Presence of Erdheim-Chester Disease and Langerhans Cell Histiocytosis in the Same Patient- A Report of 2 Cases

The histiocytic disorders Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD), can both present with multisystem involvement, with the central nervous system and the bone, skin, neuroendocrine, cardiac, respiratory, and gastrointestinal systems potentially affected. The 2 entities occasionally can be difficult to distinguish. Both rarely affect the orbit and the central nervous system, and although there are rare reports of patients with coexistent LCH and ECD, there are no reported cases of the 2 diseases that involve both the orbital and neuroendocrine systems. We report 2 such cases, and review the literature of cases of LCH and ECD occurring in the same patient. The presentation of LCH and ECD in certain patients suggests a possible abnormality in the common CD34 progenitor cell. The coexistence of the 2 disease states should be suspected in patients with atypical presentations of either disorder.

Presence of Erdheim-Chester Disease and Langerhans Cell Histiocytosis in the Same Patient: A Report of 2 Cases Stacy L. Pineles, MD, Grant T. Liu, MD, Xenia Acebes, MD, Jorge Arruga, MD, Sunita Nasta, MD, Ruchira Glaser, MD, Michelle Pramick, MD, Franz Fogt, MD, Peter Le Roux, MD, Roberta E. Gausas, MD Abstract: The histiocytic disorders Langerhans cell his-tiocytosis (LCH) and Erdheim-Chester disease (ECD), can both present with multisystem involvement, with the central nervous system and the bone, skin, neuroendo-crine, cardiac, respiratory, and gastrointestinal systems potentially affected. The 2 entities occasionally can be difficult to distinguish. Both rarely affect the orbit and the central nervous system, and although there are rare reports of patients with coexistent LCH and ECD, there are no reported cases of the 2 diseases that involve both the orbital and neuroendocrine systems. We report 2 such cases, and review the literature of cases of LCH and ECD occurring in the same patient. The presentation of LCH and ECD in certain patients suggests a possible abnor-mality in the common CD34+ progenitor cell. The co-existence of the 2 disease states should be suspected in patients with atypical presentations of either disorder. Journal of Neuro-Ophthalmology 2011;31:217-223 doi: 10.1097/WNO.0b013e31820a204e 2011 by North American Neuro-Ophthalmology Society Langerhans cell histiocytosis (LCH) and Erdheim- Chester disease (ECD) are rare histiocytic disorders that are associated with many clinical presentations with involvement of 1 or more organ systems. In particular, bone is affected, but skin, soft tissue, central nervous system, heart, lungs, or abdominal viscera can also be involved. Although the causative cell of LCH is derived from the Langerhans dendritic cell line and that of ECD is from the monocyte-macrophage lineage, the clinical presentations can be similar, with bony involvement most frequent in both disease states. There are several key features, particularly immunohistochemical profile, that allow LCH and ECD to be distinguished. There are rare reports of patients who present with features of both diseases, but none to our knowledge, with both orbital and neuro-endocrinologic involvement. CASE REPORTS Case 1 A previously healthy 26-year-old woman presented to the neurosurgical service with a new scalp mass. Neuroimaging revealed that the lesion involved the skull, and bilateral soft tissue masses were found in both orbits (Fig. 1). Neuro-ophthalmic examination revealed normal visual acuity, color vision, pupils, motility, and fundi. The scalp mass and involved skull were excised, and histopathological exami-nation (Fig. 2) was consistent with eosinophilic granuloma and a diagnosis of LCH. A skeletal survey did not reveal any other bony lesions. Three months later, the patient developed diplopia in upgaze. On examination, supraduction of the left eye was limited to 75% of normal. The motility disturbance was attributed to the orbital lesions, and the patient received bilateral orbital radiation (total dose 18 Gy in 10 fractions). Following radiotherapy, she remained stable, and a follow-up MRI is shown in Figure 3. One year later, the patient developed acute visual loss in the left eye. Her visual acuity measured 20/20 in the right eye and 20/50 in the left eye. Ductions of the right eye were Division of Neuro-Ophthalmology, Department of Neurology (SLP, GTL), Departments of Ophthalmology (SLP, GTL, REG), Hematology- Oncology (SN), Cardiology (RG), Pathology (FF), and Neurosurgery (PLR), Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; Departments of Neurology and Ophthalmology (XA, JA), Bellvitge Hospital, Barcelona, Spain; and Department of Pathology (MP), Pennsylvania Hospital, Philadelphia, Pennsylvania. The authors report no financial conflicts of interest related to this article. Address correspondence to Grant T. Liu, MD, Hospital of the Uni-versity of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104; E-mail: [e-mail] Pineles et al: J Neuro-Ophthalmol 2011; 31: 217-223 217 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. limited to 75% in all directions and 50% in all directions of the left eye. There was left optic disc edema. Repeat neu-roimaging showed increased size of the retrobulbar masses and coexistent sinusitis. The diagnosis of Wegener gran-ulomatosis was considered, but antineutrophilic cytoplas-mic antibody testing was negative. Symmetric diffuse uptake in both distal femurs and tibias was seen on bone scan. Because of presumed compressive optic neuropathy, the patient was started on 60 mg of prednisone daily. An orbital biopsy was canceled due to a pericardial effusion found on preoperative testing. She then developed peri-orbital xanthogranulomatous skin lesions (Fig. 4), which on biopsy revealed foamy macrophages, which were CD68+, S1002 and CD1a2 consistent with ECD. The patient eventually underwent orbital biopsy which revealed foamy histiocytes, which were CD68+, S1002 and CD1a2, also consistent with ECD (Fig. 5). The patient was maintained on 60 mg of prednisone daily for the following month and her visual acuity remained stable. 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 neuro-endocrine involvement was made. Visual acuity sub-sequently worsened to no light perception in the right eye, and count fingers in the left eye, and her optic nerves FIG. 1. Case 1. A. Contrast-enhanced T1 coronal MRI demonstrates a skull and dural-based lesion. B. Contrast-enhanced T1 axial orbital MRI reveals bilateral, symmetric, orbital soft tissue masses. FIG. 2. Case 1. Histopathologic specimen of scalp mass (3200). Foamy Langerhans cell histiocytes (arrow) are present with hematoxylin and eosin stain (A). These cells react positively with CD68 (B), S100 (C), and CD1a (D). 218 Pineles et al: J Neuro-Ophthalmol 2011; 31: 217-223 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. became atrophic. Once she was medically stable, chemo-therapy 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 in-terferon- alpha (IFN-a) was initiated to treat her residual pericardial and neuroendocrinologic disease. She received IFN-a 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. Case 2 A 32-year-old woman with a history of asthma and poly-cystic 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 ophthalmo-logic 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 path-ologic examination. As she was thought to have thyroid eye disease, no further treatment was given. Follow-up imaging 6 months later demonstrated en-largement 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 panhypopituitar-ism. Biopsy of the sellar mass was performed via a trans-frontal craniotomy. Foamy cells, which were CD68+, S1002, and CD1a2, 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+, S1002, and CD1a+. This result also supported the diagnosis of LCH (1,2). The patient received IFN-a, her orbital and sellar lesions decreased in size, and she has re-mained stable for over 1 year without recurrence of either disease. DISCUSSION Both LCH and ECD are rare histiocytic disorders of un-known 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 immunohis-tochemical 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. FIG. 3. Case 1. Contrast-enhanced T1 axial (A) and coronal (B) MRI showing bilateral enhancing orbital lesions. FIG. 4. Case 1. Bilateral upper eyelid periorbital xantho-granulomatous lesions. Pineles et al: J Neuro-Ophthalmol 2011; 31: 217-223 219 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. ECD, first described in 1930 (3), is characterized by diffuse bone soft tissue infiltration with foamy histiocytes that demonstrate a specific immunohistochemical profile (CD68+, S1002, CD1a2, 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 car-diac involvement have been reported (4). In large clinical case series (5,6), the most common nonskeletal manifes-tations of ECD included hypothalamic infiltration that causes diabetes insipidus (29%-47%), retroperitoneal in-volvement (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 asso-ciated 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 chemo-therapeutic regimens (2CdA and IFN-a). 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 pre-dominated by a clonal proliferation of immature Langer-hans 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 FIG. 5. Case 1. Orbital biopsy specimen (3200). Foamy histiocytes seen with hematoxylin and stain (A), react positively with CD68 (B) but not with S100 (C) or CD1a (D). FIG. 6. Case 2. Axial (A) and coronal (B) orbital CT scans demonstrate an infiltrative lesion involving the medial, lateral, and superior rectus muscles in the left orbit. 220 Pineles et al: J Neuro-Ophthalmol 2011; 31: 217-223 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 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 ra-diation 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 in-dividuals that then leads to disruption of immune regula-tion 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 in-tracerebral 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 co-existence 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 immu-nohistochemical 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 che-mokine milieu (22). In theory, an abnormality in the common progenitor cell could be responsible for co-existence 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 FIG. 7. Case 2. Contrast-enhanced T1 coronal MRI showing an infiltrative mass (arrows) involving the pituitary gland. TABLE 1. Features that differentiate Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) Immunohistochemical and Clinical Features LCH ECD CD68 + + S100 + 0 CD1a + 0 Birbeck granules + 0 Bone lesions Asymmetric, lytic, flat bones Symmetric, sclerotic, long bones Age at presentation Typically ,20 years old Typically .40 years old Male/female ratio Higher Equal Neurologic and neuroendocrinologic manifestations Diabetes insipidus, neurodegenerative disease Diabetes insipidus, cerebellar lesions, infiltrative or compressive lesions Commonly involved sites Liver, spleen, orbit Skin, lung, orbit, retroperitoneum, cardiac Pineles et al: J Neuro-Ophthalmol 2011; 31: 217-223 221 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 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 evo-lution 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. REFERENCES 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. TABLE 2. Published reports of coexistent Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) Authors Year Age/Sex Site of LCH* Diagnosis of LCH Site of ECD* Diagnosis of ECD Brower et al (13) 1984 66/M Tibia Biopsy Distal tibia, femurs Biopsy Waite et al (14) 1988 57/F Parietal bone Biopsy Distal tibias, femurs Radiologic Strouse et al (15) 1992 36/M Tibia Biopsy Distal tibias Radiologic Kambouchner et al (17) 1997 58/M Mandible Biopsy Lung, peritoneum, distal tibias and femurs Biopsy Adle-Biassette et al (11) 1997 50/F Skin Biopsy Long bones and brain Biopsy Vital et al (20) 1999 46/F Skin Biopsy Central nervous system Biopsy Narvarte et al (18) 2004 54/M Femur Biopsy Orbit, femur, lung Radiologic Andrade et al (12) 2004 40/F Hard palate Biopsy Breast mass Biopsy Furmanczyk et al (16) 2007 63/F Femur Biopsy Tibia Biopsy Granier et al (21) 2008 65/M Intracerebral Biopsy Cardiac, retroperitoneal fibrosis, lung Biopsy Kerzl et al (19) 2009 63/F Skull Biopsy Skin, femur Biopsy This study Case 1 2011 26/F Skull Biopsy Skin, orbit Biopsy Case 2 2011 32/F Bone marrow Biopsy Pituitary Biopsy M, male; F, female. *Site from which initial diagnosis was made, but not exclusive site of involvement. 222 Pineles et al: J Neuro-Ophthalmol 2011; 31: 217-223 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 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. 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. Pineles et al: J Neuro-Ophthalmol 2011; 31: 217-223 223 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.