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Primary mandibular xanthoma: case report Melissa Rodrigues de Araujo, DDS,a Rafaela Scariot, DDS,a Lucas Uetanabaro,b Larissa Luvison Gomes da Silva, MD,c and Allan Fernando Giovanini, DDSa Xanthoma is a very rare bone tumor, especially in the mandible, that can be associated with metabolic diseases such as hyperlipidemia. A 14-year-old girl presented with a non-corticated unilocular radiolucent lesion observed on panoramic radiography. The lesion was located between the roots of the left first and second premolar teeth, extending from the cervical to the apical region, measuring approximately 1 cm in greatest dimension. An excisional biopsy revealed foam cells and occasional nonfoamy mononuclear macrophageelike cells spread among a discrete fibrous stroma. Immunohistochemically, the xanthomatous cells were CD68 and vimentin positive, focally positive for S100, CD1a, and CD3 and negative for AE1/ AE3, CD20, CD117, and HMB45. Hematologic and biochemical investigations ruled out systemic disease. (Oral Surg Oral Med Oral Pathol Oral Radiol 2015;-:e1-e6)

Xanthoma is a benign lesion that originates from an abnormal deposition of yellow pigment in certain regions of the skin. This tumor is characterized by the presence of mononuclear macrophageelike cells, foam cells, and multinucleated giant cells. Occasionally, spindle cells are present, which qualifies this lesion as a subset of benign fibrous histiocytoma of bone.1 Xanthomatous lesions may be composed of lipid-laden histiocytes, which are often seen in patients with hyperlipidemic conditions.2 The lesion is deemed a primary xanthoma after other diseases are excluded.3 Xanthoma of the cranium, which is a rare diagnosis, has been observed to have a predilection for affecting the temporal bone.4 Only three cases of xanthomas of bone involving the mandible have been described.5-7 Mateo et al. (2004)5 reported an 11-year-old girl presenting with a poorly defined lesion, which caused asymmetry in the left mandible. A diffuse, unilocular, radiolucent lesion with irregular margins in the mandible was described in a 25-year-old man.6 A left mandibular intraosseous lesion was also reported.7 Xanthoma lesions are usually lytic and expansile, and cranial osteolysis with destruction of the cortical bone is considered a characteristic image of the lesion.3,4,7

CASE REPORT A 14-year-old Caucasian girl was referred to an oral and maxillofacial surgeon in order to evaluate a lesion in the mandible, which was observed after routine panoramic radiography during orthodontic treatment. There was no history of trauma or infection. The patient’s general health was good, and her medical history was uncomplicated, except for a

Professor of the Graduate Program in Clinical Dentistry, Positivo University, Paraná, Brazil. b MSc student at the Graduate Program in Clinical Dentistry, Positivo University, Paraná, Brazil. c Histopathology Physician, Citopar, Centro de Citologia e Patologia Paraná, Paraná, Brazil. Received for publication Jun 6, 2014; returned for revision Jan 20, 2015; accepted for publication Jan 25, 2015. Ó 2015 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2015.01.015

allergic bronchitis. Intraoral examination revealed normal oral mucosa and no signs of swelling or color alterations. The neighboring teeth were vital and without pain on percussion. She denied any pain. A panoramic radiography taken in 2010d3 years before initiation of the orthodontic treatmentddid not show any abnormalities (Figure 1). Panoramic radiography performed at the appointment revealed a unilocular radiolucent lesion in the mandible with non-corticated borders. The lesion was located between the roots of the left first and second premolar teeth extending from the cervical to the apical region, measuring approximately 1 cm in width. The periodontal ligament space was not preserved, and no root resorption was detected (Figure 2). In order to establish the diagnosis, an excisional biopsy was performed with the patient under local anesthesia with intravenous sedation. Aspiration was negative. During surgery, a cavity was made with a bur to access the lesion, since there was no continuity between it and the oral cavity. Curettage removed a soft, yellowish material, which was submitted for histologic analysis. Upon gross specimen examination, multiple surgical yellow and firm fragments of a mass measuring 3  2  2 mm were identified. On histologic examination, tumor mass was predominantly composed of sheets of polygonal cells, with epithelioid morphology that revealed distinct cell borders in a background stroma composed of fibrous and vascular stroma. Singly, the cell presented clear or eosinophilic cytoplasm and also exhibited a hyperchromatic nucleus without evident nucleoli (Figure 3). On immunohistochemistry analysis (Table I), the lesional cells revealed strong positivity for vimentin and CD68 while demonstrating a scarcity of S100þ, CD3þ, and CD1aþ cells. CD34 and a-smooth muscle actin were present in the vascular area that compounded the tumor stroma, and the desmin, Ki67, CD117, CD20, pan-cytokeratin (AE1/AE3), HMB-45, and mycobacterium tests were negative (Figure 4). The histopathologic and immunohistochemical findings supported a diagnosis of an intrabony mandibular xanthoma. The patient underwent biochemical investigations consisting of complete blood count, glucose, cholesterol (total, LDL and HDL), serum calcium, alkaline phosphatase, and parathyroid hormone levels, which were all within normal limits. Panoramic radiography taken 1 year (Figure 5) after surgery showed that the lesion had regressed. The lesion although present, was smaller. Both premolars have remained vital.

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Fig. 1. Panoramic radiography 3 years prior.

Fig. 2. Panoramic radiography demonstrating a unilocular radiolucent lesion with a non-corticated border located between the roots of the mandibular left first and second premolars. The patient will be followed up until complete bone repair is confirmed.

DISCUSSION Xanthoma of bone is a rare disorder caused by cholesterol deposition. It may be associated with lipid, cholesterol, or glucose metabolism and may be associated with cutaneous manifestations.8 The solitary form of the disorder appears frequently in the diaphysis of long bones; however, the cranium can also be affected.4,9,10 Other locations in the facial skeleton may be involved, including, as in our case, the mandible, which is a flat bone. The tumor appears around 20 years of age in a ratio of 2:1 in men and women, respectively,3 Boisgard et al.

(2000)11 pointed out its occurrence in the third and fifth decades. The incidence of xanthomas in the jaws is difficult to establish, since several lesions have been described as xanthomatous lesions and inaccurate terms may have been used in the diagnosis.6,12 The pathogenesis of primary bone xanthoma suggests that the lesions may be a phenomenon that is secondary to some pre-existing process, such as a senescent or degenerative stage of a fibrous defect, giant cell tumor, fibrous dysplasia, simple bone cyst, aneurysmal bone cyst, or brown tumor resulting from hyperparathyroidism.7 In our case, the lesion was not associated with a brown tumor caused by hyperparathyroidism, since the results of the

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Fig. 3. Photomicrographs of the surgical specimen stained with hematoxylin and eosin showing a solid tumor surrounded by discrete connective and hemorrhagic stroma (A). Details of lesion (100) (B), foam like cells at 200 (C), and 400 of magnification (D). A high-resolution version of this slide is available as eSlide: VM00410.

Table I. Immunohistochemical antibodies used Antibody

Type of antibody

Immunoexpression

CD68 (KP1)

Monoclonal

þþþ

CD1a (Clone MTB1)

Monoclonal



S100 protein CD34 (clone QBEND/10) SMA (clone 1 A4) CD3 Pan T CD20 Pan B (Clone L26) CD117 Ki67 (SP6) AE1/AE3 (Clone AE1/AE3) Desmin (D33) Vimentin (clone V9) HMB-45 (Clone HMB-45) Mycobacterium BCG

Polyclonal Monoclonal Monoclonal Polyclonal Monoclonal Polyclonal Monoclonal Monoclonal Monoclonal Monoclonal Monoclonal Polyclonal

   þ      þþþ  

Dilution; Laboratory 1:300; DaKoCytomation, Dako North America, Inc., Carpinteria, CA, USA 1:15; Vector, Vector Laboratories Inc., Burlingame, CA, USA. 1:1000; DaKoCytomation 1:200, DaKoCytomation 1:150 DaKoCytomation 1:100; DaKoCytomation 1:100; DaKoCytomation 1:400; DaKoCytomation 1:100 MIB-1 M0634 DaKoCytomation 1:450 DaKoCytomation 1:150; DaKoCytomation 1:300; DaKoCytomation 1:300 DaKoCytomation 1:5000 DaKoCytomation

þþþ Strong immunoreaction; þ scarce positive cells;  negative immunoreaction.

hematologic examination for alkaline phosphatase were normal. Our patient could not remember any trauma to her jaw, which would exclude simple and aneurysmal bone cysts. One particular characteristic might be considered: This is the second reported case of a xanthoma diagnosed in a patient during orthodontic treatment.6 Intraosseous lesions containing lipid-filled macrophages that are not associated with generalized lipid disorder may be seen on very rare occasions.3,6 Xanthomas in the jaw are extremely raredall cases seem to be primary and occur almost exclusively in the

mandible.5-7 Our patient did not have any altered levels of lipidemia or cholesterolemia. Bone xanthomas in the skull associated with hyperlipidemia and hypercholesterolemia are well described in the literature.4,9,13 Multiple lesions are usually associated with systemic disease6; however, our patient presented with a single lesion. Xanthomatous bone lesions may occur in all five subtypes of essential hyperlipidemia, as well as in diseases associated with secondary hyperlipidemia (e.g., diabetes mellitus); hence, it is important to investigate systemic lipid diseases.14 A medical workup involving biochemical

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Fig. 4. Immunohistochemical panel revealing positivity for CD68 (A, B). Micrographs (C) and (D) reveal a lack of substantial positivity for CD1a and S100 proteins, respectively, in the tumor, whereas CD34 (E) and a-smooth muscle actin (SMA) (F) were positive only in the vascular area of the connective stroma but not in the lesional cells. Photomicrograph (G) demonstrates scarce positivity for CD3, and (H), (I), (J), (K), and (L) reveal negativity for CD20, CD117, Ki67, AE1, AE3, and Desmin, respectively. Micrograph (M) shows intense positivity for vimentin, and (N) and (O) negativity for HMB-45 and Mycobacterium BCG (original magnification 100). High-resolution versions of the slides for use with the Virtual Microscope are available as eSlide: VM00441 (CD68); eSlide: VM00442 (CD68); eSlide: VM00446 (CD1a); eSlide: VM00443 (S100); eSlide: VM00444 (CD34); eSlide: VM00445 (SMA); eSlide: VM00447 (CD3); eSlide: VM00448 (CD20); eSlide: VM00449 (CD117); eSlide: VM00450 (CDKi67); eSlide: VM00451 (AE1/AE3); eSlide: VM00452 (Desmin); eSlide: VM00453 (Vimentin) and eSlide: VM00454 (Mycobacterium BCG), respectively.

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Fig. 5. Panoramic radiography taken 1 year after surgery demonstrating regression of the lesion.

analysis of serum cholesterol, triglycerides, protein, and lipid electrophoresis should be performed.12 The histopathologic differential diagnosis for xanthoma may include malignant melanoma, metastatic or odontogenic clear cell carcinoma, tuberculosis, and epithelioid sarcoma. However, the possibility of malignant melanoma and metastatic or odontogenic clear cell carcinoma were eliminated because of the absence of immunohistochemical positivity for HMB-45 and AE1/ AE3 cytokeratin, respectively, and the lack of mycobacteria also eliminated the possibility of epithelioid granuloma associated with tuberculosis.15 Other pathologic entities, such as epithelioid angiosarcoma, epithelioid hemangioendothelioma, and epithelioid schwannoma, were also excluded, since the lesional cells did not reveal positivity for CD34 or for S100 protein. Pathologic entities derived from the lymphoreticular system as well as blast cells from myeloid malignances, were also excluded because CD3-positive cells were scarce and CD20 and CD117 were negative.16 Similarly, the absence of a-smooth muscle actin and desmin ruled out epitheliod leiomyoma and rhabdomyoma. Since the cells present in the lesion were strongly positive for CD68, the histologic differential diagnosis included pathologic conditions derived from a macrophage or histiocyte lineage,17 including Langerhans cells histiocytosis, fibrohistiocytoma, and Rosai-Dorfman disease, which were excluded due to the lack of immunopositivity for CD1a; thus, Langerhans cell histiocytosis was excluded as well as Rosai-Dorfman disease,17 since these particular and S100 proteins.18 On the basis of the intense level of positivity for both CD68 and vimentin, only fibrohistiocytoma, reactive histiocytosis, and xanthoma were considered in the

differential diagnosis. However, the possibility of fibrohistiocytoma was excluded. Although the cells that comprise a fibrohistiocytoma may express CD68 and vimentin, the majority of them are, in fact, fibroblasts, myofibroblasts, or primitive mesenchymal cells. Thus, the lack of important fibrous tissue deposited among the foam cells as well as lack of myofibroblasts (a-smooth muscle actin positive cells) on histologic and immunohistochemical analyses ruled out the possibility of fibrohistiocytoma.15 Reactive histiocytosis was considered, despite the fact that the pathologic entity did not reveal positivity for the CD1a and S100 protein. In fact, reactive histiocytic disorders may be divided into diseases derived from macrophages that express CD68 and those of Langerhans or dendritic cell origin that express CD1a and S100.19 Since vimentin shares the same immunolocalization as CD68, its presence was considered to represent activated macrophages because in this circumstance, macrophages may secrete vimentin into the extracellular space in response to proinflammatory signaling pathways (e.g., the presence of CD3þ cells found in this case) that are involved in immune functions against bacterial action and the generation of oxidative metabolites, important functions of activated macrophages.20 The differential diagnosis for patients presenting with lytic lesions will be broad and depends on the patient’s age and the presence of other diseases. In our case, a lateral periodontal cyst was considered, since the lesion was small and located between the cervical and apical root regions of mandibular premolars, with vital teeth and an unpreserved periodontal ligament. However, the diffuse radiolucent image signalized against a cystic

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lesion. Many authors include a primary or metastatic malignant neoplasm in their differential diagnoses, since the lesions may have imprecise limits, may be diffuse, and may have irregular margins.6,10 Osteolysis with destruction of the bone cortex has been cited thus far and has subsidized radiologic differential diagnosis.8,13 Lesions are well known as being asymptomatic and lacking signs of inflammatory processes,6,10,14 as seen in our case, which was incidentally diagnosed. However, when the skull is involved, a lesion may be symptomatic. It should preferably be radically removed, as it can cause significant morbidity, especially when there is facial and vestibulocochlear nerve involvement.9 The symptoms are relieved after the lesion is removed.4,9 Unlike xanthogranuloma, the solitary xanthoma of bone has no tendency toward aggressive behavior.7 Surgical excision is the preferred treatment for a solitary xanthoma. A clinical yellowish appearance of the lesion during surgery is very characteristic and may lead to a diagnostic hypothesis.6 REFERENCES

1. Dorfman HD, Czerniak B. Fibrous and fibrohistiocytic lesions. In: Bone Tumors St. Louis: Mosby; 1998. 2. Cruz PD Jr, East C, Bergstresser PR. Dermal, subcutaneous, and tendon xanthomas: diagnostic markers for specific lipoprotein disorders. J Am Acad Dermatol. 1988;19:95-111. 3. Bertoni F, Unni KK, McLeod RA, Sim FH. Xanthoma of bone. Am J Clin Pathol. 1988;90:377-384. 4. Turk C, Bilginer B, Benli K, Yavuz K, Saglam A, Ziyal MI. Bilateral temporal bone xanthomas in type II hypercholesterolemia. Turkish Neurosurg. 2010;20:533-535. 5. Marqués Mateo M, Puche Torres M, Miragall Alba L, Iglesias Gimilio ME, Pascual Gil JV. Primary mandibular bone xanthoma a case report. Int J Oral Maxillofac Surg. 2004;33:806-807. 6. Moraes Ramos-Perez FM, de Pádua JM, Silva-Sousa YTC, de Almeida OP, da Cruz Perez DE. Primary xanthoma of the mandible. Dentomaxillofac Radiol. 2011;40:393-396. 7. Mosby EL, Albright JE, Messer EJ, Nealis MF, Werning JT. Case 44, Part II: Xanthoma of the mandible. J Oral Maxillofac Surg. 1983;41:268-270. 8. Matoba M, Tonami H, Kuginuki M, Yamamoto I, Akai T, Iizuka H. CT and MRI findings of xanthoma in the orbitofrontal region. Radiat Med. 2004;22:116-119.

OOOO Month 2015 9. Broadway SJ, Arnautovic KI, Zhang Y. Xanthoma of the occipital bone and with preserved inner and outer bone cortex: case report. J Neurol Surg Rep. 2013;74:29-32. 10. Alden KJ, McCarthy EF, Weber KL. Xanthoma of bone: a report of three cases and review of the literature. Iowa Orthopaed J. 2008;28:58-64. 11. Boisgard S, Bringer O, Aufauvre B, et al. Intraosseous xanthoma without lipid disorders. Case-report and literature review. Joint Bone Spine. 2000;67:71-74. 12. Harsanyi BB, Larsson A. Xanthomatous lesions of the mandible: osseous expression of non-X histiocytosis and benign fibrous histiocytoma. Oral Surg Oral Med Oral Pathol. 1988;65:551-566. 13. Bonhomme GR, Loevner LA, Yen DM, Deems DA, Bigelow DC, Mirza N. Extensive intracranial xanthoma associated with type II Hyperlipidemia. AJNR Am J Neuroradiol. 2000;21:353-355. 14. Chakravarthi VK, Aruna E, Rao DNC, Rao DR. Bilateral tibial xanthoma in a normolipidemic patient e report of a rare case with review of literature. Int J Clin Med. 2012;3:234-237. 15. Weiss SW. Histologic Typing of Soft Tissue Tumors. 2nd ed. Berlin, Germany: Springer-Verlag; 1994:42-95. 16. Miettinen M, Lasota JKIT. (CD117): a review on expression in normal and neoplastic tissues, and mutations and their clinicopathologic correlation. Appl Immunohistochem Mol Morphol. 2005;13:205-220. 17. Nathan DO, Mayerson JL, Wakely PE. Extranodal Rosai-Dorfman disease as solitary lesion of the tibia in a 56-year-old woman. Am J Orthop. 2013;42:420-422. 18. Foucar E, Rosai J, Dorfman R. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity. Semin Diagn Pathol. 1990;7:19-73. 19. Cline MJ. Histiocytes and histiocytosis. Blood. 1994;84: 2840-2853. 20. Starr AE, Bellac CL, Dufour A, Goebeler V, Overall CM. Biochemical characterization and N-terminomics analysis of leukolysin, the membrane-type 6 matrix metalloprotease (MMP25) chemokine and vimentin cleavages enhance cell migration and macrophage phagocytic activities. J Biol Chem. 2012;287:13382-13395.

Reprint requests: Melissa Rodrigues de Araujo, DDS Rua Professor Pedro Viriato Parigot de Souza 5300 Campo Comprido Curitiba e Paraná, Brazil [email protected]

Primary mandibular xanthoma: case report.

Xanthoma is a very rare bone tumor, especially in the mandible, that can be associated with metabolic diseases such as hyperlipidemia. A 14-year-old g...
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