Skin Tumors: Seborrheic Keratosis Overview

Tumors of the Skin

Seborrheic keratosis is a common epidermal tumor, usually affecting middle-aged or older individuals.
It arises spontaneously on the trunk, extremities, head, and neck.
Activating mutations in growth factor signaling pathways, specifically FGFR3, RAS, and PI3K, are associated with seborrheic keratosis.

Benign Lesions-Seborrheic Keratosis

Except for cosmetic concerns, seborrheic keratoses are typically of little clinical importance.
In some cases, hundreds of these lesions may appear suddenly as a paraneoplastic syndrome, associated with internal malignancies, most often in the gastrointestinal tract.
Seborrheic keratoses are typically round, exophytic, coin-like plaques. The diameter ranges from millimeters to centimeters.
They have a "stuck-on" appearance, with a velvety- to granular-appearing surface.
Their tan to dark brown color can sometimes be mistaken for melanoma, leading to surgical removal.

Benign Lesions-Fibroepithelial Polip

Clinically, it presents as acrocordon (skin tag) in middle-aged individuals, most commonly on the neck, trunk, and face.
It may be associated with Birt-Hogg-Dubé syndrome.
The lesions are polypoid, with a fibrovascular core covered by epidermis.

Benign Lesions-Epithelial/Follicular Cysts

These cysts are common in young and middle-aged adults, appearing on the face, neck, and trunk.
They appear as smooth dome-shaped swellings, varying in size from a few millimeters to a few centimeters.
Unless ruptured, they are usually mobile, but rupture may cause them to become affixed to surrounding connective tissue.
They often contain white, cheesy, macerated keratin with an odor.

Benign Lesions-Melanocytic nevi

Junctional nevus: These nevi are small, flat, or slightly elevated, with rounded nests of melanocytes located on the epidermal side of the dermoepidermal junction, originating from the tips of rete ridges.
Melanocytic nevi are benign neoplasms of melanocytes. A wide variety of types exist, showing varying appearances.
While usually only cosmetically concerning, they may cause irritation or mimic melanoma, which may require surgery for removal.

Premalignant lesions-Actinic Keratosis

Actinic keratoses are a consequence of chronic exposure to sunlight and UV-induced DNA damage.
The rate of progression to squamous cell carcinoma (SCC) varies between 0.1% to 2.6% annually.
Most regress or remain stable in size, and are typically less than 1 cm in diameter.
The lesions are usually tan-brown to red, with a rough surface.
They frequently develop on sun-exposed areas like the face, arms, and dorsum of the hands.
Mutations in TP53 and other genes frequently mutated in SCC are often present

Premalignant lesions-Actinic Keratosis (Clinical features)

Actinic keratoses are common in fair-skinned people and incidence increases with age and sun exposure.
They're often treated for cosmetic reasons or to prevent progression.
Effective treatments are local eradication techniques including cryotherapy (superficial freezing) or topical agents.

Premalignant lesions-Actinic Keratosis (Morphology)

Lower parts of the epidermis show cytologic atypia, often with basal cell hyperplasia or atrophy, and diffuse epidermal thinning.
Solar elastosis, characterized by thickened, blue-gray elastic fibers, can be observed.
Epidermal atypia that reaches full-thickness is indicative of squamous cell in situ.

Malignant epithelial tumors-Squamous Cell Carcinoma

Squamous cell carcinoma (SCC) is a common tumor arising in sun-exposed areas in older adults.
It has a higher incidence in men than women.
SCCs are often discovered small and resectable.
Metastasis rates are typically below 1% at diagnosis, but depend on lesion thickness and invasion.
Tumors arising from actinic keratoses tend to be locally aggressive but typically metastasize more slowly.

Malignant epithelial tumors-Squamous Cell Carcinoma (Pathogenesis)

UV light exposure causes widespread DNA damage and high mutation rates.
Xeroderma pigmentosum is a condition where nucleotide excision repair enzymes are mutated, placing individuals at exceptionally high risk of skin cancers.
Loss-of-function mutations in TP53 and Notch receptors and/or activating mutations in RAS are frequently observed.

Malignant epithelial tumors-Squamous Cell Carcinoma (Clinical features)

Risk factors for SCC in the skin include immunosuppression in organ transplant recipients, exposure to industrial carcinogens, chronic non-healing ulcers, old burn scars, or ingestion of arsenicals and/or ionizing radiation.

Malignant epithelial tumors-Squamous Cell Carcinoma (Morphology)

SCC in situ appears as sharply defined, red, scaling plaques and may arise in association with previous actinic keratoses.
Highly atypical cells are seen throughout the epidermis, often with signs of nuclear crowding and disorganization.
Invasive SCC is often nodular and scaly, sometimes with superimposed ulceration, and exhibits variable degrees of differentiation; cells display extensive keratinization.

Malignant epithelial tumors-Basal Cell Carcinoma

Basal cell carcinoma (BCC) is the most common skin cancer, accounting for about 80% of all skin cancers.
The major risk factor is cumulative sun exposure in fair-skinned individuals.
BCCs tend to occur at chronically sun-exposed sites.
It's typically treated with local excision.
Metastasis is extremely rare.

Malignant epithelial tumors-Basal Cell Carcinoma (Pathogenesis)

Loss-of-function mutations in the PTCH1 tumor suppressor gene, which negatively regulates Hedgehog signaling, cause constitutive activation of the Hedgehog pathway.

Malignant epithelial tumors-Basal Cell Carcinoma (Clinical features)

BCCs commonly present as pearly papules with prominent, dilated subepidermal blood vessels (telangiectasia).
Some lesions might contain melanin pigment and resemble melanocytic nevi or melanomas.
Microscopically, BCC cells resemble normal epidermal basal cells or follicular germinative elements.

Malignant epithelial tumors-Basal Cell Carcinoma (Morphology)

BCC forms a fibrotic or mucinous stromal matrix with peripheral tumor cells exhibiting 'palisading', alignment in the outermost layer, and often peritumoral clefting.

Benign Lesions-Melanocytic nevi (variants)

Congenital nevus: a large, flat, uniformly pigmented lesion present at birth
Blue nevus: appears as a bluish-black lesion composed of dendritic cells.
Spitz nevus: occurs in children and young adults; appears as a pink, nodular lesion often composed of spindled and epithelioid cells.
Halo nevus: a lesion surrounded by a zone of lymphocytic inflammation.

Dysplastic nevus

Dysplastic nevi can be sporadic or familial. Familial dysplastic nevus syndrome predisposes individuals to a high risk of melanoma development.
Characterized by being larger than most acquired nevi, with irregular borders and variable pigmentation (variegation).
In familial cases, presence of 10 or more dysplastic nevi increases melanoma risk.
Nests within the epidermis may exhibit abnormal fusion or coalescence, producing lentiginous hyperplasia.

Dysplastic nevus (Clinical Features)

Dysplastic nevi typically appear on both sun-exposed and non-sun-exposed areas of the skin.
They are more often noted for irregular borders and variegation of color than by size or location on the body.

Dysplastic nevus (Morphology)

Dysplastic nevi often exhibit irregular borders, sometimes appearing angulated, and frequent nuclear contours with hyperchromasia.
A sparse lymphocytic infiltrate surrounding the epidermal nests of melanocytes and linear fibrosis may also be observable.
The progression, or development, from dysplastic nevus to melanoma is rare compared to the direct appearance of a melanoma.

Malignant epithelial tumors-Melanoma

Melanoma is a less common but much more deadly form of skin cancer than basal or squamous cell carcinoma, often treated surgically.
The 'ABCDE's of melanoma' (asymmetry, border irregularity, color variation, diameter, and evolution) are common clinical warning signs.

Malignant epithelial tumors-Melanoma (Clinical features)

Melanoma can develop on skin and mucous membranes, including the esophagus, meninges, and eyes.
Warning signs include a rapidly enlarging preexisting nevus, a new pigmented lesion in adult life, irregular borders of a pigmented lesion, and variegation, or inconsistent color, of the pigmented lesion.
Metastasis risk is related to tumor depth of invasion, which is frequently measured by the Breslow thickness. High mitotic rates and lack of local immune response also increase metastasis risk.

Malignant epithelial tumors-Melanoma (Pathogenesis)

Primarily caused by UV-induced DNA damage, leading to stepwise driver mutations. Highest incidence occurs in sun-exposed regions and populations with light pigmentation. Damage is more significant with intense UV irradiation in youth.

Malignant epithelial tumors-Melanoma (Morphology)

Unlike benign nevi, melanomas commonly display striking variations in pigmentation, including black, brown, red, dark blue, and gray.
Irregular and often notched borders are characteristic.
Several morphological phases exist, starting with lateral expansion of melanocytes (lentiginous hyperplasia/compound nevus) and progressing to melanoma in situ before invasive horizontal vertical growth.

Malignant epithelial tumors-Melanoma (additional details)

Certain inherited predispositions for melanoma, including Gorlin syndrome, arise from germ-line mutations in CDKN2A, encoding tumor suppressors p16 and p14 that regulate cell cycle activity.
Increased genomic alterations such as aneuploidy also occur as tumors progress.
Non-sun-exposed melanomas often exhibit distinct molecular profiles, with mutations frequently found in the KIT receptor tyrosine kinase.
Immune system evasion is an important development in melanoma and often targeted with immunotherapy.
Agents that selectively inhibit mutant BRAF or KIT have been shown to produce dramatic responses in patients with metastatic melanoma with these mutations.
Immune checkpoint inhibitors have also proven effective in stabilizing and inducing tumor remission.