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Background
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.
OUTLINE
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
*Division of Anatomic Pathology daggerSection of Cytogenetics double daggerDepartment of Radiology, Mayo Clinic, Rochester, MN.
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
- Erdheim-Chester disease: case report with multisystemic manifestations including testes, thyroid, and lymph nodes, and a review of literature.
Sheu SY, Wenzel RR, Kersting C, Merten R, Otterbach F, Schmid KW.
Institute of Pathology, University of Essen, 45122 Essen, Germany.
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.
VARIANTS JAW
- Erdheim-Chester disease in a child presenting with multiple jaw lesions.
Nagatsuka H, Han PP, Taguchi K, Tsujigiwa H, Gunduz M, Fukunaga J, Sugahara T, Asaumi J, Nagai N.
Department of Oral Pathology and Medicine, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan.
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.
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
S-100 negative
CD68 positiveCD1a positive
S-100 positive
CD68 negativeProliferation index <3% 3-24%
PROGNOSIS AND TREATMENT CHARACTERIZATION PROGNOSIS TREATMENT ALPHA-INTERFERON
Hôpital Pitié-Salpêtrière, Paris, France.
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.
Phase I Program, Division of Cancer Medicine and University of Texas Graduate School of Biomedical Sciences at Houston, Texas, USA.
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.BIPHOSPHONATES
- Erdheim-Chester disease: the effect of bisphosphonate treatment--a case report.
Eyigor S, Kirazli Y, Memis A, Basdemir G.
Department of Physical Therapy and Rehabilitation, Ege University Medical Faculty, Izmir, Turkey.
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.Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fifth Edition. Mosby Elesevier 2008
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