Xanthoma disseminatum - BIR Publications

The British Journal of Radiology, 78 (2005), 153–157 DOI: 10.1259/bjr/27500851

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2005 The British Institute of Radiology

Case report

Xanthoma disseminatum: a case report and literature review 1

A S ALEXANDER, MD, 2R TURNER, MDCM, FRCP(C), 3L UNIATE, MD, FRCS(C) and 1 R G PEARCY, MBBS, FRCP(C) 1

Department of Oncology, Division of Radiaion Oncology and 2Department of Oncology, Division of Medical Oncology, Cross Cancer Institute, University of Alberta, 11560 Univerisity Avenue, Edmonton, Alberta T6G 1Z1 and 3Department of Ophthamology, University of Alberta, Edmonton, Alberta, Canada

Abstract. This case report describes the neuro-opthalmologic and respiratory manifestations of xanthoma disseminatum, a rare histiocytosis syndrome characterized by disseminated lesions in a young male adult. Multimodality management of this disease, including the role of local radiotherapy, is discussed accompanied by a review of the literature.

Xanthoma disseminatum (XD) is a rare, benign proliferative disorder in children and adults characterized by disseminated xanthomatous lesions [1]. Since this condition was first described in 1938 by Montgomery and Osterberg [2], only approximately 100 cases have been reported in the literature [3]. Categorised as a histiocytosis syndrome, XD shares the common feature of mononuclear phagocyte proliferation [4–7]. XD typically involves the skin, particularly the flexor skin folds and eyelids [8]. XD may also manifest in the central nervous system (CNS), ocular structures, and respiratory and gastrointestinal tracts [9]. While the natural history of XD is usually benign with spontaneous resolution of cutaneous lesions over 2–40 years [8, 10], lesions in critical anatomical locations may result in morbidity and mortality [1, 11]. Curative therapy for XD is lacking. While symptomatic lesions may be managed with conservative surgery, the roles of radiotherapy (RT) and chemotherapy are unclear [12–16]. We report a complex case of XD in a young male subject that illustrates the neuro-ophthalmologic and respiratory manifestations of the disease. The case highlights the importance of a multimodality approach in supportive management and describes the use of RT in stabilizing symptomatic lesions. A review of the published literature on XD is also included; a medline search was conducted to find all articles, in all languages on XD, from 1966 to 2003. Medical subject headings (MeSH) used to search the medline database included histiocytosis syndromes, including subheadings of pathophysiology, drug therapy, radiotherapy and surgery, as well as keyword search using ‘‘xanthoma disseminatum’’. A total of 591 articles were originally identified. Limiting the findings to human data and English language reduced the number of publications to 448. Titles and abstracts of potentially relevant articles were reviewed by a single author. To be accepted in the review, publications had to include data on the pathophysiology of XD, patients with CNS XD lesions, or case

Received 15 March 2004 and in revised form 13 August 2004, accepted 11 October 2004.

The British Journal of Radiology, February 2005

reports/case series involving the therapeutic management of the condition.

Methods of diagnosis The patient was diagnosed with XD on September 1999 at the age of 18 years after an initial presentation with vision loss, polyuria, polydipsia, and yellow-brown papules involving the face, eyelids, neck and trunk. MRI of the brain revealed multiple foci of abnormally high signal lesions measuring ,1 cm involving the pons, cerebellum, temporal horns, pituitary fossa and right optic nerve (Figure 1). Laboratory studies confirmed the presence of central diabetes insipidus (DI), a blunted luteinizing hormone response, but otherwise normal pituitary hormone levels. Biopsy of a cutaneous chest wall lesion revealed benign dermal histiocytes. Touton and foreign body giant cells were identified causing nodular expansion of the dermis. Langerhans cell histiocytosis (LCH) was ruled out in the absence of Birbeck granules on electron microscopy. Immunohistochemistry was positive for CD68 and negative for S-100. Based on these clinical and pathological findings, a diagnosis of XD was established.

Case Prior to the XD diagnosis, the patient’s past medical history was significant for tibial osteogenic sarcoma diagnosed at age 13 years, treated on a trial protocol with pre- and post-operative chemotherapy (etoposide, cisplatin, adriamycin, ifosfamide) in conjunction with surgery. Complete clinical and radiographic response was achieved with no evidence of recurrent sarcoma at subsequent follow-up. After the diagnosis of XD, the patient received DDAVP nasal spray therapy with improvement of his DI but a trial of high dose prednisone failed to improve his vision. In the spring of 2001, he was referred to the Radiation Oncology Department at the Cross Cancer Institute with bilateral central vision loss, confirmed on visual field (VF) testing. MRI of May 2001 revealed displacement of the optic chiasm inferiorly by a mass arising from the optic pathway and foreshortening of both optic nerves. Multiple 153

A S Alexander, R Turner, L Uniate and R G Pearcy

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(b)

Figure 1. (a) Transverse and (b) sagittal spin echo MRI images of the brain demonstrating multiple lesions in the pons, cerebellum, temporal horns, pituitary fossa and right optic nerve.

enhancing foci were noted in the pons, the cerebellar hemispheres, and the lateral ventricles. Repeat MRI of the brain 1 month later showed disease progression, accompanied by worsened vision, right hearing loss, and ataxia. A 1 week trial of intravenous cladribine was administered resulting in slight clinical improvement in vision. Given the severe, progressive vision loss and a neurosurgical opinion that resection was not feasible, the decision was made to manage the chiasm mass with radiotherapy. The patient was started on dexamethasone 4 mg po TID to prevent acute RT-induced cerebral oedema. He then underwent pre-treatment CT planning in the supine position with Perspex shell immobilization. The RT course was delivered in two phases using a 6 MV linear accelerator. Phase I consisted of a pair of parallel opposed (POP) fields encompassing the chiasm, the suprachiasmatic mass and pituitary contents, plus a 2 cm margin. The prescribed dose was 16 Gy in 8 daily fractions over 1K weeks. Phase II consisted of a reduced field boost to the chiasm and suprachiasmatic mass with a 1 cm margin, using a 3-field beam arrangement, for an additional 14 Gy in 9 fractions over 2 weeks. VF testing early in therapy showed only a small island of vision in the right eye, and worsening of the temporal field in the left eye (Figure 2a). Following RT completion, vision in the left eye stabilized, with mild improvement in the right eye (Figure 2b) Over the subsequent 4 months, continued objective improvement was demonstrated on VF testing (Figure 2c,d) accompanied by subjective improvement in vision. Although the patient’s vision stabilized, his driver’s license was revoked due to the lack of 120 ˚ of peripheral vision. Later that year the patient developed back pain, leg weakness and altered sensation. An intramedullary lesion from T6–T9 was demonstrated on MRI and was surgically 154

treated with resection and laminectomy which restored motor and sensory function In the spring of 2001 the patient developed dyspnoea and stridor confirmed on endoscopy and biopsy to be secondary to XD causing subglottic stenosis. The stenosis was managed with surgical dilatation with symptomatic relief but the patient required further repeated dilatations for recurrent airway symptoms in the subsequent months. 5 months after RT to the chiasm, the patient experienced neurological deterioration with worsening ataxia from cerebellar disease progression. A trial of intrathecal cytarbine, prednisone and etoposide was unsuccessful. Beginning in May 2002 the patient underwent RT to the posterior fossa with lateral photon fields, 21 Gy in 15 daily fractions. MRI after RT demonstrated stabilization of the brainstem and cerebellar disease with continued local control of the pituitary mass. In November 2002, the patient developed further bronchial lesions, not amenable to surgical management. Palliative RT was again used to treat the larynx, trachea, carina, and main stem bronchi with 15 Gy in 10 daily fractions. 2 months later, although the respiratory disease was stable clinically and radiologically, the pituitary lesion progressed after 1K years of control. The patient died in March 2003, of presumed respiratory failure. No autopsy was performed. The likely causes of death include airway obstruction or pulmonary embolus.

Discussion The present report illustrates a devastating course of XD in a young adult, characterized by progressive CNS and airway disease leading to numerous clinical problems. Chemotherapeutic agents and steroids produced little The British Journal of Radiology, February 2005

Case report: Xanthoma disseminatum

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Figure 2. Visual field (VF) testing at the beginning of radiotherapy (a), displaying loss of the temporal VF in the left eye (top), and a small island of vision in the right eye (bottom). VF testing at the end of radiotherapy (b) shows stabilization of left eye vision (top), and mild improvement of the right eye VF (bottom). VF testing 4 months post-radiotherapy shows (c) further improvement in the left eye inferior VF, and (d) expansion of the nasal VF in the right eye.


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A S Alexander, R Turner, L Uniate and R G Pearcy Table 1. Summary of the results of treatment of symptomatic xanthoma disseminatum lesions with various modalities from published case series and reports

Chemotherapy (n58) Clofibrate (n53) Radiotherapy (n54) Steroids only (n52) Surgery (n54) Surgery + chemotherapy (n51)

CR

PR

SD

PD

Reference

1/8 — — — 1/4 1/1

2/8 1/3 2/4 1/2 3/4 —

1/8 1/3 — — — —

4/8 1/3 2/4 1/2 — —

[8], [9], [25], [26], [31] [8], [22], [28] [9], [10], [27], [32] [8], [25] [8], [24], [33], [34] [35]

CR, complete response (complete resolution of lesion); PR, partial response (measurable decrease in lesion size); SD, stable disease (no change in size of lesion); PD, progressive disease (measurable increase in lesion size).

objective response. Surgical dilatation was useful to relieve respiratory tract obstruction. For lesions involving critical structures including the CNS and respiratory tract that were not amenable to surgical intervention, local RT temporarily provided symptom control and stabilization of disease progression. The diagnosis of XD is based on pathological and clinical grounds. Biopsy findings of histiocytic proliferation suggest a histiocytic disorder. Immunophenotyping and ultrastructural studies are required to establish the diagnosis. CD68 positivity supports a histiocytic origin [17]. Absence of S-100 binding and Birbeck granules on electron microscopy rules out LCH [4, 18–20], an important diagnostic consideration since LCH is responsive to cytostatic therapy [17]. Touton giant cells represent an exaggerated xanthomatoid reaction pattern [21] are typical of xanthomatous histiocytoses and are absent in LCH [9, 22, 23]. These pathological findings, along with the clinical manifestations involving the skin, CNS, eyes, and respiratory tract are all consistent with a diagnosis of XD. Numerous systemic modalities have been utilized in attempts to manage the disease, but none have proven particularly successful. Table 1 summarizes the results of published case series and reports utilizing various treatment modalities. While corticosteroids may produce rare responses [24], most reports utilize steroids in combination with other therapies; the efficacy of steroid monotherapy appears dubious [8, 25–27]. Occasional responses have been observed with the anti-lipemic agent clofibrate [22, 25, 28]. Antineoplastic agents including vinca alkaloids, alkylating agent, and anti-metabolites generally produce little objective responses in the limited number of reported cases [9, 10, 16, 29, 30]. Stojkovic [31] reported symptomatic improvement in a young female with non-LCH CNS lesions treated with combined corticosteroid and chemotherapy. Reports of local management for XD are also characterized by diverse approaches with various results [9, 10, 29]. Cryotherapy for single lesions has not been successful [26]. Surgery appears to give the best results for readily accessible lesions [8, 24, 33, 34]. The effectiveness of RT is unclear due to the limited number of cases reporting conflicting results. Mahrel et al [27] found no improvement in pituitary XD lesions in an adult male using an RT dose of 18 Gy combined with steroids. Another report described a lack of response after external beam RT to cutaneous XD lesions involving the face and neck [32]. In contrast, Moloney [9] reported one case where airway disease control was achieved after Cobalt 156

irradiation to a dose of 34 Gy over 22 days. Additionally, RT has shown promise in the treatment of juvenile xanthogranuloma, a non-LCH condition pathologically similar to XD [30]. It is important to note that for all therapeutic modalities, the duration of response is extremely variable. The present report suggests that RT has a role in palliating local symptoms caused by unresectable lesions invading critical structures in the CNS and respiratory tract. An objective response to RT, as illustrated by serial visual field testing, was demonstrated in this case. However, reports of clinical responses must be interpreted with caution since XD has the potential to undergo spontaneous resolution. Caputo et al [8] reported three classifications of XD characterized by their evolution and prognosis: a self-healing form, which typically regresses without intervention, a persistent form and a progressive form. From the clinical course and pattern of spread, our patient most likely suffered the progressive form, thus it is unlikely that spontaneous regression was responsible for the observed clinical response to radiotherapy. Acknowledging the difficulty in defining the optimal RT dose and fractionation for XD due its rarity, given the benign histology and potential for a prolonged clinical course, relatively low dose fractionated courses to symptomatic lesions would be reasonable to minimize the risks of late normal tissue toxicities. The objective and subjective clinical response achieved in the present case employing contemporary radiotherapy equipment and techniques suggests that targeted RT to doses of 20– 30 Gy in 1.4–1.8 Gy per fraction is safe, well-tolerated, and capable of disease stablization and symptom control.

References 1. Giller R, et al. Xanthoma disseminatum: an unusual histiocytosis syndrome. Am J Pediatric Hematology/ Oncology 1988;10:252–7. 2. Montgomery H, Osterberg A. Xanthomatous correlation of clinical, histopathalogical, and chemical studies of cutaneous xanthoma. Arch Dermatol Syphilol 1938;37:373–402. 3. Zeleger B, Cerio R, Orchard G, et al. Histologic and immunohistochmical study comparing xanthoma disseminatum and histiocytosis X. Arch Dermatol 1992;128:1207–12. 4. Casset F, Nezlof C, Ferrans V. The histiocytosis. Pathol Ann 1982;27–78. 5. Crocker A. The histiocytoses syndromes. In: Fitzpatrick TB, Eisen AZ, Wolff R, Freedberg IM, Austen FF, editors. Dermatology in general medicine. New York: McGraw-Hill, 1987:1937–46.


Case report: Xanthoma disseminatum 6. Favara B. The pathology of the histiocytoses. Am J Pediatric Hematology/Oncology 1981;3:45–56. 7. Roper SS, Spraker MK. Cutaneous histiocytosis syndromes. Pediatric Dermatology 1985;3:19–30. 8. Caputo R, et al. The various clinical patterns of xanthoma disseminatum: consideration of 7 cases and review of the literature. Dermatology 1995;190:19–24. 9. Moloney JR. Xanthoma disseminatum: its otolaryngological manifestations. J Laryngol Otology 1979;93:201–10. 10. Flach DB, Winkleman RK. Juvenile xanthogranuloma with CNS lesions. J Am Acad Dermatol 1986;14:405–11. 11. Davies CWE, Juniper MC, Wojnorowka F, Benson MK. Xanthoma disseminatum with respiratory involvement and fatal outcome. Thorax 2000;55:170–2. 12. Greenberger JS, et al. Radiation therapy in patients with histiocytosis: management of diabetes insipidus and bone lesions. Int J Radiat Oncol Biol Phys 1979;5:1749–55. 13. Greenberger JS, et al. Results of the treatment of 127 patients with systemic histiocytosis. Medicine 1981;60: 311–38. 14. Lahey ME. Histiocytosis X: comparison of 3 treatment regimens. J Pediatr 1975;87:179–83. 15. Urbano-Marquez A, et al. Etoposide in the treatment of multifocal eosinophillic granuloma. Cancer Treatment Rep 1985;69:238–9. 16. Burgdorf WHC, Duray P, Rosai J. Immunohistochemical identification of lysozyme in cutaneous lesions of alleged histiocytic nature. Am J Clin Path 1981;75:162–7. 17. Weiss N, Keller C. Xanthoma disseminatum: a rare normolipemic xanthomatosis. Clinical Investigator 1993;71: 233–8. 18. Writing group of the histiocytosis society. Histiocytosis syndromes in children. Lancet 1987;1:208–9. 19. McMillan EM, et al. Analysis of histiocytosis X infiltrates with monoclonal antibodies directed against cells of histiocytic, lymphoid, and myeliod lineage. Clin Immunol Immunopath 1986;38:295–301. 20. Harrist TJ, et al. Histiocytosis X: in situ characterization of cutanwous infiltrates with monclonal antibodies. Am J Clin Path 1983;70:204–300.


21. Zelger B, Sidoroff A, Orchard G, Cerio R. Non-Langerhans cell histiocytoses: a new unifying concept. Am J Dermatopathol 1996;18:490–504. 22. Kumakiri M, et al. Xanthoma disseminatum: report of a case with histologic and ultrastructural studies of skin lesions. J Am Acad Dermatol 1983;4:291–9. 23. Blobstein SH, Caldwell D, Carter M. Bone lesions in xanthoma disseminatum. Arch Dermatol 1985;121:1313–7. 24. Kalz F, Hoffman MM, Lafrance A. Xanthoma disseminatum – clinical & laboratory observations over a ten year period. Dermatologica 1970;140:129–41. 25. Nanda A, et al. Xanthoma disseminatum. Int J Dermatology 1990;29:727–8. 26. Kuligowski M, et al. Xanthoma disseminatum. Int J Derm 1992;31:281–3. 27. Manhrel R, et al. Problems in the differential diagnosis of non-Langerhans cell histiocytosis with pituitary involvment: case report and review of the literature. Endocrine Pathology 2002;13:363–8. 28. Miskel MA, Cocksott P, Nazir DJ, et al. Xanthoma disseminatum: clinical, metabolic, pathologic, and radiologic aspects. Arch Dermatol 1977;113:1094–100. 29. Leibman SD, et al. Corneal xanthomas in childhood. Arch Ophthalmol 1966;76:221–9. 30. Aristizabal S, Runyon T. Radiotherapy for unusual benign disease. Int J Radiat Oncol Biol Phys 1983;7:1437–40. 31. Stojkovic T, et al. Atypical form of non-Langerhans histiocytosis with disseminated brain and leptomeningeal lesions. J Neurol Neurosurg Psychiatry 2000;69:675–8. 32. Finney W, Montgomery H, New GB. Xanthoma multiplex: two cases in volving the larynx and trachea and associated with diabetes insipidus. JAMA 1932;99:1071–4. 33. Hammond RR, Mackenzie IR. Xanthoma disseminatum with massive intracranial involvement. Clin Neuropathol 1995;14: 314–21. 34. Cauro F, Houtteville JP, Mesnil JL, Guarnieri J. Cerebellar, pulmonary, and cutaneous localizations of juvenile xanthogranuloma. Ann Dematol Venereol 2002;129:307–10. 35. Rampini P, et al. Isolated cervival juvenile xanthogranuloma in childhood. Spine 2001;26:1392–5.

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