Radiographs of the right tibia (Fig 1) showed patchy sclerosis in the femoral condyles and proximal and distal tibial metaphyses extending into the adjacent diaphyses, with sparing of the mid-diaphyses and of the femoral condyles. Patchy sclerosis was also seen in the proximal and distal fibula. No periosteal reaction or cortical thickening was seen. Radiographs of the left tibia and fibula (not shown) were similar.
Whole body radionuclide scintigraphy (Fig 2) indicated marked bilateral, symmetric increased uptake in the distal femora and proximal and distal tibia with sparing of the mid-tibial diaphyses. Uptake in the right hip and midlumbar spine was felt to reflect osteoarthritis. Uptake in the facial sinuses was within normal limits.
MRI of both knees (Fig 3) showed heterogeneous marrow signal abnormality about the knee, which is predominantly low on T1 and high on T2 fat saturated images and slightly more confluent in the distal femoral diametaphysis with relative sparing of the epiphyses. Few areas of low T1 and T2 signal were seen, corresponding with some of the sclerotic lesions seen on radiographs. Similar findings, although to a lesser degree, were noted in the ilia and sacrum (Fig 4).
- Multiple bone infarcts
- Paget's disease
- SAPHO syndrome
- Adult progressive diaphyseal dysplasia (Engelmann disease)
- Ribbing disease
- Fluoride intoxication
- Erdheim-Chester disease
A core needle bone marrow biopsy was performed (Fig 5). Based on the history, physical findings, radiographic studies, and histologic picture, what is the diagnosis and how should this patient be treated?
Biopsies from the right tibia show areas of marrow fibrosis with sclerotic, thickened bone trabeculae and fibroblastic proliferation (Fig 5A). Granulomas and collections of foamy, lipid laden histiocytic cells are present (Fig 5B). There is no infiltrative process to suggest Langerhans histiocytosis. Immunoperoxidase stains for CD1A and S-100 protein were negative.
DISCUSSION AND TREATMENT
The radiographic findings of bilateral symmetric bone sclerosis and increased radiotracer uptake in the metadiaphysis of the lower extremities are characteristic for Erdheim-Chester disease. The diagnosis is supported by the histologic findings. The patient was followed up for 3 years and has not developed any other known complication of this disease.
The differential diagnosis of bilateral long bone diaphyseal and metaphyseal sclerotic lesions with increased uptake on bone scintigraphy includes: multiple bone infarcts, metastasis, Paget's disease; synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome; adult progressive diaphyseal dysplasia (Engelmann disease), hereditary multiple diaphyseal sclerosis (Ribbing disease), mastocytosis, myelofibrosis, fluoride intoxication, and Erdheim-Chester disease. It is unlikely that bone infarcts, metastasis and Paget's affect the bones with the symmetry seen in this patient. With mastocytosis, myelofibrosis, and fluoride intoxication a more diffuse involvement of the skeleton would be expected. Synovitis, acne, pustulosis, hyperostosis, and osteitis usually effects younger patients and skin manifestations are evident. Engelmann and Ribbing disease tend to affect the diaphyses rather than the metaphysis or epiphysis and produce endosteal and subperiosteal cortical thickening rather than the intramedullary patchy sclerosis seen in this patient.
Based on MRI findings, the differential diagnosis is with other diffuse bone marrow abnormalities, including metastatic disease, plasma cell dyscrasias (multiple myeloma), lymphoproliferative disorders (lymphoma, Hodgkin's disease, Waldenstrom macroblobulinemia), leukemia, marrow reconversion (anemia, post-radiation, post-chemotherapy), polycythemia vera, myelofibrosis, deposition diseases (Gaucher, amyloidosis). There are no specific findings to differentiate Erdheim-Chester disease from other bone marrow abnormalities based on MRI.
Erdheim-Chester disease (ECD) is a rare, sporadic, systemic, histiocytic proliferative disease of adulthood, with constant bone involvement. In 1930, Chester, an American pathologist, and Erdheim, a Viennese pathologist, reported two patients that radiographically presented with symmetric sclerosis at the metadiaphyseal portions of several long bones and that pathologically showed infiltration by lipid-laden histiocytes.7 They distinguished them as different from other histiocytic disorders, particularly Langerhans cell histiocytosis and other lipidoses, such as Nieman-Pick disease. The name Erdheim-Chester disease was proposed by Jaffe in 1972.11
Erdheim-Chester disease equally affects men and women, usually in the fifth through the seventh decades of life.1,24,32
The clinical manifestations and course of patients with ECD vary depending on the location and degree involvement.24,34 Approximately 1/3 of patients are asymptomatic, while another 1/3 die from causes related to the visceral involvement of the disease, which can occur in virtually any organ. Skeletal symptoms usually are limited to mild pain or tenderness in the affected areas and are present in approximately 50% of patients.33 Systemic symptoms, such as weight loss and fever, are present in approximately 18% of patients.33 The more severe manifestations are typically related to the extraosseous histiocytic accumulation, which include the heart (myocardial or pericardial infiltration, leading to cardiac failure),24,33 the lungs (upper lobe or diffuse interstitial disease),8,24 the retroperitoneum (which may simulate retroperitoneal fibrosis),1,16,20,30 the kidneys (lipogranulomatous pyelonephritis),14,16,21 the perirenal space (upper urinary tract obstruction),1,4,21,33 the testicles,1,29 the pituitary stalk (diabetes insipidus),14 the cerebellum (cerebellar syndrome),17 the brain,26,31 the orbit (fat infiltration, masses, optic nerve infiltration, eye lid xanthelasma),1,6 the dura (extraaxial mass),17 the thyroid gland,29 and the lymph nodes,29 among others. Each clinical manifestation of Erdheim-Chester disease, if considered alone, can lead to an incorrect diagnosis. The only specific signs are the radiological findings and the histological features.
Skeletal involvement is constant in ECD. Complications secondary to bone involvement, such as malignant transformation or pathologic fracture have not been reported. The long bones of the limbs are invariably affected,23 with predilection for the lower extremities,33 especially at the distal femur and proximal and distal tibia. On plain radiography, the metadiaphyseal segments typically show diffuse or patchy sclerosis, a coarse trabecular pattern, and/or cortical thickening.1,5,21,24 The epiphyses are affected to a lesser degree or spared.17 In some patients, the sclerosis ends abruptly where the physis had been located.24 Some patients have marked endosteal and periosteal new bone formation, which may lead to obliteration of the corticomedullary interface.1,24 Findings are typically symmetric. Based on these radiographic findings, ECD has also been referred to as polyostotic sclerosing histiocytosis,10 to differentiate it from Langerhans cell histiocytosis, in which the bone lesions are lytic. A mixed lytic and sclerotic pattern is seen in about 1⅓ of patients.1,5 Multiple mixed lesions with sclerotic areas surrounding smaller lytic foci have been reported.4
Radionuclide scintigraphy with bone seeking radio-pharmaceuticals typically show accumulation in the distal ends of the long bones, following the radiographic abnormalities, and also occasionally in radiographically normal areas.21,27 Imaging with gallium may show a similar distribution.23 Bone marrow scanning with sulfur colloid may show decreased radionuclide activity at the sites of most intense bone-seeking radiopharmaceutical uptake,23,27 indicating absence of the reticuloendothelial system because of bone marrow replacement. Similar findings can be seen with Indium 111 chloride.27
Magnetic resonance imaging shows a pattern of bone marrow replacement with hypointense signal on T1-weighted images, when compared with the normal fatty marrow, mixed signal on fat-suppressed T2-weighted images, and enhancement on postgadolinium T1 weighted images.1,4,15,21 The decreased signal on T1-weighted images is nonspecific and can be seen in any condition that infiltrates or replaces the fatty marrow and in marrow edema and red marrow reconversion. The heterogeneous T2-weighted signal probably reflects areas of edema or inflammation (hyperintense) and areas of sclerosis (hypointense).
As described above, our patient had bone marrow replacement in diffuse and multiple round isolated areas. The diffuse pattern may be related to the confluence of multiple round histiocytic lipogranulomas. This could be confirmed with MRI and/or pathologic correlation using autopsy or gross pathology specimens. We also noted areas of abnormal MRI signal in regions that were normal on plain radiography and bone scintigraphy. Though we did not biopsy these areas, it is likely that they also represent histiocytic lipogranulomas, and that, as in other bone marrow infiltrative processes, MRI may be more sensitive for the evaluation of the extent of the disease than plain radiography and radionuclide bone scintigraphy.
Erdheim-Chester disease is best described as a proliferative histiocytic disorder, in distinction to the primary lipid storage disorders and histiocytic malignancies.34 The most typical histologic pattern is foamy histiocytic bone marrow infiltrated with associated fibrosis and thickened bone trabeculae. Erdheim-Chester disease must be distinguished from other histiocytic proliferations, such as conventional Langerhans cell histiocytosis, storage disorders, such as Gaucher's disease, bone infarcts, and secondary foamy histiocytic reactions in other bone lesions. These cells have microscopic features of ordinary histiocytes without nuclear grooves. Electron microscopy shows numerous lysosomes and lipid vacuoles without Birbeck granules. Immunophenotypically, the majority of histiocytes are negative for S100 protein and CD1A and positive for CD68.13 This distinguishes ECD from Langerhans cell histiocytosis, where CD1A and S100 are positive. Histiocytes in ECD also express alpha1-antitrypsin, alpha1-antichymotrypsin, and lysozyme. The cells of Gaucher's disease, in contrast to ECD, display a dense, fibrillary, eosinophilic cytoplasm and eccentric nuclei and may infiltrate in large sheets of cells.
Erdheim-Chester disease has been considered to be distinct from Langerhans cell histiocytosis based on the distinct radiographic appearance and the presence of ordinary lipid-laden histiocytes. However, some authors have suggested that ECD may represent an adult, disseminated form of Langerhans cell histiocytosis that behaves indolently and has features of regression.5,16 This suggestion has been based on the presence of small clusters of cells with nuclear grooves that are positive for S100 protein and CD1A, which may be found in the proliferation of ordinary histiocytes. Even though Langerhans cell histiocytosis typically affects younger patients and manifests as lytic lesions, while ECD affects older patients and shows sclerotic lesions, some believe that they are two ends of the same spectrum, ECD being the chronic or healing stage of Langerhans cell histiocytosis.5
Several treatments similar to those used in Langerhans cell histiocytosis have been tried without success.20,33 Sensitivity to chemotherapy2 and radiation therapy18 is limited. Corticosteroid treatment can be effective in some patients, alone or in combination with other drugs. Steroids have been reported to reduce arthralgias and myalgias and to improve the vital capacity secondary to lung infiltration.32 Partial response to steroid therapy has been reported in orbital masses, with the tumors increasing in size after discontinuation of the treatment.25 Sequential treatment with vinblastine and mycophenolate mofetil in combination with steroids has been reported to improve multiple sites of systemic involvement,12 and combinations of cyclophosphamide and prednisolone has been shown to decrease lung infiltration.3 Individual case reports have described the response of orbital involvement after treatment with cladribine22,28 and interferon.9
Erdheim-Chester disease is a rare systemic adult histiocytic proliferative disease with constant bone involvement. The clinical manifestations and course vary depending on the location and degree of systemic involvement, which can affect virtually any organ. Careful attention to the characteristic radiographic findings typically is the best way to correctly diagnose ECD. Bilateral symmetric long bone metadiaphyseal sclerosis and increased radionuclide uptake are distinctive skeletal radiographic features that provide the most important clue to the diagnosis.
1. Bancroft LW, Berquist TH. Erdheim-Chester disease: Radiographic findings in five patients. Skeletal Radiol
2. Boissel N, Wechsler B, Leblond V. Treatment of refractory Erdheim-Chester disease with double autologous hematopoietic stem-cell transplantation. Ann Intern Med
3. Bourke SC, Nicholson AG, Gibson GJ. Erdheim-Chester disease: Pulmonary infiltration responding to cyclophosphamide and prednisolone. Thorax
4. Breuil V, Brocq O, Pellegrino C, Grimaud A, Euller-Ziegler L. Erdheim-Chester disease: Typical radiological bone features for a rare xanthogranulomatosis. Ann Rheum Dis
5. Brower A, Worsham GF, Dudley AH. Erdheim-Chester disease: A distinct lipoidosis or part of the spectrum of histiocytosis? Radiology
6. Caparrios-Lefebvre D, Pruvo JP, Remy M, Wallaery B, Petit H. Neuroradiological aspects of Chester-Erdheim disease. Am J Neuroradiol
7. Chester W.Ülber Lipoidgranulomatose. [in Swedish] Virchows Arch
8. Egan AJ, Boardman LA, Tazelaar HD, Swensen SJ, Jett JR, Yousem SA, Myers JL. Erdheim-Chester disease: Clinical, radiologic and histopathologic findings in five patients with interstitial lung disease. Am J Sur Pathol
9. Esmaeli B, Ahmadi A, Tang R, Schiffman J, Kurzrock R. Interferon therapy for orbital infiltration secondary to Erdheim-Chester disease. Am J Ophthalmol
10. Evans S, Williams F. Erdheim-Chester disease: Polyostotic sclerosing histiocytosis. Clin Radiol
11. Jaffe HL. Lipid (cholesterol) granulomatosis. In Jaffe HL. Metabolic, degenerative and inflammatory disease of bone and joints. Philadelphia, Lea & Febiger 535-541, 1972.
12. Jendro MC, Zeidler H, Rosenthal H, Haller H, Schwartz A. Improvement of Erdheim-Chester disease in two patients by sequential treatment with vinblastine and mycophenolate mofetil. Clin Rheumatol
13. Kenn W, Eck M, Allolio B, Jakob F, Illg A, Marx A, Mueller-Hermelink HK, Hahn D. Erdheim-Chester disease: Evidence for a disease entity different from Langerhans cell histiocytosis? Three cases with detailed radiological and immunohistochemical analysis. Hum Pathol
14. Khamseh ME, Mollanai S, Hashemi F, Rezaizadeh A, Azizi F. Erdheim-Chester syndrome, presenting as hypogonadotropic hypogonadism and diabetes insipidus. J Endocrinol Invest
15. Kushihashi T, Munechika H, Sekimizu M, Fujimaki E. Erdheim-Chester disease involving bilateral lower extremities. MR features. AJR Am J Roentgenol
16. Lieberman PH, Jones CR, Filippa DA. Langerhans cell (eosinophilic) granulomatosis. J Invest Dermatol
17. Martinez R. Erdheim-Chester disease: MR of intraaxial and extraaxial brainstem lesions. Am J Neuroradiol
18. Mascalchi M, Nencini P, Nistri M, Sarti C, Santoni R. Failure of radiation therapy for brain involvement in Erdheim-Chester disease. J Neurooncol
19. Melikow MM. Primary tumors of the retroperitoneum. J Inter Coll Surg
20. Miller RL, Sheeler LR, Bauer TW, Bukowski RM. Erdheim-Chester disease: Case report and review of the literature. Am J Med
21. Murray D, Marshall M, England E, Mander J, Chakera TM. Erdheim-Chester disease. Clin Radiol
22. Myra C, Sloper L, Tighe PJ, McIntosh RS, Stevens SE, Gregson RH, Sokal M, Haynes AP, Powell RJ. Treatment of Erdheim-Chester disease with cladribine: A rational approach. Br J Ophthalmol
23. Resnik D. Diagnosis of Bone and Joint Disorders. Philadelphia, W.B Saunders, 1994.
24. Resnik D, Greenway G, Genant H. et al: Erdheim-Chester disease. Radiology
25. Rozas Reyes P, Senaris Gonzalez A, Gonzalez Rodriguez CM. Xanthogranulomatosis orbitaria. Enfermedad de Erdheim-Chester. [in Spanish] Arch Soc Esp Oftalmol
26. Rushing EJ, Bouffard JP, Neal CJ, Koeller K, Martin J, Ozdemirli M, Mena H, Ecklund JM. Erdheim-Chester disease mimicking a primary brain tumor: Case report. J Neurosurg
27. Sandrock D, Merino MJ, Scheffknecht BH, Neumann RD. Scinti-graphic findings and follow up in Erdheim-Chester disease. Eur J Nucl Med
28. Sheidow TC, Nicolle DA, Heathcote JG. Erdheim-Chester disease: Two cases of orbital involvement. Eye
29. Sheu SY, Wenzel RR, Kersting C, Merten R, Otterbach F, Schmid KW. Erdheim-Chester disease: Case report with multisystemic manifestations including testes, thyroid and lymph nodes, and a review of literature. J Clin Pathol
30. Simpson FG, Robinson PJ, Hardy GJ, Losowsky MS. Erdheim-Chester disease associated with retroperitoneal xanthogranuloma. Br J Radiol
31. Tashjian V, Doppenberg EM, Lyders E, Broaddus WC, Pavot P, Tye G, Liu AY, Perez J, Ghatak N. Diagnosis of Erdheim-Chester disease by using computerized tomography-guided stereotactic biopsy of a caudate lesion: Case report. J Neurosurg
32. Vasakova M, Fiala P, Kinkor Z. Erdheim-Chester disease: A case report. Monaldi Arch Dis
33. Veyssier-Belot C, Cacoub P,Caparrios-Lefebvre D,. Wechsler J, Brun B, Remy M, Wallaert B, Petit H, Grimaldi A, Wechsler B, Godeau P, Erdheim-Chester disease: Clinical and radiologic characteristics of 59 cases. Medicine
© 2006 Lippincott Williams & Wilkins, Inc.
34. Waite RJ, Doherty PW, Liepman M, Woda B. Langerhans cell histiocytosis with the radiographic findings of Erdheim-Chester disease. AJR Am J Roentgenol