BENIGN EPITHELIAL NEOPLASMS AND CYSTS Richard L. Spielvogel, M.D. Friday, February 1, 2008, 3:20pm There are numerous benign neoplasms of the epidermis, which have many histologic
features in common. They are usually relatively well circumscribed and symmetric. Most
often they demonstrate a proliferation of fairly uniform cells with varying degrees of
squamous differentiation. Inflammation often leads to dyskeratotic changes along with mild
to moderate nuclear atypia. Architecturally, they are usually more exophytic than
endophytic and are characterized by both epidermal hyperplasia, as manifested by
papillomatosis or elongation of the rete ridges, and acanthosis or thickening of the stratum
spinosum. Normal mitotic figures may be seen in rapidly proliferating lesions.
I. Benign Epithelial Neoplasms A. Seborrheic keratoses
1. Classic - There is a predominantly exophytic, well circumscribed, and symmetric neoplasm demonstrating papillated epidermal hyperplasia with acanthosis of the epidermis
and interconnection of the elongated rete ridges. The hyperplastic epidermis is composed
predominantly of small, uniform, basaloid cells and there are numerous pseudohorn cysts
created by cross-sectioning the crypts between the papillary projections. The
hyperkeratotic stratum corneum is loosely laminated in some areas and orthokeratotic in
others. It forms the crypts which are seen on cross-section. The basaloid cells have an
approximately 1:1 or 1:0.5 nuclear to cytoplasmic ratio. It is important to note that although
most classic lesions lie above the plane of the surrounding skin, there is a proliferation of
connective tissue which may be seen in portions of the exophytic component of the lesion.
Melanocytes are seen in normal to slightly increased numbers at the dermal-epidermal
junction and the basilar keratinocytes are mildly hyperpigmented.
2. Early (solar lentigo) - Early lesions are macular or less palpable, lightly pigmented plaques. They are composed of uniform basaloid cells forming a slightly
acanthotic epidermis, often with early bulbous projections from the dermal-epidermal
junction. As the lesion progresses, hyperkeratosis, papillomatosis, and pseudohorn cysts
gradually appear.
3. Irritated and inflamed - The characteristic histologic feature of irritated seborrheic
keratoses is the change from basaloid cells to squamous cells with varying degrees of
keratinization. I prefer to use the term "inflamed" seborrheic keratosis for lesions which
retain the majority of their classic architectural features and demonstrate an associated
superficial perivascular or lichenoid inflammatory infiltrate of lymphocytes and histiocytes.
An "irritated" seborrheic keratosis demonstrates numerous squamous eddies, scattered
dyskeratotic keratinocytes, and focal mild to moderate keratinocytic nuclear atypia. A
chronic lymphohistiocytic inflammatory infiltrate is seen in the underlying dermis and in the
lower levels of the epidermis. Occasionally, a markedly inflamed seborrheic keratosis may
demonstrate significant nuclear atypia in association with the inflammation. In most cases,
if the classic architectural features are retained, and there is no proliferation of atypical
keratinocytes into the reticular dermis, the distinction from squamous cell carcinoma may
be made. In rare cases, the two are difficult to separate with certainty. 2 4. Pigmented - Although most seborrheic keratoses demonstrate some hyperpigmentation of the basaloid keratinocytes just above the dermal-epidermal junction,
others show much greater melanization of the keratinocytes throughout the stratum
spinosum.
5. Hyperkeratotic - Hyperkeratotic lesions develop a markedly thickened horn with varying degrees of basket weave and orthokeratosis.
6. Pedunculated - Pedunculated seborrheic keratoses demonstrate the projection of a papillary dermal core of connective tissue covered by epithelium simulating a
fibroepithelial polyp or skin tag. 7. Acanthotic - In these lesions, acanthosis or thickening of the uniform proliferation of small basaloid cells, predominates over hyperkeratosis and papillomatosis. In
areas without pseudohorn cysts, this process simulates an eccrine poroma. 8. Adenoid or reticulated - These lesions are characterized by thin, anastomosing or interweaving strands of small, uniform basaloid cells.
9. Acantholytic - Foci of acantholysis may occur in irritated and non-irritated seborrheic keratoses. Lesions which retain the classic architectural features of a
seborrheic keratosis and have foci of acantholytic basaloid or squamous appearing cells
may be termed acantholytic seborrheic keratoses instead of acantholytic acanthomas (see
below).
10. Clonal - Clonal seborrheic keratoses contain intraepidermal nests or localized collections of either uniform small basaloid cells, simulating a basal cell carcinoma, or large
squamous cells with more easily discernable intercellular bridges. These nests are
separated by uniform basaloid cells with dark nuclei.
11. Dermatosis papulosis nigra - These lesions are indistinguishable from small pigmented seborrheic keratoses. The acanthotic pattern is most common, but reticulated
patterns may be seen.
12. Melanoacanthoma - This rare tumor is considered a variant of an acanthotic seborrheic keratosis by most authors. In addition to the proliferation of small, uniform,
basaloid cells and more typical squamous cells, dendritic melanocytes are seen at all
levels of the epidermis. The heavily pigmented dendritic melanocytes are seen in
association with aggregates of small basaloid cells which do not appear to contain
significant amounts of melanin. A block in the transfer of melanin from the melanocyte
dendrites to the keratinocytes has been proposed as the etiology of this process.
13. Stucco keratosis - They demonstrate small, hyperkeratotic variants of seborrheic keratoses with a church spire pattern. Pseudocysts are rarely seen.
14. Associated with skin cancer - Two histologic variants may be seen. The most common is a collision tumor or the coexistence of two separate lesions which are
contiguous. There is usually a sharp demarcation between the basaloid or squamous cells
of the seborrheic keratosis and the adjacent or lateral basal cell carcinoma, squamous cell
carcinoma, or malignant melanoma. More unusual is the gradual change, often at the
base or lower margin of a seborrheic keratosis, from the cells of the keratosis to a basal
cell carcinoma, squamous cell carcinoma, or very rarely, a malignant melanoma.
B. Epidermal nevi
Epidermal nevi and seborrheic keratoses share many clinical and histological features.
They may be genetically related, with epidermal nevi representing the congenital variant 3 and seborrheic keratoses the acquired. Epidermal nevi are not true acanthomas, but
groupings of individual papules often separated from one another by normal skin. The
individual papules simulate acanthomas. They are congenital or developmental, usually
appearing before adulthood. There are a wide variety of clinical and histologic patterns
ranging from one or two small verrucous papules to linear or zosteriform arrangements of
papules, and occasionally slightly scaly patches or nondescript plaques. Epidermal nevi
demonstrate a variety of histologic features, with hyperplasia, papillomatosis, and
acanthosis being most apparent. Although they appear to be predominantly epidermal, by
necessity, the underlying dermis is also affected with increased volume and digitation of
the dermal papillae.

The term "epidermal nevus syndrome" associates epidermal nevi with abnormalities of the
underlying bone, cartilage, and muscle, along with systemic findings involving the central
nervous system, skeleton, cardiovascular system, or eyes.

ILVEN demonstrate a predominance of psoriasiform epidermal hyperplasia with a dense,
linear or band-like, inflammatory infiltrate in the dermis. In many lesions, alternating
hypergranulosis with overlying orthokeratosis and hypogranulosis with overlying
parakeratosis in a zonal fashion is quite distinctive. A nevus comedonicus demonstrates
widely dilated infundibulae filled with compact, whorled keratin and having atrophy of the
underlying pilar structures.

C. True Acanthomas
1. Clear cell - Clear cell acanthomas (Degos acanthoma) occur most frequently as a solitary, asymptomatic, well circumscribed, rarely pedunculated, smooth, moist, red
papule or nodule on the lower leg of an older person. There is a well circumscribed and
symmetric proliferation of keratinocytes characterized by clear or pale staining, glycogen-
laden cytoplasms with normal appearing nuclei. The acanthotic variant is most common
with the acanthosis resulting in a lesion which is partially exophytic and partially endophytic.
Occasionally, a more psoriasiform or interdigitated pattern of elongated rete ridges is
seen. Mild spongiosis is present between the pale cells in the acanthotic portion.
Acrosyringia and the infundibulae of hair follicles do not contain the clear cells filled with
glycogen and appear as thin columns of normal cells. Pigmentation is rare, although
occasional melanocytes may be seen in the acanthotic areas. At the edge of the tumor,
there is a sharp change to normal epidermis over 1-2 rete ridges. A characteristic feature
of the lesion is the presence of numerous neutrophils or neutrophil particles scattered or
sprinkled throughout the epidermis. The blood vessels in the dermal papillae are dilated
and occasional lesions are difficult to distinguish from psoriasis. Glycogen is seen on PAS
staining before diastase and is thought to accumulate due to an absence of phosphorylase
which is necessary for the degradation of glycogen.
2. Acantholytic - Acantholytic acanthomas usually occur as a solitary, asymptomatic, scaling papule or nodule on the trunk or extremities. Multiple lesions have
been described, especially on the genitals. Histologically, there is a well circumscribed, 4 predominantly exophytic neoplasm demonstrating epidermal hyperkeratosis,
papillomatosis, and predominantly acanthosis. Acantholysis is the only distinguishing
feature
3. Dyskeratotic acanthoma - These lesions have no distinguishing clinical features and are similar to acantholytic acanthomas. Although focal acantholytic dyskeratosis may
be seen as an incidental finding in normal epidermis or in foci of seborrheic keratoses, this
term is used to designate a lesion with widespread acantholysis and dyskeratosis.
4. Epidermolytic - Epidermolytic acanthomas occur as solitary and disseminated lesions and appear as a keratotic papule that resembles a wart or seborrheic keratosis.
Solitary lesions may occur anywhere on the skin and are less than 1cm in diameter.
Disseminated lesions occur as discrete, brownish papules, 2-7mm in diameter, and are
seen on the upper trunk. Hyperkeratosis, focal parakeratosis, epidermal hyperplasia, and
predominantly acanthosis are seen in well circumscribed architectural patterns similar to a
seborrheic keratosis. The distinguishing feature is the presence of epidermolytic
hyperkeratosis (also termed granular degeneration) throughout the epidermis, sparing only
the basal layer. This finding is similar to that of a linear epidermal nevus with epidermolytic
changes. Epidermolytic changes demonstrate intracellular and intercellular edema, pale
staining cytoplasms with indistinct plasma membranes, large coarse keratohyalin-like
granules and eosinophilic trichohyalin-like granules throughout the epidermis, most evident
in a thickened granular layer. Remnants of keratinized cells may be seen in the stratum
corneum as eosinophilic globules without nuclei.

D. Miscellaneous
These miscellaneous lesions are often simulants of acanthomas clinically and
histologically, although their classification is somewhat arbitrary.
1. The typical verruca vulgaris demonstrates marked hyperkeratosis above digitated epidermal hyperplasia with parakeratosis at the tips of some of the digitations.
There are dilated and tortuous blood vessels within the dermal papillae. At the periphery of
the lesion the elongated rete ridges curve inward forming a collarette. Proliferation of
uniform basaloid cells above the dermal-epidermal junction is usually not as striking and in
the lower and mid epidermis, there is a normal maturation of keratinocytes. The major
difference is the focal presence of vacuolated cells or koilocytes in the superficial layers of
the epidermis associated with clumped keratohyalin granules and overlying tiers of
parakeratotic cells in the stratum corneum, often containing collections of serum. If these
distinct cytologic changes of viral infection are not present, verrucae may be
indistinguishable from seborrheic keratoses.
2. Inverted follicular keratosis - There is a well circumscribed and symmetric exo/endophytic neoplasm with overlying parakeratotic scale. They are composed of a
proliferation of keratinocytes seen as bulbous projections into the underlying dermis.
These keratinocytes have bland, uniform nuclei and abundant eosinophilic staining
cytoplasms. Squamous eddies are present focally, especially near the base of the lesion.
Also, at the base there is a lymphohistiocytic inflammatory infiltrate. Occasionally, there
are foci demonstrating acantholysis, mucinous changes, or even duct-like structures.
Inflamed lesions may demonstrate keratinocytes with hyperchromatic and pleomorphic
nuclei, especially when admixed with the inflammation. In these cases, as in irritated 5 seborrheic keratoses, the differential diagnosis may be a superficial squamous cell
carcinoma.
3. Verrucous keratosis - Most dermatopathologists develop a histologic diagnostic term to describe lesions which do not have sufficient characteristic histologic features to
make a diagnosis of a specific type of benign keratosis or acanthoma. I choose the term
"verrucous keratosis" for these lesions rather than over and over again stating that I cannot
be certain exactly which type of keratosis this lesion represents. In fact, 99% of these
lesions are inflamed or irritated seborrheic keratoses or verrucae. Since they share many
histologic features in common, as demonstrated in this presentation, this "lumper" term has
been readily accepted by my contributors. If the clinical and histologic exams of a lesion
are performed by the same observer, separation into specific entities is easier.
4. Fibroepithelial polyp (skin tag) - Skin tags have been given a variety of names including fibroepithelial polyps, acrochordons, and papillomas. Polypoid projections with a
smooth surface, flattened rete ridges, and a fibrovascular central core may be termed
papillomas, those demonstrating papillated epidermal hyperplasia may be termed a
fibroepithelial polyp or a pedunculated seborrheic keratosis. Inflammation is often present,
but does not usually cause increased squamous differentiation in the epidermal portions.
Infarction is manifested as epidermal necrosis with collagen degeneration of the fibrous
core.
5. Hyperkeratosis lenticularis perstans - Histologically, there is marked compact orthokeratosis which is eosinophilic without columns of parakeratosis. The underlying
stratum spinosum appears flattened and quite thin with the absence of a granular layer.
The entire lesion may be slightly depressed or cup-shaped. 6. Benign lichenoid keratosis (lichen-planus-like) Benign lichenoid keratoses are also termed lichen-planus-like keratoses and usually appear as solitary lesions on the
chest, back, neck, and upper extremities of adults over 50. Histologically, the epidermis
varies from being atrophic to hyperplastic with overlying ortho and parakeratosis. There is
a variably dense, superficial perivascular infiltrate of lymphocytes and histiocytes which
focally obscures the dermal-epidermal junction where it is associated with vacuolar
alteration and variable numbers of necrotic keratinocytes. A few necrotic keratinocytes are
scattered at higher levels of the epidermis. Due to the inflammation, there can be some
mild nuclear atypia of the basilar keratinocytes. Often, residual portions of a solar lentigo
are seen at the borders of a lesion. 7. Warty dyskeratoma - There is a central invagination which is cup shaped and forms a small cyst opening to the surface. There are papillary projections which
demonstrate both dyskeratotic and acantholytic keratinocytes. In some areas there is a
villous pattern with a few normal basaloid cell layers and then progression to acantholytic
and dyskeratotic cells.

II. EPITHELIAL CYSTS OF THE SKIN
A. Epidermoid Cysts
Epidermal cysts (keratin cysts, epidermoid cysts, epidermal inclusion cysts) are defined as
true cysts lined by a stratified squamous epithelium with an intact granular layer which
includes normal melanocytes and Langerhans' cells. Clinically, they are slow growing,
round, firm, intradermal or subcutaneous tumors, often with an overlying pore, that cease 6 growing after having reached a size of 1-5 cm. There is a male-to-female ratio of 2:1.
They occur most commonly on the face, scalp, neck and trunk. Epidermoid cysts have
also been reported on plantar skin. Most epidermoid cysts are acquired. The most
common epidermoid cyst is probably derived from the follicular infundibulum and should
properly be called an infundibular cyst. Follicular plugging or perhaps infundibulo- folliculitis
and subsequent follicular plugging may lead to dilatation of the underlying follicular
epithelium leading to formation of a cyst. Some cysts may result from traumatic
implantation of epidermis into the dermis. When many cysts are present, especially on the
face and scalp, a diagnosis of Gardner's syndrome should be considered. This is a
dominantly inherited genodermatosis characterized by colonic polyposis, fibrous tissue
tumors, osteomatosis and dental anomalies. Cystic lesions of the skin may appear as the
initial clinical manifestation of the syndrome. Epidermoid cysts have a wall composed of
true epidermis. In early epidermal cysts, there may be several layers of epidermal cells in
the cyst wall. Generally, a rete pattern is not seen. In older epidermoid cysts, the wall is
often markedly atrophic and may consist of only one or two rows of flattened cells. The
cyst is filled with horny material arranged in laminated layers. Melanocytes and melanin
pigmentation of keratinocytes in the cyst wall may be seen, especially in epidermoid cysts
of individuals with pigmented skin. When an epidermoid cyst ruptures and contents are
released into the dermis, a foreign body reaction occurs. Fragments of cyst wall may be
seen in association with a marked lymphohistiocytic reaction, including numerous
multinucleated giant cells, many of which contain clefts which represent keratin fragments
whose lipid contents have been washed out during processing. In some cases, complete
disintegration of the cyst wall occurs and foreign body reaction is all that remains at the site
of the cyst.

B. Pilar Cysts
1. Common pilar cysts (trichilemmal cysts, wens) are clinically indistinguishable from
epidermoid cysts. The wall of pilar cysts is composed of several layers of well-
differentiated squamous cells. The peripheral layer of cells is palisaded. The cells close to
the cavity are swollen and pale. A granular cell layer is not present as the cyst undergoes
trichilemmal keratinization. The cyst contents consist of homogenous, keratin material.
Focal calcification may be noted in approximately 25% of trichilemmal cysts. Rupture of
cysts may result in foreign body reaction, resulting in ultimate disintegration. Secondary
infection may occur.
2. Proliferating trichilemmal or pilar cysts - Proliferating trichilemmal cysts most
commonly (90%) arise in the scalp of females. There are lobules and multiple cysts lined
by outer root sheath epithelium showing trichilemmal keratinization. Proliferation of
squamous epithelium may lead to formation of horn pearls and squamous eddies. Some
areas may show nuclear atypia and individual cell keratinization which may be mistaken for
squamous cell carcinoma. Focal calcification and ghost cells may also be seen. In some
cases, true malignant transformation may occur.
3. Malignant proliferating trichilemmal & pilar tumors - When rapid enlargement of a
trichilemmal tumor or cyst occurs, the possibility of malignant transformation should be
considered. Malignant areas show disorganization and severe cellular atypia.
7 C. Hybrid Cysts
Hybrid cysts represent a combination of cyst types. Histologically, the upper portion of the
cyst shows epidermoid keratinization in continuity with the surface epidermis. There is a
transition to trichilemmal keratinization in the lower portion of the cyst. Hybrid cysts lend
credence to the theories regarding the origin of epidermoid and trichilemmal cysts from
different portions of the follicular apparatus.

D. Steatocystoma Multiplex
Steatocystoma multiplex consists of single or multiple nodulocystic lesions measuring 1-3
cm in diameter. They are lined by one to three layers of epithelial cells. At the lumen of
the cyst, there is an eosinophilic horny layer which has a crenated or folded pattern.
Characteristically, sebaceous lobules are found associated with the cyst wall and emptying
into the cyst cavity. Occasionally, true vellus hair follicles may be associated with the wall
and hairs may be seen within the cyst cavity.

E. Eruptive Vellus Hair Cysts
Eruptive vellus hair cysts are usually seen in children and young adults. Autosomal
dominant transmission may be noted. Clinically, they appear as asymptomatic follicular
papules which are 1-2 mm in diameter, usually on the chest, but occasionally on the
extremities or posterior trunk. They may have a bluish color. The cyst is lined by
squamous epithelium and contains homogenous, laminated keratin material. Numerous
obliquely-cut vellus hairs are seen in the cyst cavity. The cyst wall may contain follicular
epithelium.

F. Rare and Unusual Cysts
1. Pigmented Follicular Cysts - Pigmented follicular cysts are similar histologically to
eruptive vellus hair cysts in that they contain many deeply pigmented hair shafts. In some
cases, amorphous pigmented material, which does not include hair shafts, is seen.
Increased pigment is not seen in the wall of pigmented cysts in Caucasians.
2. Dermoid Cysts - Dermoid cysts are thought to arise from embryonic rests of skin
occurring along lines of embryonic closure. They are located predominantly around the
eyes and occasionally on the neck. Dermoid cysts are distinguished from epidermoid cysts
by the presence of mature epidermal appendages arising from the cyst wall. The cysts are
lined by stratified squamous epithelium, along with adnexal structures such as hair follicles,
which may produce hair which projects into the lumen of the cyst. The surrounding dermis
may contain sebaceous glands, eccrine glands and apocrine glands. These adnexal
structures may open directly into the cyst lumina. The cyst contents are of a keratinous
and sometimes fatty or creamy consistency and often contain hair.
3. Bronchogenic and thyroglossal duct cysts - Bronchogenic cysts and thyroglossal
duct cysts are clinically indistinguishable. Thyroglossal duct cysts tend to be located on the
anterior aspect of the neck. Bronchogenic cysts are most commonly seen just above the
sternal notch. Bronchogenic cysts and thyroglossal duct cysts are lined by pseudostratified
squamous epithelium, which may include goblet cells and cilia. The wall of bronchogenic
cysts may contain smooth muscle and, rarely, cartilage. Thyroglossal duct cysts do not
contain smooth muscle and may frequently contain thyroid follicles. 8 4. Cutaneous Ciliated Cysts - Cutaneous ciliated cysts show numerous papillary
projections lined by simple cuboidal or columnar epithelium. The epithelium resembles that
seen in fallopian tubes.
5. Median raphe cyst of the penis - Median Raphe cysts usually are noted in young
adults arising on the ventral aspect of the penis, most commonly on the glans penis.
Median raphe cysts are lined by pseudostratified, columnar epithelium which is similar to
the transitional epithelium of the urethra. Some people believe that these cysts originate
from epithelial nests incidental to incomplete closure of urethral or genital folds. Others
believe that these represent buds of urethral columnar epithelium from the urethra.
6. Nasolabial Cysts (Nasoalveolar Cysts) - Nasolabial cysts are rare lesions
occurring most commonly in the crease under the nasal ala. Nasolabial cysts are lined by
various types of epithelium including pseudostratified columnar epithelium with goblet cells,
ciliated epithelium and keratinizing epithelium.
7. Branchial Cleft Cysts - Branchial cleft cysts are most often located along a line
anterior to the external ear, extending to the sternum along the anterior border of the
sternocleidal mastoid muscle. They may appear as cysts, sinuses, fistulas and skin tabs
containing cartilage. They are most commonly noted during the second and third decades,
but may be present at birth. These cysts are associated with swelling and occasional
infection. Branchial cleft cysts are lined by columnar epithelium, which may or may not be
ciliated. When they drain to the skin surface, the distal portion of the sinus tract may be
composed of stratified squamous epithelium.
8. Cutaneous Endometriosis - Cutaneous endometriosis most commonly occurs
within scars from caesarean sections or other surgical scars near the umbilicus. Most
patients are women between 20 and 50 years of age. Histologically, one sees a deep,
dermal or subcutaneous fat nodule containing multiple, cystic spaces lined by epithelium
which varies from columnar to cuboidal. Adjacent to the epithelium, there are stromal cells
similar to stromal cells in the endometrium. There may be associated inflammation,
fibrosis and recent or old hemorrhage characterized by the presence of hemosiderin-laden
macrophage.
9. Mucocoele - Mucocoeles do no represent true cysts. Clinically, they appear as a
cystic swelling, usually on the lip, floor of the mouth, cheek, or other portions of the oral
pharynx. Histologically, amorphous masses of mucinous material associated with acute
and chronic inflammation are seen. Minor salivary glands and dilated minor salivary gland
ducts will be seen. A true cyst wall is not seen.
10. Digital Myxoid Cysts - Myxoid cysts of the digits are not true cysts. They
represent collections of mucinous material in the dermis. Once again, a true capsule is not
seen. These cysts are thought to arise from the joint capsule. The most common sites are
the middle and index fingers. Histologically, one sees thinning of the epidermis overlying
the cyst with adjacent pseudoepitheliomatous hyperplasia. The cyst is located within the
dermis and consists of myxoid material containing fusiform and stellate fibroblasts.