1 EPIDERMAL TUMORS Tumors and cysts of epidermal origin or to develop in areas of trauma, e.g., following differentiation are among the most common abrasive injuries. They are particularly common lesions that arise in skin. In fact, just five of in the infraorbital region. They also accompany them, namely, seborrheic keratosis, epidermal several bullous disorders, notably porphyria cyst, actinic keratosis, basal cell carcinoma, and cutanea tarda and dominant dystrophic epider- squamous cell carcinoma, comprise a large per- molysis bullosa. centage of lesions seen in any dermatopathol- Pathologic Findings. Epidermal cysts are ogy practice. This situation is likely to continue, lined by a stratified squamous epithelium that particularly considering our aging, ultraviolet- resembles epidermis or follicular infundibulum. exposed population. There is also a wide variety Therefore, a granular cell layer is found adjacent of malformations, cysts, and some less common to the keratin-containing cyst lumen (fig. 1-1). or rare tumors, both benign and malignant, of The cyst wall may be thinned or acanthotic, which the pathologist needs to be aware. Even with a smooth-contoured base or with irregu- among the five common entities mentioned lar budding. The keratin contents are usually above, there are histopathologic variants that loosely woven, typically more so than the over- can create considerable diagnostic confusion. In lying epidermis. Rupture is accompanied by this chapter we review the salient clinical and neutrophilic or granulomatous inflammation, histopathologic features of epidermal tumors. or both (fig. 1-2), and scar is found adjacent to EPITHELIAL CYSTS older inflamed lesions. The cyst epithelium may respond to such events with marked acanthosis, Epidermal Cyst and Milium but in other instances the cyst wall is obliterated or replaced by granuloma. The presence of flakes Clinical Features. The epidermal cyst is a of keratin surrounded by granuloma or within smooth, dome-shaped, freely movable, some- multinucleated giant cells provides a clue to the what fluctuant subcutaneous swelling, some- diagnosis of a ruptured cyst. Milia manifest as times attached to the skin by a central pore. These lesions are common on the face, neck, and trunk but can occur in virtually any ana- tomic location. The cyst may rupture, either spontaneously or due to trauma, with resultant inflammation and tenderness. Epidermal cysts are sometimes associated with other anoma- lies, such as nevus comedonicus or the Favre- Racouchot syndrome. They are also a cutaneous manifestation of Gardner’s syndrome. It is likely that some epidermal cysts constitute a develop- mental anomaly of the follicular infundibulum, although in other instances traumatic implan- tation is probably also a cause (producing the “epidermal inclusion cyst”). A milium is a smaller version of an epidermal Figure 1-1 cyst, measuring from 1 to 4 mm in diameter. It EPIDERMAL CYST may derive from the outer root sheath of vellus The thinned epithelial lining possesses a granular cell follicles. Milia are frequently multiple and tend layer. 1 Nonmelanocytic Tumors of the Skin periphery of keratoacanthomas, and a partial biopsy of the edge of such a lesion can create confusion. A clinical history of a rapidly advanc- ing keratotic lesion may then raise suspicion of keratoacanthoma and prompt more complete sampling of the tumor. Human Papillomavirus-Associated Cyst (Verrucous Cyst) In recent years, a type of epidermal cyst has been described with microscopic features con- sistent with human papillomavirus (HPV) infec- tion. These cysts most commonly arise in the Figure 1-2 plantar areas of the foot (20), although similar EPIDERMAL CYST lesions have been reported on the scalp, face, Rupture of the cyst wall as well as acute and granulo- back, and extremities (66,85). Clinically, the matous inflammation are seen. lesions resemble conventional cysts, or suggest dermatofibroma or basal cell carcinoma (85). Microscopically, the cysts are of the infundibu- smaller, thin-walled epidermal cysts that are lar type, and feature varying degrees of papil- located in the superficial dermis. lomatosis, hypergranulosis, parakeratosis, and There have been rare reports of Bowen’s squamous eddy formation. Koilocytic changes disease, basal cell carcinoma, or squamous cell with large keratohyaline granules are noted carcinoma arising in epidermal cysts. Squamous (21,66,85). The presence of HPV has been docu- cell carcinomas that have been partly biopsied mented by immunohistochemistry (21), hy- or treated occasionally form cyst-like configu- bridization studies (20,38), and by polymerase rations without apparent connection to the chain reaction (PCR) methods that detect HPV overlying epidermis. DNA sequences (45). To date, both HPV types 57 Differential Diagnosis. Although epidermal and 60 have been found in these cysts (39,45). cysts and milia are among the most readily There is, at present, uncertainty about whether diagnosable lesions in dermatopathology, oc- these lesions result from traumatic implanta- casional problems can arise. Superficial shave tion of verrucae or from secondary infection of biopsies showing changes of epidermal cyst may preexisting epidermal cysts. miss deeper foci that would point to a different Proliferating Epidermal Cyst diagnosis such as warty dyskeratoma, branchial cleft cyst, or syringocystadenoma papilliferum. Although the proliferating trichilemmal cyst Pilar cysts (trichilemmal cysts) are usually easily is a well-established entity (see below), a similar recognized by their distinctly palisaded basilar proliferative cystic lesion characterized by in- layer, swollen periluminal keratinocytes with fundibular keratinization, with formation of a sparse or absent keratohyaline granules, and granular cell layer and laminated keratin, is not homogeneous eosinophilic keratin. Occasional as widely recognized (62,64). The proliferating hybrid cysts have areas resembling both epi- epidermal cyst has now been well documented dermal and pilar cysts. The presence of both by Sau et al. (75,76). In contrast to proliferating infundibular and trichilemmal keratinization trichilemmal cysts, these lesions show a male provides additional evidence of a follicular ori- predominance, and most occur in locations gin for these epithelial cysts. Markedly inflamed other than the scalp. They usually have a cyst- lesions may be difficult to distinguish from like clinical appearance. foreign body or infectious granulomas. In such Microscopically, several patterns have been instances, careful search for cyst wall fragments described: papillomatous and acanthotic epithe- or keratin flakes can be decisive. lium with squamous eddy formation and con- Milia-like formations may be observed in the nection to the surface through a narrow open- 2 Epidermal Tumors Figure 1-3 Figure 1-4 PROLIFERATING EPIDERMAL CYST PIGMENTED FOLLICULAR CYST This example has acanthotic and focally papillomatous Several pigmented hair shaft fragments are present in changes. spaces (arrows) within the cyst lumen. ing; inverted follicular keratosis-like changes; a follicles or sebaceous lobules may attach to the multiloculated cystic pattern lined by basaloid cyst wall (52,72). Some of these lesions appear epithelium, with peripheral palisading of nuclei; to be hybrid cysts, showing both infundibular pseudoepitheliomatous hyperplasia of the cyst and trichilemmal keratinization (72). lining; anastomosing bands reminiscent of pro- Cutaneous Keratocyst liferating trichilemmal cysts; conglomerations of numerous microcysts; and verrucous projec- Barr et al. (6) discovered that two of four tions of lining epithelium into the cyst lumen cutaneous cysts removed from patients with reminiscent of HPV-induced cysts (fig. 1-3) (76). the basal cell nevus syndrome had features re- In most of these lesions, at least focal portions sembling those of the odontogenic keratocysts of the cyst wall resemble a typical epidermal that characteristically occur in that syndrome. cyst. An example of a proliferating tumor that Subsequently, a similar lesion was reported by showed both trichilemmal and infundibular Baselga et al. (7). Microscopically, the epithelia keratinization has been described (62). Seven of of these cysts have festooned configurations, are the 33 tumors reported by Sau et al. (76) showed lined by two to five squamous cell layers, and carcinomatous histopathologic features, and le- keratinize without the formation of a granular sions with these changes were particularly prone cell layer. One of the cysts of Barr et al. also to local aggressiveness (recurrence), although showed a small follicular bud and contained metastases were not reported. lanugo hairs, features reminiscent of steatocy- stoma, although sebaceous glands were absent. Pigmented Follicular Cyst Additional reports will be necessary to deter- This unusual cyst was first described by Meh- mine if cutaneous cysts with these features are regan and colleagues in 1982 (52). It usually characteristic of the nevoid basal cell carcinoma presents as a solitary lesion in the head and syndrome. neck region of adult men (73). A patient with Epithelial Cysts in Gardner’s Syndrome multiple lesions has been reported; the lesions were present on the chest and abdomen (72). Gardner’s syndrome is a dominantly in- Clinically, these cysts have a distinctly blue herited disorder consisting of premalignant appearance, suggestive of blue nevus. Micro- colonic polyps, fibromas and desmoid tumors, scopically, they are typically