Nonmelanocytic Tumors of the Skin
Nathan C. Walk
Yumei Chen
Anne C. Lind
Friederike Kreisel
Dongsi Lu
I. BENIGN TUMORS OF THE EPIDERMIS
A. Seborrheic keratosis
1. Clinical: Single or multiple discrete papules or plaques, typically measuring 0.5 to 1.0 cm, variably pigmented and with a “stuck-on” appearance, only on hair-bearing skin; most commonly found in people >30 years of age.
2. Microscopic: Exophytic or endophytic lesion sharply demarcated from adjacent epidermis, composed of basaloid and often homogeneous cells mixed with squamoid cells. Intraepidermal pseudocysts filled with loose orthokeratotic keratin are usually present. There are many microscopic patterns of seborrheic keratoses, the most common being hyperkeratotic, acanthotic, reticulated, and clonal. Features of irritation are commonly seen (e-Fig. 39.1).
B. Clear cell acanthoma
1. Clinical: Uncommon, slow growing, pink to brown, dome-shaped nodule or small plaque, most frequently on the leg of middle-aged and elderly individuals.
2. Microscopic: Acanthotic epidermis with a sharply demarcated proliferation of keratinocytes with pale/clear cytoplasm with associated parakeratosis, agranulosis, and neutrophils in the stratum corneum and spinosum. Periodic acid-Schiff (PAS) stain highlights cytoplasmic glycogen (e-Fig. 39.2).*
C. Large cell acanthoma
1. Clinical: A sharply demarcated, scaly patch on the sun-exposed skin of middle-aged and elderly individuals.
2. Microscopic: Sharply demarcated acanthosis, keratinocyte nuclear and cytoplasmic enlargement (about 2× normal), hypergranulosis and hyperorthokeratosis (e-Fig. 39.3).
II. PREMALIGNANT AND MALIGNANT TUMORS OF THE EPIDERMIS
A. Actinic keratosis
1. Clinical: Scaly, erythematous papules or nodules on sun-exposed skin of the head and neck, upper and lower extremities; more common in fair-skinned individuals.
2. Microscopic: Patchy parakeratosis and agranulosis that often spare adnexal ostia, irregular downward buds of atypical (dysplastic) basal keratinocytes. Dyskeratotic cells are sometimes present. Dysplasia does not involve the full thickness of the epidermis, and solar elastosis is frequently seen (e-Fig. 39.4).
3. Genetics: Approximately 50% of actinic keratoses show TP53 mutations and overexpression of cyclin D1, whereas 16% have independent activation of Ras. Loss of heterozygosity is commonly seen on chromosome 3p (31%), 9p (39%), 9q (22%), 13q (52%), 17p (64%), and 17q (46%); human papilloma virus (HPV) is detected in 41% of cases.
B. Squamous cell carcinoma in situ (Bowen disease)
1. Clinical: Sharply demarcated, scaly, often hyperkeratotic macule, papule, or plaque; most common in sun-exposed areas (particularly the face and legs); more common in fair-skinned, older individuals.
2. Microscopic: Keratinocytes with enlarged, hyperchromatic nuclei and minimal cytoplasm occupy the full thickness of the epidermis; variable acanthosis, hyperparakeratosis, agranulosis, dyskeratosis, mitoses above the basal layer and loss of maturation; the neoplastic cells populate adnexal structures (e-Fig. 39.5).
3. Genetics: Increased expression and mutation of TP53 have been observed. Allelic deletion of one or more chromosome 9q markers has also been detected in occasional lesions.
C. Invasive squamous cell carcinoma (The American Joint Committee on Cancer [AJCC] Tumor, Node, Metastasis [TNM] staging scheme for cutaneous squamous cell carcinoma and other cutaneous carcinomas is given in Table 39.1.)
1. Clinical: Early lesions are firm, skin-colored, or erythematous nodules; later lesions are shallow ulcers with firm, elevated, or indurated surroundings, sometimes with crust or scale; most common in fair-skinned, older individuals on sun-exposed areas and in immunocompromised patients. Metastatic potential depends on location, histology, and precursor lesions/etiology.
2. Microscopic: Acanthosis, invasion of the dermis by individual or nested keratinocytes with variable amounts of cytoplasm and nuclear pleomorphism, dyskeratosis, and swirls of parakeratotic keratin (keratin pearls); there may be dermal desmoplasia and variable inflammation. Acantholysis, perineural invasion, and sarcomatoid change predict more aggressive behavior (e-Fig. 39.6).
D. Basal cell carcinoma
1. Clinical: Variable presentation; most commonly a dome-shaped, firm papule with a pearly, telangiectatic surface; slowly growing; primarily on the head, neck, and trunk. The most common skin cancer in Caucasians; rarely metastasizes unless neglected.
2. Microscopic:Variable histology; Common features include basaloid cells with hyperchromatic nuclei and scant cytoplasm, usually connected to an unremarkable or ulcerated epidermis. Basaloid islands show peripheral palisading, mitoses, and apoptosis; a retraction artifact separates the basaloid cells from the surrounding basophilic, variably mucinous stroma (e-Fig. 39.7).
3. Genetics: Mutations of genes PTCH1 on chromosome 9q22.3 and SMD on chromosome 7q31-32 involved in activating hedgehog signaling pathway have been identified in both sporadic basal cell carcinomas and basal cell nevus syndrome, a rare autosomal dominant (AD) disorder.
III. TUMORS OF THE CUTANEOUS APPENDAGES. Tumors of the cutaneous appendages have a somewhat nebulous nomenclature. A traditional system organizes the tumors on the basis of their origin from one of the normal cutaneous appendages: hair follicle, sebaceous gland, eccrine gland, or apocrine gland. However, complex adnexal tumors also occur that have abnormalities of two or more of the normal skin constituents, including the epidermis itself, and there is sometimes controversy as to a tumor’s precise histogenesis (i.e., eccrine vs. apocrine, and so on). The following is a succinct review of the major tumors derived from the skin appendages.
A. Benign appendage tumors. Benign adnexal tumors have architectural symmetry when viewed at low power and, usually, a distinctive cleft between the stroma of the tumor and the native dermal collagen.
1. Hair follicle tumors
a. Trichofolliculoma
i. Clinical: Rare, solitary, small (<1 cm), skin-colored papule on the face. A tuft of fine hairs protrudes from the center.
TABLE 39.1 Tumor, Node, Metastasis (TNM) Staging Scheme for Cutaneous Squamous Cell Carcinoma and Other Cutaneous Carcinomas
Primary tumor (T)a
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis
Carcinoma in situ
T1
Tumor 2 cm or less in greatest dimension with less than two high-risk featuresb
T2
Tumor >2 cm in greatest dimension or tumor any size with two or more high-risk featuresa
T3
Tumor with invasion of maxilla, mandible, orbit, or temporal bone
T4
Tumor with invasion of skeleton (axial or appendicular) or perineural invasion of skull base
Regional lymph nodes (N)
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastases
N1
Metastasis in a single ipsilaterial lymph node, 3 cm or less in greatest dimension
N2
Metastasis in a single ipsilateral lymph node, >3 cm but not >6 cm in greatest dimension; or in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension; or in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension
N2a
Metastasis in a single ipsalateral lymph node, >3 cm but not >6 cm in greatest dimension
N2b
Metastasis in multiple ipsilaterial lymph nodes, none >6 cm in greatest dimension
N2c
Metastasis in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension
N3
Metastasis in a lymph node, >6 cm in greatest dimension
Distant metastasis (M)
M0
No distant metastases
M1
Distant metastases
Anatomic stage/prognostic groups
Stage
T
N
M
Stage 0
Tis
N0
M0
Stage I
T1
N0
M0
Stage II
T2
N0
M0
Stage III
T3
N0
M0
T1
N1
M0
T2
N1
M0
T3
N1
M0
Stage IV
T1
N2
M0
T2
N2
M0
T3
N2
M0
T Any
N3
M0
T4
N Any
M0
T4
N Any
MO
T any
N Any
M1
a Excludes cSCC of the eyelid.
b High-risk features for the primary tumor (T) staging. From: Edge SB, Byrd DR, Compton CC, et al., eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010. Used with permission.
ii. Microscopic: One or more cystically dilated hair follicles with radiating follicles that project into a relatively cellular stroma. The secondary hair follicles are of variable maturity and may give rise to more hair follicles (e-Fig. 39.8).
b. Trichoepithelioma
i. Clinical: Usually solitary, skin-colored papule, most common on the central face; if multiple, associated with AD inheritance. The desmoplastic variant is a solitary, firm annular lesion with a raised border and central depression that occurs exclusively on the face.
ii. Microscopic: A relatively well-circumscribed dermal tumor composed of islands of basaloid cells with pilar differentiation in a cellular stroma; papillary mesenchymal bodies are characteristic. Small keratinous cysts and foci of calcification are often present. The tumor epithelium may mimic basal cell carcinoma, but there is no retraction artifact or mucinous stroma (e-Fig. 39.9). The desmoplastic variant shows a wellcircumscribed lesion in the upper and mid-dermis composed of cords or small nests of basaloid cells in a sclerotic stroma (e-Fig. 39.10). It may be confused with a syringoma or a morphea-form basal cell carcinoma.
c. Trichoadenoma (of Nikolowski)
i. Clinical: Rare nodule on the face or buttocks.
ii. Microscopic: A well-demarcated dermal tumor composed of multiple cyst-like structures lined by multilayered keratinizing pilar-type squamous epithelium. The cysts contain keratinous debris and no hair shafts (e-Fig. 39.11).
d. Dilated pore of Winer
i. Clinical: Common, usually solitary, comedo-like lesion on the head and neck, or trunk.
ii. Microscopic: A cystically dilated hair follicle, filled with loose keratin and lined by acanthotic stratified squamous epithelium with irregular budding (e-Fig. 39.12).
e. Trichilemmoma
i. Clinical: A solitary, small, skin-colored/pink or brown papule on the face and neck; multiple lesions are associated with Cowden syndrome.
ii. Microscopic: A well-circumscribed, endo-exophytic tumor composed of clear squamoid cells with glycogenated cytoplasm. The tumor extends from the epidermis with a lobular configuration. There is a thin peripheral rim of palisading columnar cells and variable, thick, eosinophilic basement membrane (e-Fig. 39.13).
f. Pilomatrixoma (Calcifying epithelioma of Malherbe)
i. Clinical: Firm, deeply located nodule, most common on the face and upper extremities; onset frequently in childhood.
ii. Microscopic: A sharply demarcated tumor in the lower dermis and, often, the subcutis. The tumor is composed of large, irregularly shaped tumor islands and intervening stroma. Two basic cell types are present: basaloid cells and “shadow” or “ghost” cells. The basaloid cells resemble the cells in basal cell carcinoma and are present at the periphery of the tumor islands. The shadow cells, which have eosinophilic cytoplasm, distinct cell borders, and no nuclear staining, occupy the center of tumor islands. Several layers of transitional cells with intermediate features may be present. In addition, dystrophic calcification, a mixed inflammatory infiltrate, hemosiderin, melanin, bone, and foreign body giant cells can be seen (e-Fig. 39.14).
g. Fibrofolliculoma/trichodiscoma
i. Clinical: Skin-colored papules, most common on the face; may be solitary or multiple. Multiple lesions are seen in Birt-Hogg-Dubé
syndrome, which has an AD inheritance and carries a high risk for developing renal tumors, pulmonary cysts, and pneumothorax.
ii. Microscopic: Spectrum of changes with fibrofolliculoma at one end and trichodiscoma at the other. Fibrofolliculoma is composed of thin strands of follicular epithelium extending from a hair follicle structure into a stroma that is well defined and composed of loose connective tissue with fine fibrosis. A trichodiscoma has a dominant stromal component that is characterized by strands of loose connective tissue with intermixed fibroblasts resembling an angiofibroma (e-Fig. 39.15).
2. Eccrine tumors
a. Syringoma
i. Clinical: Usually multiple, skin-colored, small, firm papules on the lower eyelids and cheeks, more common in women; onset is often at puberty.
ii. Microscopic: Multiple small ducts in a dense fibrous stroma in the dermis. The ducts are lined by two layers of cuboidal epithelium, and sometimes are “tadpole” or “comma-like.” Solid nests and strands of tumor cells can be present (e-Fig. 39.16).
b. Eccrine (or apocrine) mixed tumor (chondroid syringoma)
i. Clinical: Solitary, firm, dermal or subcutaneous nodule on the head and neck.
ii. Microscopic: Well-circumscribed dermal tumor of small epithelial cells in solid nests, small clusters, and ducts in a prominent myxoid, cartilaginous, and/or fibrous stroma (e-Fig. 39.17).
c. Cylindroma
i. Clinical: Solitary nodule on the head and neck; predominantly in middle-aged to elderly women; rarely undergoes malignant transformation; if multiple, associated with AD inheritance and an occurrence as “turban tumors”
ii. Microscopic: A poorly circumscribed dermal tumor composed of irregularly shaped nests of basaloid cells, surrounded by a thick eosinophilic basement membrane. The cellular nests fit together in a “jigsaw” pattern (e-Fig. 39.18).
d. Spiradenoma
i. Clinical: Usually solitary, firm, tender or painful dermal nodule. There is no characteristic distribution. They occur primarily in young adults.
ii. Microscopic: One or more sharply demarcated dermal nodule(s) of basaloid cells. Two types of cells are present: small lymphocyte-like cells with hyperchromatic nuclei and larger epitheliod cells with more open chromatin. There may be a thin pseudocapsule; a few duct-like structures are present (e-Fig. 39.19).
e. Poroma group (including eccrine poroma, dermal duct tumor, and hidroacanthoma simplex)
i. Clinical:
(a) Eccrine poroma–solitary, sessile or slightly pedunculated, pink nodule often on the plantar or palmar skin, or other locations with sweat glands.
(b) Dermal duct tumor–a solitary, firm nodule on the head, neck, and extremities.
(c) Hidroacanthoma simplex–a solitary plaque or nodule on the extremities and trunk; clinically resembles seborrheic keratosis or basal cell carcinoma.
ii. Microscopic:
(a) Eccrine poroma–a circumscribed tumor composed of columns of basaloid cells extending from the lower epidermis into the dermis
within a loose, vascular stroma. Ducts and, rarely, small cysts may be seen in the tumor columns. There is a sharp demarcation from the epidermis (e-Fig. 39.20).
(b) Dermal duct tumor–islands of basaloid cells similar to those of eccrine poroma, located entirely in the dermis. An epidermal connection may be found if multiple sections are examined.
(c) Hidroacanthoma simplex–islands of basaloid cells similar to those of poroma, confined to the epidermis.
f. Acrospiroma (nodular hidradenoma; solid-cystic hidradenoma; apocrine/eccrine hidradenoma; clear cell hidradenoma)
i. Clinical: Solitary nodule, 0.5 to 2.0 cm or more, no site predilection, disputed histogenesis. Nomenclature for this entity is confusing.
ii. Microscopic: Variable histologic appearance, as reflected by the nosology; usually a circumscribed, nonencapsulated, multilobular, central dermal tumor with variable proportions of cystic and solid areas; tumor cells have variable clear or eosinophilic cytoplasm and are round, fusiform, or polygonal. Duct-like structures are typically present and may have a squamous appearance. The stroma varies from rather fine fibrous tissue to dense hyalinized collagen (e-Fig. 39.21).
3. Sebaceous hyperplasia and tumors
a. Sebaceous hyperplasia
i. Clinical: Yellow to whitish papules with central umbilication, typically on the face of older individuals. It may mimic a basal cell carcinoma.
ii. Microscopic: Multiple large, but otherwise normal, sebaceous lobules centered on a large central orifice; solar elastosis is frequently present (e-Fig. 39.22).
b. Sebaceous adenoma
i. Clinical: Rare, solitary or multiple, pink or flesh-colored, usually <1 cm nodule(s) on the face or scalp of adults; may be associated with Muir-Torre syndrome (visceral carcinoma).
ii. Microscopic: Multiple circumscribed sebaceous lobules usually centered in the superficial to mid-dermis; composed of peripheral basaloid germinative cells, central mature sebaceous cells, and a variable zone of transitional forms. Mature cells usually outnumber the basaloid cells (e-Fig. 39.23).
iii. Genetics: Loss of protein expression of DNA mismatch repair genes (MSH-2, MSH-6, MLH-1, and PMS-2) has been found in a number of patients with sebaceous adenoma. There is a high correlation between lost expression of mismatch repair (MMR) proteins and microsatellite instability (MSI).
4. Apocrine tumors
a. Apocrine hidrocystoma (apocrine cystadenoma)
i. Clinical: Solitary, translucent to bluish nodule, predominantly occurring on the face.
ii. Microscopic: Several large cysts in the dermis; the cyst wall is composed of an outer myoepithelial layer and an inner layer of cuboidal to columnar cells with apocrine decapitation secretion; pseudopapillary projections may be present (e-Fig. 39.24).
b. Syringocystadenoma papilliferum
i. Clinical: Varied; most commonly a raised, warty plaque on the scalp; associated with nevus sebaceous in approximately one-third of the cases.
ii. Microscopic: Deep invaginations of duct-like structures extend from an acanthotic, variably papillomatous epidermis into the dermis; they are
lined by squamous epithelium in the upper portion and by two-layer, sweat duct-like epithelium in the lower portion; numerous plasma cells are present in the connective tissue stroma of the papillae (e-Fig. 39.25).
iii. Genetics: Allelic deletions of the patched gene on chromosome 9q22 and loss of heterozygosity of chromosome 9p21 have been reported in syringocystadenoma papilliferum.
5. Complex adnexal tumors: Nevus sebaceous of Jadassohn (organoid nevus)
a. Clinical: Solitary, yellow or waxy, patch or plaque with alopecia on the scalp (most common), face, neck, or trunk; present at birth or first noticed in early childhood.
b. Microscopic: A complex hamartoma involving the epidermis, pilosebaceous unit, and ducts/glands. There is variable epidermal acanthosis, papillomatosis, and abnormally formed/abortive hair follicles with bulbs that do not extend into the subcutis; increased numbers of large sebaceous glands are present around and after puberty; dilated apocrine glands are found in up to 50% of cases (e-Fig. 39.26). Secondary tumors may develop, such as syringocystadenoma papilliferum.
B. Malignant tumors of the cutaneous appendages are rare and far less common than their benign counterparts. As with the benign tumors discussed earlier, a malignant neoplasm can arise from any of the normal skin appendages, and there may be more than one component to a particular tumor. Only extramammary Paget disease will be discussed.
1. Clinical: A red, scaly plaque, typically in areas rich in apocrine glands such as the anogenital region and, less commonly, the axilla; usually pruritic and slowly spreading. An underlying adnexal carcinoma is present in approximately 20% to 25% of cases; visceral carcinoma (rectal, prostate, bladder, cervix, or urethra) is present in 10% to 15% of cases.
2. Microscopic: Similar to mammary Paget disease, there are large, predominantly intraepidermal, epithelioid tumor cells with large, pleomorphic nuclei and abundant pale cytoplasm that may or may not contain mucin. The tumor cells are concentrated in the lower epidermis and randomly dispersed throughout the epidermis; they may also be seen in the superficial dermis. Special stains may be needed to distinguish extramammary Paget disease from melanoma in situ and squamous cell carcinoma in situ with pagetoid features. The tumor cells are positive by mucicarmine and PAS stain; carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), and low-molecular-weight keratin immunostains are positive; Melan-A/Mart-1 and S-100 immunostains are negative (e-Fig. 39.27).
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