Epidermal cysts are lined by stratified squamous epithelium showing epidermal keratinization, that is, the formation of keratohyaline granules and flattened surface epithelium. As such, they are thought to be derived from or to mimic the infundibular portion of the hair follicle. Rupture of a non-inflamed cyst will produce a localized foreign body granulomatous reaction in the adjacent dermis, while rupture of an inflamed cyst usually results in a heavy inflammatory cell infiltrate in the adjacent dermis, sometimes with destruction of the cyst wall in the process. Fibrosis usually occurs subsequently.

The rare finding of epidermal (infundibular) cysts of the ear which contained vellus hairs and with intervening severe solar elastosis (akin to Favre–Racouchot syndrome) has been proposed as a new dermatoheliosis. ³⁰

Several histological variations in the epidermal lining have been reported. These include focal epidermal proliferation, ³¹ a seborrheic keratosis-like change, ³² basal hyperpigmentation and melanin incontinence (seen in black patients),^{33. and 34.} melanophagic proliferation, ³⁵ focal pilomatrixoma-like changes (usually in kindreds with Gardner’s syndrome),^{20.36. and 37.} clear cell change, ³⁸ cornoid lamellation, ³¹ epidermolytic hyperkeratosis,^{31. and 39.} histological changes of Darier’s disease, ⁴⁰ pyogenic granuloma formation, ⁴¹ Paget’s disease, ³¹ basal cell carcinoma, ³¹ mycosis fungoides, and Bowen’s disease. ⁴² Small papillary projections of follicular germinative cells emanating from the basal layer of the cyst wall are a rare occurrence. ⁴³ Some of these projections may branch and form a reticulate pattern. The term ‘trichoblastic infundibular cyst’ has been suggested for this histological variant. ⁴³ Melanoma in situ has been reported within the epithelial lining of a cyst, in contiguity with an adjacent malignant melanoma of epidermal origin. ⁴⁴ The only variations in cyst contents that occur are the formation of spherules of keratin which are closely packed and uniform in dimensions, ⁴⁵ and calcification, a common occurrence in cysts on the scrotum, where the cysts are sometimes multiple. ⁴⁶ Specific histological features are usually seen in HPV-related cysts (see below). In a study of epidermal cysts of the sole, most showed foci of parakeratosis and focal lack of a granular layer, particularly in the upper portion of the cyst wall. ⁴⁷ The cysts contained compact orthokeratotic material. The HPV status of these cysts was not obtained, but the histology of these cysts is remarkably similar to those described for HPV-related cysts (see below). Epidermal cysts express keratin 10 (K10), filaggrin^{48. and 49.} and some members of the S100 protein family. ⁵⁰ Cases of malignant transformation,^{51.52. and 53.} reported in the older literature, have been questioned as some, at least, represent proliferating tricholemmal cysts (see p. 444) or proliferating epidermal cysts (see below). Cases of unequivocal squamous cell carcinoma arising in epidermal cysts have been reported. ⁵⁴ Despite the low risk of malignant transformation, it is generally agreed that all suspected cysts should be submitted for histological examination. ⁵⁵

Epidermal cysts associated with HPV-60 infection are well-demarcated cysts in the dermis continuous with the overlying epidermis at the top of the cyst. Scattered keratinocytes in the upper layers of the epithelial lining contain intracytoplasmic, eosinophilic inclusions.^{73. and 74.} In addition, vacuolar structures are present in the keratinous (horny) material within the cyst. Parakeratotic nuclei are often present in this keratinous material. Ductal structures expressing carcinoembryonic antigen (CEA) may be found in the cyst walls. ⁶¹ In HPV-related cysts arising away from palmoplantar surfaces, no histopathological feature has been shown to be predictive for the presence of HPV-60. ⁵⁹

In the HPV-related verrucous cysts, there is an epidermal cyst lined by a papillated and/or digitated epithelium with focal, prominent hypergranulosis and irregular keratohyaline granules (Fig. 16.1). ⁶⁵ Squamous eddies, reminiscent of those seen in inverted follicular keratosis, are often present in the epithelial lining. Vacuolated keratinocytes, resembling koilocytes, have been present in some cases. ⁶⁷

Proliferating epidermal cysts are subepidermal cystic tumors that often connect with the overlying epidermis by a narrow opening or through a dilated hair follicle. ⁷⁵ An underlying epidermal cyst is often present, although this constitutes only a small part of the lesion. The lesion consists of multilocular cystic spaces containing keratinous material or proteinaceous fluid. The proliferating epithelium, which may show squamous eddies, extends into the adjacent stroma but there is usually still some circumscription. The squamous cells may have copious pale cytoplasm. Epidermal-type keratinization is a prerequisite for the diagnosis. The degree of cellularity and atypia is variable. ⁷⁵ Carcinomatous change is characterized by infiltration into the surrounding dermis and subcutis, marked nuclear atypia, pleomorphism, and frequent mitoses.

The cysts are lined by stratified squamous epithelium showing tricholemmal keratinization in which the individual cells increase in bulk and vertical diameter towards the lumen (Fig. 16.2). This usually occurs without the formation of keratohyaline granules and resembles that seen in the external root sheath in the region of the follicular isthmus. ⁸¹ There is an abrupt change into the eosinophilic-staining keratin within the lumen. Cholesterol clefts are common in this keratinous material and about one-quarter will show focal calcification of the contents. Tricholemmal cysts express both keratin 10 (K10) and 17 (K17). ⁴⁸About 10% have focal inflammation but this differs from that seen in epidermal cysts. In tricholemmal cysts, there is a break in the wall with entry into the cysts of inflammatory cells and fibroblasts with subsequent organization (Fig. 16.3). Irregular hyperplasia of the epithelial lining may be a consequence of this. Sebaceous and apocrine differentiation have been reported in the wall. ⁸² In one case Merkel cell carcinoma in situ developed in the wall of a tricholemmal cyst. ⁸³

A verrucous variant of tricholemmal cyst has been reported. ⁸⁴ HPV common antigens were demonstrated in the nuclei of the lining cells in this case. ⁸⁴

Sometimes, the outermost epithelial portion of the cyst wall separates from the remainder of the cyst. ⁷⁶ Focal separation is more common than complete splitting (Fig. 16.4). The retained basal epithelium may mimic an apocrine hidrocystoma or even a vascular malformation. ⁷⁶

Under polarized light, the perpendicularly oriented bundles of tonofibrils can be seen in the lining epithelial cells, a feature of tricholemmal keratinization. ⁸⁵ This mirrors the electron microscopic findings of an increase of filaments in the maturing cells which aggregate to form larger fibrillary bundles. Keratohyaline granules are not usually seen.

There is a lobular proliferation of squamous cells, often with some peripheral palisading and sometimes showing focal areas of vitreous membrane formation. There may be focal cystic areas or remnants of a more obvious tricholemmal cyst at one margin (Fig. 16.5). The lesions are usually well circumscribed. Nests of squamous cells may extend into the adjacent connective tissue, simulating squamous cell carcinoma, but the proliferation of nests is mostly inwards into the cyst (Fig. 16.6). This contrasts with the outward extension of nests seen in proliferating epidermal cysts.

There are typical areas of tricholemmal keratinization and, in some cases, focal epidermal keratinization as well. There may also be vacuolated cells, variable cellular atypia, ¹⁰⁶ focal necrosis, squamous eddies, individual cell keratinization, and scattered mitoses. Sebaceous and acrosyringeal differentiation were noted in one case. ¹⁰⁷ A spindle cell component has also been described.^{108. and 109.} Features favoring the diagnosis of proliferating tricholemmal cyst over squamous cell carcinoma include the presence of tricholemmal keratinization, cyst formation, calcification and the absence of a premalignant epidermal lesion. ¹¹⁰ Aneuploidy does not always assist in the assessment of malignancy as this feature can be present in proliferating tricholemmal cysts.^{111.112. and 113.} The diagnosis of a malignant proliferating tricholemmal tumor usually requires the identification in some areas of an underlying benign component. ⁹⁴ It also requires the presence of extensive cellular atypia and invasion, sometimes focal, of adjacent structures.^{95. and 114.} Other criteria that have been suggested as markers of malignancy include non-scalp location and size greater than 5 cm. ¹⁰¹ Uncommonly, a spindle cell carcinoma forms the malignant component. ¹¹⁵ In one case the spindle cells were positive for vimentin, but not for keratin, epithelial membrane antigen, or S100 protein. ¹¹⁶ Stromal desmoplasia may be present in areas of malignant transformation. There is loss of CD34 immunostaining in some malignant lesions, ¹¹³ but it is retained in others. ⁹⁰

Electron microscopy has confirmed the presence of areas of tricholemmal keratinization. ¹¹⁷

There are free-lying cysts within the dermis of the nail bed although they appear to form by elongation of the rete ridges with cyst formation and the subsequent pinching off of the connection to the nail bed epithelium. The cysts contain onycholemmal keratin and calcification. There is no granular layer.

The tumor is composed of small keratinous cysts with abrupt central keratinization and of solid nests and strands of atypical keratinocytes. ¹¹⁹

The cyst wall is composed of several layers of basaloid cells that mature to squamoid cells near the lumen (Fig. 16.7). This pattern recapitulates that seen in the normal hair matrix and cortex. Small cystic spaces are often present within the cyst wall. The lumen contains amorphous, keratinous material. If rupture occurs, a florid granulomatous reaction develops in the surrounding dermis.

The cystic variant has a thin wall about 0.1 cm in thickness. It is lined by infundibular epithelium having a granular layer. Solid aggregates of dark follicular germinative cells are present. Bulbs and papillae form in these areas. Matrical differentiation and shadow cells, as well as trichohyalin granules, are seen. Cytokeratin 903 and CK5/6 stain the tumor cells, while Ber-EP4 labels the germinative cells but not the follicular papillae.

The cyst is located in the dermis and has a narrow, pore-like opening to the surface. It contains laminated keratin as well as multiple, pigmented hair shafts (Fig. 16.8). Degenerating hair shafts may be present. ¹⁴⁰ The cyst is lined by stratified squamous epithelium showing epidermal keratinization, but in addition the lining may show rete ridges and dermal papillae, features not seen in epidermal cysts. Both epidermal and tricholemmal keratinization were present in the cysts removed from one of the patients with multiple lesions. ¹³⁸

Closely related is the occurrence of a small follicular cyst containing pigmented hair shafts arising in a melanocytic nevus. ¹⁴¹

The cysts have a corrugated or festooned configuration with a lining of several layers of squamous epithelium, but with no granular layer. Lanugo hairs were present in one cyst. There is a superficial resemblance to steatocystoma multiplex (see below), but there are no sebaceous lobules in the wall.

The author uses the term sebaceous duct cyst for cysts with a corrugated lining but no sebaceous lobules of steatocystoma on routine sectioning (Fig. 16.9). They are not as rare as the paucity of reports would suggest. There is a possibility that rare sebaceous lobules would be found on complete sectioning of the cyst. Keratocyst is an acceptable alternative term but this term is usually associated with the cysts of the nevoid basal cell carcinoma syndrome.

These small dermal cysts are lined by stratified squamous epithelium which may show focal tricholemmal as well as epidermoid keratinization. The lumen contains keratin and numerous transversely and obliquely sectioned vellus hair shafts (Fig. 16.10). These shafts are doubly refractile with polarized light. A rudimentary hair follicle may be attached to the wall. Hybrid cysts with features of both vellus hair cysts and steatocystoma are sometimes seen.^{123. and 163.} There may be focal rupture of the cyst wall with a foreign body granulomatous reaction and associated dermal fibrosis and mild chronic inflammation.

Some cysts may show a connecting pore at the skin surface, the likely mechanism of the spontaneous regression mentioned above.

If the cyst contents are expelled through a small incision, and then placed in potassium hydroxide, the vellus hairs can be identified in a typical serpentine array. ¹⁵⁰

The lining of the dermal cysts is usually undulating due to collapse of the cyst. It is composed of stratified squamous epithelium, only a few cells thick and without a granular layer. The characteristic feature is the presence of sebaceous glands of varying size in or adjacent to the wall (Fig. 16.11). A ribbon-like cord of epithelial cells connects the cyst with the epidermis, but this may not be seen in the plane of section. One pilar unit is associated with each cyst, and the cyst may contain one or more lanugo hairs. Large polygonal cells with abundant granular cytoplasm form part of the lining of the cyst on rare occasions. Such cells have the immunohistochemical characteristics of the macrophage/monocyte lineage. ¹⁷⁸ Spherules (‘myospherulosis’), formed by masses of erythrocytes in the presence of oil-containing substances, have been reported in the lumen. ¹⁹¹ Smooth muscle has been noted in the wall. ¹⁹²

Hybrid cysts with features of both steatocystoma and vellus hair cysts are sometimes seen;^{123.163.193. and 194.} epidermal cysts may form a third component. ¹²⁸ Cysts without sebaceous lobules in the wall resemble keratocysts. The author uses the term sebaceous duct cyst for these solitary lesions (see above). The presence of a sebaceous adenoma in the wall of a steatocystoma has been called a ‘steatosebocystadenoma’. ¹⁹⁵

The small cysts are lined by several layers of stratified squamous epithelium with central keratinous material, resembling a small epidermal cyst. They may be connected to a vellus hair follicle or eccrine sweat duct, usually the latter. ²²⁶ Milia differ from comedones, which are keratinous plugs in dilated pilosebaceous orifices. Closed comedones, which may be particularly prominent in the condition known as nodular elastoidosis with cysts and comedones (Favre–Racouchot disease),^{227. and 228.} may superficially resemble milia. However, comedones are more likely to contain old hair shafts and laminated keratinous material containing numerous bacteria. ²²⁹ The term comedonal cyst has been used for comedones with cystic dilatation (see below). Some ruptured milia produce an unusually florid granulomatous reaction of foreign body type that has a distinctive appearance, even though the milium has been destroyed.

A comedo is a cystically dilated hair follicle containing abundant keratinous material. As discussed above, they may have a patulous orifice (open comedones) or a narrow orifice, not always seen in plane of section (closed comedones). Severe solar elastosis accompanies those seen in the Favre–Racouchot syndrome. No criteria have been proposed for the designation ‘comedonal cyst’ as opposed to ‘comedo’.

The cysts are unilocular and situated in the dermis, often in close proximity to eccrine glands. The wall is composed of two layers of cuboidal epithelium with eosinophilic cytoplasm (Fig. 16.12). Sometimes the lumen contains small amounts of pale eosinophilic secretions. There is no evidence of decapitation secretion but this may simply be a consequence of marked flattening of the lining cells by the intraluminal contents.

The cysts may be unilocular or multilocular with a lining of columnar epithelium with basal nuclei and an underlying flattened layer of elongated, basal myoepithelial cells. Characteristically, there is ‘pinching off’ (‘decapitation’) of the cytoplasm of the luminal border of the lining cells, typical of apocrine secretory activity (Fig. 16.13). Sometimes the epithelium is flattened, making distinction from eccrine hidrocystoma difficult.^{255. and 256.} It is now thought that most eccrine hidrocystomas are of apocrine origin. In nearly half the cases there are local areas of hyperplastic epithelium with microcysts in the lining and intracystic papillary projections with a core of vascularized connective tissue. The presence of keratinizing squamous epithelium adjacent to apocrine epithelium occurs in one variant of hybrid cyst (see p. 446).

The secretory cells may contain PAS-positive diastase-resistant granules. Carcinoembryonic antigen (CEA) may also be present in both apocrine and eccrine cystadenomas.

The cysts are lined by ciliated and mucin-producing pseudostratified columnar or cuboidal epithelium (Fig. 16.14). Stratified squamous epithelium may be present in the outer part of the cyst in those presenting as a sinus on the skin surface. ²⁷³ Gastric mucosa of antral type has been reported in one bronchogenic cyst. ²⁷⁴ Smooth muscle and even mucous glands are found commonly in the wall, but cartilage is present only occasionally. There may be some inflammation and fibrosis adjacent to the cyst, but lymphoid follicles, common in the wall of branchial cleft cysts (see below), are very rare in bronchogenic cysts.^{275.276. and 277.}Ectopic respiratory mucosa, without an associated cyst, is a rare finding in the skin.^{278. and 279.}

The cysts are lined mostly by stratified squamous epithelium, but deeper parts may have a lining of ciliated columnar epithelium. A heavy lymphoid infiltrate invests the cyst or sinus wall, and this includes lymphoid follicles. Mucinous glands and cartilage are occasionally present in the wall; ²⁷⁰ thymic tissue has also been reported. ²⁸⁵

Branchial cleft anomalies differ from bronchogenic cysts by their location, the common occurrence of lymphoid follicles and stratified squamous epithelium, and the rarity of smooth muscle. ²⁷⁶

Thymic cysts are lined by one or more of the following epithelia: squamous, columnar, cuboidal, or pseudostratified columnar. Occasionally, the cyst is devoid of an epithelial lining and has a fibrous tissue lining only. The wall characteristically contains Hassall’s corpuscles and in addition there may be lymphoid tissue, cholesterol granulomas, and sometimes parathyroid tissue. ²⁸⁸

Thymic remnants, without cyst formation, have been reported in the skin of the neck. ²⁹²

The cyst is lined by ciliated cuboidal to columnar epithelium with pseudostratified areas (Fig. 16.15). Focal squamous metaplasia is sometimes present; mucinous cells are rare. ³⁰⁸ The cysts may be multilocular and there are often papillary projections into the lumen. Glandular and smooth muscle elements are absent. ³⁰⁹ Strong dynein positivity has been observed in the apical portion of the lining cells with immunohistochemistry. ³⁰⁶ This pattern is similar to normal salpingeal epithelium, support for a müllerian origin.

The epithelial lining cells express progesterone receptor and epithelial membrane antigen but not carcinoembryonic antigen. ²⁹⁷

The cysts are lined by pseudostratified ciliated columnar epithelium and/or mucinous epithelium. There may be areas of squamous metaplasia.

Median raphe cysts are situated in the dermis, but they do not connect with the overlying surface epithelium. They are lined by pseudostratified columnar epithelium, which may be quite attenuated in some areas. Occasionally, mucous glands are present in the wall, but ciliated cells are rare.^{321. and 322.} Pigmented cysts, resulting from the presence of melanocytes, have been reported. ³²³ In cysts situated near the meatus, the lining is usually of stratified squamous epithelium (Fig. 16.16).

Immunohistochemistry of two cases showed strong staining of the epithelial lining cells with CK7 and CK13 but not CK20. ³²⁴

Dermoid cysts are lined by keratinizing squamous epithelium with attached pilosebaceous structures (Fig. 16.17). Non-keratinizing squamous epithelium with admixed goblet cells resembling conjunctival epithelium has been reported in orbital dermoid cysts. ³⁴⁰ Another rare finding is the presence of basaloid proliferations of the cyst wall, possibly representing primordial hair follicles. ³⁴¹ Sebaceous glands may empty directly into the cyst, the lumen of which contains hair shafts and keratinous debris. Eccrine and apocrine glands, as well as smooth muscle, may be present in the wall of up to one-quarter of the cases. Partial rupture of the cyst, resulting in a local foreign body granulomatous reaction, may be found. Focal calcification is a rare finding.

The fistulous tract sometimes found in association with midline dermoids of the nose is lined by the same elements as are found in the cyst wall. ³³⁰ The dermoid fistula of the anterior chest (see above) was a thin sinus tract lined by stratified squamous epithelium with hair follicles and sebaceous glands arising from the lining. ³³⁶

A diversity of tissue types may be present. One of the reported cases was composed of respiratory epithelium, thyroid, and nervous tissue as well as striated and smooth muscle. ³⁴² Another case was lined by gastrointestinal mucosa, ³⁴³ while another resembled a dermoid cyst with the addition of areas lined by pseudostratified, ciliated epithelium with goblet cells and occasional seromucinous glands and some surrounding smooth muscle. ³³⁸

The cysts may be connected to the skin surface, with gastrointestinal mucosa adjoining the stratified squamous epithelium of the adjacent skin. The mucosa may be of gastric, colonic, or small bowel type. Smooth muscle may be present in the wall.

The cyst lining resembles hyperplastic synovium with partly hyalinized synovial villi. Sometimes only slit-like spaces lined by synovium are present (Fig. 16.19). The cystic cavities may communicate with the surface epidermis.