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The differential diagnosis of syringoma and milia based on the imaging of reflectance confocal microscopy

Editor, Syringoma is a benign adnexal tumor derived from intraepidermal eccrine ducts, and it occurs predominantly in women at puberty or later in life,1 which typically presents as multiple, small, firm, skincolored papules, usually 1-3 mm in diameter, and symmetrically distributed on the lower eyelids.1,2 Milia are small, epithelium-lined keratinous cysts in the dermis thought to result from plugging of pilosebaceous or eccrine sweat ducts, and milia present as 1 ~ 2 mm, white, domed papules,3 most commonly on the lower eyelids or other areas on the face. Thus, the clinical presentation and predilection site of syringoma and milia are similar, which need to be discriminated. Histological analysis could easily differentiate these two diseases; however, the invasive biopsy reduced the patients’ compliance. The reflectance confocal microscopy (RCM) is a noninvasive imaging technique that provides high-resolution cellular imaging of the epidermis and superficial dermis,4 which has been used in the diagnosis and differential diagnosis of skin tumors and inflammatory diseases for more than two decades with high sensitivity and specificity.5 Jiménez MR6 described the RCM features of syringoma, but until now, there was no differential diagnosis report of syringoma and other microcystic adnexal carcinomas with RCM. In 2018, cases with lesions suspicious of syringoma or milia on the lower or upper eyelids (Figure 1A) were enrolled in the study. After written informed consent obtained and the related history recorded, the clinical pictures were taken and the lesions and adjacent normal skin were imaged by a commercially available, near-infrared, reflectance mode confocal microscope (VivaScope 1500; Lucid Inc.). A detailed description of the technique and the device used has been published previously.4-7 After imaging with RCM, the same lesions were biopsied and analyzed histologically to investigate the accuracy of RCM imaging. Then, the exact lesions imaged were suggested to be biopsied and analyzed histologically. The excisions were fixed in formalin and embedded in paraffin. After routine processing, slides were stained with hematoxylin and eosin (H-E). The RCM features of the lesions were analyzed layer by layer and correlated to the findings of histology analysis. Totally 5 cases of syringoma and 3 cases of milia with confocal image and histology confirmation were recruited. When the syringoma lesions were imaged with RCM, there were no significant cellular changes, but just slight thinning of epidermis compared with the adjacent normal skin, and the presence of round to oval high refractive, and relatively monomorphous substances of varying sizes in the superficial and middle dermis, is clearly exhibited, with 1-2 layers of light-dark line structure around the high refractive substances (Figure 1B). Hematoxylin-eosin stain shows the presence of multiple small ducts and epithelial cords within the dermis. The ducts are lined by two rows of flattened epithelial cells, the outer layer bulging outwards to create a comma-like tail. Ductal lumina are filled with an amorphous, periodic acid-Schiff–positive material (Figure 1C). The amorphous material correlates to the high refractive substances in confocal image, while the two rows of flattened epithelial cells correspond to the 1-2 layers of light-dark line structures around the refractive center (Figure 1B). And when imaged deeper, the refraction of the round structures tends to be slowly decreased. As to the milia, the confocal images showed the relatively high refractive, but not monomorphous, global keratin in superficial dermis (Figure 1D). The histological examination of the lesions revealed subepidermal keratin-filled cysts lined with stratified epithelium (Figure 1E). The major differential points between syringoma and milia in confocal images are the evenly or unevenly refractive substance in dermis and the presence of the line structures around the refractive substance or not (Figure 1F). And the histological results confirmed our findings. Reflectance confocal microscopy imaging noninvasively shows nuclear and cellular-level morphology in human skin in vivo.7,8 The RCM had been widely used in the screening of skin tumors,9 such as melanoma, basal cell carcinoma, and actinic keratosis, and in recent years, the RCM was found to be useful in the diagnosis, differential diagnosis, and follow-up of pigmentary10,11 and inflammatory skin disorders12 with high sensitivity and specificity. As the clinical manifestations and prediction sites of syringoma and milia are similar, the lesions are easily confused and need to be identified. Furthermore, most of the female patients with the lesions on facial areas do not accept the biopsy, the noninvasive skin imaging methods, especially RCM, show specific advantages. In this study, we conducted a correlation study of RCM and histology analysis in the differential diagnosis of syringoma and milia. And we found that the major findings of both diseases were located in superficial and middle dermis. For syringoma lesions, the confocal image revealed the presence of round to oval high refractive, and relatively monomorphous masses of varying sizes, with 1-2 layers of light-dark line structure around the high refractive substances, which correlated to the ductal lumina filled with an