An Approach To Acanthosis Nigricans: Review Article
An Approach To Acanthosis Nigricans: Review Article
An Approach To Acanthosis Nigricans: Review Article
194]
Review Article
deliver IGFs to target tissues and regulate levels of metabolically and AN through their proliferative and differentiating
active “free” IGF-1. IGFBP-1 and IGFBP-2 are both decreased properties.[4]
in obese subjects with hyperinsulinemia, increasing plasma
concentrations of free IGF-1, which promotes cell growth and MALIGNANCY ASSOCIATED ACANTHOSIS
differentiation [Flow Chart 1]. NIGRICANS OR ACANTHOSIS NIGRICANS
MALIGNA
Observations that insulin-dependent activation of IGF-1Rs can
facilitate AN development are (1) IGF receptors are found in
Acanthosis nigricans maligna (ANM) might be explained
cultured fibroblasts and keratinocytes. (2) Insulin can cross DEJ
by elevated levels of transforming growth factor (TGF-α),
and at high concentrations can stimulate growth and replication
exerting effects on epidermal tissue through epidermal growth
of fibroblasts. (3) Severity of AN in obesity correlates positively
factor (EGF) receptor. IGF-1, fibroblast growth factor, and
with fasting insulin concentration. Thus, insulin may promote
melanocyte stimulating hormone α that regulates melanocyte
AN through direct activation of the IGF-1 signaling pathway.
pigmentation and stimulates growth of keranocytes, can play a
The predilection of AN for areas such as neck and axillae
role in the pathogenesis of hyperplasia and hyperpigmentation.
suggests that perspiration and/or friction may be necessary
TGF-α produced by cancer cells is structurally similar to EGF-α,
cofactors [Flow Chart 1].
interacts with the same receptor on the cell surface, probably
binding with it in different sites. The receptor for EGF is found on
Unknown autoantibodies other than insulin-receptor antibody
normal epidermal cells, particularly on actively proliferating cells
have been implicated; this could explain the effectiveness of
of the basal layer where it is involved in growth and differentiation
cyclosporine in treating AN with autoimmune manifestations.[3]
of normal keratinocytes. TGF-α and its receptor participate in
tumor progression through auto and paracrine secretion leading
Insulin and IGF-1 levels are affected by hepatitis C infection and
to autostimulation. When these growth factors are produced by
both of them may be implicated in etiogenesis of acrochordons
the primary tumor and circulate in large quantities, they may cause
epidermal cell proliferation, leading to AN. Systemic immunologic
Table 1: AN classification response to the primary tumor as a cause cannot be discarded.[5]
Benign AN
Obesity associated AN Clinical features
Syndromic AN Acanthosis nigricans is characterized by dark, coarse,
Malignant AN thickened skin with a velvety texture [Figure 2a and b].[6] The
Acral AN earliest change is grey-brown/black pigmentation with dryness
Unilateral AN and roughness that is palpably thickened and covered by
Medication associated AN-Systemic steroids, nicotinic acid, small papillomatous elevations, giving it a velvety texture. As
estrogen, insulin, niacin, OC pills, pituitary extract, triazinate, thickening increases, skin lines are further accentuated and the
methyltesteosterone, fusidic acid, protease inhibitors, surface becomes mammilated and rugose, with the development
diethylstilbestrol, melanocyte stimulating hormone preparation
of larger warty excrescences.[7] AN is usually asymptomatic, but
Mixed AN
occasionally, it can be pruritic. The lesions are symmetrically
AN: Acanthosis nigricans
distributed and affect back and sides of neck, axillae, groin, and
ante-cubital and popliteal areas [Figures 3 and 4].[6,7] Neck is the
most common site affected (99%) in children when compared
with axillae (73%). Face, eyelids, flexor and extensor surface
a b
Figure 1: Etiopathogenesis of acanthosis nigricans (Image courtesy Figure 2: (a) Characteristic dark, coarse, thickened skin with a velvety
of Dr. Ashwin Kosambia, Consultant Dermatologist, Mumbai, India) texture of acanthosis nigricans (AN). (b) AN of the axillae with skin tags
of elbows and knees, dorsa of joints of hands, umbilicus, More than half the adults who weigh >200% of their ideal
external genitalia, inner aspects of thighs and anus are also body weight have AN. Lesions are weight dependent, with
involved [Figures 5 and 6].[7] With extensive involvement, regression following weight reduction. Insulin resistance is
lesions can be found over the areolae, conjunctiva, and often present in these patients.
lips. Involvement of mucous membranes is uncommon, but
oral mucous membrane may show delicate velvety furrows. Medication associated acanthosis nigricans
[7]
Generalized involvement can be a rare manifestation of This may appear as an adverse effect of several
certain types of AN, being common in adults with underlying medications [Table 1] that promote hyperinsulinemia. Lesions
malignancy. Tripe palms presents as rugose hyperkeratosis regress following discontinuation of the offending medication.
and prominent dermatoglyphics of palms, likened to bovine Erickson et al. first described AN as a rare local cutaneous
gut lining. It is paraneoplastic in occurrence associated with side-effect of insulin injection. Prescription of the correct insulin
malignancy in 90%, gastric cancer being the most frequent. and use of proper technique will prevent AN development.[8]
Periocular distribution is seen in insulin resistance (IR).[6]
Syndromic acanthosis nigricans
TYPES OF ACANTHOSIS NIGRICANS It may occur as two types: type A and Type B. The Type A
syndrome hyperandrogenism IR (HAIR-AN syndrome) presents
Obesity associated acanthosis nigricans with hyperandrogenemia, IR, and AN. The Type B syndrome
(pseudo-acanthosis nigricans) occurs in women with uncontrolled diabetes mellitus, ovarian
Obesity is the most common cause of AN. Lesions may HA, or autoimmune disease.
appear at any age, but are more common in adulthood.
Figure 5: Acanthosis nigricans on the dorsal aspect of interphalangeal Figure 6: Acanthosis nigricans of the external genitalia and inner
joints aspect of thighs
Insulin
Stimulation of
keratinocytes and
fibroblasts
Acanthosis nigricans
Hyperinsulinemia
Flow chart 1: Highlighting role of IGF on signal pathways and on keratinocytes and melanocytes
Unilateral acanthosis nigricans (nevoid acanthosis Diagnosis is largely clinical with histopathology needed
nigricans) only for confirmation. Histological findings are similar
It is a rare form of AN, inherited as an autosomal dominant trait. in all forms of AN with papillomatosis, hyperkeratosis
Lesions are unilateral along lines of Blaschko and may become and hyperpigmentation of the basal layer. The dermal
evident during infancy, childhood, or adulthood. Lesions occur papillae project upwards as fi nger-like projections. The
over the face, scalp, chest, abdomen, especially periumbilical valleys between papillae show mild acanthosis and
area, back and thigh. Lesions can enlarge gradually before are filled with keratotic material. Clinically observed
stabilizing or regressing.[6,7] Unilateral nevoid AN is not related hyperpigmentation is due to hyperkeratosis and clinical
to endocrinopathy.[10] thickening rather than to melanin.[6,9] In ANM proliferation
of kerantinocytes with hyperkeratosis dominates and with
minimal hyperpigmentation. Spectroscopic and colorimetric
Familial acanthosis nigricans
measurements combined with chemometric analysis
It is a rare autosomal dominant genodermatosis beginning
methods provide sensitive and specific diagnosis of AN.[13]
during early childhood, but may manifest at any age. The
condition often progresses until puberty after which it stabilizes
or regresses. DIFFERENTIAL DIAGNOSIS
Acanthosis nigricans maligna occurs in the course of Patients with AN, especially childhood benign AN, are at risk
adenocarcinomas of abdominal organs (70-90%), particularly for obesity, hypertension, hyperinsulinemia, IR and type 2
gastric cancer (55-61%)[7] followed by adenocarcinoma of diabetes and AN may be used as reliable index of IR.[14] But
pancreas, ovary, kidneys, bladder, bronchi, thyroid, bile duct, obesity is a more important determinant of IR than AN, hence
breast, and esophagus. Onset may be related to medication AN should not be used as exclusive marker for predicting which
usage. It is clinically indistinguishable from benign forms, overweight children have excess insulin levels.
but ANM appears abruptly and exuberantly. Acrochordons
are often found in affected areas [Figure 4]. Lesions may be Urrutia-Rojas et al. suggested that mothers of AN-positive
present over the oral, nasal and laryngeal mucosa, esophagus children are likely to have abnormalities of fuel metabolism
and areola of nipple. Papillomatous lesions on the eyelids and compared with mothers of AN-negative children. Fathers of
conjunctiva may occur. Leukonychia and nail hyperkeratosis AN-positive children are more likely to have blood glucose
has been reported. In one-third of cases skin changes occur levels ≥26 mg/dL. They suggested that screening children
before signs of cancer, in another one-third AN and neoplasm for AN is an effective strategy for identifying adults with
arise simultaneously and in remaining one third, skin findings prediabetes.[15] Investigations for all overweight adults and
manifest after diagnosis of cancer. [8] Warning signs that children include fasting lipoprotein profile, fasting glucose,
call for evaluation for malignancy in AN patients include hemoglobin, fasting insulin, and alanine aminotransferase.
age >40 years, not having any previous endocrine disorder
or any genetically determined disease, unintentional weight ACANTHOSIS NIGRICANS AND INSULIN
loss, rapid onset of extensive AN, symptomatic lesions, atypical RESISTANCE
sites, tripe palms, florid cutaneous papillomatosis, and sign
of Leser–Trélat.[11] Regression of AN occurs with treatment of Insulin resistance is a metabolic disorder in which target cells
the malignancy. Reappearance may suggest recurrence or fail to respond to normal levels of circulating insulin, resulting
metastasis of the primary tumor. in compensatory hyperinsulinemia. IR has been associated
Marfan syndrome
Hirschowitz syndrome
Table 4: Types of insulin resistance
Capozucca syndrome
Type of IR Cause
Hermansky-Pudlack syndrome
Type A Reduced number and dysfunction of insulin receptors
Kabuki syndrome
Type B Formation of antibodies against insulin receptors
Rud syndrome
Type C Post-receptor defect
Prader-Willi syndrome
IR: Insulin resistance
Alstrom syndrome
Rabson-Mendenhall syndrome
Hypogonadal syndrome Methods for detecting insulin resistance
Acral hypertrophy syndrome Hyperinsulinemic euglycemic glucose clamp technique
Ataxia telangiectasia This technique is a gold standard and reference method for
Crouzon’s syndrome quantifying insulin sensitivity because it directly measures
AN: Acanthosis nigricans effects of insulin in promoting glucose utilization under
steady-state conditions in vivo. However, its calculation is
with AN and acrochordons which may represent an easily complicated and impractical.
identifiable sign of IR and noninsulin-dependent diabetes.
AN is so closely associated with IR that it has been called a Homeostasis model assessment-insulin resistance
clinical surrogate for laboratory determined hyperinsulinemia. The mathematical model of the normal physiological dynamics
Katie S in their study observed that posterolateral neck texture of insulin and glucose produced the homeostasis model
had the highest sensitivity (96%) for IR compared with neck/ assessment (HOMA), which provided equations for estimating
axillary texture and pigment and proposed the term insulin IR (HOMA-IR) and β-cell function from simultaneous fasting
neck (visibly increased texture on posterolateral neck appearing measures of insulin and glucose levels. HOMA was first
as visible lines and/or furrows and ridges) for this finding. They developed in 1985 by Matthews et al. It has been proved
concluded that neck texture exhibits both greater sensitivity to be a robust clinical and epidemiological tool for the
and specificity than neck pigment for AN detection, because assessment of IR. It has a good and linear correlation with the
visible roughness of the neck is recognizable without touching hyperinsulinemic-euglycemic clamp method.
or disrobing patient, affording an instant assessment of AN.
Furthermore, texture grading avoids possible confounding by It is calculated as
sun-induced pigmentation. They suggested that all patients HOMA-IR = Fasting glucose (mmol) × Fasting insulin (uU/mL)/
with elevated BMI should be examined for insulin neck and 22.5. IR is diagnosed when the result is >2.71.
if neck texture is normal, IR is less likely to be present.[16] IR
occurs in 20-25% of the individuals. Types of IR are mentioned Fasting insulin level
in Table 4. Obese patients and patients with polycystic ovary Measurement of fasting insulin level has been considered
syndrome have Type A IR. most practical approach for the measuring of IR as it correlates
well with IR. Its use is limited because of a high proportion of ACANTHOSIS NIGRICANS AND
false-positive results and lack of standardization.
ADIPOKINES
Glucose/insulin Acanthosis nigricans patients have hyperinsulinemia and may
This ratio has been used in studies as an index of IR. It is a be at greater risk of atherosclerotic cardiovascular disease.[19]
highly sensitive and specific measurement of insulin sensitivity. The commonest underlying cause of IR is excess abdominal
In adults, a ratio of <4.5 is abnormal, whereas in prepubertal adipose tissue which releases increased amounts of free fatty
children <7 is abnormal.[6] acids which directly affect insulin signaling, diminish glucose
uptake in muscle, drive exaggerated triglyceride synthesis and
Quantitative insulin sensitivity check index induce gluconeogenesis in liver. Other factors presumed to play
Quantitative insulin sensitivity check index (QUICKI) proves a role in IR are tumor necrosis factor α, adiponectin, leptin,
to be a first-rate index of IR in comparison with clamp-IR. It interlukin-6 and other adipokines. When β-cells fail to secrete
provides a consistent and precise index of insulin sensitivity excess insulin needed, diabetes mellitus Type 2 and coronary
with better positive predictive power. It is calculated as: heart disease occur as a complication of IR.[20]
Several novel markers such as IGFBP-1, hs-CRP, adiponectin, Chronic state of IR is associated with secondary changes
ferritin, HbA1c, C3 complement, TNF alpha and sCD36 are now in levels of “adipokines” (decreased serum adiponectin,
surfacing as surrogate markers of IR.[17] Other investigations increased serum resistin and decreased adiponectin gene
for IR are fasting glucose and lipoprotein profile, hemoglobin expression). Decrease in adiponectin levels by genetic and
A1c, body weight, blood pressure, and an alanine transferase environmental factors contributes to the development of the
test for evaluation of fatty liver.[6] metabolic syndrome. Adiponectin is important because of its
antidiabetic and antiatherogenic effects; hence it is expected
ACANTHOSIS NIGRICANS AND
CARDIOVASCULAR DISEASE
to be a novel therapeutic tool for the metabolic syndrome. hyperkeratosis and causes near complete reversion to normal
The thiazolidinedione (TZD) class of antidiabetic drugs, state. Lahiri and Malakar in their study have reported that
having pleiotropic effects on cardiovascular diseases and lipid intermittent tretinoin application is needed to maintain improved
metabolism exert their effects partly through increasing levels status.[25]
of adiponectin. Adiponectin expression and levels in circulation
are upregulated by rosiglitazone.[22] Ammonium lactate and tretinoin
Retinoids affect cell growth, differentiation, and morphogenesis
TREATMENT OF ACANTHOSIS NIGRICANS and alter cell cohesiveness. Lactic acid is an alpha-hydroxy
acid that works as a peeling agent and also via release of
Therapeutic approach involves treatment of underlying disease or desmogleins, indicating disintegration of desmosomes. Though
tumor, cessation/avoidance of the inciting agent in drug-induced the exact mechanism of action of the two agents is unknown,
AN, use of topical/oral agents and cosmetic surgery.[12] synergistic interaction is thought to play a role.[11]
Adult with AN
Calcipotriol
Weight
reduction
Exercise
Treat AN
and effective therapeutic modality for AN in comparison to other oil.[11,27] 20% podophyllin in alcohol[29] (for benign AN) topical
topical treatments. Topical tretinoin needs frequent application colecalciferol[30] and surgical excision.[27] Urea, salicylic acid
for long duration (2 months) and improves hyperkeratosis, but and triple-combination depigmenting cream (tretinoin 0.05%,
not hyperpigmentation. Topical salicylic acid, podophyllin, urea, hydroquinone 4%, fluocinolone acetonide 0.01%) with
and calcipotriol need frequent application, while TCA peel is sunscreens are other options.[24]
done in two to three sessions. Dermabrasion or alexandrite
laser are expensive and may lead to postinflammatory ORAL TREATMENT
hyperpigmentation. Zayed et al. have reported improvement
of AN in six female patients after TCA peeling.[26] Oral retinoids
Oral retinoids (isotretinoin, acitretin) can be effective;[30] improvement
Calcipotriol requires large doses and extended courses, and relapses are
Calcipotriol is another beneficial treatment in AN.[11,27] It inhibits described. The mechanism of action is probably normalization
keratinocyte proliferation and promotes differentiation by of epithelial growth and differentiation.[2] Acitretin has been rarely
increasing intracellular calcium levels and cyclic GMP levels reported for AN treatment and has showed good success in cases
in keratinocytes. Gregoriou et al. concluded that it is safe, with syndromic and benign AN. Since acitretin has a less terminal
well-tolerated, alternative treatment for AN when an etiological elimination half-life and fewer lipophilic properties, its effect may
treatment is not possible or necessary. Bohm et al. reported a be limited leading to early recurrence. Oral isotretinoin has been
case of mixed-type AN responding favorably to calcipotriol.[28] used successfully treat to extensive AN.[31]
Child with AN
Suspension Treat AN
Refer to specialist in pediatric
of drug
endocrinology.
Lipid profile.
by IR. Paula et al. observed reduction in fasting insulin levels related to type B insulin resistance syndrome: A case report. Cutis
with rosiglitazone when compared to metformin and modest 2010;86:299-302.
3. Kondo Y, Umegaki N, Terao M, Murota H, Kimura T, Katayama I.
improvement of skin texture with both. Duration of treatment
A case of generalized acanthosis nigricans with positive lupus
may be related to improvement as metformin improves AN and erythematosus-related autoantibodies and antimicrosomal antibody:
IR if given for 6 months or more [Figure 7a and b].[23] Metformin Autoimmune acanthosis nigricans? Case Rep Dermatol 2012;4:85-91.
reduces glucose production by increasing peripheral insulin 4. El Safoury OS, Shaker OG, Fawzy MM. Skin tags and acanthosis
responsiveness, reduces hyperinsulinemia, body weight and nigricans in patients with hepatitis C infection in relation to insulin
resistance and insulin like growth factor-1 levels. Indian J Dermatol
fat mass and improves insulin sensitivity.[30,32,33] The combined
2012;57:102-6.
use of metformin and TZDs which increase sensitivity to insulin 5. Jakubovic BD, Sawires HF, Adam DN. Occult cause of paraneoplastic
in peripheral muscles, also give good results.[34] The combined acanthosis nigricans in a patient with known breast dcis: Case and review.
metformin and glimepiride (at low dose) is superior in the Curr Oncol 2012;19:e299-302.
management of IR studied through HOMA with reduction in 6. Endocrine diseases. In: James WD, Elston DM, Berger TG, editors.
Andrews’ Diseases of the Skin: Clinical Dermatology. 11th ed. Elsevier;
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2011. p. 494-5.
performance in patients with high HOMA-IR possibly by 7. Judge MR, McLean WH, Munro CS. Disorders of keratinization. In:
favorable effects on endothelial dysfunction.[18] Burns T, Breathnach S, Cox N, Griffiths C, editors. Rook’s Textbook
of Dermatology. 8th ed. UK: Blackwell Publishing; 2010. p. 19.119-21.
Cosmetic treatment 8. Sawatkar GU, Dogra S, Bhadada SK, Kanwar AJ. Acanthosis
Because darkening of affected areas is common in AN, nigricans – An uncommon cutaneous adverse effect of a common
Alan Rosenbach considered the possibility that long-pulsed medication: report of two cases. Indian J Dermatol Venereol Leprol
2013;79:553.
alexandrite laser, which was designed to target melanin in hair
9. Pavithran K, Karunakaran M, Palit A. Disorders of keratinization. In:
could improve this condition. They hypothesized that thermal Valia RG, Ameet RV, editors. IADVL Textbook of Dermatology. 3rd ed.
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and pigment reduction. They reported 95% clearance of AN 10. Jeong JS, Lee JY, Yoon TY. Unilateral nevoid acanthosis nigricans with
of axillae after seven sessions and concluded that long-pulsed a submammary location. Ann Dermatol 2011;23:95-7.
11. Higgins SP, Freemark M, Prose NS. Acanthosis nigricans: a practical
alexandrite laser can effectively and safely treat acanthosis
approach to evaluation and management. Dermatol Online J 2008;14:2.
nigricans of the axillae.[11,27,36] 12. Roy N, Das T, Kundu AK, Maity A. Atypical presentation of acanthosis
nigricans. Indian J Endocrinol Metab 2012;16:1058-9.
Treatment of acanthosis nigricans maligna 13. Devpura S, Pattamadilok B, Syed ZU, Vemulapalli P, Henderson M,
Rehse SJ, et al. Critical comparison of diffuse reflectance spectroscopy and
There is a case report of AMN regressing rapidly following
colorimetry as dermatological diagnostic tools for acanthosis nigricans:
treatment with cyproheptadine despite progression of metastatic A chemometric approach. Biomed Opt Express 2011;2:1664-73.
disease. Rothman in 1925 suggested that both AMN and juvenile 14. Fu JF, Liang L, Dong GP, Jiang YJ, Zou CC. Obese children with
AN might be associated with some growth promoting substance benign acanthosis nigricans and insulin resistance: Analysis of 19 cases.
in the blood causing papillary hypertrophy of skin. Therefore it Zhonghua Er Ke Za Zhi 2004;42:917-9.
15. Urrutia-Rojas X, McConathy W, Willis B, Menchaca J, Luna-Hollen M,
was proposed that flattening of AN occurs after administration
Marshall K, et al. Abnormal glucose metabolism in Hispanic parents of
of cyproheptadine due to reduction of growth hormone children with acanthosis nigricans. ISRN Endocrinol 2011;2011:481371.
released from pituitary, or from the tumor or metastasis.[37] 16. Payne KS, Rader RK, Lastra G, Stoecker WV. Posterolateral neck
Bonnekoh et al. successfully treated AMN associated with texture (insulin neck): Early sign of insulin resistance. JAMA Dermatol
bronchial carcinoma with psoralen and ultraviolet A radiation 2013;149:875-7.
17. Singh B, Saxena A. Surrogate markers of insulin resistance: A review.
therapy (patient received oral 8-methoxypsoralen and a total
World J Diabetes 2010;1:36-47.
UVA dose of 52 J/cm2 over 18 exposures) Flow Charts 2 and 3 18. Cadeddu C, Nocco S, Deidda M, Cadeddu F, Bina A, Demuru P, et al.
detail the treatment of adult and childhood AN respectively.[34] Relationship between high values of HOMA-IR and cardiovascular
response to metformin. Int J Cardiol 2012;9:302-3.
CONCLUSION 19. Katz AS, Goff DC, Feldman SR. Acanthosis nigricans in obese patients:
Presentations and implications for prevention of atherosclerotic vascular
disease. Dermatol Online J 2000;6:1.
Though mainly a disease of cosmetic concern, AN can be 20. Mlinar B, Marc J, Janez A, Pfeifer M. Molecular mechanisms of insulin
pointer to underlying metabolic syndrome or malignancy. resistance and associated diseases. Clin Chim Acta 2007;375:20-35.
A thorough investigation and treatment is therefore mandatory 21. Grundy SM. Hypertriglyceridemia, insulin resistance, and the metabolic
to prevent long term consequences. syndrome. Am J Cardiol 1999;83:25F-9.
22. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K.
Adiponectin and adiponectin receptors in insulin resistance, diabetes,
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32. Atabek ME, Pirgon O. Use of metformin in obese adolescents Cite this article as: Phiske MM. An approach to acanthosis nigricans. Indian
Dermatol Online J 2014;5:239-49.
with hyperinsulinemia: a 6-month, randomized, double-blind,
Source of Support: Nil, Conflict of Interest: None declared.
placebo-controlled clinical trial. J Pediatr Endocrinol Metab