Acanthosis Nigricans

Introduction

• Asymptomatic and symmetrical darkening affecting the

skin of intertriginous areas, particularly the axillae, groins,
submammary folds and neck
• Skin - thickened, velvety texture, may be studded with
skin tags
• Particularly associated with obesity and insulin resistance
 Epidemiology

• Can occur at any age

• Equal sex ratio
• More common in people with darker skin
• Benign AN - very common (7% children, 20% adults)
• Malignant AN - rare, usually arises in older age groups

Judge MR, McLean WH, Munro CS. Disorders of keratinization. In: Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook's Textbook of Dermatology. 8 th ed.
UK: Blackwell Publishing; 2010. p. 19.119-21.
 Pathophysiology
• Insulin-derived growth factor (IGF-1) receptors overexpressed in obese
patients with hyperinsulinaemia and insulin resistance
• IGF-1 can stimulate the proliferation of keratinocytes and dermal fibroblasts
• Epidermal growth factor receptors (EGFR) and fibroblast growth factor
receptors (FGFR) also implicated
• FGFR activation can be produced by certain medications such as palifermin,
and insulin can provoke the development of AN at injection sites by activation
of IGF receptors
• In malignant AN, tumour-derived stimulating factors are produced,especially
TGF-α, which is recognized by epidermal growth factor receptors
• Perspiration and/or friction are mechanical contributing factors

Phiske MM. An approach to acanthosis nigricans. Indian Dermatol Online J 2014;5:239-49

 Histology

• No or minimal acanthosis or hyperpigmentation

microscopically
• Hyperkeratosis and papillomatosis with finger‐like upward
projections of dermal papillae
• Pigmentation is due to the hyperkeratosis; no increase in
melanocyte numbers or in melanin production
• Pseudo-horn cysts may be present
• In mucosal lesions, parakeratosis may be observed
 Clinical Features
• Usually starts as asymptomatic darkening (symmetrical velvety dark patches)
of the skin of the neck, axillae and groins
• Other involved areas - face, inner thighs, antecubital and popliteal fossae,
umbilicus, and perianal area
• Most common site in children - back of the neck
• With time, the patches become thicker, may develop skin tags in the affected
areas
• Pruritus uncommon
• In malignancy associated Acanthosis Nigricans, Tylosis (palmoplantar
hyperkeratosis) and acanthosis palmaris or pachydermatoglyphy
(exaggeration of fingerprints) may also occur
• May become widespread with delicate velvety furrowing of mucosal surfaces
and involvement of the eyelids and conjunctivae
• Associated nail changes - leukonychia and subungual hyperkeratosis
 Associated diseases
• Obesity most common, can
regress with weight loss
• Many syndromes, usually
involve the endocrine system
or accompany autoimmune
disorders
• Malignant AN - extensive range of internal
cancers, over 90% seen in patients with
gastrointestinal cancer of which two-thirds
are gastric
• Rapid onset of hyperpigmented velvety
changes of the flexural surfaces (e.g. neck,
axillae and groin)
• May also involve extensor surfaces
(elbows, knees and knuckles) and, in
malignancy-associated cases, the lips, oral
mucosa and palms (tripe palms)
• Glossitis frequently present
• Other cutaneous paraneoplastic
phenomena, particularly florid cutaneous
papillomatosis
 Insulin Resistance
• Hyperinsulinemia inappropriate for the concurrent plasma
glucose level
• In the skin, stimulation of IGF-1 receptors on keratinocytes leads
to excessive epidermal growth. AN therefore today is considered
as an Epiphenomenon of Insulin resistance state
• AN is so closely associated with IR that it has been called a
clinical surrogate for laboratory determined hyperinsulinemia
• AN appears to be a surrogate for hyperinsulinemia and Type 2
diabetes

Texas Department of Health, January 14, 2002, Vol.62, No.2

 Calculating Insulin Resistance
• Hyperinsulinemic euglycemic glucose clamp technique
- gold standard and reference method for quantifying insulin sensitivity

• Homeostasis model assessment-insulin resistance (HOMA - IR)

- mathematical model of the normal physiological dynamics of insulin and
glucose
- HOMA-IR = Fasting glucose (mmol) × Fasting insulin (uU/mL)/ 22.5.
- (divided by 405 if glucose is in mg/dl)
IR is diagnosed when the result is >2.71

• Fasting insulin level

- practical approach for the measuring of IR
- high proportion of false-positive results and lack of standardization
• Glucose/insulin
- highly sensitive and specific measurement of insulin sensitivity
- in adults, a ratio of <4.5 is abnormal, whereas in prepubertal children <7 is
abnormal

• Quantitative insulin sensitivity check index

• Glucose insulin product

• Log (homeostasis model assessment-insulin-insulation resistance)

 Metabolic Syndrome

• Obesity
• Low HDL Cholesterol
• Hypertension
• Impaired Fasting Glucose
• Elevated Triglycerides
• Reflects underlying insulin resistance
 Clinical Variants
• HAIR-AN - familial syndrome - hyperandrogenaemia, insulin
resistance and acanthosis nigricans
- Typically affects young black girls, who develop polycystic
ovaries, hirsutism, clitoral hypertrophy and frequently have
high plasma testosterone levels
- Also known as type A insulin resistance syndrome
• Type B insulin resistance syndrome is characterized by the
association of AN with diabetes and hyperandrogenism, or with an
autoimmune disease (including systemic lupus erythematosus,
systemic sclerosis, Hashimoto thyroiditis and Sjögren syndrome).
• Familial AN
- rare, autosomal dominant trait with variable penetrance
- manifests early in life and tends to stabilize in the teenage years
- can improve with age in some patients
• Drug induced AN
- particularly hormones
- insulin - systemic corticosteroids
- testosterone - exogenous oestrogens including oral
- nicotinic acid contraceptives
- somatotropin - fusidic acid
- tends to resolve after discontinuation of the offending agent
• Generalized AN
- very rare, seen only in children
- generalized hyperpigmenation and velvety thickening of the skin
- extensive investigation fails to show any associated systemic
abnormality
• Acral AN
- more common in skin phototypes 5 and 6
- not associated with systemic disease, manifests as velvety
thickening and hyperpigmentation of the skin on the dorsa of the
hands and feet, especially the knuckles
• Unilateral AN (naevoid AN)
- very rare, assumed to arise from a somatic mutation during
embryogenesis
- can appear in infancy, but not always, and cases have been
reported with onset in childhood or adulthood
- appears as a pigmented plaque, solitary or along a line of
Blaschko, and resembles an epidermal naevus
- has been described on the face and scalp, chest and abdomen,
back and thighs
 Differential Diagnosis

• Addison disease
• Pellagra
• Haemochromatosis
• Intertriginous Granular Parakeratosis
• Confluent and reticulated papillomatosis
• Haber Syndrome
• Dowling-Degos disease
• Agropigmentation reticularis of Kitamura
 Disease course and prognosis

• Benign AN - not associated with systemic disease but

generally persists, may be a significant cosmetic problem
• AN associated with metabolic abnormalities and insulin
resistance may improve with treatment of the underlying
condition
• AN associated with obesity may improve with dietary
restriction and weight loss
• The prognosis of patients with malignant AN is poor, with
an average survival of only 2 years from diagnosis
 Treatment

• Management of underlying
condition
• Lifestyle modifications
• Weight loss
 Topical Treatment
• Retinoids
- first-line treatment
- epidermopoietic, causes a reduction of the stratum corneum replacement time
- corrects hyperkeratosis and may cause near complete reversion
- intermittent tretinoin application may be needed to maintain improved status

• Ammonium lactate and tretinoin

- lactic acid is an alpha-hydroxy acid that works as a peeling agent and also via
release of desmogleins, indicating disintegration of desmosomes
- synergistic interaction is thought to play a role.

Jeong JS, Lee JY, Yoon TY. Unilateral nevoid acanthosis nigricans with a submammary location. Ann Dermatol 2011;23:95-7.
• Peels
- Trichloroacetic acid (TCA 15%) - superficial chemical exfoliating agent causing
destruction of the epidermis with subsequent repair and rejuvenation
- causes coagulation of skin proteins leading to frosting
- safe, easily available, cheap, and easy to prepare

• Calcipotriol
- inhibits keratinocyte proliferation and promotes differentiation by increasing
intracellular calcium levels and cyclic GMP levels in keratinocytes

Higgins SP, Freemark M, Prose NS. Acanthosis nigricans: a practical approach to evaluation and management. Dermatol Online J 2008;14:2
 Oral Treatment
• Oral retinoids

- Improvement requires large doses and extended courses, and relapses are
possible
- Normalization of epithelial growth and differentiation
- Acitretin showed good success in cases with syndromic and benign AN
- Oral isotretinoin in extensive AN

Hermanns-Lê T, Scheen A, Piérard GE. Acanthosis nigricans associated with insulin resistance: Pathophysiology and management. Am J Clin Dermatol
2004;5:199-203.
 • Metformin and rosiglitazone
- reduction in fasting insulin levels and modest improvement of skin texture
- duration of treatment may be related to improvement
- combined use of metformin and TZDs increases sensitivity to insulin in peripheral muscles,
also gives good results
- combined metformin and glimepiride (at low dose) superior in the management of IR with
reduction in HOMA-IR
- Metformin known to improve cardiopulmonary performance in patients with high HOMA-IR

• Cosmetic - Long-pulsed alexandrite laser

- thermal heating of epidermis and dermis results in tissue remodeling and pigment reduction
- effectively and safely treat acanthosis nigricans of the axillae

Bermúdez-Pirela VJ, Cano C, Medina MT, Souki A, Lemus MA, Leal EM, et al. Metformin plus low-dose glimeperide significantly improves Homeostasis Model
Assessment for insulin resistance (HOMA (IR)) and beta-cell function (HOMA (beta-cell)) without hyperinsulinemia in patients with type 2 diabetes mellitus. Am J
Ther 2007;14:194-202.
 • Metformin and rosiglitazone
- reduction in fasting insulin levels and modest improvement of skin texture
- duration of treatment may be related to improvement
- combined use of metformin and TZDs increases sensitivity to insulin in peripheral muscles,
also gives good results
- combined metformin and glimepiride (at low dose) superior in the management of IR with
reduction in HOMA-IR
- Metformin known to improve cardiopulmonary performance in patients with high HOMA-IR

• Cosmetic - Long-pulsed alexandrite laser

- thermal heating of epidermis and dermis results in tissue remodeling and pigment reduction
- effectively and safely treat acanthosis nigricans of the axillae

Bermúdez-Pirela VJ, Cano C, Medina MT, Souki A, Lemus MA, Leal EM, et al. Metformin plus low-dose glimeperide significantly improves Homeostasis Model
Assessment for insulin resistance (HOMA (IR)) and beta-cell function (HOMA (beta-cell)) without hyperinsulinemia in patients with type 2 diabetes mellitus. Am J
Ther 2007;14:194-202.