Acanthosis Nigricans (AN)

Presentation

• Lesion characteristics: Velvety papillomatous overgrowth with darkening and thickening (hyperkeratosis)

• Typical sites: Axillae, neck (posterior and lateral), groin, inframammary regions

• Common symptoms: Usually asymptomatic, may have mild pruritus

• Significance: Often a cutaneous marker of insulin resistance (e.g. obesity, type 2 diabetes mellitus)

Classification & Aetiology

1. Obesity-associated AN

• Most common type in primary care

• Linked to insulin resistance and metabolic syndrome

• Often seen in adults with elevated BMI; can occur in any age group

• GP consideration: Screen for T2DM (e.g. HbA1c, fasting glucose), assess cardiovascular risk (lipid profile, blood pressure)

2. Syndromic AN

• Associated with conditions causing hyperinsulinaemia (e.g. PCOS, Cushing’s syndrome, total lipodystrophy), or certain genetic syndromes (e.g. Crouzon syndrome)

• More severe and widespread than obesity-associated AN

• GP consideration: Evaluate for underlying endocrine or genetic disorders; check for features like hirsutism, menstrual irregularities, abnormal growth parameters

3. Benign/Acral Acanthotic Anomaly

• Thick, velvety lesions primarily on hands and feet

• Seen more often in darker-skinned individuals

• No systemic disease association

• GP consideration: Reassure if no other abnormalities; no specific systemic workup required in the absence of risk factors

• Drug-induced AN

• Uncommon; linked to drugs increasing insulin levels or causing dysregulation (e.g. nicotinic acid, high-dose corticosteroids, insulin, oral contraceptives, HRT)

• May improve or resolve once the offending medication is ceased

• GP consideration: Review medications, consider changing therapy if feasible and clinically appropriate

5. Hereditary Benign AN

• Autosomal dominant inheritance

• Can manifest from infancy onwards

• GP consideration: Family history is key; lesions may be stable or slowly progressive over time

6. Malignant AN

• Red flag: Rapid onset, more extensive and symptomatic (pruritus, pain), or involvement of atypical sites (e.g. mucous membranes)

• Strong association with underlying malignancies, particularly gastric adenocarcinoma and other GI malignancies

• Oral involvement occurs in ~25-50% of cases (tongue, lips)

• Urgent investigation for internal malignancy (e.g. gastroscopy, imaging, and referral to oncology/gastroenterology)

7. Mixed-type AN

• Coexistence of different forms (e.g. long-standing obesity-associated AN with a later onset of malignant AN)

• GP consideration: Remain vigilant for any change in lesion characteristics or new systemic symptoms that may suggest malignancy

Differential Diagnosis

Malignancy-associated AN vs. Benign AN

• Malignancy-associated AN often presents more acutely, with rapid progression and extensive or atypicaldistribution. Systemic ‘red flags’ might include:

  • Rapid onset (over weeks to months)

  • Significant pruritus or pain

  • Weight loss

  • Advanced age

  • Other paraneoplastic signs (e.g. Leser-Trélat sign – sudden eruption of multiple seborrhoeic keratoses; tripe palms)

Duncan Dirty / Terra Firma-Forme Dermatosis

• Occurs in peripubertal children

• Brownish plaques resembling AN but can be rubbed off with isopropyl alcohol or vigorous scrubbing

• GP consideration: Simple in-office “wipe test” helps distinguish it from AN

Diagnosis & Patient Evaluation

History

• Onset and progression: Rapid (suspicious for malignancy) vs. gradual (often benign)

• Associated symptoms: Polydipsia/polyuria (possible diabetes), menstrual irregularities (PCOS), Cushingoid features

• Medications: Check for offending drugs (e.g. nicotinic acid, OCP, steroids)

• Family history: May suggest hereditary pattern

Physical Examination

• Anthropometry: Height, weight, BMI

• Skin examination: Distribution of lesions, presence of mucosal or acral involvement

• Endocrine signs: Hirsutism, striae, buffalo hump (Cushing’s)

• Cardiometabolic assessment: Blood pressure, waist circumference (metabolic syndrome)

Investigations

1. Diabetes screening

   • HbA1c and/or fasting plasma glucose; consider oral glucose tolerance test (OGTT) if needed

2. Assessing insulin resistance

   • May include fasting insulin, HOMA-IR (not routinely done in all GP settings, but can be considered in complex cases)

3. Further investigations based on clinical suspicion:

   • Cortisol levels or overnight dexamethasone suppression test (if Cushing’s suspected)

   • Androgen profile (if PCOS suspected)

   • Malignancy workup (if red flag features present; e.g. gastroscopy, imaging, referral to oncology/gastroenterology)

Management Approach

1. Obesity-associated AN

   • Lifestyle modifications (dietary changes, exercise, weight reduction) can lead to significant improvement or resolution of AN.

   • Consider metformin in patients with insulin resistance or prediabetes, especially if standard lifestyle interventions are inadequate.

2. Syndromic / Endocrine-related AN

   • Address the underlying endocrine disorder (e.g. PCOS, Cushing’s).

   • Medications such as metformin can help if hyperinsulinaemia is a factor.

3. Malignant AN

   • Urgent referral for investigation of occult malignancy (especially GI malignancies) if there are suspicious or red flag features.

   • Management of the tumour may result in improvement of AN, but AN can persist.

4. Drug-induced AN

   • Review and modify medications if feasible (e.g. consider alternative agents or dose adjustments).

5. Symptomatic treatments (for cosmetic concerns or pruritus)

   • Topical keratolytics (e.g. salicylic acid, urea creams)

   • Topical retinoids (e.g. tretinoin)

   • Laser therapy in refractory cases

6. Referral considerations

   • Dermatology: Diagnostic uncertainty, severe or resistant lesions, cosmetic therapy

   • Endocrinology: Complex endocrine pathology (e.g. severe insulin resistance, suspected lipodystrophy, or Cushing’s)

   • Oncology / Gastroenterology: If malignancy is suspected

Notes

• Always consider underlying causes: AN in primary care most commonly signals obesity and insulin resistance. However, always be alert for malignant AN if rapid onset, atypical features, or in older patients.

• Investigate and manage comorbidities: Diabetes, metabolic syndrome, and other endocrinopathies frequently coexist.

• Medication review: Drug-induced AN is uncommon but potentially reversible.

• Long-term follow-up: If initial workup is unrevealing but clinical suspicion remains, ongoing surveillance for malignancy or evolving endocrine disorders may be warranted.