans y enfermedad de Erdheim-Chester) en varón de 64 años con mutaciones en BRAF y NRAS: a propósito de un caso.

We present a case of a 64-year-old male with a history of Crohn's disease who presented with an episode of acute abdominal pain. He was being investigated for a dermatological lesion. A skin and lung biopsy both revealed histiocytosis of the "L" (Langerhans) group. The skin biopsy showed a proliferation of histiocytic cells expressing Langerin, CD1a and S100 and the molecular study was positive for the BRAF p.V600E mutation. In the lung biopsy, a proliferation of histiocytic cells was found, which were positive for CD68 and S100 and negative for Langerin and CD1a; mutations in NRAS c.38G>A in exon 2 (p.G13D) were also detected.

How I Diagnose Rosai-Dorfman Disease.

OBJECTIVES: Rosai-Dorfman disease (RDD) is one of 3 major types of histiocytosis, along with Erdheim-Chester disease and Langerhans cell histiocytosis. While historically, RDD was considered a benign self-limited condition, current data show MAPK/ERK pathway mutations in 30% to 50% of cases, indicative of a clonal process. Rosai-Dorfman disease was incorporated as a histiocytic neoplasm in the fifth edition of the World Health Organization classification of hematopoietic tumors and the International Consensus Classification. METHODS: We discuss the diagnosis of RDD using 2 illustrative cases, interpretative challenges, and a diagnostic algorithm. RESULTS: Rosai-Dorfman disease involves nodal and extranodal sites, including skin, sinuses, salivary gland, orbit, central nervous system, kidney, and bone. In a subset, RDD can coexist with other neoplasms (lymphomas, other histiocytosis) or autoimmune disease. Morphologically, RDD histiocytes are characterized by enlarged round to oval nuclei, distinct nucleoli, and voluminous cytoplasm with engulfment of inflammatory cells (emperipolesis). By immunohistochemistry, they express CD68, CD163 (majority), S100, OCT2, and cyclin D1. Appropriate use of ancillary studies is important to support the diagnosis of RDD while excluding other histiocytic neoplasms and reactive histiocytic proliferations. CONCLUSIONS: Management of RDD is dependent on the extent of organ involvement and clinical symptoms. In patients who require therapy, next-generation sequencing is recommended to identify MAPK/ERK pathway mutations for targeted therapy.

PU.1 is a useful nuclear marker to distinguish between histiocytosis and histiocyte-rich tumours.

AIMS: The aim was to test the expression of PU.1 on different types of histiocytoses and to test the utility of PU.1 in confirming or excluding a histiocytic origin in tumour samples with suspicion of histiocytosis. METHODS AND RESULTS: We analysed 66 biopsies of nonmalignant histiocytoses represented by Langerhans-cell histiocytosis (n = 13), Erdheim-Chester disease (ECD) (n = 19), Rosai-Dorfman disease (RDD) (n = 14), mixed ECD-RDD (n = 3), ALK-positive histiocytosis (n = 6), and juvenile xanthogranuloma (n = 11). All cases were positive for PU.1 in reactive and neoplastic histiocytes. In addition, 39 cases of tumours with high-grade cytological atypia were referred to our center as suspicion of malignant histiocytosis/histiocytic sarcoma and only 18 were confirmed. Indeed, more than half of these tumours (21/39) were either undifferentiated malignant tumours with a stroma rich in histiocytes, diffuse large B-cell lymphoma, or high-grade dedifferentiated liposarcoma. PU.1 was useful to distinguish between the negativity of large atypical nuclei and the positivity of stromal reactive histiocytes. CONCLUSION: PU.1 is expressed by all types of histiocytosis. It distinguishes histiocytosis from histiocyte-rich tumours with an easy interpretation due to its sharp nuclear staining. Its negativity in lesional/tumour cells in histiocyte-like lesions is useful to eliminate a histiocytosis.

Ophthalmologic Findings in Pediatric Erdheim-Chester Disease: A Literature Review With a Novel Case Report.

PURPOSE: The authors aim to describe the ophthalmologic manifestations of pediatric Erdheim-Chester disease (ECD). METHODS: The authors describe a novel case of ECD presenting as isolated bilateral proptosis in a child and provide a comprehensive review of the documented pediatric cases to observe overall trends and ophthalmic manifestations of disease. Twenty pediatric cases were identified in the literature. RESULTS: The mean age at presentation was 9.6 years (1.8-17 years) with a mean time of symptom presentation to diagnosis of 1.6 years (0-6 years). Nine patients (45%) had ophthalmic involvement at diagnosis, 4 who presented with ophthalmic complaints: 3 with observable proptosis and 1 with diplopia. Other ophthalmic abnormalities included eyelid findings of a maculopapular rash with central atrophy on the eyelids and bilateral xanthelasmas, neuro-ophthalmologic findings of a right hemifacial palsy accompanied by bilateral optic atrophy and diplopia, and imaging findings of orbital bone and enhancing chiasmal lesions. No intraocular involvement was described, and visual acuity was not reported in most cases. CONCLUSIONS: Ophthalmic involvement occurs in almost half of documented pediatric cases. Typically presenting with other symptoms, the case highlights that isolated exophthalmos may be the only clinical sign, and ECD should be included in the differential diagnosis of bilateral exophthalmos in children. Ophthalmologists may be the first to evaluate these patients, and a high index of suspicion and an understanding of the varied clinical, radiographic, pathologic, and molecular findings are critical for prompt diagnosis and treatment of this unusual disease.

Erdheim-Chester Disease Involving the Left Uterine Adnexa: Mimicking an Ovarian Carcinoma Clinically.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis (LCH) that results in multiorgan disease involving the skin, bones, lungs, and kidneys. Female reproductive system manifestation of ECD was rare. Herein, we report a case of ECD involving the left ovary and fallopian tube. A 69-year-old woman presented with abdominal pain for 20 days. Magnetic resonance imaging revealed a solid and cystic mass on the left pelvic cavity. Histological examination revealed ovarian and fallopian tube infiltration by abundant histiocytes, with single small nuclei and foamy cytoplasm, reactive small lymphocytes, and plasma cells. Based on histopathological and immunohistochemical findings of positivity for CD68, CD163, and BRAF V600E and negativity for CD1α and S100, the molecular finding of BRAF V600E mutation, the patient was diagnosed with ECD. Positron emission tomography examination did not reveal any other lesions. The patient recovered well 12 months after surgery without any treatment. ECD involving the left fallopian tube and ovary was rare and needed to be differentiated from LCH, Rosai-Dorfman disease (RDD), juvenile xanthogranuloma (JXG), IgG4+-related disease (IgG4+RD), and metastatic signet ring cell carcinoma.

Erdheim-Chester Disease.

Erdheim-Chester disease is a rare non-Langerhans cell histiocytosis. The disease is widely variable in its severity, ranging from incidental findings in asymptomatic patients to a fatal multisystem illness. CNS involvement occurs in up to one-half of patients, most often leading to diabetes insipidus and cerebellar dysfunction. Imaging findings in neurologic Erdheim-Chester disease are often nonspecific, and the disease is commonly mistaken for close mimickers. Nevertheless, there are many imaging manifestations of Erdheim-Chester disease that are highly suggestive of the disease, which an astute radiologist could use to accurately indicate this diagnosis. This article discusses the imaging appearance, histologic features, clinical manifestations, and management of Erdheim-Chester disease.

OCT2 expression in histiocytoses.

Diagnosis of histiocytosis can be difficult and one of the biggest challenges is to distinguish between reactive and neoplastic histiocytes on histology alone. Recently, OCT2 nuclear expression was reported in Rosai-Dorfman disease (RDD). Our purpose was to expand the testing of OCT2 on a broader variety of sporadic or H syndrome-related histiocytoses. Cases of histiocytoses were retrieved from the files of Ambroise Paré Pathology Department. All slides and molecular analyses were reviewed, and staining was completed with immunohistochemistry for OCT2. A total of 156 samples from different localizations were tested. Among sporadic cases, 52 patients had RDD, and 10 patients had mixed histiocytosis combining RDD with Erdheim Chester disease (ECD, n = 8), Langerhans cell histiocytosis (LCH, n = 2) or juvenile xanthogranuloma (JXG, n = 1). All these patients were positive for OCT2 in RDD characteristic histiocytes. Twenty-three patients had ECD and all but two (91% - 21/23) were negative for OCT2. By contrast, OCT2 was positive in 11/27 (41%) LCH and 6/16 (38%) JXG. Among the 10 samples of H syndrome-associated histiocytosis, 3 had typical RDD histology, 6 had unclassified histiocytosis, and one had mixed RDD-LCH; all were positive for OCT2. On 16 samples of granulomatous lymphadenitis, OCT2 was negative in epithelioid histiocytes. Our study shows that OCT2 has a sensitivity of 100% for RDD cases and mixed histiocytoses with an RDD component. It is negative in 92% of ECD but expressed in at least 38% of LCH, JXG, and C group histiocytoses. Finally, OCT2 is positive in all H syndrome-related histiocytoses, independent of their histology.

Erdheim-Chester disease: diffusion-weighted imaging and dynamic contrast-enhanced MRI provide useful information.

This is, to our knowledge, the first case report with in-depth analysis of bone marrow and bone lesions with diffusion-weighted imaging and dynamic contrast-enhanced MRI in Erdheim-Chester disease to date. We present a case of a 70-year-old woman who was referred for an X-ray of the pelvis, right femur and right knee after complaints of migratory arthralgia in hip and knee five months after an initial hip and knee trauma. Bone lesions on X-ray were identified. This case report highlights the strength and complementary use of modern multimodality multiparametric imaging techniques in the clinical radiological manifestations of Erdheim-Chester disease, in the differential diagnosis and in treatment response assessment, which is classically performed using 18FDG PET-CT. Erdheim-Chester disease is a rare form of non-Langerhans' cell histiocytosis, mainly affecting individuals in their fifth-seventh decade of life and without sex predominance. Apart from the typical bilateral symmetric lesions in long bone diaphyseal and metaphyseal regions and classically sparing the epiphyses, this multisystemic disease causes significant morbidity by infiltrating critical organs (the central nervous system, cardiovascular system, retroperitoneum, lungs and skin). With non-traumatic bone pain being the most common complaint, Erdheim-Chester disease is diagnosed most often in an incidental setting on imaging. The imaging workup classically consists of a multimodality approach using conventional radiography, CT, MRI, bone scintigraphy and 18FDG PET-CT. This case report extends this evaluation with diffusion-weighted imaging and dynamic contrast-enhanced imaging techniques.