acanthosis nigricans

**Clinical presentation:** Symmetric, brown-to-black, velvety, hyperkeratotic plaques with accentuated skin markings, typically on the posterior and lateral neck, axillae, groin, antecubital and popliteal fossae, and under the breasts. Usually asymptomatic, though it can be mildly pruritic. Skin tags (acrochordons) often coexist.

**Pathophysiology:** In insulin-resistant states, hyperinsulinemia leads to spillover binding of insulin to IGF-1 receptors on keratinocytes and dermal fibroblasts. This stimulates their proliferation, causing papillomatosis, hyperkeratosis, and increased pigmentation. Histology shows hyperkeratosis, papillomatosis, and acanthosis (epidermal thickening). The hyperpigmentation is not due to increased melanocyte number, and the dark color is mostly from hyperkeratosis. In the malignancy-associated form, tumor-secreted growth factors (e.g., TGF-α, which acts on the EGFR) are thought to stimulate keratinocytes.

**Etiologies/associations:** - **Insulin resistance/hyperinsulinemia (most common):** obesity, metabolic syndrome, type 2 diabetes, prediabetes, PCOS (hyperandrogenism with insulin resistance), Cushing syndrome, acromegaly, and hypothyroidism. Other causes include lipodystrophy and rare severe insulin receptor defects (e.g., type A insulin resistance, Leprechaunism). - **Malignancy (paraneoplastic):** Most often gastric adenocarcinoma, but also other GI, lung, breast, and ovarian cancers. Clues are sudden onset, extensive involvement, mucosal and palmar involvement ("tripe palms"), and weight loss in a non-obese patient. It can parallel the Leser-Trélat sign (sudden eruption of multiple seborrheic keratoses) and runs in parallel with the tumor's course. - **Medications:** niacin, systemic glucocorticoids, oral contraceptives, insulin, growth hormone, protease inhibitors. - **Genetic/familial:** Autosomal dominant benign forms; FGFR3 mutations (e.g., achondroplasia variants, Crouzon syndrome with acanthosis nigricans, thanatophoric dysplasia).

**Diagnosis:** Clinical. Evaluate for insulin resistance with fasting glucose, HbA1c, and lipids, and assess BMI. Consider PCOS evaluation in women with menstrual irregularity or hirsutism. If the presentation is abrupt, extensive, or atypical in a non-obese older patient, pursue malignancy workup (e.g., upper endoscopy).

**Management:** Treat the underlying cause: weight loss, metformin, and lifestyle changes improve insulin resistance and may reverse the lesions. Discontinue offending drugs. Cosmetic options include topical retinoids, keratolytics (e.g., salicylic acid, urea), and topical vitamin D analogs. Malignancy-associated disease may improve with tumor treatment and recur with relapse.

**Boards pearls:** - Acanthosis nigricans in a child or teen is a marker for future type 2 diabetes risk. - A velvety, hyperpigmented neck plaque in an obese patient points to insulin resistance. - Sudden, extensive onset in an older adult suggests gastric adenocarcinoma. - Key terms: acanthosis (thickened stratum spinosum), papillomatosis, hyperkeratosis.