Dermatology: Practical and Conceptual Research Letter | Dermatol Pract Concept. 2023;13(1):e2023039 1 Dermoscopy and Reflectance Confocal Microscopy of Apocrine Hidrocystoma Joanna Ludzik1,2, Claudia Lee2,3, Stephanie Mengden2, Huong Nguyen2, Dennis Pleshakov2, Alexander Witkowski2 1 Department of Telemedicine and Bioinformatics, Jagiellonian University Medical College, Krakow, Poland 2 Department of Dermatology, Oregon Health and Sciences University, Portland, Oregon 3 School of Medicine, University of California Riverside, Riverside, California Key words: nivolumab, regression, melanocytic nevi, melanoma, dermoscopy Citation: Ludzik J, Lee C, Mengden S, Nguyen H, Pleshakov D, Witkowski A. Dermoscopy and Reflectance Confocal Microscopy of Apocrine Hidrocystoma. Dermatol Pract Concept. 2023;13(1):e2023039. DOI: https://doi.org/10.5826/dpc.1301a39 Accepted: May 30, 2022; Published: January 2023 Copyright: ©2023 Ludzik 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: Claudia Lee, BS, Department of Dermatology, Oregon Health and Sciences University, Portland, Oregon 3181 SW Sam Jackson Park Rd Portland, OR 97239 Email: leecla@ohsu.edu Introduction Hidrocystomas (AHC) are benign cystic tumors that origi- nate from apocrine or eccrine sweat glands. While rare, apo- crine AHC are typically found as solid, asymptomatic blue to black papules or nodules on the face and neck, especially around the eyelid margin. AHC arises from cystic prolifer- ation of the apocrine gland [1], while the eccrine variant is caused by the retention of eccrine glands [2]. The etiology of apocrine AHC is largely unknown [1]. Pigmented AHC of the nasal epithelium of the eccrine origin have been reported [3], but to our knowledge, our case is one of few [4] AHC on the nasal ala reported. Additionally, we report another case of pigmented AHC and describe the reflectance confocal microscopy (RCM) findings, which are scarce in current literature [5]. Although AHC are benign lesions, based off clinical appearance alone they are often mistaken for basal cell carcinomas, blue nevi, or even melanoma. RCM can noninvasively differentiate between benign and malignant cutaneous lesions, and we review the potential application of this imaging technique in the clinical management of AHC. Case Presentation Case 1 is a 69-year-old male with Fitzpatrick Skin type III presented with concerns for a 2-mm homogenous, well de- marcated blue-gray papule on a background of sun- damaged hyperpigmented skin (Figure 1, A and B). Initial clinical assessment was determined as a blue nevus potentially su- perimposed upon a solar lentigo, and a shave biopsy was done to rule out malignant melanoma given the patient re- ported history of excessive sun exposure and rapid growth of the lesion. The specimen routinely stained with hematox- ylin and eosin and histologically diagnosed as a pigmented AHC. Microscopic examination revealed a cystic structure containing focal granular pigmented material whose upper portion was lined by cuboidal epithelial cells. The lesion was histologically diagnosed as a pigmented AHC. The specimen 2 Research Letter | Dermatol Pract Concept. 2023;13(1):e2023039 routinely stained with hematoxylin and eosin and histologi- cally diagnosed as a pigmented AHC (Figure 1C). Case 2 is a 63-year-old male presented with a history of non-melanoma skin cancer who presented with concerns for an asymptomatic lesion located on his central forehead. The patient reported that the lesion has been present for an unknown amount of time but has recently grown in size over the last few months. Clinical and dermoscopic exam- ination revealed a well demarcated 4-mm blue homogenous papule (Figure 2, A and B). The lesion was further evalu- ated with RCM (Vivascope 1500) which revealed a normal honey-combed epidermal architecture surrounding a hypo reflective space. Deeper images reveal dark lacunae near nor- mal adnexal structures (Figure 3A), representative of cystic spaces. These findings along with the absence of concerning features such as pagetoid cells or non-edged papillae favored diagnosis of a benign AHC. However, due to patient con- cern for the growing lesion, the lesion was removed using a shave biopsy technique and histopathological assessment illustrated a cystic space lined by several layers of cuboidal epithelial cells, confirming the diagnosis of pigmented AHC (Figure 3B). Figure 1. (A) Clinical image of a darkly pigmented papule located on the left nasal ala. (B) Dermoscopic image of the lesion showing a 2-mm homogenous blue-gray papule on a background of brown to red sun-damaged skin. (C) Histopathologic image showing a cystic structure lined by single-to-several layers of cuboidal epithelial cells (arrows) with focal granular pigmented material in the cyst lumen (H&E, x100). Research Letter | Dermatol Pract Concept. 2023;13(1):e2023039 3 Conclusions This paper reports a unique anatomical presentation of an apocrine variant of pigmented AHC and discusses the dif- ferential diagnosis of pigmented papules or nodules on the body, specifically blue nevi and melanoma. AHC can grossly present as a blue papule or nodule that can be mistakenly clinically diagnosed as a blue nevus, pigmented basal cell car- cinoma (BCC), or even melanoma. While AHCs and blue nevi are benign, skin cancers like BCC and melanoma have malig- nant potential, thus histologic evaluation can be of benefit. Blue nevus-like melanomas have two reported pathogenesis: melanoma arising coincidentally with a benign blue nevus or arising de novo and mimicking a blue nevus  [6]. While rare, it is important to note an initially benign blue nevus also has the potential to become malignant [7-9]. AHC may be benign, however it is important to be familiar of other malignancies with similar clinical presentations as potential differential diagnosis. Familiarity with features of AHC may promote accu- rate clinical diagnosis and avoid the unnecessary finan- cial, cosmetic, and psychological implications associated with physical biopsies. AHC tend to appear as a solitary, homogeneous papule or nodule, typically ranging in size from 3-15mm [10], either skin-colored or with pink, yellow or blue color hue, and can have secondary features such as arborizing vessels seen under dermoscopy  [11]. AHC most commonly appears on the eyelid margins [12-15], oral mucosa [16,11,17] and ear [11,17,18]. We would like to report that both our cases of AHC, when compared to more classical presentations, do not have ar- borizing vessels, and has a less common location on the nasal ala, contributing to the literature of other variants, including eccrine [19] and planar AHC variants [20], reported on the nasal ala. It is important to utilize advanced imaging technologies to discern differential diagnosis of blue skin lesions with malignant potential, such as blue nevi, BCC, and melanoma from a completely benign entity like hidrocystoma. Recog- nizing the absence of certain features of BCC such as bright tumor islands with abundant vasculature and pleomorphism of the overlying epidermis [21-24] or features like nucleated round, dendritic, or spindled cells and non-edged papillae which can be found in melanocytic lesions with malignant potential like blue nevi or melanoma [25] can provide cli- nicians with enough confidence to safely monitor the lesion without sampling. The clinical benefits of utilizing RCM include prevention of unnecessary biopsies, decreased pain, improved cosmetic outcomes, and enhanced surveillance for recurrent malignancy [26]. Data on RCM characteris- tic findings for hidrocystomas is scarce in current literature [4,22] and we provide further evidence supporting the fea- tures of hidrocystoma commonly seen on RCM including homogenous cystic structures adjacent to normal‐appearing adnexal structures. The variations and overlapping features in the clin- ical presentation of AHC, blue nevus, melanoma and non-melanoma skin cancer may make it challenging to dic- tate appropriate management therefore, it is important to consider the diagnosis of pigmented AHC clinically when there is a suspicion of blue nevus, BCC, or melanoma. Dermoscopic and reflectance confocal microscopic assess- ment of the lesion aids in an accurate diagnosis which may to guide appropriate patient care. Figure 2. (A) Clinical image of a single darkly pigmented papule located on the central forehead. (B) Dermoscopy image demonstrating a 4-mm blue-violet homogenous well-demarcated papule. 4 Research Letter | Dermatol Pract Concept. 2023;13(1):e2023039 Figure 3. (A) Reflectance confocal microscopic image of the superficial dermis reveals adnexal structures (yellow star) surrounded by several hypoechogenic lacunae (yellow arrows) representative of cystic spaces. (B) Histopathologic image showing a cystic lumen with the upper por- tion demonstrating an attenuated lining containing 2 layers of flattened to cuboidal epithelial cells (arrows) and pigmented brown granular material (star) in the cystic space (H&E, x100). Research Letter | Dermatol Pract Concept. 2023;13(1):e2023039 5 14. Belaldavar BP, Suranagi V, Kalakuntla M, Raj B, Tiwari A. Apocrine Hidrocystoma: A Rare Case Report. Indian J Otolar- yngol Head Neck Surg. 2019;71(Suppl 1):59-61. DOI: 10.1007/ s12070-016-1012-2. PMID: 31741931. PMCID: PMC6848530. 15. Alagheband M, Maida M. Asymptomatic periorbital, bluish cys- tic papule. Cortlandt Forum. 2004;18:36-41. 16. Jakobiec FA, Stacy RC, Colby KA. Pigmented apocrine hidro- cystoma of the caruncle. Cornea. 2010;29(11):1320-1322. DOI: 10.1097/ICO.0b013e3181d4fd71. PMID: 20697277. 17. Poli PP, Creminelli L, Moramarco V, Del Gobbo A, Ferrante F, Maiorana C. Diagnostic Workup and Treatment of a Rare Apo- crine Hidrocystoma Affecting the Oral Mucosa: A Clinical and Histological Case Report. Case Rep Dent. 2017;2017:9382812. DOI: 10.1155/2017/9382812. PMID: 28781903. PMCID: PMC5525067. 18. Ozel HE, Kaynar A. A case of an apocrine hidrocystoma treated by sublabial approach. Kulak Burun Bogaz Ihtis Derg. 2012;22(5):284-287. DOI: 10.5606/kbbihtisas.2012.054. PMID: 22991989. 19. Ioannidis DG, Drivas EI, Papadakis CE, Feritsian A, Bizakis JG, Skoulakis CE. Hidrocystoma of the external auditory canal: a case report. Cases J. 2009;2(1):79. DOI: 10.1186/1757-1626-2- 79. PMID: 19161624. PMCID: PMC2637255. 20. Rappazoo KC, Cohen PR. Pigmented hidrocystoma of nasal ep- ithelium (PHONE): report of a man with a pigmented hidro- cystoma of his nose and literature review. Dermatol Online J. 2016;22(5):13030/qt9c50d26x. PMID: 27617522. 21. Yanagi T, Sawamura D, Nishie W, Abe M, Shibaki A, Shimizu H. Multiple apocrine hidrocystoma showing plane pigmented macules. J Am Acad Dermatol. 2006;54(2 Suppl):S53-S54. DOI: 10.1016/j.jaad.2005.07.039. PMID: 16427998. 22. Kitamura S, Yanagi T, Imafuku K, Hata H, Shimizu H. Lipofuscin deposition causes the pigmentation of apocrine hidrocystoma. J Dermatol. 2018;45(1):91-94. DOI: 10.1111/1346-8138.14037. PMID: 28925089. 23. Willard K, Warschaw KE, Swanson DL. Use of reflectance confocal microscopy to differentiate hidrocystoma from basal cell carcinoma. Dermatol Surg. 2011;37(3):392-394. DOI: 10.1111/j.1524-4725.2011.01893.x. PMID: 21314800. 24. González S, Tannous Z. Real-time, in vivo confocal reflectance microscopy of basal cell carcinoma. J Am Acad Dermatol. 2002;47(6):869-784. DOI: 10.1067/mjd.2002.124690. PMID: 12451371. 25. Pellacani G, Witkowski A, Cesinaro AM, et al. Cost-benefit of reflectance confocal microscopy in the diagnostic performance of melanoma. J Eur Acad Dermatol Venereol. 2016;30(3):413-419. DOI: 10.1111/jdv.13408. PMID: 26446299. 26. Agero AL, Busam KJ, Benvenuto-Andrade C, et al. Reflec- tance confocal microscopy of pigmented basal cell carcinoma. J Am Acad Dermatol. 2006;54(4):638-643. DOI: 10.1016/j. jaad.2005.11.1096. PMID: 16546585.. References 1. Hafsi, W. and T. Badri, Apocrine Hidrocystoma, in StatPearls. 2020, StatPearls Publishing Copyright © 2020, StatPearls Publishing LLC.: Treasure Island (FL). 2. Alfadley A, Al Aboud K, Tulba A, Mourad MM. Multiple eccrine hidrocystomas of the face. Int J Dermatol. 2001;40(2):125-129. DOI: 10.1046/j.1365-4362.2001.01126.x. PMID: 11328394. 3. Rappazzo KC, Cohen PR. Pigmented hidrocystoma of nasal epithelium (PHONE): report of a man with a pigmented hidro- cystoma of his nose and literature review. Dermatol Online J. 2016;22(5):13030/qt9c50d26x. PMID: 27617522. 4. Anandasabapathy N, Soldano AC. Multiple apocrine hidrocysto- mas. Dermatol Online J. 2008;14(5):12. PMID: 18627748. 5. Walker A, Sahni VN, Sahni DR, Curtis J. Use of Reflectance Confocal Microscopy for Hidrocystomas: An Emerging, Cost- Effective, and Powerful Tool. Case Rep Dermatol Med. 2021; 2021:5543803. DOI:10.1155/2021/5543803 PMID: 33898070. PMCID: PMC8052164. 6. Granter SR, McKee PH, Calonje E, Mihm MC Jr, Busam K. Melanoma associated with blue nevus and melanoma mimicking cellular blue nevus: a clinicopathologic study of 10 cases on the spectrum of so-called ‘malignant blue nevus’. Am J Surg Pathol. 2001;25(3):316-323. DOI: 10.1097/00000478-200103000-00 005. PMID: 11224601. 7. González-Cámpora R, Galera-Davidson H, Vázquez-Ramírez FJ, Díaz-Cano S. Blue nevus: classical types and new related entities. A differential diagnostic review. Pathol Res Pract. 1994;190(6): 627-635. DOI: 10.1016/S0344-0338(11)80402-4. PMID: 7984522. 8. Connelly J, Smith JL Jr. Malignant blue nevus. Cancer. 1991;67(10):2653-7. DOI: 10.1002/1097-0142(19910515)67: 10<2653::aid-cncr2820671041>3.0.co;2-u. PMID: 2015566. 9. Lee HY, Na SY, Son YM, et al. A malignant melanoma associated with a blue nevus of the lip. Ann Dermatol. 2010;22(1):119-124. DOI: 10.5021/ad.2010.22.1.119. PMID: 20548900. PMCID: PMC2883390. 10. Johansson M, Brodersen J, Gøtzsche PC, Jørgensen KJ. Screening for reducing morbidity and mortality in malignant melanoma. Cochrane Database Syst Rev. 2019;6(6):CD012352. DOI: 10.1002/14651858.CD012352.pub2. PMID: 31157404. PMCID: PMC6545529. 11. Cheung WY, Bayliss MS, White MK, et al. Humanistic burden of disease for patients with advanced melanoma in Canada. Support Care Cancer. 2018;26(6):1985-1991. DOI: 10.1007/ s00520-017-4025-9. PMID: 29322243. PMCID: PMC5919988. 12. Zaballos P, Bañuls J, Medina C, Salsench E, Serrano P, Guion- net N. Dermoscopy of apocrine hidrocystomas: a morphologi- cal study. J Eur Acad Dermatol Venereol. 2014;28(3):378-381. DOI: 10.1111/jdv.12044. PMID: 23198900. 13. Sarabi K, Khachemoune A. Hidrocystomas--a brief review. Med- GenMed. 2006;8(3):57. PMID: 17406184. PMCID: PMC1781304.