1

EPIDERMAL TUMORS1Tumors and cysts of epidermal origin or

differentiation are among the most common lesions that arise in skin. In fact, just five of them, namely, seborrheic keratosis, epidermal cyst, actinic keratosis, basal cell carcinoma, and squamous cell carcinoma, comprise a large per-centage of lesions seen in any dermatopathol-ogy practice. This situation is likely to continue, particularly considering our aging, ultraviolet-exposed population. There is also a wide variety of malformations, cysts, and some less common or rare tumors, both benign and malignant, of which the pathologist needs to be aware. Even among the five common entities mentioned above, there are histopathologic variants that can create considerable diagnostic confusion. In this chapter we review the salient clinical and histopathologic features of epidermal tumors.

EPITHELIAL CYSTS

Epidermal Cyst and Milium

Clinical Features. The epidermal cyst is a smooth, dome-shaped, freely movable, some-what fluctuant subcutaneous swelling, some-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 cyst, measuring from 1 to 4 mm in diameter. It may derive from the outer root sheath of vellus follicles. Milia are frequently multiple and tend

to develop in areas of trauma, e.g., following abrasive injuries. They are particularly common in the infraorbital region. They also accompany several bullous disorders, notably porphyria cutanea tarda and dominant dystrophic epider-molysis bullosa.

Pathologic Findings. Epidermal cysts are lined by a stratified squamous epithelium that resembles epidermis or follicular infundibulum. Therefore, a granular cell layer is found adjacent to the keratin-containing cyst lumen (fig. 1-1). The cyst wall may be thinned or acanthotic, with a smooth-contoured base or with irregu-lar budding. The keratin contents are usually loosely woven, typically more so than the over-lying epidermis. Rupture is accompanied by neutrophilic or granulomatous inflammation, or both (fig. 1-2), and scar is found adjacent to older inflamed lesions. The cyst epithelium may respond to such events with marked acanthosis, but in other instances the cyst wall is obliterated or replaced by granuloma. The presence of flakes of keratin surrounded by granuloma or within multinucleated giant cells provides a clue to the diagnosis of a ruptured cyst. Milia manifest as

Figure 1-1

EPIDERMAL CYSTThe thinned epithelial lining possesses a granular cell

layer.

Nonmelanocytic Tumors of the Skin

2

smaller, thin-walled epidermal cysts that are located in the superficial dermis.

There have been rare reports of Bowen’s disease, basal cell carcinoma, or squamous cell carcinoma arising in epidermal cysts. Squamous cell carcinomas that have been partly biopsied or treated occasionally form cyst-like configu-rations without apparent connection to the overlying epidermis.

Differential Diagnosis. Although epidermal cysts and milia are among the most readily diagnosable lesions in dermatopathology, oc-casional problems can arise. Superficial shave biopsies showing changes of epidermal cyst may miss deeper foci that would point to a different diagnosis such as warty dyskeratoma, branchial cleft cyst, or syringocystadenoma papilliferum. Pilar cysts (trichilemmal cysts) are usually easily recognized by their distinctly palisaded basilar layer, swollen periluminal keratinocytes with sparse or absent keratohyaline granules, and homogeneous eosinophilic keratin. Occasional hybrid cysts have areas resembling both epi-dermal and pilar cysts. The presence of both infundibular and trichilemmal keratinization provides additional evidence of a follicular ori-gin for these epithelial cysts. Markedly inflamed lesions may be difficult to distinguish from foreign body or infectious granulomas. In such instances, careful search for cyst wall fragments or keratin flakes can be decisive.

Milia-like formations may be observed in the

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 plantar areas of the foot (20), although similar lesions have been reported on the scalp, face, back, and extremities (66,85). Clinically, the lesions resemble conventional cysts, or suggest dermatofibroma or basal cell carcinoma (85). Microscopically, the cysts are of the infundibu-lar type, and feature varying degrees of papil-lomatosis, hypergranulosis, parakeratosis, and squamous eddy formation. Koilocytic changes with large keratohyaline granules are noted (21,66,85). The presence of HPV has been docu-mented by immunohistochemistry (21), hy-bridization studies (20,38), and by polymerase chain reaction (PCR) methods that detect HPV DNA sequences (45). To date, both HPV types 57 and 60 have been found in these cysts (39,45). There is, at present, uncertainty about whether these lesions result from traumatic implanta-tion of verrucae or from secondary infection of preexisting epidermal cysts.

Proliferating Epidermal Cyst

Although the proliferating trichilemmal cyst is a well-established entity (see below), a similar proliferative cystic lesion characterized by in-fundibular keratinization, with formation of a granular cell layer and laminated keratin, is not as widely recognized (62,64). The proliferating epidermal cyst has now been well documented by Sau et al. (75,76). In contrast to proliferating trichilemmal cysts, these lesions show a male predominance, and most occur in locations other than the scalp. They usually have a cyst-like clinical appearance.

Microscopically, several patterns have been described: papillomatous and acanthotic epithe-lium with squamous eddy formation and con-nection to the surface through a narrow open-

Figure 1-2

EPIDERMAL CYSTRupture of the cyst wall as well as acute and granulo-

matous inflammation are seen.

3

Epidermal Tumors

ing; inverted follicular keratosis-like changes; a multiloculated cystic pattern lined by basaloid epithelium, with peripheral palisading of nuclei; pseudoepitheliomatous hyperplasia of the cyst lining; anastomosing bands reminiscent of pro-liferating trichilemmal cysts; conglomerations of numerous microcysts; and verrucous projec-tions of lining epithelium into the cyst lumen reminiscent of HPV-induced cysts (fig. 1-3) (76). In most of these lesions, at least focal portions of the cyst wall resemble a typical epidermal cyst. An example of a proliferating tumor that showed both trichilemmal and infundibular keratinization has been described (62). Seven of the 33 tumors reported by Sau et al. (76) showed carcinomatous histopathologic features, and le-sions with these changes were particularly prone to local aggressiveness (recurrence), although metastases were not reported.

Pigmented Follicular Cyst

This unusual cyst was first described by Meh-regan and colleagues in 1982 (52). It usually presents as a solitary lesion in the head and neck region of adult men (73). A patient with multiple lesions has been reported; the lesions were present on the chest and abdomen (72).

Clinically, these cysts have a distinctly blue appearance, suggestive of blue nevus. Micro-scopically, they are typically cysts of infundibu-lar type; the cyst lining maintains a rete ridge pattern. Within the lumen of the cyst are mul-tiple pigmented hair shafts (fig. 1-4), and hair

Figure 1-4

PIGMENTED FOLLICULAR CYSTSeveral pigmented hair shaft fragments are present in

spaces (arrows) within the cyst lumen.

Figure 1-3

PROLIFERATING EPIDERMAL CYSTThis example has acanthotic and focally papillomatous

changes.

follicles or sebaceous lobules may attach to the cyst wall (52,72). Some of these lesions appear to be hybrid cysts, showing both infundibular and trichilemmal keratinization (72).

Cutaneous Keratocyst

Barr et al. (6) discovered that two of four cutaneous cysts removed from patients with the basal cell nevus syndrome had features re-sembling those of the odontogenic keratocysts that characteristically occur in that syndrome. Subsequently, a similar lesion was reported by Baselga et al. (7). Microscopically, the epithelia of these cysts have festooned configurations, are lined by two to five squamous cell layers, and keratinize without the formation of a granular cell layer. One of the cysts of Barr et al. also showed a small follicular bud and contained lanugo hairs, features reminiscent of steatocy-stoma, although sebaceous glands were absent. Additional reports will be necessary to deter-mine if cutaneous cysts with these features are characteristic of the nevoid basal cell carcinoma syndrome.

Epithelial Cysts in Gardner’s Syndrome

Gardner’s syndrome is a dominantly in-herited disorder consisting of premalignant colonic polyps, fibromas and desmoid tumors, osteomatosis, and cutaneous cysts. The cysts largely have the microscopic characteristics of epidermal cysts, but pilomatrixoma-like changes have been described in a number of

Nonmelanocytic Tumors of the Skin

4

them (17,50,57,70). There are aggregates of shadow cells that are arranged as columns projecting into cyst lumens, lying free within the lumens, or present within pericystic con-nective tissue and associated with granuloma formation (17). When arranged as columns, the shadow cells appear to arise from basaloid, hair matrix-like cells within the cyst lining (fig. 1-5) (17). Narisawa and Kohda (57) have also reported trichilemmal keratinization, sebaceous glands attached to the cyst wall, and epithelial islands that are cytokeratin (CK) 19 positive and contain CK20-positive Merkel cells. The latter changes are consistent with the “bulge area” of follicular epithelia, and suggest that these cysts could arise from stem cells within the bulge.

Trichilemmal Cyst (Pilar Cyst, Isthmus-Catagen Cyst)

Clinical Features. The trichilemmal, or pilar, cyst commonly arises on the scalp, although it may also develop on the face, trunk, or ex-tremities. Multiple cysts are not uncommon, particularly on the scalp, and the development of these cysts may be inherited as an autosomal dominant trait. Chromosomal mosaicism has been detected in a case of epidermal nevi as-sociated with trichilemmal cysts (36).

The microscopic appearance of trichilemmal cysts suggests that they originate from the mid-portion, or isthmus, of the hair follicle, the zone located between the follicular entry of the seba-

ceous duct and the insertion of the arrector pili muscle. Ultrastructural studies indicate a close resemblance between these cysts and the trichi-lemmal sac surrounding catagen follicles (43), hence the alternative name, isthmus-catagen cyst. These cysts are distinguishable from most epidermal cysts because of the relative ease of their surgical enucleation.

Pathologic Findings. Histologically, there is keratinization of the wall of a trichilemmal cyst without the formation of a granular cell layer (although a few keratohyaline granules are occa-sionally identified). Instead, cells progress from a distinctly palisaded basilar layer to a swollen, pale cell layer adjacent to a cyst lumen that contains homogeneous, eosinophilic keratin material (fig. 1-6). As pointed out, this configu-ration closely resembles that of the follicular isthmus. Hybrid cysts have mixed features of trichilemmal and epidermal (infundibular) cysts (12). Foci of calcification occur within the cyst lumen in about 25 percent of cases. Occasion-ally, rupture of the cyst wall is observed, associ-ated with a granulomatous response to the cyst contents. Cystic rupture may be followed by repair of the defect: by marsupialization to the epidermis, with partial or complete resolution of the cyst, or by proliferation of the cyst wall. The latter change may account for the prolifer-ating trichilemmal cyst (proliferating trichilemmal tumor) (51).

Figure 1-5

EPITHELIAL CYST IN GARDNER’S SYNDROMEA column of shadow cells projects into the cyst lumen.

At its base are basaloid cells reminiscent of hair matrix. Aggregates of shadow cells are also present within the pericystic connective tissue.

Figure 1-6

TRICHILEMMAL CYSTSwollen, pale epithelial cells; absence of a granular cell

layer; and homogeneous eosinophilic keratin are within the cyst lumen.

5

Epidermal Tumors

Proliferating Trichilemmal Cyst (Proliferating Trichilemmal Tumor,

Pilar Tumor, Proliferating Pilar Tumor)

Clinical Features. The proliferating trichilem-mal cyst is usually a solitary tumor that most often occurs on the scalp, particularly in middle-aged or elderly women. These lesions may occur in multiples (8,32,98); arise in locations such as the trunk (76), arm (98), or hand (46); and are occasionally encountered in young persons (98). They occur in men in about 30 percent of cases (76).

Proliferating trich ilemmal cysts present as subcutaneous nodules or lobulated masses that may ulcerate or “marsupialize.” As the name implies, it is widely believed that these lesions result from repeated episodes of rupture and re-epithelialization of trichilemmal (pilar) cysts (13,51). Massive cutaneous horns of the scalp have been reported to arise from proliferating trichilemmal tumors (53).

Pathologic Findings. Microscopically, there are lobules of squamous epithelium of varying sizes, some of which demonstrate peripheral palisading and are surrounded by basement membrane material. Sometimes, these changes arise in the wall of a trichilemmal cyst (13). The formation of amorphous eosinophilic keratin without the interposition of a granular cell layer in islands of squamous epithelium is the characteristic feature of trichilemmal keratiniza-tion (figs. 1-7, 1-8). Occasionally, keratinization

of the infundibular type can also be identified, resulting in the configuration of a “hybrid” proliferating cyst (62). Other findings include apocrine or sebaceous (primary epithelial germ) differentiation (71), squamous eddy formation, calcification, and foci of clear cell change that demonstrate differentiation towards outer root sheath epithelium. Nuclear pleomorphism, a mitotic rate of up to one per high-power field, and small foci of stromal infiltration may be seen. Such findings occur in lesions that other-wise show benign biologic behavior. Since recur-rences have been reported, complete excision is indicated for these lesions.

The malignant proliferating trichilemmal (pilar) tumor (giant hair matrix tumor, tricho-chlamydocarcinoma) shows considerable clinical overlap with the proliferating trichilemmal cyst, although it is most common in older women and averages 4 cm or more in diameter. Histo-logically, this tumor also resembles the prolif-erating trichilemmal cyst, or may even arise from a proliferating trichilemmal cyst. There are several characteristic features, however, that set malignant proliferating trichilemmal tumor apart: squamoid or basaloid cells showing little tendency toward pilar differentiation, conspicu-ous nuclear atypia, high mitotic activity (4 to 5 per high-power field), dyskeratotic cells, foci of necrosis, and stromal invasion (97). One metastasizing tumor showed areas of transition from proliferating trichilemmal cyst to spindle

Figure 1-7

PROLIFERATING TRICHILEMMAL CYSTThe epithelium is lobulated and there are foci of

trichilemmal keratinization.

Figure 1-8

PROLIFERATING TRICHILEMMAL CYSTThis high-power view shows foci of trichilemmal

keratinization, one with calcium deposition, and lobules of relatively bland-appearing epithelium.

Nonmelanocytic Tumors of the Skin

6

cell carcinoma (56). Recognition of these tumors is important since they are capable of regional lymph node metastasis or visceral spread, and therefore wide local excision and close clinical follow-up are indicated.

Recent studies have demonstrated p53 posi-tivity in a proliferating trichilemmal cyst as well as in a malignant proliferating trichilemmal tumor (96). Nondiploid DNA has been detected by flow cytometry in two of four proliferating trichilemmal cysts, and these results appeared to correlate with higher mitotic counts and increased staining with the Ki-67 monoclonal antibody (83). Takata and colleagues (89) used PCR-based microsatellite loss of heterozygosity (LOH) analysis to demonstrate complete loss of the wild type p53 in a trichilemmal carcinoma arising from a proliferating trichilemmal cyst. These analyses may eventually permit early identification of those histologically borderline proliferating trichilemmal tumors that are ca-pable of greater biologic aggressiveness.

Differential Diagnosis. Proliferating trich-ilemmal tumor can be mistaken for squamous cell carcinoma, and in the past some of these cases may have accounted for reports of “squa-mous cell carcinomas arising in pilar cysts.” Foci of trichilemmal keratinization, an adjacent pilar cyst, and limited cytologic atypia or mitotic activity are all features that tend to support a diagnosis of proliferating trichilemmal tumor.

Steatocystoma

Clinical Features. Steatocystoma consists of one or more cystic papules or nodules that measure between 1 and 3 cm in diameter. The multiple form, steatocystoma multiplex, can be inherited as an autosomal dominant trait. The lesions arise most often on the trunk, scalp, face, and arms; tend to manifest during ado-lescence or early adult life; and occur equally in both sexes. They are generally flesh colored, and when incised, discharge an oily fluid. An association with pachyonychia congenita has repeatedly been described (27,34,42), and re-cently, missense mutations in keratin 17 have been linked to both pachyonychia congenita type 2 and stea to cystoma multiplex (18,84).

Pathologic Findings. The steatocystoma of-ten has folded or undulating contours (fig. 1-8). It is lined by several layers of epithelial cells; a distinct, eosinophilic, cuticular layer lines the luminal surface. There are small, flattened seba-ceous lobules along the outer layer of the cyst wall (figs. 1-9, 1-10). Pale-staining flocculent material is present within the cyst lumen, and occasionally, small hair shafts. These features in aggregate suggest differentiation towards sebaceous ductal epithelium (44).

Differential Diagnosis. Steatocystomas, as a rule, are easily distinguished microscopically from epidermal (infundibular) or trichilemmal cysts. Steatocystoma does resemble a dermoid cyst (see below). Dermoid cysts, however, are

Figure 1-10

STEATOCYSTOMAA sebaceous lobule is present in the cyst wall. There is a

cuticular layer lining the luminal surface of the cyst.

Figure 1-9

STEATOCYSTOMAThe thin-walled cyst has undulating contours. Small,

flattened sebaceous lobules are present along the outer portion of the cyst wall.

7

Epidermal Tumors

larger, tend to occur along embryonic lines of closure, have thicker walls, lack the thick cu-ticular luminal border, and contain prominent pilosebaceous and sometimes other adnexal elements. Eruptive vellus hair cysts (see below) resemble steato cystoma clinically, but clearly have a structural relationship to the vellus follicle. Coexistence of vellus hair cysts and steato cystomas (41,54), and even hybrids of the two (1,35), have been described. The no-tion of a relationship between the two cysts is not conceptually difficult, given the primary epithelial germ derivation of both hair follicle and sebaceous duct. This is further supported by the reported patterns of keratin expression for these cysts (keratin 17 for eruptive vellus hair cysts, keratins 10 and 17 for steatocystoma) (91).

Dermoid Cyst

Clinical Features. Dermoid cysts are subcu-taneous cysts of ectodermal origin that arise along embryonic lines of closure. They are believed to be congenital lesions, but they may not become apparent until the second or third decades of life, due to episodes of rapid growth, inflammation, or trauma. They are most com-mon in the head and neck area, particularly the supraorbital region, brow, upper eyelid, glabella,

and scalp. They constitute the most common cause of periorbital mass lesions in infants and children (40). Dermoid cysts are more common in males than females. Sequestration of cutane-ous epithelium during embryonic life is widely believed to explain the origin of these cysts; this may occur by several mechanisms, depending in part upon the location of the cyst (5,11).

Dermoid cysts present as subcutaneous swell-ings, with either an intact overlying epidermis or a depression connecting to a draining sinus tract. A collar of tufted hairs may surround scalp lesions. Cysts may be immobile due to attach-ment to periosteum, and those that rest on the dura or extend intracranially may fluctuate when a child cries. Infection, including bacterial meningitis, may be a complication, depending upon the location of the cyst and its associated sinus tracts.

Pathologic Findings. On gross examination, the dermoid cyst is a firm, tan, cystic mass with protruding hair shafts; it contains a yellow, oily material. Microscopic features include a cyst lined by stratified squamous epithelium, into which are inserted a number of small hair follicles (fig. 1-11). The cyst lumen contains keratin debris and hair shaft fragments. Seba-ceous glands are associated with the follicles and

Figure 1-11

DERMOID CYSTAbove: This cyst is lined by stratified squamous epithelium and

contains keratin debris.Right: A hair follicle enters the cyst wall. Sweat glands can be identified

in the vicinity.

Nonmelanocytic Tumors of the Skin

8

are usually not flattened against the cyst wall, as is the case in steatocystoma. Sweat glands, both eccrine and apocrine, can be identified in the vicinity of the cyst (fig. 1-11), and smooth muscle is present in up to one third of cases. This constellation of findings usually allows distinction from steatocystoma.

Differential Diagnosis. In addition to steatocystoma, the dermoid cyst should be distinguished from the recently described folliculo sebaceous cystic hamartoma. The lat-ter is more superficially located in the dermis, is less cystic, has more prominent sebaceous glands, and is not associated with hair follicles or other adnexal structures (44). Cystic teratoma is sometimes casually called a “dermoid,” but this lesion is rare in skin (55,94), or in the head and neck region in general, and has tissues derived from all three germ layers. Dermoid cysts also differ from the corneal and epibulbar “der moids” that are associated with a variety of syndromes; these lesions consist mainly of dense, hyalinized connective tissue that may contain pilosebaceous units.

Eruptive Vellus Hair Cyst

Clinical Features. Eruptive vellus hair cysts, first reported by Esterly et al. in 1977 (22), are characterized by an eruption of yellow to brown papules over the chest and proximal extremi-ties of children and young adults. Lesions may be localized to the face, and a solitary lesion was associated with a melanocytic nevus and a conventional epidermal cyst (95). Spontaneous clearing after several years has been reported. The condition may be inherited as an autosomal dominant disorder (87).

Pathologic Findings. The epithelial-lined cyst contains keratin and sections of vellus hairs (fig. 1-12). In addition to these vellus hairs, evidence of a follicular origin includes invagina-tion of the cyst wall by follicle-like elements or the presence of portions of a telogen follicle or arrectores pilorum muscle, which may extend beneath the cyst. The cysts may communicate with the skin surface, discharging their contents and causing granulomatous inflammation; the latter changes may explain the crusting that is associated with some lesions (10). The microscopic findings suggest a developmental anomaly involving vellus follicles, with occlu-sion and cystic dilatation (14,22).

Differential Diagnosis. The microscopic fea-tures of eruptive vellus hair cysts are character-istic. The clinical resemblance to and occasional histopathologic association with steatocystoma multiplex has already been discussed.

Cutaneous Cysts and Related Structures that May Be Ciliated

There is a group of cysts or related struc-tures that uncommonly occur in the skin and may feature ciliated epithelium. These include structures of possible müllerian or urogenital sinus origin (endometriosis, endosalpingiosis, mucinous and ciliated vulvar cyst, and cutane-ous ciliated cyst), bronchogenic cyst, thyroglos-sal duct cyst, branchial cleft cyst, and thymic cyst. Median raphe cysts of the penis have also been reported to contain cilia on rare occasion. Despite their differing modes of origin, these cysts are discussed here collectively because of their common microscopic feature of ciliated epithelium (see separate discussion of the me-dian raphe cyst below).

Cilia have a characteristic cross-sectional appearance on ultrastructural examination: two central fibrils surrounded by nine double fibrils. This 9+2 arrangement is constant in cilia throughout the plant and animal kingdoms (15,24). Cilia, however, are not normal constitu-ents of cutaneous epithelia, and their presence in the skin is distinctly unusual.

Figure 1-12

ERUPTIVE VELLUS HAIR CYSTThis epithelial-lined cyst contains keratin material

and sections of vellus hairs. There is an adjacent cord of epithelium containing a few sebaceous cells.

9

Epidermal Tumors

There are several possible explanations for finding ciliated epithelia. Sequestration and migration during embryogenesis have been in-voked as explanations for the cutaneous ciliated cyst, which often arises in the lower extremi-ties, and for the cutaneous bronchogenic cyst. Cutaneous ciliated cysts are believed by some to be of müllerian origin, as are the fallopian tubes, uterus, and upper third of the vagina. Their appearance in the lower extremities may be explained by the common coelomic wall origin of limb buds and müllerian ducts during embryogenesis, with later migration of these müllerian elements within the developing limb (29), although other explanations have also been proposed. In the case of bronchogenic cysts, bronchial epithelium is known to derive from the ventral portion of the primitive fore-gut, and sequestrations from the foregut may migrate into the developing skin or be pinched off by the subsequent fusing of sternal bars.

Failure of regression of embryonic structures could play a role in the formation of some ciliated cysts. Dysontogenesis, or defective em-bryonic development, is theoretically possible. Embryonic sweat ducts and glands feature cilia at 16 weeks’ gestation (30), and, therefore, ar-rested sweat gland development could theoreti-cally result in persistence of ciliated epithelia.

Prosoplasia, or abnormal development re-sulting in a “higher” state of organization, has been suggested as an explanation for vaginal adenosis, the appearance of ciliated glandu-

lar epithelium in the vagina or vulva (68,81). Transplantation of tissue could occur following surgical procedures, via either direct inoculation or lymphatic or hematogenous metastasis. This mechanism has been proposed for cutaneous endometriosis.

Finally, metaplasia of pluripotential cells to form ciliated epithelia is a theoretical explana-tion that has been proposed for the develop-ment of endometriosis (86) and ciliated odonto-genic keratocysts (65). However, hard evidence for the role of metaplasia in producing ciliated cysts in skin is lacking.

Endometriosis. First described in the latter part of the 19th century, endometriosis occa-sionally arises in skin. Locations include the umbilicus, lower abdomen, inguinal region, labia, or perineum. The lesions are often present within surgical scars (especially cesarean section or laparotomy scars). They are typically papules to small nodules (approximately 5 mm in di-ameter) and brownish in color, although they may appear blue-black due to cyclical bleeding.

Microscopically, there are combinations of glands and stroma, the former showing the characteristic features of uterine endometrium expected during the proliferative, secretory, or menstruation phases of the menstrual cycle. Cil-ia may sometimes be identified (fig. 1-13). One study has shown a poor correlation between the histologic features of these lesions and the actual stage of the menstrual cycle (90). Decidu-alized changes can sometimes be encountered,

Figure 1-13

CUTANEOUS ENDOMETRIOSISLeft: Endometrial glands and stroma in a cutaneous lesion.Right: Cilia can sometimes be identified in the glandular epithelium.

Nonmelanocytic Tumors of the Skin

10

particularly in lesions detected during preg-nancy, and such lesions may be confused with malignancy by the unwary pathologist. Similar problems can arise when fine-needle aspiration biopsies are performed (4).

Endosalpingiosis. This rare condition is characterized by the development of brown papules (resembling nonhemor rhagic lesions of cutaneous endometriosis) in a periumbilical distribution following salpingectomy. Micro-scopically, there is a cyst lined by columnar epithelial cells, some of which are ciliated. Papil-lary projections are present within the lumen. These features resemble fallopian tube as well as the cutaneous ciliated cyst (see below) (19).

Mucinous and Ciliated Vulvar Cyst. Muci-nous and ciliated cysts occur in the vulvar re-gion. Their origin has been the subject of debate. Robboy et al. (68) found small mucinous glands in 53 percent of vulvas examined at autopsy, and, in addition, encountered 11 cysts in clini-cal practice that featured varying combinations of mucinous and ciliated epithelium. They sug-gested that glands lined by mucinous or ciliated epithelium are normal vulvar constituents, and that cysts develop due to inflammation and obstruction of their outlets (68). They and oth-ers (58) favor an origin from entoderm of the urogenital sinus, although a müllerian origin or metaplasia of apocrine glands have also been considered (37).

The cysts are lined by cuboidal to tall colum-nar or pseudostratified columnar epithelium

with variable amounts of mucin and/or cilia (fig. 1-14). Squamous metaplasia and neutro-philic infiltration of the cyst wall have also been reported (37,58,68).

Cutaneous Ciliated Cyst. This type of cili-ated cyst was first reported by Hess in 1890 (33), and was defined as a distinct entity by Farmer and Helwig (23). It usually presents as a solitary lesion on the lower extremities, and most com-monly occurs in women. Similar lesions have been reported on the sole of the foot, buttock, scapular area, and scalp, and there has been one reported case in a male (93). The cysts may extend to several centimeters in diameter, are unilocular or multilocular, and on incision contain clear or serous fluid.

Microscopically, the cyst is lined by cuboi-dal or columnar ciliated epithelium, arranged in folds or papillary projections (fig. 1-15). Mucinous cells are usually not observed but have been reported (88). The lining resembles that of fallopian tube. Immunohistochemical staining is positive for epithelial membrane antigen, CAM5.2, and AE1/AE3, and negative for carcino embryonic antigen, similar to the results seen in normal fallopian tube; positive staining for estrogen or progesterone receptors has been reported (80).

Bronchogenic Cyst. Bronchogenic cysts oc-cur in both males and females, and are usually first recognized early in life. They typically occur as solitary dermal or subcutaneous nodules over the suprasternal notch or manubrium sterni, but other locations have been reported, including the scapular area, shoulder (26), chin (2), and back (92). The cysts have a firm wall and con-tain clear fluid. Bronchogenic cysts are lined by cuboidal to columnar ciliated epithelium that may be pseudostratified (fig. 1-16, left) and form folds or papillary projections into the lumen. Goblet cells are usually present (fig. 1-16, right), and the stroma may include smooth muscle, mucous glands, or cartilage. A mixed inflamma-tory infiltrate is sometimes present (63).

Thyroglossal Duct Cyst, Branchial Cleft Cyst, and Thymic Cyst. These cysts normally do not fall within the purview of the dermatolo-gist or dermatopathologist, but they occasion-ally have cutaneous manifestations and each may contain cilia. The thyroglossal duct cyst arises from embryonic remnants of the duct

Figure 1-14

MUCINOUS AND CILIATED VULVAR CYSTThis cyst features low columnar epithelium.

11

Epidermal Tumors

that remain after the descent of the developing thyroid gland. The cyst is usually located near the hyoid bone, and is brought to the attention of the patient and physician due to infection or formation of a cutaneous fistula. These cysts may be associated with thyroid follicles and lack smooth muscle or cartilage in their walls (fig. 1-17) (78). Branchial cleft cysts typically occur on the lateral neck, are lined by stratified squa-mous and/or columnar epithelium, and have walls containing lymphoid tissue (fig. 1-18) (60). Thymic cysts are believed to arise from embryonic remnants of the thymopharyngeal

duct and may be present in the neck. Micro-scopically, they resemble the bronchogenic cyst but lack goblet cells; thymic tissue is present and cholesterol granulomas are in the surrounding stroma (74).

Other Cutaneous Cysts

Metaplastic Synovial Cyst. This recently described cutaneous lesion arises most often in areas subjected to surgical or other types of trauma, although one reported case was asso-ciated with a basal cell carcinoma and no his-tory of trauma (9). Other associations include

Figure 1-15

CUTANEOUS CILIATED CYSTLeft: The epithelium is folded and has papillary projections.Right: At high power, cilia can be identified.

Figure 1-16

BRONCHOGENIC CYSTLeft: Ciliated epithelium is evident.Right: Goblet cells are often in the lining epithelium.

Nonmelanocytic Tumors of the Skin

12

chronic inflammatory states such as rheumatoid arthritis (82) or heritable disorders of connec-tive tissue such as Ehlers-Danlos syndrome (59). Similar lesions have been identified in soft tissue, usually related to prior surgery or experimental induction (28).

Microscopically, the changes characteristic of metaplastic synovial cyst are identified at varying levels of the dermis and may extend to the cutaneous surface. These consist of cystic structures with villous protrusions within lu-mens, lined by a thin fibrinous exudate and a connective tissue core consisting of loosely orga-nized connective tissue, prominent vessels, and

spindled to epithelioid cells (fig. 1-19). These changes closely resemble those of hyperplastic synovium. Immunohistochemical staining is generally negative except for vimentin among the lining and stromal cells. Although some le-sions slightly resemble digital mucous cyst, the constellation of features is relatively distinctive for metaplastic synovial cyst.

Median Raphe Cyst. The median raphe cyst is most often encountered in young men, but can present in boys or older men as well. It typically occurs along the ventral portion of the penis, particularly in the region of the glans, but can arise anywhere along the median raphe, including the perianal region (77). The lesions are usually solitary, but multiple lesions occur (79). The presenting complaint is usually that of a mass or distortion of penile contour.

Histologically, these cysts are lined by pseudo stratified columnar epithelium that vari-ably contains mucous cells (fig. 1-20) (3,16). Cilia have also been reported (69). Thus, the cysts have a urothelial lining, a conclusion supported by positive staining for cytokeratins (13, 67). Serotonin-containing cells have also been reported in these cysts (25). Theories of their origin have included failure of closure of the median raphe or derivation from the periurethral glands of Littre. Sequestration of ectopic urethral mucosa during embryonic de-velopment seems a reasonable explanation (16).

Omphalomesenteric Duct Polyp. During early embryonic development, the omphalo-

Figure 1-17

THYROGLOSSAL DUCT CYSTLeft: Portion of a cyst associated with thyroid tissue.Right: The epithelium of the cyst is ciliated.

Figure 1-18

BRANCHIAL CLEFT CYSTFocally stratified epithelium and lymphoid tissue are

13

Epidermal Tumors

mesenteric duct communicates between the midgut and the yolk sac. It typically disappears during the seventh week of development, but persistence results in polyp, sinus, or cyst forma-tion. This may present as a red umbilical polyp that is usually noted soon after birth or in early childhood. A central depression indicates an underlying sinus or cyst. Pyogenic granuloma is sometimes suspected clinically, although bleed-ing and exudation are not typical features (49).

Histologically, the polyp contains branching epithelium that may have the appearance of gastric or small or large intestinal mucosa, some-times with connections to the epidermal surface

(fig. 1-21). Aberrant pancreatic tissue has been reported in one case (47). Other findings include smooth muscle, lymphoid nodules (99), and varying degrees of erosion, acanthosis, inflam-mation, and vascular proliferation (31). Defini-tive removal of these lesions should be preceded by studies to rule out associated anomalies, such as enteric fistulae and Meckel’s diverticulum (48,49). There has also been a rare report of an umbilical polyp associated with urachal rather than omphalomesenteric remnants (61).

BENIGN EPIDERMAL TUMORS

Figure 1-19

METAPLASTIC SYNOVIAL CYSTLeft: There is an ill-defined cystic structure in the subcutis.Right: Within the lumen are several villous structures. One of these contains numerous spindled to epithelioid cells.

Figure 1-20

MEDIAN RAPHE CYSTLeft: Low-power view of a cyst.Right: The cyst is lined by pseudostratified columnar epithelium. Rare cilia can be identified.

Nonmelanocytic Tumors of the Skin

14

Epidermal Nevus

Clinical Features. Epidermal nevi generally present as verrucous papules that are either pres-ent at birth or develop during early childhood, although adult onset has been documented. Papules may be solitary or arranged in clusters that often assume a linear configuration. Exten-sive linear lesions are said to follow Blaschko’s lines. Several names have been applied to clinical variants, including nevus unius lateris for unilateral lesions and ichthyosis hystrix for bilat-eral systematized lesions. An epidermal nevus syndrome has been proposed, linking extensive epidermal nevi with abnormalities of the central

nervous and cardiovascular systems, eyes, and skeleton. Some of these patients also have other cutaneous findings, including nevocellular nevi, café au lait spots, and hemangiomas. This syn-drome may be congenital or show autosomal dominant inheritance (142,143). Happle (118) disputes the concept of a single “epidermal ne-vus syndrome,” as several different birth defects can be associated with epidermal nevi.

Other variants of epidermal nevi include nevoid hyperkeratosis of the nipple, nevus comedo-nicus, and inflammatory linear verrucous epidermal nevus (ILVEN). In nevoid hyperkeratosis of the nipple, verrucous change resembling epidermal nevus involves one or both areolae (111,133). Nevus comedonicus consists of linear arrange-ments of comedones, sometimes with small cysts, abscesses, or fistulae that tend to form on the trunk. An association with other stigmata of the epidermal nevus syndrome has been reported. Lesions of ILVEN commonly occur on the lower extremities of females but can be seen in other locations and in males. These lesions are typically inflamed and pruritic, and clinically resemble psoriasis.

Pathologic Findings. The most typical features of epidermal nevi are hyperkeratosis, acanthosis, and papillomatosis (figs. 1-22, 1-23). The papillomatosis may be irregular (fig. 1-24), and flattening of the surfaces of the papillary projections (the “mesa” sign) is sometimes encountered (fig. 1-25). Regular, “church-spired” papillomatosis, such as encountered in acrokeratosis verruciformis of Hopf or stucco

Figure 1-22

EPIDERMAL NEVUSThis lesion displays hyperkeratosis, regular papi l-

lomatosis, and acanthosis.

Figure 1-21

OMPHALOMESENTERIC DUCT POLYPLeft: This polyp extends to the epidermal surface.Right: The polyp is composed of intestinal epithelium.

15

Epidermal Tumors

keratosis, is sometimes observed. Changes of epider molytic hyperkeratosis are sometimes present, especially in the clinical variant known as ichthyosis hystrix. Less commonly, there are changes of acantholytic dyskeratosis resembling Darier’s disease. These include suprabasilar acantholysis and formation of dyskeratotic ker-atinocytes (113,144). Such lesions have some-times been designated acantholytic, dyskera totic epidermal nevus. In a study by Submoke (145), 62 percent of epidermal nevi had the typical hyperkeratosis-papillomatosis-acanthosis con-figuration, while 16 percent showed changes

of epidermolytic hyperkeratosis.Nevoid hyperkeratosis of the nipple shows

varying degrees of hyperkeratosis, acanthosis, and papillomatosis (fig. 1-26). In nevus com-edonicus, there are dilated follicles filled with keratin in the manner of comedones, some-times with milia or proliferations of the lining epithelium (fig. 1-27). Changes of epidermo-lytic hyperkeratosis have also been reported in these lesions (114). Lesions of ILVEN show psoriasiform acanthosis with an underlying perivascular lymphohistiocytic infiltrate. Spon-giosis may be present. A characteristic feature

Figure 1-23

EPIDERMAL NEVUSPapillomatosis and pronounced acanthosis are the

major findings.

Figure 1-24

EPIDERMAL NEVUSThis epidermal nevus displays marked irregular

papillomatosis.

Figure 1-25

EPIDERMAL NEVUSLow-power (left) and high-power (right) views show flattening of the papillary projections (the “mesa” sign).