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Nonlipidized juvenile xanthogranuloma: An unusual variant with a potential diagnostic pitfall
International Journal of Pediatric Otorhinolaryngology 76 (2012) 295–299
Contents lists available at SciVerse ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Case report
Nonlipidized juvenile xanthogranuloma: An unusual variant with a potential diagnostic pitfall Aline Carvalho Batista a, Elismauro Francisco Mendonc¸a a, Larissa Santana Arantes Elias a, Bruno Augusto Benevenuto Andrade b, Oslei Paes Almeida b, Jorge Esquiche Leo´n c,* a b c
Department of Stomatology (Oral Pathology), Dental School, Federal University of Goia´s, Goiaˆnia, Brazil Department of Oral Pathology, Dental School, University of Campinas (UNICAMP), Piracicaba, Sa˜o Paulo, Brazil Department of Stomatology (Oral Pathology), Dental School of Ribeira˜o Preto, University of Sa˜o Paulo (USP), Av. do Cafe´ s/n Monte Alegre 14040-904, Ribeira˜o Preto, Sa˜o Paulo, Brazil
A R T I C L E I N F O
A B S T R A C T
Article history: Received 2 November 2011 Accepted 12 November 2011 Available online 26 December 2011
Juvenile xanthogranuloma (JXG) is a histiocytic inflammatory disorder that can present different histologic patterns. Classic JXG consists of sheets of foamy histiocytes and numerous multinucleated Touton giant cells. Nonlipidized JXG (NJXG) is one of the unusual variants of JXG, consisting of a diffuse monomorphic infiltrate of mononuclear histiocytes, suggesting an aggressive or malignant tumor due the high mitotic index. However, NJXG behaves clinically as classic JXG. We present an unusual case of a 6year-old boy who presented an exophytic ulcerated nodule on the lower lip diagnosed as NJXG. The boy is currently well without recurrence three years after surgical excision. ß 2011 Elsevier Ireland Ltd. All rights reserved.
Keywords: Juvenile xanthogranuloma Nonlipidized juvenile xanthogranuloma Mitotic activity Touton cells Lip Immunohistochemistry
1. Introduction Juvenile xanthogranuloma (JXG) is a benign histiocytic process of uncertain histogenesis, characterized by red to yellow, single or multiple cutaneous nodules usually located on the head and neck. Oral involvement is very rare. Most JXG appear early in life, although it can onset in adulthood [1,2]. Histologically, it consists of roundish cells with indistinct borders and clear, finely vacuolated cytoplasm. Nuclei are typically crescent shape or round, mitoses although rare may be present. The hallmark of JXG is the presence of Touton giant cells [3]. Nonlipidized, intramuscular, subcutaneous, giant, plaque-like, lichenoid, clustered, intraocular, and systemic JXG are unusual clinical and histological variants of JXG [2]. Histologically, nonlipidized JXG (NJXG) consists of a diffuse, monomorphic, histiocytic infiltrate with a relative absence or lack of inflammatory cells, foamy histiocytes, foreign body and Touton giant cells, usually showing a high mitotic index. To date, about 28 NJXG cases affecting extra-oral sites have been described in the literature [2,4–12]. Only 4 cases of non-classic JXG involving the mouth, described as ‘‘early JXG’’ or ‘‘mononuclear variant of JXG’’, have been reported [13,14] and none of them showed mitotic activity nor it was considered the possibility of
* Corresponding author. Tel.: +55 16 36024063; fax: +55 16 36024794. E-mail address: [email protected] (J.E. Leo´n). 0165-5876/$ – see front matter ß 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2011.11.010
malignancy. We report an unusual case of NJXG in a 6-year-old Brazilian boy which showed a clinically ulcerated nodule on the mucosa of the lower lip, histologically mimicking a malignant neoplasm. 2. Case report An otherwise healthy 6-year-old Brazilian boy presented with a 3-cm firm, painless, exophytic ulcerated nodule on the mucosa of the lower lip. The lesion had been growing for the last 3 months (Fig. 1). Medical history was noncontributory, and nothing else remarkable was found during his physical examination. The main clinical differential diagnosis was non-neoplastic reactive/proliferative processes, as pyogenic granuloma. Three years after surgical excision the patient is well, without recurrence. Microscopically, the lesion showed a solid proliferation of plump epithelioid to spindle-shaped mononuclear cells, intermixed with focal areas of hyaline collagen, eventually arranged in a storiform pattern. The cells displayed round to oval irregular nuclei with vesicular chromatin, conspicuous nucleoli, and subtle nuclear grooves. The surface showed extensive area of ulceration covered by a fibrinopurulent membrane, and peripherally elongated epithelial rete ridges and submucosal vesicles filled with clear proteinaceous fluid containing scarce inflammatory cells. Multiple small slit-like vascular structures and a diffuse mild lymphocytic infiltrate were also seen. The most striking feature was the high
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enolase (NSE), CD1a, HMB45, factor XIIIa, HAM56, HLA-DR, lysozyme, bcl-2, p53, and Ki-67 (MIB-1) (DAKO, Carpinteria, CA, USA), and CD56 (Novocastra, Newcastle upon Tyne, England). Most cells were strongly positive for vimentin, CD10, CD63 (NKI-C3), CD68 (PG-M1 and KP-1), factor XIIIa, lysozyme, and weakly positive for HAM56 and HLA-DR (Fig. 3). Scarce cells showed weak positivity for CD45 and S100. Ki-67 labeling index was 34% and 11% in the superficial and deep areas, respectively (Fig. 4). All other immunomarkers used were negative. A diagnosis consistent with mitotically active JXG with absence of foam and giant cells (NJXG) was made. 3. Discussion
Fig. 1. Clinical view showing a firm, painless, exophytic ulcerated nodule on the mucosa of the lower lip of a 6-year-old boy.
number of mitotic figures, varying from 12 to 22 per 10 high-power fields, especially numerous on the superficial areas (Fig. 2). Some cells contained fine diastase-resistant periodic acid-Schiff (PAS) positive cytoplasmic granules. A presumptive diagnosis of malignant spindle-shaped neoplasm, probably of mesenchymal origin, was made. Immunohistochemical analysis included a large panel of markers: AE1/AE3 pan-cytokeratin, epithelial antigen membrane (EMA), vimentin, alpha-smooth muscle actin, muscle-specific actin, desmin, calponin, p63, h-caldesmon, Myo-D1, myogenin, myeloperoxidase, OPD4, CD10, CD21, CD23, CD31, CD34, CD35, CD45, CD57, CD63 (NKI-C3), CD68 (PG-M1 and KP-1), CD117, D240, S100, glial fibrillary acidic protein (GFAP), neuron-specific
Clinically, JXG is characterized by asymptomatic yellowish cutaneous nodules that usually appear in early infancy and childhood, with approximately 75% of cases occurring in the first 9 months of life. About 10% of cases manifest in adulthood, being known as ‘‘adult xanthogranuloma’’. The most common location is the head and neck region, solitary lesions are found in 60–82% of the cases, and usually regresses spontaneously within 3–6 years, although an area of hyperpigmentation, slight atrophy, or anetoderma may remain [1,2]. Microscopically, JXG consists typically of sheets of foamy histiocytes and numerous Touton giant cells, showing few mitoses, and a variable number of lymphocytes and eosinophils [3]. JXG can be associated with systemic conditions that include neurofibromatosis, Niemann-Pick disease, urticaria pigmentosa, and myelogenous leukemia [2,13,15]. To our knowledge, approximately 31 cases of oral JXG have been previously reported in the English- and Japanese-language literature. The mean age at diagnosis was 14 years, showing male predilection (2.4–1), with approximately 20% occurring either during the first year of life or between 34 and 64 years old [16].
Fig. 2. Microscopical aspects of nonlipidized juvenile xanthogranuloma (H&E stain). (A) Solid proliferation of monomorphous spindle-shaped to epithelioid cells. Note the overlying epithelium showing slender elongated rete ridges and submucosal vesicles (original magnification 5) (B) Plump spindle-shaped to epithelioid mononuclear cells arranged in fascicular growth pattern (original magnification 20). (C) Proliferation of plump spindle-shaped mononuclear cells intermixed with focal areas of entrapment hyaline bundles of collagen and mild chronic inflammatory infiltrate (original magnification 20). (D) High power, showing the cellular details and mitotic figures (original magnification 40).
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Fig. 3. Immunohistochemical findings of the nonlipidized juvenile xanthogranuloma. The mononuclear histiocytic cells were strongly positive for vimentin (A) and CD10 (B) (original magnification 20). CD63 (NKI-C3) highlighted a stronger cytoplasmic positivity in granular pattern (C, original magnification 20). Numerous cells were positive for factor XIIIa, including both lesional and nonlesional (intersticial dendritic) stromal cells (D, original magnification 10). CD68 (KP-1) (E), and lysozyme (F) produced particularly stronger staining in numerous cells (original magnification 20).
Unlike the cutaneous lesions, oral JXG tend to occur in an older age group, but similarly affects predominantly male patients. Moreover, it is interesting that oral JXG lesions are infrequently associated with cutaneous lesions and/or systemic involvement, and unlike to cutaneous JXG lesions, multiple lesions, and
Fig. 4. Numerous cells were positive for Ki-67, more on the superficial areas (upper left) than on deep areas (lower right) (IHC, original magnification 10).
spontaneous regression are rare [13]. The most affected sites in the oral cavity are the tongue, palate, gingiva, and lip [16,17]. Four out of 31 oral cases of JXG with non-classic microscopical features, showing an epithelioid-shaped histiocytic population with ‘‘benign appareance’’ and described as ‘‘early JXG’’ or ‘‘mononuclear variant of JXG’’, have been reported [13,14]. The case described here is the sixth JXG affecting the lip, but the first with mononuclear/monomorphic and nonlipidized cells and presenting ‘‘malignant appareance’’. Unusual clinical and histological variants of JXG often require IHC analysis to establish the diagnosis. Amongst these variants nonlipidized, intramuscular and subcutaneous JXG present rare or no Touton giant cells, difficulting the diagnosis [2]. NJXG is a welldocumented histological subtype, with over 28 published cases in the English-language literature, most affecting the skin [2,4–12]. Clinically, NJXG predominantly occurs in infants 6 months of age or younger. Histologically, NJXG consists of a diffuse, monomorphic infiltrate of epithelioid to spindle-shaped mononuclear histiocytes with a relative absence of inflammatory cells, foamy histiocytes and Touton giant cells. Eventually the two latter can be found at the deepest portions of the specimen, indicating that deep biopsies may facilitate diagnosis. Mitoses are frequent and may be abundant, especially in the superficial areas of ulcerated lesions (4–21 per 10 high-power fields) [4]. The current case presented several of the clinicopathological features mentioned above. The large exophytic ulcerated nodule, with 3 months of evolution, affecting the lower lip of a pediatric patient, was clinically
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suggestive of a reactive process, as pyogenic granuloma. Nevertheless, histologically a solid monomorphous proliferation of epithelioid to plump spindle-shaped mononuclear cells, showing high mitotic index was observed; suggesting a malignant spindleshaped neoplasm. The differential diagnosis included spindle cell carcinoma, spindle cell melanoma, malignant peripheral nerve sheath tumor, fibrosarcoma, myofibrosarcoma, leiomyosarcoma, spindle cell rhabdomyosarcoma, follicular dendritic cell sarcoma, and granulocytic sarcoma. All these neoplasms were excluded through an extensive IHC panel. However, due to the positivity for histiocytic/mesenchymal markers, atypical fibrous histiocytoma, spindle cell xanthogranuloma, and nonneural granular cell tumor were also considered. The first is a distinctive variant of fibrous histiocytoma that typically presents on the extremities of middle-aged adults, and microscopically include a population of pleomorphic fibroblast-like and histiocyte-like cells admixed with multinucleate giant cells, set in a background of classic fibrous histiocytoma. Moreover, atypical mitosis, geographic necrosis, tendency to recur locally, and variable immunopositivity for histiocytic markers, are observed [18,19]. Spindle cell xanthogranuloma typically occurs in young adults affecting preferentially the skin of the head and neck. Histologically, it is characterized as a well circumscribed nodule composed predominantly of spindle-shaped histiocytes arranged in a storiform pattern, intermingled with mononuclear cells showing vacuolated, xanthomatized, scalloped, or oncocytic morphologies and Touton giant cells. Mitotic activity is generally absent [20,21]. Although nonneural granular cell tumor shares some histopathological and IHC features with NJXG, the former is clearly a distinctive entity. It is composed of spindled to ovoid cells with abundant granular, eosinophilic cytoplasm and vesicular nuclei with small prominent nucleoli, showing mild to moderate focal atypia and some mitotic activity. Epidermal hyperplasia is minimal or absent. By IHC analysis, nonneural granular cell tumor shows consistent diffuse cytoplasmic staining for NKI-C3, a very sensitive marker of granular cell change, NSE positivity is detected in about half of the cases, and only focal and weak CD68 staining is apparent, while factor XIIIa is negative in most cases. Local recurrence or metastasis is possible, therefore complete excision is advised [22]. Thus, in the current case a diagnosis consistent with NJXG was favored. As mentioned, the classic JXG contains only isolated mitotic figures, and NJXG usually shows a higher mitotic index, especially in ulcerated lesions. The high number of mitoses found in some NJXG cases could be explained by their immature or evolving character [4,9,10]. Nevertheless, two unusual cases of mitotically active classic JXG have been reported [23,24], demonstrating that mitotically active cases are not restricted to NJXG. Kubota et al. [12] presented other interesting case of JXG on the scalp of an 8month-old girl. The initial biopsy showed NJXG-like microscopic features and the possibility of a malignant neoplasm was considered, however on the surgical specimen areas of classic JXG was found. It seems that in the early stages (‘‘mononuclear variant’’ or nonlipidized form), the lesion is monomorphous and highly cellular, composed of a sheetlike proliferation of small histiocytic cells with some cytoplasmic vacuolation. In the fully developed stage, a more prominent cytoplasmic vacuolization leads to xanthomatized cells and Touton giant cells formation, intermingled with inflammatory cells [25]. JXG is positive for vimentin, CD68, factor XIIIa, HLA-DR, HAM56, fascin, CD45, variable for CD4, MAC-387, lysozyme, and S100, and it is negative for CD1a, CD21, CD34, and CD35 [4,6,9,26,27]. Based on this IHC analysis, it has been suggested that the dermal dendrocyte is the cell of origin of JXG [26,28]. All NJXG lesions are consistently positive for factor XIIIa and only focally positive or negative in classic JXG [9], as found in the current case. The strong
positivity for both CD68 and CD63 (NK1-C3) observed in the present case are very probably related to a relevant number of lysosomes [29]. Moreover, lysozyme was also positive. CD10 is expressed on a variety of tumor cell types, including fibrohistiocytic tumors [30]. The present case was strongly positive by CD10 and was useful adjunct to supplement the diagnosis of JXG. 4. Conclusion We report a unique case of oral mitotically active NJXG in a 6-year-old boy. Pathologists should consider this peculiar form of JXG to avoid confusing this histiocytic disorder with other malignant neoplasms. In circumstances where distinction cannot be made with certainty, evaluation of clinical features and/or immunohistochemistry can almost always lead to a definitive diagnosis. Conflict of interest The authors declare no conflict of interest. Acknowledgements This work was supported by FAPESP (Fundac¸a˜o de Amparo a` Pesquisa do Estado de Sa˜o Paulo). References [1] S. Weitzman, R. Jaffe, Uncommon histiocytic disorders: the non-Langerhans cell histiocytoses, Pediatr. Blood Cancer 45 (2005) 256–264. [2] M.W. Chang, Update on juvenile xanthogranuloma: unusual cutaneous and systemic variants, Semin. Cutan. Med. Surg. 18 (1999) 195–205. [3] B. Newman, W. Hu, K. Nigro, A.C. Gilliam, Aggressive histiocytic disorders that can involve the skin, J. Am. Acad. Dermatol. 56 (2007) 302–316. [4] P.E. Shapiro, D.N. Silvers, R.K. Treiber, P.H. Cooper, L.D. True, R. Lattes, Juvenile xanthogranulomas with inconspicuous or absent foam cells and giant cells, J. Am. Acad. Dermatol. 24 (1991) 1005–1009. [5] R. Caputo, R. Grimalt, C. Gelmetti, F. Cottoni, Unusual aspects of juvenile xanthogranuloma, J. Am. Acad. Dermatol. 29 (1993) 868–870. [6] A.L. Claudy, L. Misery, D. Serre, S. Boucheron, Multiple juvenile xanthogranulomas without foam cells and giant cells, Pediatr. Dermatol. 10 (1993) 61–63. [7] W.S. Tanz, Y.A. Kim, R.A. Schwartz, T. Walters, C.K. Janniger, W.C. Lambert, Juvenile xanthogranuloma with inconspicuous foam cells and giant cells, Int. J. Dermatol. 34 (1995) 653–655. [8] O.P. Sangueza, J.K. Salmon, C.R. White Jr., J.H. Beckstead, Juvenile xanthogranuloma: a clinical, histopathologic and immunohistochemical study, J. Cutan. Pathol. 22 (1995) 327–335. [9] C.C. Newman, S.S. Raimer, R.L. Sa´nchez, Nonlipidized juvenile xanthogranuloma: a histologic and immunohistochemical study, Pediatr. Dermatol. 14 (1997) 98–102. [10] F.C. Iwuagwu, H.S. Rigby, F. Payne, C.D. Reid, Juvenile xanthogranuloma variant: a clinicopathological case report and review of the literature, Br. J. Plast. Surg. 52 (1999) 591–593. [11] K.J. Busam, J. Rosai, K. Iversen, A.A. Jungbluth, Xanthogranulomas with inconspicuous foam cells and giant cells mimicking malignant melanoma: a clinical, histologic, and immunohistochemical study of three cases, Am. J. Surg. Pathol. 24 (2000) 864–869. [12] Y. Kubota, H. Kiryu, J. Nakayama, T. Koga, Histopathologic maturation of juvenile xanthogranuloma in a short period, Pediatr. Dermatol. 18 (2001) 127–130. [13] C. Flaitz, C. Allen, B. Neville, J. Hicks, Juvenile xanthogranuloma of the oral cavity in children: a clinicopathologic study, Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 94 (2002) 345–352. [14] G. Fabrizi, G. Massi, Mononuclear variant of juvenile xanthogranuloma in the oral cavity of an adult patient, Br. J. Dermatol. 144 (2001) 909–911. [15] R. Caputo, A.V. Marzano, E. Passoni, E. Berti, Unusual variants of non-Langerhans cell histiocytoses, J. Am. Acad. Dermatol. 57 (2007) 1031–1045. [16] A. Consolaro, E. Sant’Ana, M.A. Lawall, M.F. Consolaro, C.E. Bacchi, Gingival juvenile xanthogranuloma in an adult patient: case report with immunohistochemical analysis and literature review, Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 107 (2009) 246–252. [17] T. Shimoyama, N. Horie, F. Ide, Juvenile xanthogranuloma of the lip: case report and literature review, J. Oral Maxillofac. Surg. 58 (2000) 677–679. [18] B. Luzar, E. Calonje, Cutaneous fibrohistiocytic tumours – an update, Histopathology 56 (2010) 148–165. [19] S. Kaddu, M.E. McMenamin, C.D. Fletcher, Atypical fibrous histiocytoma of the skin: clinicopathologic analysis of 59 cases with evidence of infrequent metastasis, Am. J. Surg. Pathol. 26 (2002) 35–46.
A.C. Batista et al. / International Journal of Pediatric Otorhinolaryngology 76 (2012) 295–299 [20] F.L. Glavin, H. Chhatwall, K. Karimi, Progressive nodular histiocytosis: a case report with literature review, and discussion of differential diagnosis and classification, J. Cutan. Pathol. 36 (2009) 1286–1292. [21] J.J. DeStafeno, J.A. Carlson, D.R. Meyer, Solitary spindle-cell xanthogranuloma of the eyelid, Ophthalmology 109 (2002) 258–261. [22] A.J. Lazar, C.D. Fletcher, Primitive nonneural granular cell tumors of skin: clinicopathologic analysis of 13 cases, Am. J. Surg. Pathol. 29 (2005) 927–934. [23] J. Koren, L. Matecek, M. Zamecnik, Mitotically active deep juvenile xanthogranuloma, Ann. Diagn. Pathol. 14 (2010) 36–40. [24] A. Migue´lez, J.L. Rodrı´guez-Peralto, A. Santos-Briz, J. Vargas, F. Lo´pez-Rı´os, Mitotically active juvenile xanthogranuloma, Arch. Pathol. Lab. Med. 126 (2002) 1219–1221. [25] B. Zelger, R. Cerio, G. Orchard, E. Wilson-Jones, Juvenile and adult xanthogranuloma. A histological and immunohistochemical comparison, Am. J. Surg. Pathol. 18 (1994) 126–135.
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[26] L.P. Dehner, Juvenile xanthogranulomas in the first two decades of life: a clinicopathologic study of 174 cases with cutaneous and extracutaneous manifestations, Am. J. Surg. Pathol. 27 (2003) 579–593. [27] M.D. Kraus, J.C. Haley, R. Ruiz, L. Essary, C.A. Moran, C.D. Fletcher, Juvenile’’ xanthogranuloma: an immunophenotypic study with a reappraisal of histogenesis, Am. J. Dermatopathol. 23 (2001) 104–111. [28] L. Misery, S. Boucheron, A.L. Claudy, Factor XIIIa expression in juvenile xanthogranuloma, Acta Derm. Venereol. 74 (1994) 43–44. [29] G.M. Groisman, M. Amar, I. Scha¨fer, The histiocytic marker PG-M1 is helpful in differentiating histiocytes and histiocytic tumors from melanomas, Appl. Immunohistochem. Mol. Morphol. 10 (2002) 205–209. [30] S. de Feraudy, N. Mar, T.H. McCalmont, Evaluation of CD10 and procollagen 1 expression in atypical fibroxanthoma and dermatofibroma, Am. J. Surg. Pathol. 32 (2008) 1111–1122.
Contents lists available at SciVerse ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Case report
Nonlipidized juvenile xanthogranuloma: An unusual variant with a potential diagnostic pitfall Aline Carvalho Batista a, Elismauro Francisco Mendonc¸a a, Larissa Santana Arantes Elias a, Bruno Augusto Benevenuto Andrade b, Oslei Paes Almeida b, Jorge Esquiche Leo´n c,* a b c
Department of Stomatology (Oral Pathology), Dental School, Federal University of Goia´s, Goiaˆnia, Brazil Department of Oral Pathology, Dental School, University of Campinas (UNICAMP), Piracicaba, Sa˜o Paulo, Brazil Department of Stomatology (Oral Pathology), Dental School of Ribeira˜o Preto, University of Sa˜o Paulo (USP), Av. do Cafe´ s/n Monte Alegre 14040-904, Ribeira˜o Preto, Sa˜o Paulo, Brazil
A R T I C L E I N F O
A B S T R A C T
Article history: Received 2 November 2011 Accepted 12 November 2011 Available online 26 December 2011
Juvenile xanthogranuloma (JXG) is a histiocytic inflammatory disorder that can present different histologic patterns. Classic JXG consists of sheets of foamy histiocytes and numerous multinucleated Touton giant cells. Nonlipidized JXG (NJXG) is one of the unusual variants of JXG, consisting of a diffuse monomorphic infiltrate of mononuclear histiocytes, suggesting an aggressive or malignant tumor due the high mitotic index. However, NJXG behaves clinically as classic JXG. We present an unusual case of a 6year-old boy who presented an exophytic ulcerated nodule on the lower lip diagnosed as NJXG. The boy is currently well without recurrence three years after surgical excision. ß 2011 Elsevier Ireland Ltd. All rights reserved.
Keywords: Juvenile xanthogranuloma Nonlipidized juvenile xanthogranuloma Mitotic activity Touton cells Lip Immunohistochemistry
1. Introduction Juvenile xanthogranuloma (JXG) is a benign histiocytic process of uncertain histogenesis, characterized by red to yellow, single or multiple cutaneous nodules usually located on the head and neck. Oral involvement is very rare. Most JXG appear early in life, although it can onset in adulthood [1,2]. Histologically, it consists of roundish cells with indistinct borders and clear, finely vacuolated cytoplasm. Nuclei are typically crescent shape or round, mitoses although rare may be present. The hallmark of JXG is the presence of Touton giant cells [3]. Nonlipidized, intramuscular, subcutaneous, giant, plaque-like, lichenoid, clustered, intraocular, and systemic JXG are unusual clinical and histological variants of JXG [2]. Histologically, nonlipidized JXG (NJXG) consists of a diffuse, monomorphic, histiocytic infiltrate with a relative absence or lack of inflammatory cells, foamy histiocytes, foreign body and Touton giant cells, usually showing a high mitotic index. To date, about 28 NJXG cases affecting extra-oral sites have been described in the literature [2,4–12]. Only 4 cases of non-classic JXG involving the mouth, described as ‘‘early JXG’’ or ‘‘mononuclear variant of JXG’’, have been reported [13,14] and none of them showed mitotic activity nor it was considered the possibility of
* Corresponding author. Tel.: +55 16 36024063; fax: +55 16 36024794. E-mail address: [email protected] (J.E. Leo´n). 0165-5876/$ – see front matter ß 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2011.11.010
malignancy. We report an unusual case of NJXG in a 6-year-old Brazilian boy which showed a clinically ulcerated nodule on the mucosa of the lower lip, histologically mimicking a malignant neoplasm. 2. Case report An otherwise healthy 6-year-old Brazilian boy presented with a 3-cm firm, painless, exophytic ulcerated nodule on the mucosa of the lower lip. The lesion had been growing for the last 3 months (Fig. 1). Medical history was noncontributory, and nothing else remarkable was found during his physical examination. The main clinical differential diagnosis was non-neoplastic reactive/proliferative processes, as pyogenic granuloma. Three years after surgical excision the patient is well, without recurrence. Microscopically, the lesion showed a solid proliferation of plump epithelioid to spindle-shaped mononuclear cells, intermixed with focal areas of hyaline collagen, eventually arranged in a storiform pattern. The cells displayed round to oval irregular nuclei with vesicular chromatin, conspicuous nucleoli, and subtle nuclear grooves. The surface showed extensive area of ulceration covered by a fibrinopurulent membrane, and peripherally elongated epithelial rete ridges and submucosal vesicles filled with clear proteinaceous fluid containing scarce inflammatory cells. Multiple small slit-like vascular structures and a diffuse mild lymphocytic infiltrate were also seen. The most striking feature was the high
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enolase (NSE), CD1a, HMB45, factor XIIIa, HAM56, HLA-DR, lysozyme, bcl-2, p53, and Ki-67 (MIB-1) (DAKO, Carpinteria, CA, USA), and CD56 (Novocastra, Newcastle upon Tyne, England). Most cells were strongly positive for vimentin, CD10, CD63 (NKI-C3), CD68 (PG-M1 and KP-1), factor XIIIa, lysozyme, and weakly positive for HAM56 and HLA-DR (Fig. 3). Scarce cells showed weak positivity for CD45 and S100. Ki-67 labeling index was 34% and 11% in the superficial and deep areas, respectively (Fig. 4). All other immunomarkers used were negative. A diagnosis consistent with mitotically active JXG with absence of foam and giant cells (NJXG) was made. 3. Discussion
Fig. 1. Clinical view showing a firm, painless, exophytic ulcerated nodule on the mucosa of the lower lip of a 6-year-old boy.
number of mitotic figures, varying from 12 to 22 per 10 high-power fields, especially numerous on the superficial areas (Fig. 2). Some cells contained fine diastase-resistant periodic acid-Schiff (PAS) positive cytoplasmic granules. A presumptive diagnosis of malignant spindle-shaped neoplasm, probably of mesenchymal origin, was made. Immunohistochemical analysis included a large panel of markers: AE1/AE3 pan-cytokeratin, epithelial antigen membrane (EMA), vimentin, alpha-smooth muscle actin, muscle-specific actin, desmin, calponin, p63, h-caldesmon, Myo-D1, myogenin, myeloperoxidase, OPD4, CD10, CD21, CD23, CD31, CD34, CD35, CD45, CD57, CD63 (NKI-C3), CD68 (PG-M1 and KP-1), CD117, D240, S100, glial fibrillary acidic protein (GFAP), neuron-specific
Clinically, JXG is characterized by asymptomatic yellowish cutaneous nodules that usually appear in early infancy and childhood, with approximately 75% of cases occurring in the first 9 months of life. About 10% of cases manifest in adulthood, being known as ‘‘adult xanthogranuloma’’. The most common location is the head and neck region, solitary lesions are found in 60–82% of the cases, and usually regresses spontaneously within 3–6 years, although an area of hyperpigmentation, slight atrophy, or anetoderma may remain [1,2]. Microscopically, JXG consists typically of sheets of foamy histiocytes and numerous Touton giant cells, showing few mitoses, and a variable number of lymphocytes and eosinophils [3]. JXG can be associated with systemic conditions that include neurofibromatosis, Niemann-Pick disease, urticaria pigmentosa, and myelogenous leukemia [2,13,15]. To our knowledge, approximately 31 cases of oral JXG have been previously reported in the English- and Japanese-language literature. The mean age at diagnosis was 14 years, showing male predilection (2.4–1), with approximately 20% occurring either during the first year of life or between 34 and 64 years old [16].
Fig. 2. Microscopical aspects of nonlipidized juvenile xanthogranuloma (H&E stain). (A) Solid proliferation of monomorphous spindle-shaped to epithelioid cells. Note the overlying epithelium showing slender elongated rete ridges and submucosal vesicles (original magnification 5) (B) Plump spindle-shaped to epithelioid mononuclear cells arranged in fascicular growth pattern (original magnification 20). (C) Proliferation of plump spindle-shaped mononuclear cells intermixed with focal areas of entrapment hyaline bundles of collagen and mild chronic inflammatory infiltrate (original magnification 20). (D) High power, showing the cellular details and mitotic figures (original magnification 40).
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Fig. 3. Immunohistochemical findings of the nonlipidized juvenile xanthogranuloma. The mononuclear histiocytic cells were strongly positive for vimentin (A) and CD10 (B) (original magnification 20). CD63 (NKI-C3) highlighted a stronger cytoplasmic positivity in granular pattern (C, original magnification 20). Numerous cells were positive for factor XIIIa, including both lesional and nonlesional (intersticial dendritic) stromal cells (D, original magnification 10). CD68 (KP-1) (E), and lysozyme (F) produced particularly stronger staining in numerous cells (original magnification 20).
Unlike the cutaneous lesions, oral JXG tend to occur in an older age group, but similarly affects predominantly male patients. Moreover, it is interesting that oral JXG lesions are infrequently associated with cutaneous lesions and/or systemic involvement, and unlike to cutaneous JXG lesions, multiple lesions, and
Fig. 4. Numerous cells were positive for Ki-67, more on the superficial areas (upper left) than on deep areas (lower right) (IHC, original magnification 10).
spontaneous regression are rare [13]. The most affected sites in the oral cavity are the tongue, palate, gingiva, and lip [16,17]. Four out of 31 oral cases of JXG with non-classic microscopical features, showing an epithelioid-shaped histiocytic population with ‘‘benign appareance’’ and described as ‘‘early JXG’’ or ‘‘mononuclear variant of JXG’’, have been reported [13,14]. The case described here is the sixth JXG affecting the lip, but the first with mononuclear/monomorphic and nonlipidized cells and presenting ‘‘malignant appareance’’. Unusual clinical and histological variants of JXG often require IHC analysis to establish the diagnosis. Amongst these variants nonlipidized, intramuscular and subcutaneous JXG present rare or no Touton giant cells, difficulting the diagnosis [2]. NJXG is a welldocumented histological subtype, with over 28 published cases in the English-language literature, most affecting the skin [2,4–12]. Clinically, NJXG predominantly occurs in infants 6 months of age or younger. Histologically, NJXG consists of a diffuse, monomorphic infiltrate of epithelioid to spindle-shaped mononuclear histiocytes with a relative absence of inflammatory cells, foamy histiocytes and Touton giant cells. Eventually the two latter can be found at the deepest portions of the specimen, indicating that deep biopsies may facilitate diagnosis. Mitoses are frequent and may be abundant, especially in the superficial areas of ulcerated lesions (4–21 per 10 high-power fields) [4]. The current case presented several of the clinicopathological features mentioned above. The large exophytic ulcerated nodule, with 3 months of evolution, affecting the lower lip of a pediatric patient, was clinically
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suggestive of a reactive process, as pyogenic granuloma. Nevertheless, histologically a solid monomorphous proliferation of epithelioid to plump spindle-shaped mononuclear cells, showing high mitotic index was observed; suggesting a malignant spindleshaped neoplasm. The differential diagnosis included spindle cell carcinoma, spindle cell melanoma, malignant peripheral nerve sheath tumor, fibrosarcoma, myofibrosarcoma, leiomyosarcoma, spindle cell rhabdomyosarcoma, follicular dendritic cell sarcoma, and granulocytic sarcoma. All these neoplasms were excluded through an extensive IHC panel. However, due to the positivity for histiocytic/mesenchymal markers, atypical fibrous histiocytoma, spindle cell xanthogranuloma, and nonneural granular cell tumor were also considered. The first is a distinctive variant of fibrous histiocytoma that typically presents on the extremities of middle-aged adults, and microscopically include a population of pleomorphic fibroblast-like and histiocyte-like cells admixed with multinucleate giant cells, set in a background of classic fibrous histiocytoma. Moreover, atypical mitosis, geographic necrosis, tendency to recur locally, and variable immunopositivity for histiocytic markers, are observed [18,19]. Spindle cell xanthogranuloma typically occurs in young adults affecting preferentially the skin of the head and neck. Histologically, it is characterized as a well circumscribed nodule composed predominantly of spindle-shaped histiocytes arranged in a storiform pattern, intermingled with mononuclear cells showing vacuolated, xanthomatized, scalloped, or oncocytic morphologies and Touton giant cells. Mitotic activity is generally absent [20,21]. Although nonneural granular cell tumor shares some histopathological and IHC features with NJXG, the former is clearly a distinctive entity. It is composed of spindled to ovoid cells with abundant granular, eosinophilic cytoplasm and vesicular nuclei with small prominent nucleoli, showing mild to moderate focal atypia and some mitotic activity. Epidermal hyperplasia is minimal or absent. By IHC analysis, nonneural granular cell tumor shows consistent diffuse cytoplasmic staining for NKI-C3, a very sensitive marker of granular cell change, NSE positivity is detected in about half of the cases, and only focal and weak CD68 staining is apparent, while factor XIIIa is negative in most cases. Local recurrence or metastasis is possible, therefore complete excision is advised [22]. Thus, in the current case a diagnosis consistent with NJXG was favored. As mentioned, the classic JXG contains only isolated mitotic figures, and NJXG usually shows a higher mitotic index, especially in ulcerated lesions. The high number of mitoses found in some NJXG cases could be explained by their immature or evolving character [4,9,10]. Nevertheless, two unusual cases of mitotically active classic JXG have been reported [23,24], demonstrating that mitotically active cases are not restricted to NJXG. Kubota et al. [12] presented other interesting case of JXG on the scalp of an 8month-old girl. The initial biopsy showed NJXG-like microscopic features and the possibility of a malignant neoplasm was considered, however on the surgical specimen areas of classic JXG was found. It seems that in the early stages (‘‘mononuclear variant’’ or nonlipidized form), the lesion is monomorphous and highly cellular, composed of a sheetlike proliferation of small histiocytic cells with some cytoplasmic vacuolation. In the fully developed stage, a more prominent cytoplasmic vacuolization leads to xanthomatized cells and Touton giant cells formation, intermingled with inflammatory cells [25]. JXG is positive for vimentin, CD68, factor XIIIa, HLA-DR, HAM56, fascin, CD45, variable for CD4, MAC-387, lysozyme, and S100, and it is negative for CD1a, CD21, CD34, and CD35 [4,6,9,26,27]. Based on this IHC analysis, it has been suggested that the dermal dendrocyte is the cell of origin of JXG [26,28]. All NJXG lesions are consistently positive for factor XIIIa and only focally positive or negative in classic JXG [9], as found in the current case. The strong
positivity for both CD68 and CD63 (NK1-C3) observed in the present case are very probably related to a relevant number of lysosomes [29]. Moreover, lysozyme was also positive. CD10 is expressed on a variety of tumor cell types, including fibrohistiocytic tumors [30]. The present case was strongly positive by CD10 and was useful adjunct to supplement the diagnosis of JXG. 4. Conclusion We report a unique case of oral mitotically active NJXG in a 6-year-old boy. Pathologists should consider this peculiar form of JXG to avoid confusing this histiocytic disorder with other malignant neoplasms. In circumstances where distinction cannot be made with certainty, evaluation of clinical features and/or immunohistochemistry can almost always lead to a definitive diagnosis. Conflict of interest The authors declare no conflict of interest. Acknowledgements This work was supported by FAPESP (Fundac¸a˜o de Amparo a` Pesquisa do Estado de Sa˜o Paulo). References [1] S. Weitzman, R. Jaffe, Uncommon histiocytic disorders: the non-Langerhans cell histiocytoses, Pediatr. Blood Cancer 45 (2005) 256–264. [2] M.W. Chang, Update on juvenile xanthogranuloma: unusual cutaneous and systemic variants, Semin. Cutan. Med. Surg. 18 (1999) 195–205. [3] B. Newman, W. Hu, K. Nigro, A.C. Gilliam, Aggressive histiocytic disorders that can involve the skin, J. Am. Acad. Dermatol. 56 (2007) 302–316. [4] P.E. Shapiro, D.N. Silvers, R.K. Treiber, P.H. Cooper, L.D. True, R. Lattes, Juvenile xanthogranulomas with inconspicuous or absent foam cells and giant cells, J. Am. Acad. Dermatol. 24 (1991) 1005–1009. [5] R. Caputo, R. Grimalt, C. Gelmetti, F. Cottoni, Unusual aspects of juvenile xanthogranuloma, J. Am. Acad. Dermatol. 29 (1993) 868–870. [6] A.L. Claudy, L. Misery, D. Serre, S. Boucheron, Multiple juvenile xanthogranulomas without foam cells and giant cells, Pediatr. Dermatol. 10 (1993) 61–63. [7] W.S. Tanz, Y.A. Kim, R.A. Schwartz, T. Walters, C.K. Janniger, W.C. Lambert, Juvenile xanthogranuloma with inconspicuous foam cells and giant cells, Int. J. Dermatol. 34 (1995) 653–655. [8] O.P. Sangueza, J.K. Salmon, C.R. White Jr., J.H. Beckstead, Juvenile xanthogranuloma: a clinical, histopathologic and immunohistochemical study, J. Cutan. Pathol. 22 (1995) 327–335. [9] C.C. Newman, S.S. Raimer, R.L. Sa´nchez, Nonlipidized juvenile xanthogranuloma: a histologic and immunohistochemical study, Pediatr. Dermatol. 14 (1997) 98–102. [10] F.C. Iwuagwu, H.S. Rigby, F. Payne, C.D. Reid, Juvenile xanthogranuloma variant: a clinicopathological case report and review of the literature, Br. J. Plast. Surg. 52 (1999) 591–593. [11] K.J. Busam, J. Rosai, K. Iversen, A.A. Jungbluth, Xanthogranulomas with inconspicuous foam cells and giant cells mimicking malignant melanoma: a clinical, histologic, and immunohistochemical study of three cases, Am. J. Surg. Pathol. 24 (2000) 864–869. [12] Y. Kubota, H. Kiryu, J. Nakayama, T. Koga, Histopathologic maturation of juvenile xanthogranuloma in a short period, Pediatr. Dermatol. 18 (2001) 127–130. [13] C. Flaitz, C. Allen, B. Neville, J. Hicks, Juvenile xanthogranuloma of the oral cavity in children: a clinicopathologic study, Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 94 (2002) 345–352. [14] G. Fabrizi, G. Massi, Mononuclear variant of juvenile xanthogranuloma in the oral cavity of an adult patient, Br. J. Dermatol. 144 (2001) 909–911. [15] R. Caputo, A.V. Marzano, E. Passoni, E. Berti, Unusual variants of non-Langerhans cell histiocytoses, J. Am. Acad. Dermatol. 57 (2007) 1031–1045. [16] A. Consolaro, E. Sant’Ana, M.A. Lawall, M.F. Consolaro, C.E. Bacchi, Gingival juvenile xanthogranuloma in an adult patient: case report with immunohistochemical analysis and literature review, Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 107 (2009) 246–252. [17] T. Shimoyama, N. Horie, F. Ide, Juvenile xanthogranuloma of the lip: case report and literature review, J. Oral Maxillofac. Surg. 58 (2000) 677–679. [18] B. Luzar, E. Calonje, Cutaneous fibrohistiocytic tumours – an update, Histopathology 56 (2010) 148–165. [19] S. Kaddu, M.E. McMenamin, C.D. Fletcher, Atypical fibrous histiocytoma of the skin: clinicopathologic analysis of 59 cases with evidence of infrequent metastasis, Am. J. Surg. Pathol. 26 (2002) 35–46.
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