High frequency of clonal hematopoiesis in Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a clonal hematopoietic disorder characterized by the accumulation of foamy histiocytes within organs (in particular, frequent retroperitoneal involvement) and a high frequency of BRAFV600E mutations. Although ECD is not commonly recognized to have overt peripheral blood (PB) or bone marrow (BM) disease, we recently identified that ECD patients have a high frequency of a concomitant myeloid malignancy. We thus conducted a systematic clinical and molecular analysis of the BM from 120 ECD patients. Surprisingly, 42.5% of ECD patients (51 of 120) had clonal hematopoiesis whereas 15.8% of patients (19 of 120) developed an overt hematologic malignancy (nearly all of which were a myeloid neoplasm). The most frequently mutated genes in BM were TET2, ASXL1, DNMT3A, and NRAS. ECD patients with clonal hematopoiesis were more likely to be older (P < .0001), have retroperitoneal involvement (P = .02), and harbor a BRAFV600E mutation (P = .049) than those without clonal hematopoiesis. The presence of the TET2 mutation was associated with a BRAFV600E mutation in tissue ECD lesions (P = .0006) and TET2-mutant ECD patients were more likely to have vascular involvement than TET2 wild-type ECD patients. Clonal hematopoiesis mutations in ECD were detected in cells derived from CD34+CD38- BM progenitors and PB monocytes but less frequently present in PB B and T lymphocytes. These data identify a heretofore unrecognized high frequency of clonal hematopoiesis in ECD patients, reaffirm the development of additional high risk of myeloid neoplasms in ECD, and provide evidence of a BM-based precursor cell of origin for many patients with ECD.

MAP-Kinase-Driven Hematopoietic Neoplasms: A Decade of Progress in the Molecular Age.

Mutations in members of the mitogen-activated protein kinase (MAPK) pathway are extensively studied in epithelial malignancies, with BRAF mutations being one of the most common alterations activating this pathway. However, BRAF mutations are overall quite rare in hematological malignancies. Studies over the past decade have identified high-frequency BRAF V600E, MAP2K1, and other kinase alterations in two groups of MAPK-driven hematopoietic neoplasms: hairy cell leukemia (HCL) and the systemic histiocytoses. Despite HCL and histiocytoses sharing common molecular alterations, these are phenotypically distinct malignancies that differ in respect to clinical presentation and suspected cell of origin. The purpose of this review is to highlight the molecular advancements over the last decade in the histiocytic neoplasms and HCL and discuss the impact these insights have had on our understanding of the molecular pathophysiology, cellular origins, and therapy of these enigmatic diseases as well as perspectives for future research directions.

Histiocytic disorders: insights into novel biology and implications for therapy of Langerhans cell histiocytosis and Erdheim-Chester disease.

Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are caused by mutations of the MAPK pathway, most often BRAFV600E, in myeloid dendritic cells that lead to some overlapping and other unique presentations of the two diseases. LCH occurs in both children and adults, but ECD is primarily found in the latter. The challenges in diagnosing these conditions relates to the rarity of the conditions and that they mimic diseases that are more widely understood, such as certain rashes; bone, lung, and renal diseases; and other malignancies. The histopathology of LCH is definitive, but not so for ECD. Treatment with BRAF and MEK inhibitors has become one of the important advances in the care of these patients.

Clinical presentation, imaging and response to interferon-alpha therapy in Erdheim-Chester disease: case-based review.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis associated with BRAFV600E mutations in more than 50% of cases and presenting with 95% with skeletal lesions. However, cutaneous, pulmonary, large vessels and central nervous system involvement can also occur. We report a case of a 25-year-old woman who was admitted in 2018 for exploration of diffuse bone pain and rashes on the face. Her current symptoms had started 14 months earlier and consisted of bone pain, affecting the legs. She had periodic low-grade fever, asthenia and xanthelasma-like papules appeared on face. At admission, physical examination showed bilateral and symmetrical long bone pain, especially in the knees and multiple xanthelasma-like papules around the eyelids, cheeks and chin. Laboratory tests revealed elevated erythrocyte sedimentation rate and C-reactive protein. Magnetic resonance (MR) imaging showed multiple mixed bone lesions with a hyperintensive MR signal on PD FS and hypointense signal on T1of the femur and tibia. Bone scintigraphy indicated bilateral and symmetrical metaphyseal and diaphyseal increased uptake. Abdominal computed tomography (CT) scan showed infiltration of the perirenal fat. Biopsy of the skin revealed histiocytic infiltration, which was CD68-positive and CD100-positive, confirming the diagnosis of ECD. Patient was treated with interferon-α (IFN-α) plus methylprednisolone. After 6 months of treatment her clinical condition partly improved: a reduction of pain on visual analogue scale (VAS) scale, significant decrease of methylprednisolone dose and specific dynamics according to bone MR imaging data, however, no change in symptoms attributed to skin rash was noted. We also provide the literature review results of IFN-α treatment efficacy in Erdheim-Chester disease involving the skin and musculoskeletal system with MR imaging changes.

Intracranial Erdheim-Chester Disease Mimicking Parafalcine Meningioma: Report of Two Cases and Review of the Literature.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare, non-Langerhans cell histiocytosis that typically occurs in middle-aged patients. It is usually characterized by multifocal osteosclerotic lesions of the long-bones, however many cases have extraskeletal involvement. Central nervous system (CNS) involvement is common, but isolated CNS involvement at presentation has rarely been reported. CASE DESCRIPTION: Here we report two cases of dural-based ECD mimicking meningioma on imaging with no other identified sites of disease. CONCLUSION: ECD is a rare disease, with isolated CNS involvement reported only a few times in the literature. The significance of this presentation requires additional study and long-term follow up.

Erdheim-Chester disease: atypical presentation of a rare disease.

We report the clinical case of an adult patient referred to our hospital because of trismus due to a tumour in the right infratemporal and pterygomaxillary fossa. He referred hyporexia, weight loss and right trigeminal neuralgia. On physical examination, he had trismus and diplopia. On neuroimaging, the tumour invaded the central nervous system affecting the right temporal lobe and orbit, and the sellar region. Tumour biopsy revealed foamy histiocytes and isolated giant multinuclear cells immunoreactive to CD68 and negative to CD1a and S100. A diagnosis of Erdheim-Chester disease was made. Non-evidence of large bone involvement was found in neither plain radiographs nor Technetium 99 m bone scintigraphy. BRAFV600E mutation analysis was negative. Because of raised intracranial pressure, a debulking surgery of the intracranial histiocytic process was performed. The patient improved his symptoms and remains clinically stable after 12 months of treatment with pegylated interferon-α-2a 180 µg/weekly.

Case 245: Erdheim-Chester Disease.

History A 53-year-old man experienced headache and double vision that progressed over 1 year. After a traumatic fall, he was hospitalized, and proptosis was identified at physical examination. Laboratory tests were remarkable for leukocytosis. Hematocrit level, thyroid stimulating hormone level, autoimmune antibody level, erythrocyte sedimentation rate, and C-reactive protein level were normal. Computed tomography (CT) of the head revealed bilateral intraconal masses, for which magnetic resonance (MR) imaging of the orbits was subsequently performed ( Fig 1 ). CT imaging of the chest and abdomen ( Fig 2 ) revealed periaortic and retroperitoneal stranding. Perinephric biopsy was performed, and a diagnosis of immunoglobulin G4 (IgG4)-related disease was made based on identification of a few plasma cells per high-power field that were positive for IgG4. Orbital biopsy was then performed, but the results were inconclusive for IgG4-related disease. The patient was discharged and given steroid therapy for presumed IgG4-related disease. [Figure: see text][Figure: see text][Figure: see text][Figure: see text][Figure: see text][Figure: see text] Several months later, the patient returned to our institution with progressive symptoms despite ongoing steroid treatment. His case was reviewed by several specialists to develop alternative treatments for IgG4-related disease. After review of the available images, a neuroradiology fellow (M.D.M.) performed history taking and a physical examination and subsequently recommended radiography of the lower extremities ( Fig 3 ). [Figure: see text][Figure: see text].

[Erdheim-Chester disease : a differential diagnosis of retroperitoneal fibrosis]. / La maladie d'Erdheim Chester : un diagnostic différentiel de fibrose rétropéritonéale.

Erdheim-Chester disease is a rare multisystemic non-Langerhans histiocytosis with about 500 reported cases. Typical features include retroperitoneal and perirenal fibrosis (hairy kidney), periaortitis with a coated aorta, osteosclerosis of the lower limbs, and sometimes exophthalmia or diabetes insipidus. Histology is the cornerstone for diagnosis showing an infiltrate with foamy histiocytes and occasional multinucleated giant cells (Touton cells). There is no standard treatment regimen, current options include corticosteroids, interferon alpha, systemic chemotherapy, and radiation therapy ; however, a better understanding of the pathophysiological mechanisms has allowed the emergence of novel targeted treatments such as vemurafenib, imatinib, and anakinra.

La maladie d'Erdheim-Chester, une histiocytose non langerhansienne, caractérisée par une atteinte multisystémique, est rare avec environ 500 cas décrits. Les manifestations typiques sont une fibrose rétropéritonéale et périrénale (reins chevelus), une périaortite avec engainement circulaire (manchon aortique), une ostéosclérose des membres inférieurs et parfois une exophtalmie ou un diabète insipide. L'histologie montre un infiltrat d'histiocytes spumeux et parfois de cellules géantes polynucléées (cellules de Touton). Il n'y a pas de traitement standard et les options actuelles comprennent les corticoïdes, l'interféron alpha, la chimiothérapie et la radiothérapie ; cependant, une meilleure compréhension des phénomènes physiopathologiques a permis l'émergence de traitements ciblés comme l'anakinra, l'imatinib et le vémurafénib.

[Erdheim-Chester disease].

Erdheim-Chester disease is an orphan condition which involves the ongoing proliferation, migration and infiltration of the typical CD68(+), CD1a(-) histiocytes to various target foci. Consequently, both the infiltrating and fibrosing elements of the disease promote end organ damage and ultimately, failure. Presentation of the Erdheim-Chester disease typically involves longstanding diabetes insipidus in conjunction with intensifying bone pain that classically affects the femurs and tibiae. Alternatively, the disease may present with neurological deterioration of cerebellar nature. Thus, a high index of clinical suspicion is required when facing a patient with the combination of longstanding diabetes insipidus in conjunction with bone pain or cerebellar dysfunction. Typical symmetric, bilateral increased tracer uptake on a 99mTc bone scintigraphy invoLving the femurs and tibiae, is strongly suggestive of the Erdheim-Chester disease. interferon alpha is considered as the first line of treatment. Nevertheless, recent accumulated data suggests that this disease heavily relies on the Ras/Raf/MEK/ERK signal transduction pathway as inhibition of the V600E mutant BRAF by the small molecule vemurafenib among patients who are carriers of this mutation, yielded dramatic clinical responses.

Erdheim-Chester disease: characteristics and management.

Erdheim-Chester disease is a rare CD68(+), CD1a(-) non-Langerhans cell histiocytosis with multiorgan involvement. The etiology of Erdheim-Chester disease is unclear; there are no known associated infectious or hereditary genetic abnormalities. However, somatic BRAF mutations have recently been identified in these patients. Historically, the literature regarding the management of Erdheim-Chester disease consisted of case reports and small case series with anecdotal therapeutic responses to agents including, but not limited to, cytotoxic chemotherapy, bone marrow transplantation, cladribine, corticosteroids, IFN-α, the BCR-ABL/KIT inhibitor imatinib mesylate, the IL-1 receptor antagonist anakinra, the TNF-inhibitor infliximab, and recently the BRAF inhibitor vemurafenib. We performed a search of the literature using PubMed with the terms Erdheim Chester disease, without date limitations, including case reports, case series, original articles, and previous review articles. In the absence of large-scale studies, experience-based management prevails. The present review details our approach to the management of patients with Erdheim-Chester disease.

Erdheim-Chester disease: an uncommon cause of upper urinary tract obstruction.

Erdheim-Chester disease is a rare non-Langerhans form of systemic histiocytosis of unknown origin. We describe a 45-year-old man presenting with bilateral hydronephrosis suggestive of extrinsic urinary tract obstruction. Computed tomography revealed extensive hypodense soft tissue infiltration in the retroperitoneum surrounding the kidneys. Needle biopsy of the retroperitoneal soft tissue revealed aggregates of lipid-laden histiocytes expressing CD68 but negative for CD1a and S100 protein. The diagnosis of Erdheim-Chester disease was supported by typical radionuclide bone scinitigraphic findings. Treatment with prednisolone, sirolimus, and regular ureteric stent revision was initiated to achieve adequate urinary tract drainage. To our knowledge, this is the second patient with Erdheim-Chester disease reported in Hong Kong. A high index of suspicion is required to avoid delay in the diagnosis of this rare disease.

Postoperative cardiac homograft involvement in Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a rare multisystem disorder which is known to affect the skin, lungs, bone, pituitary gland, retroperitoneum and cardiovascular system. The case is described of a patient with ECD who had previously undergone a Ross procedure for presumed endocarditis involving the aortic valve and aortic root. The patient subsequently developed arthralgias, abdominal pain (requiring an exploratory laparotomy) and polydipsia. Furthermore, he developed progressive, symptomatic stenosis of the pulmonic homograft. A reoperative replacement of the homograft was required. The clinically suspected diagnosis of ECD was confirmed by a pathologic analysis of the explanted pulmonary homograft, and also (retrospectively) of previously resected mesenteric tissue. It is postulated that the patient may have developed ECD as a result of an immunologic reaction to the homograft tissue used for the Ross procedure.