This rare disease is characterized by a symmetrical sclerosis at the diametaphyseal portions of the lower extremities with additional extraskeletal involvement. It is rare with less than 100 cases reported in the literature. Radiographic studies reveal a bilateral, patchy or diffuse increase in density, coarsened trabecular pattern, sclerosis, and cortical thickening mainly in the metaphyses with minor changes or sparing of the epiphyses. Many internal organs and tissue sites, including the kidney and retroperitoneum, lung, pericardium, skin, orbit, and brain may occur. The symptoms and clinical manifestations depend upon the organ involved. Infiltration of the pituitary stalk may lead to diabetes insipidus while involvement of the lungs may lead to diffuse pulmonary fibrosis.
Under the microscope, there is diffuse infiltration of the affected organs by lipid-laden histiocytes and Touton-type giant cells. These cells resemble Langerhans cells but immunohistochemistry reveals important differences (see table below).
For many years, this disease has been considered a variant of Langerhans cell histiocytosis (LCH). In particular, there was similarity to a variant of LCH known as Hand-Schuller-Christian disease. However, there are important differences. Based upon these recent studies, it is likely that this disease is distinct from LCH. The prognosis is poor with progressive disease with resultant organ-system dysfunction. Mortality is 57% usually from respiratory distress, cardiac failure, or pulmonary fibrosis.
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DISEASE ASSOCIATIONS CHARACTERIZATION DIABETES INSIPIDUS
Erdheim-Chester syndrome, presenting as hypogonadotropic hypogonadism and diabetes insipidus.
Khamseh ME, Mollanai S, Hashemi F, Rezaizadeh A, Azizi F.
Endocrine Research Center, Shaheed Beheshti University of Medical Sciences, Tehran, IR Iran.
J Endocrinol Invest 2002 Sep;25(8):727-9 Abstract quote
Erdheim-Chester syndrome is a rare multisystem disease in which progressive xanthogranulomatous infiltration of several tissues are seen. Knee and leg pain are the most common symptoms and bilateral symmetric sclerosis of metaphyseal region of long bones of the lower extremity is typical. Histologically, it resembles Langerhans cell histiocytosis (LCH). However, it is still a matter of discussion whether Erdheim-Chester syndrome is a distinct entity or a type of LCH.
The present case is a 46-yr-old man, that presented with signs and symptoms of diabetes insipidus and hypogonadotropic hypogonadism simultaneously. X-rays and bone scintigraphy showed typical and pathogonomic findings of Erdheim-Chester syndrome.
Bone biopsy and immunohistochemical staining strongly support the diagnosis of non-Langerhans cell histiocytosis.
PATHOGENESIS CHARACTERIZATION CLONALITY
- Am J Surg Pathol. 2007 Feb;31(2):319-321. Abstract quote
Erdheim-Chester disease (ECD) is a rare histiocytic disorder of unknown etiology that involves predominantly bone and viscera. Whether ECD represents a reactive or neoplastic process has been debated since its initial description.
Herein, we report for the first time the cytogenetic findings of a case of ECD diagnosed at Mayo Clinic Rochester. The tumor occurred in the right tibia of a 35-year-old man and showed the balanced chromosomal translocation t(12;15;20)(q11;q24;p13.3), among other numeric chromosomal abnormalities. The lesion was positive for CD68 and negative for CD1a and S100.
These findings support the idea that some cases of ECD are clonal neoplastic disorders of putative histiocytic differentiation. However, additional studies are warranted to confirm whether the chromosomal abnormalities found in this case represent recurrent cytogenetic events.
Erdheim-Chester Disease: Case Report, PCR-Based Analysis of Clonality, and Review of Literature.
Al-Quran S, Reith J, Bradley J, Rimsza L.
Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Shands Hospital, Gainesville, Florida.
Mod Pathol 2002 Jun;15(6):666-72 Abstract quote
Erdheim-Chester disease (ECD) is a rare, distinct clinicopathologic entity with nearly pathognomonic radiographic features. The lesions consist of lipid-storing CD68 (+), CD1a (-) non-Langerhans' cell histiocytes, either localized to the bone or involving multiple organ systems in the body. Whether these histiocytic proliferations represent monoclonal neoplastic populations or are part of a polyclonal reactive process is unclear.
We present a case report of ECD in a 35-year-old African-American woman with a progressive course over 6 years. We investigated the clonality of the histiocytes using the HUMARA assay on paraffin-embedded tissue sections but did not find any evidence that these cells represent a monoclonal population.
In this report, the characteristics of ECD are reviewed, the genetic basis of the HUMARA assay is discussed, and our results in the context of other clonality investigations reported in the literature to date are summarized.
LABORATORY AND RADIOLOGIC RADIOLOGIC
- Diagnosis of Erdheim-Chester disease by using computerized tomography-guided stereotactic biopsy of a caudate lesion. Case report.
Tashjian V, Doppenberg EM, Lyders E, Broaddus WC, Pavot P, Tye G, Liu AY, Perez J, Ghatak N.
Department of Neurosurgery, Medical College of Virginia Hospitals, Virginia Commonwealth University, Richmond, Virginia 23298-0631, USA.
J Neurosurg. 2004 Sep;101(3):521-7. Abstract quote
The authors present the case of a 27-year-old woman with Erdheim-Chester disease (ECD) and extensive intracranial involvement, in whom the initial diagnosis of ECD was established based on computerized tomography (CT)-guided stereotactic biopsy of a caudate lesion. Erdheim-Chester disease is a rare non-Langerhans cell histiocytosis of unknown origin that is clinically characterized by bone pain, diabetes insipidus, and exophthalmos.
The radiological hallmarks of the disease include symmetrical sclerosis of the long bones with epiphysial sparing and increased tracer uptake in lesions seen on scintigraphic imaging. Erdheim-Chester disease is characterized histologically by the presence of infiltrating lipid-laden histiocytes that commonly involve the retroperitoneum, orbits, skin, pericardium, lungs, and long bones. Although the occurrence of diabetes insipidus often precedes the diagnosis of ECD by more than a decade in most patients, magnetic resonance imaging- and CT-documented central nervous system involvement is exceedingly rare. In the setting of neurological involvement, neurosurgical biopsy has been reported seven times in the literature, with only one of these biopsies being the basis for the initial diagnosis of the disease.
The authors' case represents only the second time the disease has been diagnosed by means of neurosurgical biopsy, highlighting the diagnostic difficulties that patients with EDC present. Skeletal radiographs were confirmatory in this case and this modality should be emphasized as the simplest and most direct route to the diagnosis. The degree of neurological involvement further distinguishes the case presented from prior reports in the literature. The multiple bilateral intraaxial lesions were intensely enhancing on contrast CT scans, distributed infra- and supratentorially, involving both white and gray matter, and associated with diffuse cerebral edema. The case presented is also remarkable by virtue of the symmetrical involvement of the caudate nuclei, representing the first such example documented in the literature.
The diagnosis, treatment, and outcome in this patient are discussed, and a review of the literature is presented.
CLINICAL VARIANTS CHARACTERIZATION GENERAL
J Clin Pathol. 2004 Nov;57(11):1225-8. Abstract quote
Erdheim-Chester disease is a rare non-Langerhans' cell histiocytosis with characteristic radiological and histological features. This entity is defined by a mononuclear infiltrate consisting of lipid laden, foamy histiocytes that stain positively for CD68. About half of those affected have extraskeletal manifestations, including involvement of the hypothalamus-pituitary axis, lung, heart, retroperitoneum, skin, liver, kidneys, spleen, and orbit.
This report describes the case of a 50 year old white man who presented with hypogonadism and diabetes insipidus. At necropsy, extensive organ involvement was found, including the testes, thyroid, and lymph nodes. This is the first report of thyroid and lymph node infiltration in this disease. Because of the endocrinological symptoms, neurosarcoidosis and hypophysitis are important diseases in the differential diagnosis.
This report also includes a review of the literature concerning rare organ manifestations and patients presenting primarily with similar symptoms.
J Oral Pathol Med. 2005 Aug;34(7):420-2. Abstract quote
BACKGROUND: Erdheim-Chester disease is a rare histiocytic disease entity related to juvenile xanthogranuloma. It is a systemic condition, usually occurs in adult, characterized by infiltration of foamy histiocytes within the bone and soft tissues.
METHODS AND RESULTS: We report a case of 13-year-old female patient who first presented with multiple osteolytic lesions of the jaws followed by bilateral symmetrical bone lesions affecting the lower extremities, as well as brain and abdominal involvement. Histological findings of the jaw lesions showed lipid-storing CD68 (+), CD1a (-) histiocytes with Touton type giant cells.
CONCLUSION: To the best of our knowledge, this is the first case of Erdheim-Chester disease with jaw bone lesions occurring as initial presenting symptom.
Erdheim-Chester disease with extensive marrow necrosis: a case report and literature review.
Kim NR, Ko YH, Choe YH, Lee HG, Huh B, Ahn GH.
Department of Diagnostic Pathology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea.
Int J Surg Pathol 2001 Jan;9(1):73-9 Abstract quote
Erdheim-Chester disease is a rare systemic disorder characterized by a fibrosing xanthogranulomatous infiltration of multiple organs.
We report a case of Erdheim-Chester disease with diffuse necrosis leading to difficulty in making a prompt diagnosis. Radiologically, osteosclerotic lesions with osteolytic element involved metadiaphyses of both proximal tibia, and retroperitoneal infiltrations encasing both kidneys, both adrenals, and aorta were found. A biopsy of the tibia showed diffuse infiltration of foamy histiocytes, Touton-type giant cells, and fibroblastic cells associated with extensive coagulative necrosis. Immunohistochemically, foamy histiocytes were positive for CD68 and peanut agglutinin and negative for S-100 protein. A few Langerhans' cells, which were difficult to identify in hematoxylin-eosin stain, were highlighted by immunostain for S-100 protein.
The patient received supportive therapy and was alive 1 1/2 years after diagnosis, with newly developed bilateral retrobulbar lesions and worsened heart failure.
Pulmonary pathology of Erdheim-Chester disease.
Rush WL, Andriko JA, Galateau-Salle F, Brambilla E, Brambilla C, Ziany-bey I, Rosado-de-Christenson ML, Travis WD.
Department of Dermatopathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.
Mod Pathol 2000 Jul;13(7):747-54 Abstract quote
Erdheim-Chester disease (ECD) is a rare non-Langerhans' cell histiocytosis that may present with pulmonary symptoms. The condition seems to be nonfamilial and typically affects middle-aged adults. Radiographic and pathologic changes in the long bones are diagnostic, but patients often present with extraskeletal manifestations. Advanced pulmonary lesions are associated with extensive fibrosis that may lead to cardiorespiratory failure.
The clinical, radiologic, and pathologic features of six patients with ECD with lung involvement are presented. The patients were three men and three women (mean age, 57). Five presented with progressive dyspnea, and one presented with diabetes insipidus. Open-lung biopsies showed histiocytic infiltrates in a lymphangitic pattern with associated fibrosis and lymphoplasmacytic inflammatory infiltrates. The histiocytes did not stain with periodic acid-Schiff. Immunoperoxidase studies performed on specimens from five of six patients showed that the histiocytes were positive for CD68 and Factor XIIIa and negative for CD1a. Specimens from two patients exhibited immunoreactivity for S-100 protein. Electron microscopy studies performed on specimens from two patients showed phagocytic lysosomes but no Birbeck granules. Clinical follow-up of up to 16 years was available. At the end of that time, five patients were dead of complications related to their disease; one patient remains alive 4 years after diagnosis but with severe respiratory compromise. ECD is a rare non-Langerhans' cell histiocytosis that may present as interstitial lung disease and resemble other pulmonary conditions, particularly usual interstitial pneumonitis and pulmonary Langerhans' cell histiocytosis.
Recognition of this entity will allow better assessment of its true incidence, therapeutic options, and prognosis.
Erdheim-Chester disease: evidence for a disease entity different from Langerhans cell histiocytosis? Three cases with detailed radiological and immunohistochemical analysis.
Kenn W, Eck M, Allolio B, Jakob F, Illg A, Marx A, Mueller-Hermelink HK, Hahn D.
Department of Radiology, University of Wurzburg, Germany.
Hum Pathol 2000 Jun;31(6):734-9 Abstract quote
Erdheim-Chester (EC) disease is a rare pathological entity with a highly specific and characteristic pattern of radiographic bone changes. Histologically it resembles Langerhans cell histiocytosis (LCH), and it is still a matter of discussion whether EC disease is a distinct entity or a type of LCH.
In this study, 3 cases of Erdheim-Chester disease were followed up over years and examined in detail both radiologically and immunohistochemically. All 3 cases showed the pathognomonic skeletal features for EC disease as well as an identical immunohistochemical phenotype quite different from LCH. Macrophages and Touton cells reacted strongly positive with the histiocytic marker CD 68, whereas staining with S100 and CD1a, markers for Langerhans cells, were negative.
Both the immunohistochemical phenotype and the bone changes were clearly distinct from LCH.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
Characteristic Erdheim-Chester Disease Hand-Schuller-Christian Disease Skeletal Symmetrical distribution of mixed lytic/sclerotic lesions Lytic lesions predominate Age 21-77 yrs with average of 54 yrs Children, adolescents, young adults Immunophenotype CD1a negative
Proliferation index <3% 3-24%
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS TREATMENT ALPHA-INTERFERON
- Variability in the efficacy of interferon-alpha in Erdheim-Chester disease by patient and site of involvement: results in eight patients.
Hôpital Pitié-Salpêtrière, Paris, France.
- Arthritis Rheum. 2006 Oct;54(10):3330-6. Abstract quote
OBJECTIVE: Erdheim-Chester disease (ECD) is a rare, non-Langerhans form of histiocytosis of unknown origin, characterized by infiltration of tissues by spumous histiocytes. ECD features heterogeneous systemic manifestations, and the general prognosis remains poor despite various treatment options.
METHODS: We treated 8 patients with multisystemic ECD with subcutaneous interferon-alpha (IFNalpha) at a dosage of 3-9 x 10(6) units 3 times weekly, for a median duration of 23 months (range 1-46 months).
RESULTS: Treatment was generally well tolerated, and side effects remained limited to fever following injections. Treatment was discontinued in 1 patient, because of severe depression. During treatment, some manifestations of ECD disappeared (i.e., xanthelasma, exophthalmos, papilledema, and intracranial hypertension). The efficacy of IFNalpha on cardiovascular ECD was variable, however. Treatment resulted in partial regression of "coated aorta" in some cases and clear failure in others; 2 patients died. The level of C-reactive protein diminished sharply in 5 patients.
CONCLUSION: IFNalpha might be a valuable first-line therapy for prolonged treatment of ECD. However, the efficacy of IFNalpha varies among patients and according to the sites of disease involvement, and symptoms may fail to respond to treatment, especially in patients with severe multisystemic forms of ECD with central nervous system and cardiovascular involvement.
- Successful treatment of Erdheim-Chester disease, a non-Langerhans-cell histiocytosis, with interferon-alpha.
Phase I Program, Division of Cancer Medicine and University of Texas Graduate School of Biomedical Sciences at Houston, Texas, USA.
- Blood. 2005 Nov 1;106(9):2992-4. Abstract quote
Erdheim-Chester disease is a rare non-Langerhans histiocytosis with multisystem involvement. To date, there is no standard treatment for this disorder, and more than half of the patients succumb within 3 years. Because interferon-alpha promotes the terminal differentiation of histiocytes and dendritic cells, we hypothesized that this molecule would be a useful therapy for Erdheim-Chester disease.
We therefore treated 3 patients with advanced disease with interferon-alpha at a starting dose of 3 to 6 x 10(6) units, which was later reduced, during maintenance, to 1 x 10(6) units subcutaneous 3 times per week. Marked improvement was noted in all patients, with substantial retro-orbital disease regression within 1 month. Improvement in bone lesions, pain, diabetes insipidus, and other manifestations was gradual over many months. Responses were durable (3+ to 4.5+ years).
Our observations suggest that this well-tolerated therapy has a significant effect on the course and outcome of Erdheim-Chester disease.
Arch Phys Med Rehabil. 2005 May;86(5):1053-7. Abstract quote
Erdheim-Chester disease is a distinctive pathologic and radiographic entity characterized by bilateral symmetric sclerosis of the diametaphyseal regions of long bones and infiltration of foamy lipid-laden histiocytes. It is a rare histiocytic disease of unknown etiology that is characterized pathologically by xanthogranulomatous infiltrates of multiple organs.
We present a patient in her early sixties with bilateral mild knee and leg pain. The patient showed a typical bilateral symmetric medullary sclerosis at the diametaphyseal portions of long bones of the lower extremity. The diagnosis was confirmed by a bone biopsy, and bisphosphonate (alendronate, 70 mg/wk) was given to the patient. After 9 months of treatment, biochemical markers of bone turnover, which were high at baseline, decreased to normal ranges. However, the radiographs showed that bone lesions had changed to lytic lesions.
We propose use of bisphosphonates, such as alendronate, to decrease the biochemical markers of bone turnover. But we suggest that it is premature to conclude that bisphosphonates have any effect on lytic lesions and the progression of the disease as shown by changes in radiographs. Further studies with long-term follow-up and ultrastructural evaluation are needed.
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