Pigmentation Disorders & Benign Skin Growths

Melanocytes and melanin

The pigment unit. Melanocytes migrate from the neural crest to the basal layer of the epidermis. Inside melanosomes, copper-dependent tyrosinase converts tyrosine (from the diet or from phenylalanine) to DOPA and dopaquinone, which polymerizes into brown-black eumelanin or red-yellow pheomelanin. Dendrites pass melanosomes to neighboring keratinocytes, where melanin forms caps over the nuclei and absorbs UV. People of every skin tone have about the same number of melanocytes; color depends on the number, size and type of melanosomes.

Hormonal control. ACTH and α-MSH, both cleaved from pro-opiomelanocortin (POMC), stimulate melanogenesis through the melanocortin-1 receptor (MC1R). Loss-of-function MC1R variants shift production toward pheomelanin, giving red hair, freckling and sun sensitivity.

For any pigment lesion, ask whether the number of melanocytes has changed or the same melanocytes are making more or less melanin.

Too little or too much pigment

Vitiligo. Autoimmune, CD8⁺ T-cell–mediated destruction removes melanocytes, leaving sharply demarcated chalk-white macules, often around the eyes and mouth, on the hands and feet and at sites of trauma (Koebner phenomenon); a Wood lamp accentuates them. Associations include autoimmune thyroid disease (the most common), type 1 diabetes, pernicious anemia, Addison disease and alopecia areata. Halo nevi and the depigmentation some melanoma patients develop on checkpoint inhibitors reflect the same T-cell attack.

Albinism. Melanocytes are normal in number but cannot make adequate melanin. Oculocutaneous albinism type 1 is autosomal recessive tyrosinase (TYR) deficiency; type 2 (OCA2, the P protein) is the most common form worldwide. Expect white hair, pale skin, translucent irises, nystagmus, photophobia, foveal hypoplasia and misrouted optic fibers at the chiasm. Unprotected skin develops skin cancer early, especially squamous cell carcinoma. Syndromic forms include Chédiak-Higashi syndrome (LYST; giant granules, pyogenic infections, neuropathy) and Hermansky-Pudlak syndrome (platelet storage-pool bleeding, pulmonary fibrosis).

Melasma. Symmetric brown patches on the cheeks, forehead and upper lip appear mostly in women with darker skin. Estrogen and progesterone (pregnancy, as the "mask of pregnancy," and oral contraceptives) plus UV push melanocytes to overproduce melanin. It often fades after delivery or stopping the pill; strict sun protection, hydroquinone and topical retinoids help.

Ephelides and lentigines. Freckles are small tan macules on sun-exposed skin of fair, often red-haired people; they appear in childhood, darken in summer and fade in winter because normal numbers of melanocytes make extra melanin. Solar lentigines ("age spots") arise on chronically sun-damaged skin of older adults; melanocytes are increased along the basal layer with elongated rete ridges, and the spots persist year-round. Lentigines of the lips and buccal mucosa suggest Peutz-Jeghers syndrome.

Café-au-lait macules. These uniform light-brown macules contain extra melanin with normal melanocytes. One or two are common in healthy people, but six or more larger than 5 mm before puberty (15 mm after) point to neurofibromatosis type 1, whose macules have smooth "coast of California" borders. McCune-Albright syndrome, a postzygotic (mosaic) activating GNAS mutation that locks Gsα into constant cAMP signaling, produces large unilateral patches with jagged "coast of Maine" borders plus polyostotic fibrous dysplasia and precocious puberty.

Melanocytic nevi

Acquired nevi. Common moles are benign clonal proliferations of melanocytes, often driven by BRAF V600E and then halted by oncogene-induced senescence. A junctional nevus has nests at the dermal-epidermal junction and is a flat, evenly dark macule; a compound nevus adds dermal nests and becomes a raised pigmented papule; an intradermal nevus has only dermal nests and is a dome-shaped, often flesh-colored papule typical of adults. Nevus cells become smaller and less pigmented as they descend (maturation), a reassuring feature that melanoma lacks.

Congenital nevi. Present at birth and often NRAS-mutated, congenital nevi carry a melanoma risk that scales with size, highest in large or giant nevi (≥20 cm projected adult size). Large nevi over the posterior axis with many satellites can accompany neurocutaneous melanosis, in which leptomeningeal melanocytes cause hydrocephalus or seizures.

A Mongolian spot is not a nevus: it is blue-gray congenital dermal melanocytosis over the lumbosacral area of Asian, African and Hispanic infants that fades in childhood. Do not mistake it for abuse bruising.

Dysplastic nevi. Atypical nevi are larger than usual (>5–6 mm), with irregular borders and variegated color, and are often numerous on the trunk. Histology shows bridging junctional nests, cytologic atypia and lamellar fibroplasia. They mark increased melanoma risk and occasionally progress. Familial atypical multiple mole melanoma syndrome is autosomal dominant, usually from germline CDKN2A (p16) mutations, and also raises pancreatic cancer risk.

Benign epidermal and dermal growths

Seborrheic keratosis. The commonest benign epidermal tumor after age 40 is a waxy, verrucous, tan-to-black plaque that looks stuck on, mainly on the trunk and face. Bland basaloid keratinocytes (often FGFR3-mutated) proliferate around keratin-filled horn cysts. The Leser-Trélat sign, a sudden eruption of many seborrheic keratoses, is a paraneoplastic marker, classically of gastric or other GI adenocarcinoma.

Actinic keratosis. Rough, sandpaper-like, scaly pink papules develop on chronically sun-exposed skin (face, bald scalp, dorsal hands) of fair older adults. UV-signature TP53 mutations produce atypical keratinocytes in the lower epidermis with parakeratosis above and solar elastosis below. Progression to squamous cell carcinoma becomes likelier as atypia increases; full-thickness atypia is SCC in situ. Cryotherapy, topical 5-fluorouracil or imiquimod and photodynamic therapy treat them. A cutaneous horn, a projection of compact keratin, can sit on an actinic keratosis, SCC or seborrheic keratosis, so its base must be biopsied.

Keratoacanthoma. A dome-shaped nodule with a central keratin-filled crater grows over weeks on sun-exposed skin of older adults and may involute over months. Because it mimics well-differentiated SCC histologically, it is usually excised. Multiple keratoacanthomas with sebaceous tumors suggest Muir-Torre syndrome, a Lynch syndrome variant.

Epidermal inclusion cyst. The commonest skin cyst is a dermal nodule with a central punctum, lined by stratified squamous epithelium with a granular layer and filled with laminated, cheesy keratin ("sebaceous cyst" is a misnomer). Rupture triggers painful foreign-body inflammation. Pilar cysts of the scalp lack a granular layer. Multiple epidermoid cysts with jaw osteomas and colonic polyps suggest Gardner syndrome (APC), in which colorectal cancer is nearly certain without colectomy.

Dermatofibroma and acrochordon. A dermatofibroma is a firm tan-brown dermal papule, often on the legs and sometimes after an insect bite or minor trauma; pinching it from the sides makes it dimple (Fitzpatrick sign). Fibroblasts trap collagen bundles beneath a hyperpigmented epidermis. Acrochordons (skin tags) are soft, pedunculated, flesh-colored papules in skin folds (neck, axilla, groin) linked to obesity, insulin resistance and pregnancy.

Hyperpigmentation as a systemic clue

Addison disease. In primary adrenal insufficiency, low cortisol removes feedback, so the pituitary cleaves more POMC into ACTH and α-MSH; both act on MC1R and darken the skin diffusely, most visibly in palmar creases, knuckles, recent scars and the buccal mucosa. Secondary (pituitary) and tertiary (hypothalamic or glucocorticoid-withdrawal) insufficiency have low ACTH and no hyperpigmentation. Ectopic ACTH from small cell lung carcinoma also darkens the skin.

Hemochromatosis. Iron overload (HFE C282Y) causes "bronze diabetes": skin darkens mainly from increased melanin, with hemosiderin in the dermis, alongside cirrhosis, diabetes, arthropathy, cardiomyopathy and hypogonadism.

Other clues. Amiodarone and minocycline cause blue-gray pigmentation, and blue-black ear cartilage and sclerae (ochronosis) mark alkaptonuria.