Dermatology: Practical and Conceptual Research Letter | Dermatol Pract Concept. 2023;13(2):e2023137 1 Visualizing Touton Giant Cells Under Reflectance Confocal Microscopy in Two Cases of Juvenile Xanthogranuloma Dominga Peirano1, Francisca Donoso1, Sebastián Vargas1, Leonel Hidalgo1, Teo Feuerhake2, Alon Scope3,4, Caterina Longo5,6, Cristian Navarrete-Dechent1,7 1 Department of Dermatology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile 2 Department of Pathology, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile 3 The Kittner Skin Cancer Screening & Research Institute, Sheba Medical Center, Ramat Gan, Israel 4 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel 5 Department of Dermatology, University of Modena and Reggio Emilia, Modena, Italy 6 Centro Oncologico ad Alta Tecnologia Diagnostica-Dermatologia, Arcispedale Santa Maria Nuova, Azienda Unità Sanitaria Locale - IRCCS Reggio Emilia, Reggio Emilia, Italy 7 Melanoma and Skin Cancer Unit, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile Key words: confocal microscopy, Touton cells, diagnosis, juvenile xanthogranuloma Citation: Peirano D, Donoso F, Vargas S, et al. Visualizing Touton Giant Cells Under Reflectance Confocal Microscopy in Two Cases of Juvenile Xanthogranuloma. Dermatol Pract Concept. 2023;13(2):e2023137. DOI: https://doi.org/10.5826/dpc.1302a137 Accepted: November 28, 2022; Published: April 2023 Copyright: ©2023 Peirano et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Cristian Navarrete-Dechent, MD, IFAAD, Department of Dermatology, Escuela de Medicina, Pontificia Universidad Católica de Chile Diagonal Paraguay 362, 6th floor Santiago, Chile. 8330077 Phone: +56-2-2435 3574 E-mail: ctnavarr@gmail.com Introduction Juvenile xanthogranuloma (JXG) is a benign non- Langerhans -cell histiocytosis occurring most frequently in childhood [1]. As JXG is rare in adults, it may clinically simulate malignant skin tumors, such as basal cell carcinoma (BCC) or amela- notic melanoma [2]. Histopathologically, JXG is characterized by a granu- lomatous inflammation pattern, whereby the dermal infil- trate consists of histiocytes with abundant cytoplasm and of Touton giant cells with a ring-like arrangement of multiple nuclei, separating a central eosinophilic area from the pe- ripheral foamy and pale cytoplasm [3]. Reflectance confocal microscopy (RCM) is a non-invasive optical imaging tool that allows for in vivo visualization of skin at cellular-level resolution [4]. Herein, we report that an infiltrate of Touton giant cells, a key criterion for diagnosis of JXG, can be read- ily identified via RCM. Case Presentation Case 1. A 63-year-old female was referred for evaluation of a long-standing lesion on the back. On physical examina- tion, a 4-mm orange-pink papule was seen (Figure 1A). On dermoscopy, the lesion showed a red-yellow center and discrete 2 Research Letter | Dermatol Pract Concept. 2023;13(2):e2023137 erythematous halo (“setting-sun appearance”) (Figure 1B). On RCM, at the superficial dermis level, an infiltrate of round- ish large cells was seen. These were characterized by a hyper-re- fractile peripheral rim and a hypo-reflective center, measuring 40-50 microns in diameter, suggestive of Touton cells (Figure 1C). A punch excision of the lesion showed a dense dermal in- filtrate of histiocytes. At higher magnification, multinucleated giant cells with nuclei surrounding a central homogeneous cy- toplasm measuring 30-50 microns corresponding with Touton giant cells, were seen. Foamy histiocytes were also visualized (Figure 1D). These findings pointed to the diagnosis of JXG. When performing a side-by-side RCM to histopathologi- cal correlation, it became clear that the roundish large cells under RCM corresponded to the Touton giant cells seen on histopathology. Case 2. A 13-year-old healthy boy was referred for evalua- tion of a solitary pink-yellow lesion on the left arm (Figure 2A). Dermoscopy revealed homogeneous yellow color (Figure 2B). On RCM, a dense infiltrate of roundish, large cells with dark center, surrounded by a hyper-refractile peripheral ring, were visualized (Figure 2C). The lesion was excised and diagnosed histopathologically as XGJ (Figure 2D). Figure 1. Juvenile xanthogranuloma. A. 4-mm orange-pink papule B. Dermoscopy showed a red-yellow center and discrete erythematous halo (‘setting-sun appearance’) (polarized light dermoscopy, original magnification 10x). C. On reflectance confocal microscopy (RCM), a disarranged dermal-epidermal junction was seen, filled with clusters of roundish, large, cells. These were large cells (40-50 microns largest diameter) with a hyperrefractile cytoplasm forming a peripheral rim and a large hypo-reflective nucleus, suggestive of Touton cells (yellow arrow). Horizontal blood vessels were also seen (red arrows) (0.5 x 0.5 mm, 30x) D. Large cells seen on RCM corresponded to the Touton cells seen on histopathology (yellow arrows), blood vessels (red arrow) and foamy histiocytes (blue arrows) (H&E, 40x). Research Letter | Dermatol Pract Concept. 2023;13(2):e2023137 3 Conclusions JXG is a benign disease, mostly presenting as a solitary pap- ule or nodule in childhood. We present two cases of JXG, in an adult and in a child, whereby RCM revealed large round- ish cells with hypo-reflective center and surrounding hy- per-refractile rim appearing as bright halo, corresponding to Touton giant cells upon comparison with histopathology. In contrast to Touton cells, the foamy cytoplasm of foamy his- tiocytes does not provide reflectance and are not readily vis- ible under RCM, despite being seen under histopathology in both cases. As the identification of Touton giant cells is a key diagnostic finding in JXG, these cases highlight the potential for the bedside diagnosis of JXG with the aid RCM [4,5]. References 1. Lacarrubba F, Verzì AE, Puglisi DF, Broggi G, Caltabiano R, Micali G. Line-field confocal optical coherence tomography of xanthogranuloma: Correlation with vertical and horizontal histopathology. J Cutan Pathol. 2021;48(9):1208-1211. DOI: 10.1111/cup.14067. PMID: 34028070. PMCID: PMC8453847. Figure 2. Juvenile xanthogranuloma. A. A solitary pink-yellow lesion on the left arm B. On dermoscopy, a homogeneous yellow color was seen (polarized light dermoscopy, original magnification 10x) C. Reflectance confocal microscopy shows dilated dermal papillae at dermal-epidermal junction filled with clusters of roundish, large, multinucleated and hyper-refractile atypical cells corresponding to Tou- ton cells (yellow arrows) (0.5 x 0.5 mm, 30x). D. Histopathology showed a dense histiocytic infiltrate with Touton cells (yellow arrows) and foamy histiocytes (blue arrows) (H&E, 40x). 4 Research Letter | Dermatol Pract Concept. 2023;13(2):e2023137 4. Lovato L, Salerni G, Puig S, Carrera C, Palou J, Malvehy J. Adult xanthogranuloma mimicking basal cell carcinoma: dermoscopy, reflectance confocal microscopy and pathological correlation. Dermatology. 2010;220(1):66-70. DOI: 10.1159/000264670. PMID: 19996569. 5. Pimenta R, Leal-Filipe P, Oliveira A. 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