One month later, the patient was admitted for syncope. She had profound hypotension, and a cystic lesion in the pericardium was found on echocardiogram. In addition, she had diabetes insipidus. Although brain MRI did not reveal any visible abnormalities of the hypothalamus or pituitary stalk or gland, a presumptive clinical diagnosis of neuroendocrine involvement was made. Visual acuity subsequently worsened to no light perception in the right eye, and count fingers in the left eye, and her optic nerves became atrophic. Once she was medically stable, chemotherapy with 2-chlorodeoxyadenosine (2CdA) was begun. Cardiac and endocrine abnormalities improved, as did ocular motility. Vision remained unchanged. On MRI, the orbital masses had become smaller.
The patient received 2CdA for 1 year, and then interferon-alpha (IFN-α) was initiated to treat her residual pericardial and neuroendocrinologic disease. She received IFN-α for approximately 2 years. Her disease is now stable, and she has been maintained on thyroid replacement and desmopressin for the past year. Follow-up MRI and bone scans have shown resolution of all previous bone disease.
A 32-year-old woman with a history of asthma and polycystic ovarian syndrome presented with a 4-year history of gradually increasing proptosis and blurred vision of the left eye. Visual acuity was worse than 20/400 in the left eye, and there was a left relative afferent pupillary defect. Apart from 3 mm of left proptosis, the remainder of her ophthalmologic examination was normal. The CT scan revealed an infiltrative lesion involving the medial, lateral, and superior rectus muscles in the left orbit (Fig. 6). Left orbital biopsy and decompression were performed. Nonspecific inflammatory tissue with very few cells was seen on pathologic examination. As she was thought to have thyroid eye disease, no further treatment was given.
Follow-up imaging 6 months later demonstrated enlargement of the intraorbital process and thickening of the left temporal bone. During the next 6 months, the patient developed a bitemporal hemianopia, and neuroimaging revealed an infiltrative process within the pituitary gland (Fig. 7). Laboratory evaluation revealed panhypopituitarism. Biopsy of the sellar mass was performed via a transfrontal craniotomy. Foamy cells, which were CD68+, S100−, and CD1a−, consistent with ECD were seen on histological examination. A bone scan was performed demonstrating lytic lesions of the distal femurs and skull, which were consistent with LCH. Bone marrow biopsy showed histiocytes with an immunohistochemical profile of CD68+, S100−, and CD1a+. This result also supported the diagnosis of LCH (1,2). The patient received IFN-α, her orbital and sellar lesions decreased in size, and she has remained stable for over 1 year without recurrence of either disease.
Both LCH and ECD are rare histiocytic disorders of unknown etiology that can involve multiple organ systems that share a common CD34+ progenitor cell. However, the causal cell of LCH is derived from the Langerhans dendritic cell line, while that of ECD is derived from the monocyte-macrophage group. The disorders are characterized by specific radiographic appearances with LCH causing asymmetric lytic lesions of the flat bones and skull and ECD causing symmetric sclerosis of the long bones. However, with multisystem involvement, the disorders occasionally can be difficult to differentiate clinically, and immunohistochemical analysis is required (Table 1). Both of our patients had bony involvement due to LCH, and orbital lesions and neuroendocrine involvement presumably due to ECD.
ECD, first described in 1930 (3), is characterized by diffuse bone soft tissue infiltration with foamy histiocytes that demonstrate a specific immunohistochemical profile (CD68+, S100−, CD1a−, and no Birbeck granules). The symmetric, distal, long bone osteosclerotic lesions are considered almost pathognomonic for the disease (4). In addition, retroperitoneal, skin, brain, lung, orbit, and cardiac involvement have been reported (4). In large clinical case series (5,6), the most common nonskeletal manifestations of ECD included hypothalamic infiltration that causes diabetes insipidus (29%-47%), retroperitoneal involvement (3%-29%), exophthalmos (17%-27%), and skin lesions (19%). When ECD affects the orbit, the disease often affects the intraconal space (7). Mortality rate has been reported between 48% and 57% and most often is associated with neuroendocrinologic, cardiac, and respiratory involvement (5,6). Several treatments have been employed in ECD, including steroids (which control acute symptoms approximately 50% of the time (5)), and various chemotherapeutic regimens (2CdA and IFN-α). Radiation may also be effective, although it generally does not reduce the size of orbital lesions (5).
LCH is characterized by a mixed cellular infiltrate predominated by a clonal proliferation of immature Langerhans cells (CD68+, S100+, CD1a+, and Birbeck granules) without atypia (8). LCH can be multiostotic (formerly called eosinophilic granuloma), multisystemic (formerly called Hand-Schuller-Christian disease), or multiostotic and multisystemic (formerly called Letterer-Siwe disease). Eosinophilic granuloma represents 60%-80% of LCH (8), and bony lesions typically affect the flat bone of the skull, ribs, or pelvis (8). However, patients also can present with exophthalmos due to a nonskeletal infiltrative lesions of the orbit, diabetes insipidus, or infiltrative central nervous system lesions that involve the cerebellum, pons, or cerebral hemispheres (8). The treatment for LCH depends in part on which site is involved. Surgical curettage and/or local radiation are usually sufficient for local disease (8). However, with systemic involvement, various chemotherapeutic agents may be necessary.
The causal cell of LCH is monoclonal but not malignant (9). It is not clear whether LCH is primarily a neoplastic process or a cytokine-driven reactive disease. The pathogenesis that leads to a clonal proliferation of benign cells in LCH is poorly understood. It may be related to an undiscovered inciting event in genetically predisposed individuals that then leads to disruption of immune regulation and culminates in an alteration in cytokine production that influence histiocyte stem cells. This eventually leads to uncontrolled accrual of antigen-presenting cells at an early, yet active, stage of the cell cycle (9). In contrast, whether there is monoclonality in ECD is debated (10), and therefore, the pathogenesis of ECD remains poorly elucidated.
Coexistence of ECD and LCH in the same patient is rare (Table 2). While there are 3 reported cases (11-13) where the presence of ECD and LCH is probable in the same patient, but not proven by biopsy, we are aware of 8 reported patients with biopsy-proven ECD and LCH (14-21). Among these 8 cases, 3 had both ECD and LCH solely in the skeletal system (14-16). Among the other 4 cases, there was bony involvement of LCH combined with varying systemic involvement of ECD (bone (17-19), lung (17,18), peritoneum (17), orbit (18), or skin (19)) skin LCH with ECD involvement of the central nervous system (pontine and hypothalamic infiltration) (20), or intracerebral LCH combined with cardiac ECD (21). In our literature review, we were unable to find another case with systemic involvement similar to ours.
Several theories have been proposed to explain the coexistence of ECD and LCH. Initially, it was thought that ECD might be a manifestation of “late-stage healing” of LCH (22). However, this theory is now thought unlikely since features of the 2 disease states, including the immunohistochemical features, have been further characterized. In addition, the progenitor cell to both cell lineages has been traced to a common CD34+ cell that can be cultured in vitro to differentiate into either pathway based on its chemokine milieu (22). In theory, an abnormality in the common progenitor cell could be responsible for coexistence of the 2 disease states. Alternatively, the same inciting factor may be implicated in both diseases. Finally, it is possible that ECD and LCH fall within a spectrum of diseases attributable to an abnormal CD34+ progenitor cell. Some patients may be in an “intermediate zone” of this spectrum and demonstrate features of both diseases, based on the cytokine milieu at different points in time or in different organs. Additionally, the presence of both disease states at different points in time could represent an evolution of the disease from a Langerhans cell predominance (LCH) to a non-Langerhans cell predominance (ECD) due to a change in the patient's immune response perhaps driven by therapeutic interventions.
1. Mierau GW,
Favara BE. S-100 protein immunohistochemistry and electron microscopy in the diagnosis of Langerhans cell proliferative disorders: a comparative assessment. Ultrastruct pathol. 1986;10:303-309.
2. Favara BE,
Feller AC, Jaffe ES, Weiss LM, Arico M, Bucsky P, Egeler RM, Elinder G, Gadner H, Gresik M, Henter JI, Imashuku S, Janka-Schaub G, Jaffe R, Ladisch S, Nezelof C, Pritchard J. Contemporary classification of histiocytic disorders. The WHO committee on histiocytic/reticulum cell proliferations. Reclassification working group of the histiocyte society. Med Pediatr Oncol. 1997;37:545-555.
3. Chester W.
Uber Lipoidgranulomatose. Virchows Arch. 1930;279:561-602.
4. Stoppacciao A,
Ferrarini M, Salmaggi C, Colarossi C, Praderio L, Tresoldi M, Beretta AA, Sabbadini MG. Immunohistochemical evidence of a cytokine and chemokine network in three patients with Erdheim-Chester disease. Arthritis Rheum. 2006;54:4018-4022.
5. Veyssier-Belo C,
Cacoub P, Caparros-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 (Baltimore). 1996;75:157-169.
6. Lachenal F,
Cotton F, Desmurs-Clavel H, Haroche J, Taillia H, Magy N, Hamidou M, Salvatierra J, Piette JC, Vital-Durand D, Rousset H. Neurological manifestations and neuroradiological presentation of Erdheim-Chester disease: report of 6 cases and systematic review of the literature. J Neurol. 2006;253:1267-1277.
7. Sivak-Callcott JA,
Rootman J, Rasmussen SL, Nugent RA, White VA, Paridaens D, Currie Z, Rose G, Clark B, McNab AA, Buffam FV, Neigel JM, Kazim M. Adult xanthogranulomatous disease of the orbit and ocular adnexa: new immunohistochemical findings and clinical review. Br J Ophthalmol. 2006;90:602-608.
8. Lipton JM,
Arceci JM. Histiocytic disorders. In: Hoffman R, ed: Hematology: Basic Principles and Practice, 5th edition. London, United Kingdom: Churchill Livingston, 2008:747-760.
9. Margo CE,
Goldman DR. Langerhans cell histiocytosis. Surv Ophthalmol. 2008;53:332-357.
10. Gong L,
He XL, Li YH, Ren KX, Zhang L, Liu XY, Han XJ, Yao L, Zhu SJ, Lan M, Zhang W. Clonal status and clinicopathological feature of Erdheim-Chester disease. Pathology. 2009;205:601-607.
11. Adle-Biassette H,
Chetritt J, Bergemer-Fouquet AM, Wechsler J, Mussini JM, Gray F. Pathology of the central nervous system in Chester-Erdheim disease: report of three cases. J Neuropathol Exp Neurol. 1997;56:1207-1216.
12. Andrade VP,
Nemer CCV, Prezotti ANL, Goulart WSL. Erdheim-Chester disease of the breast associated with Langerhans-cell histiocytosis of the hard palate. Virchows Arch. 2004;445:405-409.
13. Brower AC,
Worsham F, Dudley AH. Erdheim-Chester disease: a distinct lipidosis or part of the spectrum of histiocytosis. Hematol Oncol Clin North Am. 1984;1:75.
14. Waite RJ,
Doherty PW, Liepman M, Woda B. Langerhans cell histiocytosis with radiographic findings of Erdheim-Chester disease. AJR Am J Roentgenol. 1988;15:869-871.
15. Strouse PJ,
Ellis BI, Shifrin LZ, Shah AR. Case report 710. Skeletal Radiol. 1992;21:64-67.
16. Furmanczyk PS,
Bruckner JD, Gillespy T, Rubin BP. An unusual case of Erdheim-Chester disease with features of Langerhans cell histiocytosis. Skeletal Radiol. 2007;36:885-889.
17. Kambouchner M,
Colby TV, Domenge C, Battesti JP, Soler P, Tazi A. Erdheim-Chester disease associated with prominent pulmonary involvement associated with eosinophilic granuloma of mandibular bone. Histopathology. 1997;30:353-358.
18. Narvarte S,
Sanjurjo N, Rodriguez G, Badiola A. [Erdheim-Chester disease and Langerhans histiocytosis. A fortuitous association?] An Med Interna. 2004;21:593-596.
19. Kerzl R,
Eyerich K, Eberlein B, Hein R, Weichenmeier I, Behrendt H, Clemm C, Fend F, Mempel S, Waldt S, Ring J, Mempel M. Parallel occurrence of Erdheim-Chester disease and eosinophilic granuloma in the same patient. J Eur Acad Dermatol Venereol. 2009;23:224-226.
20. Vital C,
Bioulac-Sage P, Tison F, Rivel J, Begueret H, Gomez C, Leaute-Labreze C, Diard F, Vital A. Brain stem infiltration by mixed Langerhans cell histiocytosis and Chester-Erdheim disease: more than just an isolated case? Clin Exp Path. 1999;47:71-76.
21. Granier M,
Micheau A, Serre I. A rare cause of cardiac tumour: an Erdheim-Chester disease with cardiac involvement co-existing with an intracerebral Langerhans cell histiocytosis. Eur Heart J. 2008;29: 1929.
© 2011 Lippincott Williams & Wilkins, Inc.
22. Reid CDL,
Stackpoole A, Meager A. Interactions of tumor necrosis factor with granulocyte-macrophage colony-stimulating factor and other cytokines in the regulation of dendritic cell growth in vitro from early bipotent CD34+ progenitors in human bone marrow. J Immunol. 1992;149:2681-2688.