Dermatopathology of Cutaneous Cystic Lesions: a Practical Review with Diagnostic Clues and Pitfalls

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CME ARTICLE

Dermatopathology of Cutaneous Cystic Lesions: A Practical Review With Diagnostic Clues and Pitfalls

Noelia Pérez-Muñoz, MD,* Mar Llamas-Velasco, PhD,† Gonzalo Castillo-Capponi, MD,‡ Daniel Morgado-Carrasco, MD,§ Maribel Iglesias-Sancho, MD,¶ Miguel-Ángel Carrasco-García, PhD,║ and María-Teresa Fernández-Figueras, PhD**

Conclusions: Knowledge of the histopathology of cystic lesions Background: Cystic lesions are common in the daily practice of contributes to their correct diagnosis, improving the management of dermatologists and dermatopathologists, and in most cases, patients. a straightforward diagnosis can be done. Yet, some variants and situations may cause diagnostic problems or carry prognostic and/or Key Words: cyst, pseudocyst, histopathology, classification, review systemic implications. (Am J Dermatopathol 2019;41:783–793) Objective: To review the histopathological features of the most frequent cystic lesions, either true cysts or pseudocysts, and provide LEARNING OBJECTIVES some clues and pitfalls to bear in mind for troublesome situations After participating in this activity, physicians should be such as solid–cystic tumors; uncommon variants; incidental findings; better able to: artifactual, reactive, or infectious cavities; cysts as a warning of 1. Identify the correct histopathological diagnosis of most systemic and hereditary diseases; and malignant cystic tumors, either cystic lesions, either true cysts or pseudocysts. primary or metastatic. 2. Distinguish cysts with malignant features and/or their pos- Methods: The histopathological diagnostic criteria of most cystic sible association to hereditary or systemic diseases. lesions and their potential caveats will be discussed, offering some 3. Explain indications of the histopathological diagnosis of diagnostic clues. these lesions. Results: Cystic lesions of the skin can primarily be classified into true cysts and pseudocysts. The most frequent pseudocysts are sinus pilonidalis and mucin-filled cavities. True cysts can be divided INTRODUCTION according to their epithelial origin or differentiation into epidermal/ Cystic lesions are very frequent in daily practice. Some pilar cysts, cysts from glandular appendages, and from embryonic of them are true cysts, lined by benign epithelium and filled remnants. Diagnostic dilemmas and possible pitfalls in cystic lesions with liquid or semisolid materials, whereas pseudocysts are are reviewed, offering some keys to solve them. cavities devoid of any epithelial lining, such as fistulae, or malignant cystic neoplasms.1 This brief overview constitutes a practical approach to From the *Faculty, Department of Pathology, Hospital Universitari General de the diagnosis of the most common cutaneous cysts providing Catalunya-Quirónsalud, Universitat Internacional de Catalunya, Sant Cugat some helpful clues and underlining the most important del Vallès, Barcelona, Spain; †Faculty, Department of Dermatology, Hos- caveats. pital de la Princesa, Madrid, Spain; ‡Resident, Department of Dermatology, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain; §Resident, Department of Dermatology, Hospital Clinic de Barcelona, Bar- celona, Spain; ¶Faculty, Department of Dermatology, Hospital Universitari PSEUDOCYSTS Sagrat Cor-Quirónsalud, Barcelona, Spain; ║Director of Department, Many pseudocysts are secondary to inflammatory pro- Department of Pathology, Hospital Universitari General de Catalunya-Quir- ónsalud, Universitat Internacional de Catalunya, Sant Cugat del Vallès, cesses, as is the case of the sinus pilonidalis in the sacral Barcelona, Spain; and **Head of Surgical Pathology, Department of region. The wall consists of granulation tissue containing Pathology, Hospital Universitari General de Catalunya-Quirónsalud, Uni- numerous multinucleated giant cells, often related to hair versitat Internacional de Catalunya, Barcelona, Spain. shafts. The presence of hair shafts is a constant finding in the All authors, faculty, and staff in a position to control the content of this CME initial stage of sinus pilonidalis and can be highlighted using activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interests in, any polarization lens, but they can be absent in specimens from commercial organizations relevant to this educational activity. relapses2 (Fig. 1A). Recurrences are better characterized by Correspondence: María-Teresa Fernández-Figueras, PhD, Head of Surgical the presence of draining sinuses, similar to suppurative hidra- Pathology, Department of Pathology, Hospital Universitari General de denitis. Any kind of fistulae, if persistent, can undergo squa- Catalunya-Quirónsalud, Universitat Internacional de Catalunya, c/Pedro i Pons, 1 CP 08190, Sant Cugat del Vallès, Barcelona, Spain (e-mail: mous metaplasia and generate true cysts (Fig. 1B). maiteffi[email protected]). Aggressive squamous cell carcinomas (SCCs) may come Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. forth those cysts.3

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FIGURE 1. A, Scanning magnification of a long-standing sinus pilonidalis showing an epidermal invagination surrounded by granulation tissue and extensive fibrosis (at this stage, the presence of hair shafts is not mandatory to make the diagnosis). B, Squamous metaplastic epithelium in a relapsed sinus pilonidalis. C, Synovial cyst riveted by histiocytes, confirmed by CD68 staining (insert). D, Synovial metaplasia secondary to surgical suture.

Mucin-filled pseudocysts are relatively frequent. The cysts from glandular appendages, and cysts from embryonic early stage of digital mucoid cyst consists of an interstitial remnants. Hybrid combinations of the former categories can accumulation of mucin, intermixed with collagen fibers. also occur. Gradually the mucinous material accumulates, giving rise to a cavity of viscous content. In the advanced stage, digital Epidermal/Pilar Cysts mucoid cyst is usually a mucin-filled cavity closely related to This group comprises, by far, the most frequently the basal layer of the acral epidermis, which tends to be very excised lesions, having many names traditionally given to thin and hyperkeratotic.4 A similar progression from intersti- them, of which sebaceous cyst, the most widely used by tial deposition to pseudocyst formation occurs in ganglion physicians outside the field of dermatology, includes infun- cysts leading to the development of the so-called synovial dibular cysts, acral epidermal cysts, milium cysts, vellus cysts or cutaneous metaplastic synovial cysts. Despite their eruptive cysts, pigmented terminal hair cysts, trichilemmal name, their wall is usually riveted by a layer of CD68-positive cysts, proliferating trichilemmal cysts, and pilomatricomas, histiocytes, which are reminiscent of synovial cells5 (Fig. 1C). all of them lined by keratinizing squamous epithelium. Another site-specific pseudocystic lesion is the oral mucocele Infundibular cysts, also known as follicular cysts that often appears in the lip but can also grow elsewhere in the infundibular type, are the most common cystic lesions in oral cavity. This lesion must be considered particularly in adults, often developed in the cheeks, neck, or on the back of pediatric patients, but cases in adults are also frequent. His- patients with previous acne. They can occasionally be tology reveals a mucin-filled cavity with abundant mucus- multiple, especially in the scrotal area,12 sometimes associ- filled macrophages. Minor salivary glands, the origin of this ated with scrotal calcinosis,13,14 although it is not clear process, can often be identified at the periphery of the whether the 2 processes are pathogenically related. They are lesion.6,7 characterized by an epidermal-type keratinization with a gran- Organized hematomas, recanalization of thrombi, in- ular layer and an even transition into loosely packed central jected materials, and foreign bodies can also originate keratin, as in the follicular infundibulum (Fig. 2A). Because pseudocysts.8 Occasionally, pseudocysts engulfing foreign of their follicular origin, a small open pore connecting to the bodies may undergo synovial metaplasia in their walls similar surface is often present. Widening of this pore, as a result of to capsular synovial metaplasia of breast implants9,10 (Fig. inflammation, is probably the origin of the dilated pore of 1D). Winer. Its hyperplastic epithelium, originally interpreted as a trichoepithelioma, is probably induced by the peripheral scar.15–17 CYSTS Acral epidermal cysts are usually located in the soles, Cysts can be classified into several ways,11 but the most probably secondary to traumatic epidermal inclusion, so that simple approach is to divide them into 3 categories according they can be considered real epidermal inclusion cysts. Their to their histological features or origin: epidermal/pilar cysts, inner aspect is covered by squamous epithelium with

FIGURE 2. A, Scrotal infundibular cyst containing loose keratin, with keratinization identical to the over- lying epidermis. B, Acral epidermal cyst showing acral-type keratinization, identical to the surface epithelium. C, Trichilemmal cyst lined by squamous epithelium showing isthmic-type keratinization. D, Pilo- matricoma with basaloid cells undergoing apoptosis with archi- tectural preservation (“ghost or shadow cells”). a granular layer and compact eosinophilic keratin, identical to slightly deeper than infundibular cysts and often present the epidermis in this location. Areas of reactive parakeratosis a cleavage plane with the adjacent tissues that facilitates the without granular layer are not rarely found (Fig. 2B).18 surgical enucleation. Microscopically, they are characterized Milium cysts, also known as small epidermal inclusion by an abrupt and uneven keratinization with central accumu- cyst, are small round cysts 1–2 mm in diameter, located in the lation of compact eosinophilic keratin, similar to the follicular superficial dermis, generally involving the face although they isthmus, mostly in the catagen phase25–27 (Fig. 2C). Some can affect any area of the skin. Histopathologically, they are cases contain proliferative areas in their wall in transition with almost identical to infundibular cysts, although an origin from proliferating trichilemmal cysts. eccrine acrosyringia has been suggested.19 Often, there is Proliferating trichilemmal cysts, mainly located in the a history of rubbing, erosions, blistering diseases, and actinic scalp, are made up of cords, whorls, and lobules of squamous damage. Not rarely, they are multiple and interconnected. cells with central collections of compact eosinophilic keratin. Multiple milium cysts closely packed in an area are called The epithelium is thicker than in common trichilemmal cysts “milia en plaque.” This condition can be idiopathic or sec- but quickly undergoes trichilemmal keratinization. Charac- ondary to other processes, including lupus erythematous.20 teristically, it exhibits atypical features such as vesicular and The thin epithelial lining of cysts in “milia en plaque,” pleomorphic nuclei with prominent nucleoli and occasional lacking any atypical features, is the best clue to differentiate it mitoses. Some proliferating trichilemmal cysts have a pre- from infundibulocystic SCC.21 dominantly solid appearance, whereas others exhibit a notice- Vellus eruptive cysts and pigmented follicular cysts are able cystic component or can be considered a hybrid form similar to infundibular cysts but contain vellus hair shafts or with features of both trichilemmal and epidermal cysts. Some pigmented terminal hair type, respectively.22 In some occa- authors suggest that proliferating trichilemmal cysts might be sions, the bulb of the hair follicles that originated the hair better classified as tumors.28 Histological examination must shaft can be identified, attached to its wall. Vellus eruptive be exhaustive because malignant transformation has been re- cysts can be multiple and may be associated to ported, especially in large lesions located outside the scalp steatocystomas.22 with a history of recent growth.28,29 Proliferating epidermal cysts are poorly defined lesions. Pilomatricomas are more frequent on the head and neck The term was coined by Wilson Jones to describe solid–cystic and upper extremities of children, but they can occur at any tumor of the scalp made up of anastomosing epithelial strands age and may be located anywhere. They are nodulocystic containing some cystic spaces filled with keratin. It may proliferations of pilomatricial and squamous cells with contain foci of calcification and necrotic debris. These lesions a striking tendency to massive apoptosis, preserving the bear a risk of transformation into SCC of about 20%, raising cytoarchitectural features, being denominated shadow cells or doubts about its real nature.23,24 ghost cells (Fig. 2D). There are focal areas of epidermal-type Trichilemmal cysts, also known as isthmus-catagen keratinization and variable amounts of orthokeratotic keratin. type of follicular cysts, tend to be located in the scalp, The fully developed and regressing stage is characterized by

Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Pérez-Muñoz et al Am J Dermatopathol Volume 41, Number 11, November 2019 calcification and formation of mature bone.30,31 Some cases this disease varies depending on environmental factors and can reach a remarkable size being misinterpreted as soft tissue androgenetic stimulation. In children or young adults, multi- masses by imaging techniques and can be very challenging ple steatocystomas are often associated with eruptive vellus due to their heterogeneity, especially in partial biopsy speci- hair cysts and hybrid forms. mens.32 Sonography may help orientate diagnosis, as most of these tumors appear as an oval-shaped hypoechoic mass with Hybrid Cysts internal calcifications and internal vascularity.33 Hybrid cysts that show a mixture of infundibular, vellus, trichilemmal, or matrical areas are also known as Cysts From Glandular Appendages follicular hybrid cysts.37,38 Not rarely, areas of steatocystoma The 2 main lesions in this group are hidrocystomas, are also encountered. The most frequent combination is infun- originated from sweat glands, and steatocystomas, originated dibular and trichilemmal cysts.37 These hybrid lesions are from sebaceous ducts. a frequent finding in Gardner syndrome, but their overall high Hidrocystomas are lined by a cuboidal epithelium, often frequency makes them an incidental finding in adults.37 Con- monolayered, which usually shows apocrine secretion (Fig. versely, their presence in childhood merits further 3A). The existence of eccrine hidrocystomas is debated investigation. because cases with flattened epithelium without evidence of secretion could correspond to atrophic apocrine lining. The Cysts Derived of Embryonic Remnants most frequently involved areas are the head and neck (peri- Cysts derived of embryonic remnants include dermoid, orbital and scalp) and the perineal region. Although they are cervical, bronchogenic, ciliated, and median raphe cysts.39–41 mostly unilocular, cases with a multilocular silhouette or with Dermoid cyst is lined by an epithelium equal to normal small solid and papillary projections within the lumen are not skin, including folliculosebaceous units and sweat glands. Its exceptional.34 A remarkable and infrequent variant of this most characteristic location is the end of the eyebrow, entity has been designated as PHONE, acronym for pig- although they can arise in other areas.42 mented hidrocystoma of the nasal epithelium.35 Cervical cysts are usually lined by squamous and upper Steatocystomas have a thin wall of squamous epithe- respiratory airway epithelium, often surrounded by abundant lium that, characteristically, shows a crenulated surface with mixed inflammatory infiltrate (Fig. 3C). This group includes a thin eosinophilic refractile membrane, attached to the thyroglossal cysts, which are more frequently and typically luminal pole. Sometimes, sebaceous glands are seen attached located in the midline between the base of the tongue and the to the outer wall (Fig. 3B). The content is made up of pro- thyroid gland.43 They usually contain remnants of thyroid teinaceous material and scattered squamous flakes. Steatocys- tissue (Fig. 3D) forming islets and follicular structures con- tomas can appear either isolated or as multiple lesions, in taining homogeneous eosinophilic protein-like (colloid) mate- which case they associate with an autosomal dominant muta- rial. Thymic cysts are also centrally located and can contain tion in the cytokeratin 17 gene KRT17.36 The penetrance of traces of thymic tissue with characteristic corpuscles of

FIGURE 3. A, Hidrocystoma lined by cuboidal cells, with apocrine secretion. B, Steatocystoma lined by squamous epithelium with crenulated surface and a thin eosinophilic membrane, presenting a sebaceous gland attached to the wall (*). C, Embryonic remnant cyst lined by respiratory airway and squamous epithelium. D, Thyroid tissue with follicular structures ﬁlled with colloid eosinophilic material, in a thyroglossal cyst.

Hassall.44 Branchial cleft cysts are located along the lateral leaving a pseudocystic cavity. The same phenomenon can occur aspect of the neck,45 originated after failure of fusion of the with trichilemmal cysts. In this case, the detachment occurs often branchial arches. Often, but not always, branchial cleft cysts above the basal layer, leaving a thin line of epithelial cells develop draining fistulae with inflammatory infiltrate and attached to the wall, simulating a hidrocystoma (Fig. 4C).52 lymphoid aggregates. Bronchogenic cysts tend to involve deep tissues. Unusual Variants of Common Cysts However, some subcutaneous cases have been described.46 Despite the lack of clinical relevance, some variants They are frequently located at the suprasternal notch or may pose exceedingly large differential diagnoses. Verrucous behind the manubrium due to abnormal budding of the tra- cysts are most probably secondary to human papillomavirus cheal diverticulum. Typically, they are lined by respiratory (HPV) infection in the follicular epithelium. This variant can epithelium surrounded by muscle, mucous glands, and carti- cause major diagnostic problems, especially in a fragmented lage, such as bronchial structures.46 biopsy, because of its resemblance to verrucous carcinoma. Ciliated cysts are solitary lesions that usually occur in Their origin is considered to be infundibular,53 although they the lower limbs or the perineum of women. They are lined by may rarely show trichilemmal keratinization (Fig. 4D). cuboidal ciliated epithelium, which can sometimes show Acuriousfinding in some infundibular cysts is the papillary projections similar to the uterine fallopian tube. presence of tangles of keratin originated by a not fully Because they have a demonstrably Müllerian embryological understood mechanism,54 but their significance seems not rele- origin, it is possible to find them in deep locations. The vant (Fig. 4E). Cystic lesions can also arise from the perianal and immunohistochemical profile reveals positivity for markers perineal mammary-type glands, and this possibility should also of female genital organs such as estrogen receptors, PAX-8, be kept in mind.55 Endometriosis56 is another genital-related and WT1.41 Male cases are rare; they have been mostly lesion that can sometimes present in the dermis as a cyst. described on the back and might have eccrine origin.47 Median raphe cyst is almost exclusive to males, and Reactive Cysts and Pseudocysts most cases are diagnosed in children. It is located in the These lesions may sometimes show features pointing to midline between the meatus and the anus, the glans being its the triggering event, not only in the cyst itself but also in the most common location. They are optically empty cavities that adjacent tissue. For instance, pseudocysts secondary to local may contain protein-like material. The wall has a variable, fi injections or injuries may contain foreign materials (splinters, squamous, pseudostrati ed, glandular or mixed epithelial fillers, drugs, etc.) that are a clue to their origin.8 Hair shaft lining. In some cases, apocrine secretion, mucinous or ciliated penetration of the epithelium into the dermis can cause si- fi 40 cells can be identi ed. nuses and pseudocysts in palms and soles. This condition was initially described in barbers and hairdressers57 but can also CLUES AND CAVEATS IN THE DIAGNOSIS OF appear in fur industry workers and veterinarians (Fig. 4F). CYSTIC LESIONS Most cystic lesions do not pose diagnostic problems. Infectious Cysts The most common cystic infections are caused by Mol- However, there are circumstances that should be considered fi to avoid diagnostic delays or errors. luscum contagiosum, which can be dif cult to recognize at low magnification (Figs. 4G, H). This possibility should be Solid–Cystic Tumors considered in children because of the rarity of infundibular – cysts in pediatric patients. Fungal58 and parasitic infections, A partial biopsy from a solid cystic tumor can contain 59 exclusively a representation of the cystic component, which is such as hydatid cysts, can also lead to the formation of cysts usually less informative for diagnosis. This incomplete rep- and pseudocysts. resentation has little significance in lesions such as the solid– cystic nodular hidradenoma, but it is very relevant when Misleading Incidental Findings dealing with malignant tumors such as a digital papillary Cysts with microscopical foci of acantholysis with adenocarcinoma that can contain areas that simulate a hi- dyskeratosis should not be interpreted as cystic warty drocystoma.48 Digital hidrocystomas are rare,49 and the dyskeratomas or cystic Darier disease because the epithelium existence of a solid component of adenocarcinoma should be lacks the characteristic acanthosis and lentiginous projections totally ruled out before this diagnosis is established. (Figs. 4I, J). An additional caveat applies when the cystic compo- Pigmented infundibular cysts can give rise to the nent of a lesion is so predominant that it makes the solid suspicion of a melanocytic neoplasia. Melanin can be so component to be neglected, like in the original description of abundant that pigmentation involves not only the cyst wall the adenodermatofibroma (hemosiderotic apocrine dermatofi- but also the keratin content (Fig. 4K). However, they are broma)50 (Figs. 4A, B), initially misinterpreted as an apocrine relatively common in patients with dark skin. gland cyst with hemosiderotic dermatofibroma-like stroma.51 Warning Sign of Systemic/Hereditary Artifactual Cysts Diseases It is well known that basal cell carcinomas have a marked The presence of multiple epidermal cysts can be related tendency to fall off in the processing of histological sections, to both Gardner and Lowe syndromes.60 Two or more facial

FIGURE 4. Histopathological clues for the diagnosis of cystic lesions. A and B, Adenodermatofibroma containing 2 large cysts that at higher magnification are riveted by an epithelial apocrine lining. C, Partially detached trichilemmal cyst, leaving a single layer of epithelial cells at the periphery, simulating a hidrocystoma. D, Trichilemmal verrucous cyst, with central papillomatosis. E, Keratin whorls are an incidental finding in common epidermal cysts. F, Interdigital epidermal cyst with included hair shaft fragments. G and H, Lesion resembling a conventional infundibular cyst at low magnification; a closer examination revealing the presence of viral inclusions enables the diagnosis of cystic molluscum contagiosum. I and J, Focal areas of acantholysis with dyskeratosis can be found incidentally in the wall of infundibular cysts. K, Extensive melanin pigmentation of an infundibular cyst. L, Cystic lesion of Darier disease. M, Keratoacanthoma-like squamous-cell carcinoma arising in hidradenitis suppurativa (arrows showing preexisting benign cysts). N, Squamous cell carcinoma (arrow) at the bottom of a syringocystadenoma papilliferum. O, Cystic metastasis of HPV-related squamous-cell carcinoma mimicking an embryonic cyst of the cervical area. periocular hidrocystomas are indicative of Goltz–Gorlin increased risk of developing SCC (Fig. 4M) with a relatively syndrome.61 Center-facial hidrocystomas should raise suspi- high metastatic potential.67,68 cion of Graves disease, and their periocular presentation Notoriously, syringocystadenoma papilliferum is prob- should prompt investigation of Schopf–Schulz–Passarge ably the cystic sweat gland tumor with the highest risk of syndrome.62 Steatocystomas, often associated with eruptive malignant transformation, either in the form of adenocarci- vellus hair cysts, have also been reported in Jadassohn– noma69 or SCC (Fig. 4N), comprising verrucous SCC.70 As Lewandowsky syndrome (formerly pachyonychia congenita previously commented, perianal cystic lesions with breast- type 1).62,63 The appearance of multiple pilomatricomas in type glands can develop malignant mammary-type gland a patient who had survived a WNT-activated medulloblas- tumors identical to the ones in the breast.55 Merkel-cell car- toma led to the discovery of a heterozygous germline APC cinomas can arise in the wall of epidermal cysts,71 and a case mutation and the diagnosis of familial adenomatous poly- of in situ Merkel carcinoma has also been reported in a trichi- posis.64 Patients with Darier disease can also develop cystic lemmal cyst.72 The possibility of a malignant focal compo- lesions with the characteristic features of acantholysis and nent in a cyst warrants a thorough histopathological work-up dyskeratosis65 (Fig. 4L). of large lesions.

Malignant Transformation in a Benign Cystic Malignant Cystic Tumors Lesion A neoplasm as common as basal-cell carcinoma can Malignant transformation has been reported in almost present as one or several cysts, usually mucin-filled. In those any cystic lesion, and being malignant proliferating trichi- cases, the wall can be very thin, even a monolayer of basaloid lemmal tumor is one of the most typical.28,29 SCC developed cells, masking their true nature. Cystic trichiblastomas and in the wall of an epidermal cyst or pilonidal sinus with long- cystic panfolliculomas must be carefully examined because standing and intense inflammation is rare but not excep- the finding of differentiation of the inner or outer root sheath tional.66 Hidradenitis suppurativa characterized by the enables differential diagnosis with a cystic basal-cell carci- presence of sinuses, tracts, and cysts seems to have an noma.27 Infundibular cystic SCC consists of numerous cystic

Copyright © 2019 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Am J Dermatopathol Volume 41, Number 11, November 2019 Dermatopathology of Cutaneous Cystic Lesions structures resembling infundibular cysts, but the behavior of 3. Scheinfeld N. A case of a patient with stage III familial hidradenitis these lesions corresponds to a well-differentiated SCC.21 suppurativa treated with 3 courses of infliximab and died of metastatic squamous cell carcinoma. Dermatol Online J. 2014;20:doj_21764. 4. Karte K, Bocker T, Wollina U. Acquired clubbing of the great toenail. Cystic Metastases Digital mucoid cyst (pseudocyst). Arch Dermatol. 1996;132:228. Many metastatic tumors may simulate cutaneous cysts, 5. Choonhakarn C, Tang S. Cutaneous metaplastic synovial cyst. J Derma- tol. 2003;30:480–484. either clinically or microscopically. The most typical location 6. Lewandowski B, Brodowski R, Pakla P, et al. Mucoceles of minor sal- 73 of cystic metastasis is the cervical region. Lymph node ivary glands in children. Own clinical observations. Dev Period Med. metastasis of papillary thyroid carcinoma74 is probably the 2016;20:235–242. most frequent cause, and it is characterized by proliferation 7. Conceição JG, Gurgel CA, Ramos EAG, et al. Oral mucoceles: a clinical, of papillary or follicular structures formed by cells with fre- histopathological and immunohistochemical study. Acta Histochem. “ ” 2014;116:40–47. quent grooves or empty -appearing nuclei and colloid mate- 8. Alijotas-Reig J, Fernández-Figueras MT, Puig L. Pseudocystic encapsu- rial that can be dark with a consistency that ranges from lation: a late noninflammatory complication of hyaluronic acid filler in- slender to thick. Sometimes, concentric spheroidal calcifica- jections. Dermatol Surg. 2013;39:1726–1728. tions (psammoma bodies) are also evident. 9. Pantanowitz L, Balogh K. Breast implant capsule with synovial meta- Metastatic SCC can also mimic cervical cysts, often plasia. Breast J. 2003;9:428. 10. Krishnanandan S, Abbassian A, Sharma AK, et al. Capsular synovial simulating embryonic remnants. These tumors are frequently metaplasia mimicking silicone leak of a breast prosthesis: a case report. originated from oropharyngeal HPV-related SCC. This pos- J Med Case Rep. 2008;2:277. sibility must always be considered when squamous atypia is 11. Kaya G, Saurat JH. Cutaneous adnexal cysts revisited: what we know present, even if focal (Fig. 4O). This diagnosis will be sup- and what we think we know. Dermatopathol (Basel). 2018;5:79–85. ported by p16 positivity, and HPV infection can be confirmed 12. Prasad KK, Manjunath RD. Multiple epidermal cysts of scrotum. Indian fi J Med Res. 2014;140:318. by PCR. However, possibility of nonspeci c p16 overexpres- 13. Solanki A, Narang S, Kathpalia R, et al. Scrotal calcinosis: pathogenetic sion or HPV infection in benign brachial cysts, although rare, link with epidermal cyst. BMJ Case Rep. 2015; 2015. doi:10.1136/bcr- should also be considered in the absence of atypical features 2015-211163. and after ruling out a primary neoplasia.75,76 Cutaneous or 14. Tareen A, Ibrahim RM. Idiopathic scrotal calcinosis—a case report. Int J – lung primary SCC can rarely have identical presentation.73 Surg Case Rep. 2018;44:51 53. 15. Winer LH. The dilated pore, a tricho-epithelioma. J Invest Dermatol. An alternative source of cystic cervical metastases is naso- 1954;23:181–188. pharyngeal lymphoepithelial carcinoma, an undifferentiated 16. Morikawa T, Takizawa H, Ohnishi T, et al. Dilated pore: a case report carcinoma associated to Epstein–Barr virus infection, that and an immunohistochemical study of cytokeratin expression. J Derma- can be confirmed by EBER in situ hybridization73 tol. 2003;30:556–558. 17. Requena L, Yus ES, Simón P, et al. Induction of cutaneous hyperplasias by altered stroma. Am J Dermatopathol. 1996;18:248–268. 18. Shimizu Y, Sakita K, Arai E, et al. Clinicopathologic features of epidermal cysts of the sole: comparison with traditional epidermal cysts and DISCUSSION trichilemmal cysts. J Cutan Pathol. 2005;32:280–285. Cystic lesions are very common in the daily routine of 19. Tatsuno K, Yagi H, Tokura Y. Eruptive milium-like syringoma showing dermatopathology, and in most cases a straightforward diag- eccrine duct origin of milia. J Dermatol. 2012;39:878–879. nosis can be done. Nonetheless, these lesions deserve the 20. de Wet J, Jordaan HF, Visser WI. Bilateral malar milia en plaque as same attention and careful analysis as other biopsies because primary presentation of discoid lupus erythematosus. JAAD Case Rep. 2017;3:106–109. they can comprise a wide range of alterations from striking 21. Kim SM, Kim H, Kim HS, et al. Infundibulocystic squamous cell carci- incidental findings to highly relevant occult threats. noma. Ann Dermatol. 2015;27:319–321. Careful macroscopical evaluation and representative 22. Espinoza Hernández CJ, Fonte Ávalos V. Eruptive vellus hair cysts: sampling are also essential, paying special attention to solid prevalence and clinical features [in Spanish]. Gac Med Mex. 2013;149: fl 406–408. or in amed areas, including perilesional skin, which can 23. Jones EW. Proliferating epidermoid cysts. Arch Dermatol. 1966;94:11. provide the clue for diagnosis. Clinicopathological correlation 24. Sau P, Graham JH, Helwig EB. Proliferating epithelial cysts. Clinico- is mandatory, as in any other area of dermatopathology. pathological analysis of 96 cases. J Cutan Pathol. 1995;22:394–406. There are 3 main potential pitfalls that should be taken 25. Tellechea O, Cardoso JC, Reis JP, et al. Benign follicular tumors. Bras into consideration. First, the observer must contemplate the Dermatol. 2015; 90:780–796; quiz 797–798. 26. Ramaswamy AS, Manjunatha HK, Sunilkumar B, et al. Morphological possibility of facing a partial biopsy specimen with mis- spectrum of pilar cysts. N Am J Med Sci. 2013;5:124–128. representation of one of its components. Second, as regards 27. López-Takegami JCH, Wolter M, Löser C, et al. Classification of cysts malignancy, it is necessary to be aware of the possibility of with follicular germinative differentiation. J Cutan Pathol. 2016;43:191– focal malignant transformation of a benign preexisting lesion. 199. Third, cystic metastases can be extremely well-differentiated, 28. Folpe AL, Reisenauer AK, Mentzel T, et al. Proliferating trichilemmal tumors: clinicopathologic evaluation is a guide to biologic behavior. J with predilection for the head and neck area. Cutan Pathol. 2003;30:492–498. 29. Lobo L, Amonkar AD, Dontamsetty VVSMK. 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CME EXAM INSTRUCTIONS FOR OBTAINING AMA PRA CATEGORY 1 CREDITSTM

The American Journal of Dermatopathology includes CME-certified content that is designed to meet the educational needs of its readers. An annual total of 12 AMA PRA Category 1 Credits™ is available through the twelve 2019 issues of The American Journal of Dermatopathology. This activity is available for credit through October 31, 2021. Accreditation Statement Lippincott Continuing Medical Education Institute, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Credit Designation Statement Lippincott Continuing Medical Education Institute, Inc., designates this journal-based CME activity for a maximum of one (1) AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. To earn CME credit, you must read the article in The American Journal of Dermatopathology and complete the quiz, answering at least 80 percent of the questions correctly. Mail the Answer Sheet along with a check or money order for the $15 processing fee, to Lippincott CME Institute, Inc., Wolters Kluwer Health, Two Commerce Square, 2001 Market Street, 3rd Floor, Philadelphia, PA 19103. Only the first entry will be considered for credit and must be postmarked by the expiration date. Answer sheets will be graded and certificates will be mailed to each participant within 6 to 8 weeks of participation. Visit http:// cme.lww.com for immediate results, other CME activities, and your personalized CME planner tool.

CME EXAMINATION NOVEMBER 2019 Please mark your answers on the ANSWER SHEET. After participating in this activity, physicians should be better able to: 1. Identify the correct histopathological diagnosis of most cystic lesions, either true cysts or pseudocysts, 2. Distinguish cysts with malignant features and/or their possible association to hereditary or systemic diseases, and 3. Explain indications of the histopathological diagnosis of these lesions.

CME QUESTIONS

1. A 65-year-old man developed a nodule on the dorsum of the wrist. Microscopically, it shows a central cavity lined by mononucleated CD68+ cells. The most probable diagnosis is: a. Synovial cyst b. Foreign body reaction c. Cystic histiocytosis d. Hidrocystoma e. Mucoid cyst 2. Please select the false sentence related to sinus pilonidalis: a. Hair shafts are always present within the inflammatory infiltrate b. Sinus pilonidalis can undergo benign squamous metaplasia c. The wall consists of granulation tissue d. Persistent inflammation can derive in squamous metaplasia e. Sinus pilonidalis is a pseudocyst 3. The histopathological examination of a cyst located in the sole reveals squamous epithelium with granular layer and compact eosinophilic keratin. Which is the diagnosis? a. Verrucous cyst b. Milium cyst c. Epidermal inclusion cyst d. Trichilemmal cyst e. Infundibular cyst

4. A 55-year-old man, otherwise healthy, presented with a cystic cervical lesion lined by slightly atypical squamous epithelium surrounded by a dense lymphocytic infiltrate. Select the incorrect approach: a. Suggest exploration of the oropharynx b. Perform PCR for HPV detection c. Perform immunohistochemistry for p16 d. Perform ISH for EBER detection e. Because the diagnosis is an inflamed brachial cyst, no further investigation is needed 5. A biopsy of a cystic lesion in a fingertip shows the upper portion of a cavity lined by a monolayer of apocrine epithelium. Please select the correct sentence: a. The most probable diagnosis is hidrocystoma b. Hidrocystomas never occur in the digits c. Papillary digital adenocarcinoma should be suspected d. Embryonic remnants cannot be ruled out e. The most probable diagnosis is cystic metastasis 6. Which of these sweat-gland tumors most frequently presents malignant transformation: a. Hidrocystoma b. Syringoma c. Hidradenoma papilliferum d. Syringocystadenoma papilliferum e. Spiradenoma 7. All these situations generate pitfalls in cystic lesions, except: a. Artifact secondary to detachment during the sample processing b. Incomplete excision of the lesion c. Melanin in the cyst wall and the keratin d. Predominantly cystic lesion with a small solid component e. Identification of hair shafts