Acanthosis nigricans

Meet the patient

A 58-year-old, lean, non-diabetic man is referred because over eight weeks his axillae, neck, palms and the inside of his lips have turned velvet-black — and he has lost six kilograms. Two beds away, a 14-year-old girl with obesity has had a "dirty neck" that "will not wash off" for two years.^[1][9]

Same lesion. Opposite stakes. The girl has the common, benign, insulin-resistance form that lightens with weight loss; the man has paraneoplastic acanthosis nigricans until a gastroscope proves otherwise. Hold those two beds in your head and every section below falls into place.^[1][9]

One lesion, two prognoses — name the fork first

Your single diagnostic task is to split benign from malignant AN before you reassure anyone. The morphology is identical because several growth-factor systems converge on the same keratinocyte; what diverges is the tempo, the territory, and what eventually kills the patient.^[1][7]

^{[1] [9] [1] [2]}

The classic trap: reassuring the thin adult with rapidly progressive AN that it is "just obesity". Obesity-associated AN does not erupt over eight weeks in a lean man who is losing weight — that tempo is cancer until the gastroscope says otherwise, and the cost of the error is measured in months of life.^[9]

The triad and where it lives

Three morphological descriptors define the lesion, and examiners want all three named in one breath: velvety (finely papillated, soft to the touch), hyperpigmented (brown to grey-brown or near-black), and thickened (palpably raised, often studded with skin tags).^[1][2]

The pigmentation fools the eye. It looks like excess melanin, but histology shows only mild basal hyperpigmentation — the dark colour is an optical trick of thickened, undulating epidermis. Remember this when a patient is upset about a "dirty neck" that no amount of scrubbing will shift: it was never dirt.^[7]

The territory, in descending order of frequency: axillae first, then the posterior and lateral neck, then the groin, with the umbilicus, antecubital and popliteal fossae, inframammary folds and anogenital skin as supporting cast. The neck — the so-called "dirty neck" — is the site that stigmatises and bullies adolescents, so examine it last and kindly.^[1][4]

Why the lesion forms — insulin spilling onto the IGF-1 receptor

The unifying mechanism is growth-factor-driven proliferation of keratinocytes and dermal fibroblasts. In the common insulin-resistance form the driver is insulin itself, behaving badly at high concentration.^[7][6]

Insulin and insulin-like growth factor 1 share structural homology. When the pancreas pumps out ever-more insulin to overcome receptor-level resistance, the surplus spills over and binds IGF-1 receptors on keratinocytes and fibroblasts, driving the papillomatosis, acanthosis and hyperkeratosis you see and feel.^[7]

This is also why AN is the cutaneous companion of obesity, T2DM, PCOS and Cushing's — and is not a feature of type 1 diabetes, where absolute insulin deficiency means there is no surplus insulin to spill. The lesion tracks hyperinsulinaemia, not hyperglycaemia.^[6]

The five-step cascade examiners want reproducedShowHide

1. Peripheral insulin resistance at the receptor level.
2. Compensatory hyperinsulinaemia — the pancreas secretes more to hold the glucose.
3. Excess insulin spills onto IGF-1 receptors on keratinocytes and fibroblasts.
4. Proliferation — papillomatosis, acanthosis, hyperkeratosis.
5. The clinically apparent velvety, hyperpigmented, thickened plaque.

^[1][7]

Histology is rarely needed but is characteristic when obtained: papillomatosis, hyperkeratosis and acanthosis, with only mild basal-layer hyperpigmentation. The biopsy confirms AN — it does not distinguish benign from malignant, so never send a sample to settle that question.^[7]

The Curth eight — name the categories

The Curth classification sorts AN into eight aetiological buckets, and the list is examiner currency. The split that matters at the bedside is benign versus malignant; the other seven are how you defend "benign" once you have said it.^[3][1]

1. Obesity-associated ("benign acquired") — by far the commonest; resolves with weight loss.
2. Syndromic insulin-resistance — Type A (genetic INSR defect), Type B (anti-insulin-receptor antibodies), Rabson-Mendenhall, Berardinelli-Seip lipodystrophy.
3. Benign familial (hereditary) — autosomal dominant, childhood onset, no metabolic abnormality.
4. Malignant (paraneoplastic) — abrupt, generalised, mucosal; gastric adenocarcinoma in roughly half.
5. Acral — dorsa of hands and feet in otherwise well patients; no systemic cause.
6. Unilateral (naevoid) — a localised epidermal naevus along Blaschko's lines; not metabolic.
7. Drug-induced — nicotinic acid, systemic steroids, OCPs, growth hormone, protease inhibitors.
8. Mixed — classify by the dominant clinical driver.^[3][2]

Who gets it — the metabolic substrate

AN prevalence tracks obesity and insulin resistance like a shadow. In community surveys of overweight and obese adolescents and adults it appears in anywhere from a quarter to two-thirds, and it correlates with body mass index, waist circumference, fasting insulin and a family history of T2DM.^[1][7]

In lean adults the prevalence drops to roughly 5 to 7 percent — and a lean patient with new AN should send you hunting for an endocrine, drug or malignant driver rather than reaching for "obesity" as the answer.^[2]

The risk factors to run on autopilot: obesity and central adiposity (dose-dependent with BMI), family history of T2DM, ethnicity (higher in Hispanic, African, South Asian and Native American populations, paralleling insulin resistance), endocrinopathy (T2DM, PCOS, Cushing's, acromegaly, hypothyroidism), drug exposure, malignancy over 40, and darker skin phototype (more visible, and more common through the same metabolic substrate).^[1][6][4]

Drug-induced AN — nicotinic acid is the prototype

When AN is drug-induced, nicotinic acid (niacin) is the named culprit examiners expect. The mechanism is a direct stimulant effect on epidermal growth-factor signalling rather than insulin, and the lesions resolve on withdrawal.^[11]

The rest of the drug list: systemic corticosteroids and growth hormone (working through induced insulin resistance or the GH/IGF-1 axis), oral contraceptives and oestrogens, HIV protease inhibitors (which produce a lipodystrophy/insulin-resistance syndrome), and occasionally fusidic acid and cobalt.^[11][1]

The syndromic extremes — Type A versus Type B

Two rare syndromes of severe insulin resistance produce florid AN, and the discriminator examiners love is gene mutation versus antibody.^[8]

^[8]

Down the severity slope of recessive INSR mutations sit Rabson-Mendenhall (AN, pineal hyperplasia, dental and nail dysplasia, precocious puberty) and Donohue syndrome (leprechaunism) — the most extreme, fatal in infancy. Berardinelli-Seip congenital lipodystrophy reaches the same endpoint by a different road: near-total absence of adipose tissue and severe insulin resistance.^[8]

Is it the pancreas or the stomach? — recognising paraneoplastic AN

This is the section that prevents a preventable death. In paraneoplastic AN the proliferation is driven not by insulin but by tumour-derived transforming growth factor-alpha and fibroblast growth factors, acting on epidermal growth factor receptors to produce explosive, generalised proliferation.^[1][9]

That mechanism explains every feature that distinguishes malignant from benign AN: the abrupt tempo (weeks, not years), the extensive territory (beyond the flexures), and the mucosal and palmar involvement. None of these belongs to obesity-associated disease.^[9]

The features that should trigger a paraneoplastic work-up, committed to memory:^[1][9]

• Rapid onset and progression over weeks to months.
• Extensive distribution beyond the flexures, onto non-intertriginous skin.
• Mucosal involvement — oral mucosa, lips, tongue, pharynx.
• Tripe palms and/or sign of Leser-Trélat accompanying the AN.
• Onset in a non-obese adult, especially over 40, with weight loss and GI symptoms.
• AN that precedes, accompanies or flares with a known malignancy — a surrogate tumour marker.^[9]

Tripe palms — a velvety, rugose, moss-like thickening of the palms with exaggerated dermatoglyphics — are malignant in roughly 90 percent of cases when AN coexists. The sign of Leser-Trélat is a sudden eruption of multiple seborrhoeic keratoses alongside AN; both are cutaneous alarms for GI malignancy.^[9][10]

^{[9] [10]}

The mimics — discriminators, not lists

The differential of velvety pigmented flexural change is finite and examinable. Ask first whether the lesion is truly thickened and velvety (AN, CARP, pemphigus vegetans — implying proliferation) or flat pigment only (post-inflammatory hyperpigmentation, Addison's, pityriasis versicolor — implying deposition).^[1][2]

^[1]

The single most commonly confused entity is CARP — reticulated rather than flexural, in younger leaner patients, and it responds dramatically to oral minocycline. A therapeutic trial of minocycline is a legitimate diagnostic move when AN and CARP cannot be separated clinically.^[1]

The bedside round — three questions in sequence

There is no named sign specific to AN, so the focused assessment answers three questions in order: is this AN? what is the metabolic background? is this malignant?^[1][4]

General inspection. Note distribution and morphology, calculate BMI and measure waist circumference, and look for skin tags, seborrhoeic keratoses and the stigmata of Cushing's or acromegaly.^[1]

Site examination. Inspect every flexural site — axillae, neck, groins, umbilicus, antecubital and popliteal fossae, inframammary folds, anogenital skin. Then examine the oral mucosa, lips and tongue (mucosal involvement favours malignancy) and the palms (velvety thickening equals tripe palms), and look specifically for a sudden eruption of seborrhoeic keratoses.^[1]

Systemic examination. Palpate for lymphadenopathy, hepatomegaly and abdominal masses (gastric cancer), and look for endocrine signs — moon facies and buffalo hump of Cushing's, prognathism and large hands of acromegaly, clitoromegaly of Type A insulin resistance. Measure the blood pressure for the metabolic syndrome.^[1]

Consultant confession: I document BMI and waist circumference on every AN patient. A waist above 94 cm in men or 80 cm in women (lower in South and East Asians) alongside AN marks high metabolic risk before any laboratory result is back.^[6]

Investigations — directed by the fork

Investigations follow the clinical fork, not a blanket panel. An obese child with long-standing AN needs a metabolic work-up; a lean adult with explosive AN needs paraneoplastic screening. Skin biopsy is reserved for diagnostic doubt — the diagnosis is clinical.^[1]

First-line metabolic work-up

For every newly diagnosed AN patient, run a focused metabolic screen:^[2][6]

• Fasting plasma glucose and HbA1c — to identify dysglycaemia early; abnormal results are then staged against standard glycaemic criteria, because there are no AN-specific cutoffs.
• Fasting insulin and HOMA-IR — the homeostasis model assessment of insulin resistance is a validated tool for quantifying the insulin resistance that drives the skin.^[1]
• Lipid panel and blood pressure — to complete the metabolic assessment, because AN usually sits within a wider picture of obesity and insulin resistance.^[2]

Interpreting the screen. A raised fasting insulin or an elevated HOMA-IR confirms significant insulin resistance and explains the skin. Record central obesity, blood pressure and lipids at the same visit, since AN marks a metabolic state rather than an isolated skin finding.^[1][6]

Endocrine screen (selected)

When an endocrinopathy is suspected clinically:^[4]

• TSH and free T4 — hypothyroidism.
• 9 am cortisol and 24-hour urinary free cortisol or dexamethasone suppression — Cushing's syndrome.
• IGF-1 and growth hormone — acromegaly.
• Testosterone, LH, FSH, oestradiol and pelvic ultrasound — PCOS.
• Anti-insulin-receptor antibodies and INSR sequencing — Type B and Type A insulin resistance.^[8]

Paraneoplastic work-up (critical)

For rapidly progressive, extensive, mucosal or tripe-palm-associated AN, investigate urgently:^[1][9]

• Upper gastrointestinal endoscopy — the single highest-yield test, because gastric adenocarcinoma accounts for roughly half of paraneoplastic AN.
• CT chest, abdomen and pelvis with contrast — to stage and find non-gastric primaries (lung, liver, ovary, colon, pancreas).
• Tumour markers — CEA, CA 19-9 and alpha-fetoprotein; limited sensitivity but useful for monitoring.
• Mammography and pelvic ultrasound — for breast and ovarian primaries.
• Repeat endoscopy if the first is negative but suspicion remains — small early gastric cancers are missed.^[9]

Management — treat the cause, not the skin

There is no cure for the lesion of AN itself; management is entirely directed at the underlying cause. Topicals and procedures are reserved for residual cosmetic concern after the cause is addressed.^[1][7]

For residual cosmetic concern once the cause is addressed, the symptomatic ladder is retinoids, keratolytics and procedure:^[1][7]

^[1]

Management — insulin-resistance / obesity-associated AN

Weight loss is the single most effective intervention. A loss of 5 to 10 percent of body weight lowers circulating insulin, relieves the IGF-1-receptor spillover, and visibly lightens and thins the plaques. Caloric restriction plus at least 150 minutes a week of aerobic and resistance exercise is the foundation.^[1]

Metformin, an oral insulin sensitiser, has been reported to clear acanthosis nigricans, but control of obesity does more for the skin than any single drug — reversing the process largely by reducing insulin resistance and compensatory hyperinsulinaemia.^[7]

GLP-1 receptor agonists (semaglutide, liraglutide, tirzepatide) produce substantial weight loss and improve insulin sensitivity, and emerging case series report improvement in AN severity — a logical escalation for obese patients with AN and T2DM.^[5]

One trap worth naming: exogenous insulin can worsen AN by recreating the hyperinsulinaemic drive. Where AN is prominent, prefer insulin-sensitisers and weight loss over escalating insulin doses.^[6]

^{[1] [7]}

Management — malignant (paraneoplastic) AN

The only effective treatment for the skin disease is treatment of the underlying tumour. AN that regresses after successful resection and flares with recurrence is a useful surrogate tumour marker — document it during oncological follow-up.^[1][9]

• Urgent upper GI endoscopy and CT staging within two weeks of suspicion; biopsy any lesion.
• Surgical resection with curative intent where operable — gastrectomy for gastric adenocarcinoma; resection of lung, ovarian, renal or colonic primaries.
• Chemoradiotherapy for advanced disease; AN may regress with tumour control and flare with recurrence.
• Symptomatic topicals (retinoids, keratolytics) for comfort and appearance.
• Honest prognosis — most paraneoplastic AN presents with advanced disease; median survival is often measured in months.^[9]

Management — drug-induced AN

Stop, switch or reduce the causative drug; lesions resolve over weeks to months. For nicotinic acid, switch lipid-lowering strategy (statin with or without ezetimibe, or a PCSK9 inhibitor). For systemic steroids, taper where possible; for OCPs, consider progestogen-only or non-hormonal alternatives; for growth hormone, review the indication; for protease inhibitors, switch within the antiretroviral class.^[11][1]

Special populations

Children and adolescents. AN is common in obese children and a recognised early marker of insulin resistance — the right response is a metabolic work-up and a structured weight programme, not reassurance that it is "just cosmetic". Frame it for the family as a visible warning light, not a disease, set a concrete goal of a 5 to 10 percent BMI-percentile reduction, and never let it be called a hygiene problem.^[2]

Pregnancy. New AN reflects the physiological insulin resistance of late gestation; screen for gestational diabetes with an oral glucose tolerance test at 24 to 28 weeks rather than reassuring alone.^[4]

Darker skin phototypes (Fitzpatrick IV to VI). AN is more visually striking and more easily mistaken for Addisonian pigmentation or post-inflammatory change — the velvety thickening on palpation and the flexural distribution are the discriminators. Start topicals at low concentration; post-inflammatory hyperpigmentation from irritants is more prominent here.^[2]

Regional deltas and the evidence base

The evidence base for AN management is largely observational — there are no large randomised trials for topical or systemic therapy. The strongest evidence supports weight loss and metformin, with emerging evidence for GLP-1 receptor agonists.^[5][7]

Exam pearls

The mantra

Tempo and territory, not texture, decide who gets scoped. The velvety plaque is the same in the obese adolescent and the man with gastric cancer — what separates reassurance from endoscopy is how fast it came and how far it has spread, not how it looks or feels.^[1][9]

Etymology for viva gold: acanthosis is from the Greek akantha, "thorn" — the epidermal projections on histology. Nigricans is from the Latin niger, "black" — the visible pigmentation that is, delightfully, mostly an optical illusion of thickened skin rather than true melanin excess. Both words outlived their metaphors because the pathology is unchanged.^[7]

Ward-round test — three stems, thirty seconds each

Stem 1 — the thin man with the velvet neck (answer)ShowHide

The 58-year-old from the top of the topic: new, rapidly progressive velvety pigmentation of the axillae, neck, palms and oral mucosa over eight weeks, with a six-kilogram weight loss. What is the next best step? Model: This is textbook paraneoplastic AN — a thin adult, abrupt onset, mucosal and palmar (tripe palms) involvement, and weight loss. The next best step is urgent upper gastrointestinal endoscopy with biopsy plus CT chest, abdomen and pelvis to identify and stage gastric adenocarcinoma. Topical retinoids and metformin are inappropriate here and would delay a diagnosis that is already late.^[1][9]

Stem 2 — the girl with the dirty neck (answer)ShowHide

The 14-year-old with obesity whose "dirty neck" will not wash off has been present for two years and is stable. What is the lesion, and what do you do? Model: This is benign, obesity-associated acanthosis nigricans — gradual, flexural, mucosa spared. Reassure that it is not a hygiene problem and not contagious, run a metabolic screen (BMI, fasting glucose and insulin, HOMA-IR, lipids), and start a structured weight-management programme with a concrete 5 to 10 percent weight-loss goal. The lesion will lighten as insulin falls. Topical retinoids and keratolytics have a role once metabolic management is under way.^[1][2]

Stem 3 — the mimic that responds to minocycline (answer)ShowHide

A 22-year-old lean man has reticulated, net-like brown papules over the upper trunk and interscapular area, sparing the flexures. It is not AN. What is it, and what is the therapeutic discriminator? Model: This is confluent and reticulated papillomatosis (CARP, Gougerot-Carteaud) — reticulated rather than flexural, in a young lean patient. The therapeutic discriminator is a dramatic response to oral minocycline, which AN does not share. Confirm clinically; biopsy only if in doubt.^[1]

References11ShowHide

1. [1]Das A, Datta D, Kassir M, et al. Acanthosis nigricans: A review J Cosmet Dermatol, 2020.PMID 32516476
2. [2]Leung AKC, Lam JM, Barankin B, et al. Acanthosis Nigricans: An Updated Review Curr Pediatr Rev, 2022.PMID 36698243
3. [3]Curth HO. Acanthosis nigricans Birth Defects Orig Artic Ser, 1971.PMID 5173298
4. [4]Lause M, Kamboj A, Fernandez Faith E. Dermatologic manifestations of endocrine disorders Transl Pediatr, 2017.PMID 29184811
5. [5]Lal K, Herringshaw E. The Use of GLP-1 Agonists in the Management of Cutaneous Disease J Clin Aesthet Dermatol, 2024.PMID 39263264
6. [6]Abate MCMO, Aroucha PMT, Nóbrega DVMD, et al. Cutaneous manifestations of diabetes mellitus: a narrative review Einstein (Sao Paulo), 2025.PMID 40105573
7. [7]Hermanns-Lê T, Scheen A, Piérard GE. Acanthosis nigricans associated with insulin resistance : pathophysiology and management Am J Clin Dermatol, 2004.PMID 15186199
8. [8]Moller DE, Flier JS. Detection of an alteration in the insulin-receptor gene in a patient with insulin resistance, acanthosis nigricans, and the polycystic ovary syndrome (type A insulin resistance) N Engl J Med, 1988.PMID 2460770
9. [9]Lam CPM, Chan MWM. Metastatic adenocarcinoma of the stomach presenting as malignant acanthosis nigricans and tripe palms: a case report Hong Kong Med J, 2023.PMID 37489275
10. [10]André R, Laffitte E, Abosaleh M. Sign of Leser-Trélat and Cutaneous T-Cell Lymphoma: A Rare Association Dermatopathology (Basel), 2018.PMID 29998101
11. [11]Stals H, Vercammen C, Peeters C. Acanthosis nigricans caused by nicotinic acid: case report and review of the literature Dermatology, 1994.PMID 8075456