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Acanthosis nigricans (AN) is a velvety, hyperpigmentation of the skin that usually occurs in intertriginous areas. AN is most commonly associated with benign disorders like diabetes, insulin resistance, endocrinopathies and exogenous medications, but can be a valid cutaneous marker of a wide range of internal malignancies, which makes it important for the physicians across specialties to have awareness about it. With an increase in the prevalence of obesity and diabetes in recent decades, the prevalence of AN has also shown a significant increase. This article will review in detail the epidemiology, pathophysiology, clinical features and treatment of acanthosis nigricans in the light of the literature.
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Journal of Pakistan Association of Dermatologists. 2021;31(2):273-288.
273
Address for correspondence
Dr. Sajad Ahmad Salati
Department of Surgery,
Unaizah College of Medicine,
Qassim University Saudi Arabia.
Email: docsajad@yahoo.co.in
Review Article
Acanthosis nigricans: An extensive review
Introduction
Acanthosis nigricans (AN) is a dermatosis with
aesthetic implications and is characterized by the
focal or diffuse development of a velvety,
hyperpigmented cutaneous thickening in
intertriginous areas. This hyperpigmentation,
which has poorly defined borders, usually occurs
in skin fold areas symmetrically, such as the
back of the neck, axilla and groin, and may
rarely involve oral mucosa.1 The lesions may be
related to a wide range of benign conditions and
may occur as a paraneoplastic manifestation of
various potentially fatal malignancies. There are
reports in literature recommending the
utilization of AN as a straight-forward, non-
invasive and cost-effective clinical marker for
screening, prevention, diagnosis and follow
up.2-6 The term acanthosis nigricans was
originally proposed by Paul Gerson Unna in
1889, but the first case was described by
Pollitzer and Janovsky in 1891.7
This review discusses in detail the
epidemiology, pathophysiology, clinical features
and treatment of acanthosis nigricans in the light
of literature.
Methods
The observational studies, review articles and
case reports dealing with acanthosis nigricans
were searched in PubMed, HINARI, Google
Scholar, Web of Science and Cochrane library
databases. The search was based on the
keywords: acanthosis nigricans, paraneoplastic
syndrome and metabolic syndrome. Only the
literature published in English up to June 2020
was included and all articles in languages other
than English were excluded. Preference was
given to articles published in the last two
decades, but references from earlier dates that
appeared as cross-references in the included
articles were also reviewed and used if found
highly significant, particularly from the
historical point of view.
Sajad Ahmad Salati, Leenah Abdullah Alqarawi, Yomna Fozan Alquraishi
Department of Surgery, Unaizah College of Medicine, Qassim University, Saudi Arabia.
Abstract
Acanthosis nigricans (AN) is a velvety, hyperpigmentation of the skin that usually occurs in
intertriginous areas. AN is most commonly associated with benign disorders like diabetes, insulin
resistance, endocrinopathies and exogenous medications, but can be a valid cutaneous marker of a
wide range of internal malignancies, which makes it important for the physicians across specialties
to have awareness about it. With an increase in the prevalence of obesity and diabetes in recent
decades, the prevalence of AN has also shown a significant increase. This article will review in
detail the epidemiology, pathophysiology, clinical features and treatment of acanthosis nigricans in
the light of the literature.
Key words
Acanthosis nigricans (AN), insulin resistance, endocrine disorders, obesity, paraneoplastic
syndrome, growth factors, hyperpigmentation, differential diagnosis.
Journal of Pakistan Association of Dermatologists. 2021;31(2):273-288.
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Pathogenesis
The definite pathogenesis for AN has not yet
been ascertained, although several factors have
been suggested that may be involved in the
development of acanthosis nigricans in various
disorders.8
i) Increased circulating insulin result in direct
and indirect activation of keratinocyte
insulin-like growth factor (ILGF) receptors,
particularly IGF-1. At high concentrations,
insulin may displace IGF-1 from IGF
binding protein. Increased circulating IGF
may lead to suprabasal keratinocyte and
dermal fibroblast proliferation. Other
tyrosine kinase receptors such as fibroblast
growth factor receptor (FGFR), epidermal
growth factor receptor (EGFR) may also
play a contributory role in the
hyperproliferation of keratinocytes and
fibroblasts.9
ii) Increased transforming growth factor (TGF)
appears to be the mechanism for
malignancy-associated acanthosis nigricans.
TGF acts on epidermal tissue via the
epidermal growth factor receptor.
iii) Early development of extensive acanthosis
nigricans (AN) is a key feature in some
patients who have hypochondroplasia
(HCH) and are supposed to be related to the
Fibroblast growth factor receptor (FGFR)
3 mutations. Muguet Guenot L et al.10 in
2019 reported that the Lys650Thr mutation
was the predominantly reported mutation of
FGFR 3.
iv) Malignancy-associated AN might be
possibly explained by the elevated levels of
growth factors such as alpha transforming
growth factor (TGF-α), which can stimulate
the epidermal growth factor receptor
(EGFR). Normalization of urine and serum
TGF-alpha levels with subsequent
regression of skin lesions have been reported
to occur after surgical tumor removal.11
However, it has not yet been discovered, as
to what causes the intertriginous areas to be
most affected though perspiration or friction
may be playing a contributory role.12-14
v) Very long-chain fatty acids (VLCFAs) are
essential for the functioning of biological
membranes. ELOVL fatty acid elongase-1
catalyzes the elongation of saturated and
monounsaturated C22-C26-VLCFAs.
Mutation of ELOV1 gene that encoded
ELOVL fatty acid elongase-1 has been
postulated as a possible factor in the
development of AN in the recent studies.15
vi) Hereditary variants of AN have been linked
to the fibroblast growth factor defects.
Exogenous medications, including insulin
injections have been implicated as etiologic
factors and the likely mechanism is proposed to
be the activation of IGF receptors.16 Kudo-
Watanuki et al. in 2013 reported the
development of AN over anterior abdomen at
the insulin injection site of a 59-year-old patient
with diabetes mellitus coexisting with
amyloidosis.17
Agents such as palifermin (recombinant
keratinocyte growth factor used to decrease
mucositis with chemotherapy and stem cell
transplantation) have been reported by Lane et
al. to produce transient but dramatic acanthosis
nigricans-like lesions, presumably due to
activation of the fibroblast growth factor
receptors (FGFR).18
Familial forms of AN have been documented in
the literature. These familial forms may be
isolated or syndromic forms. The syndromic
forms have been subdivided into:
(a) Insulin-resistance syndromes: these include
those with mutations in the insulin receptors
(i.e. leprechaunism, Rabson-Mendenhall
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275
syndrome), peroxisome proliferator-
activated receptor-gamma (i.e., type 1
diabetes with acanthosis nigricans and
hypertension), 1-acylglycerol-3-phosphate
O-acyl transferase-2 or seipin (primary
lipoatrophy or Berardinelli-Seip syndrome),
lamin A/C (Dunnigan syndrome), and
Alstrom syndrome gene.19
(b) Fibroblast growth factor defects include
activating mutations in FGFR2 (Beare-
Stevenson syndrome), FGFR3 (Crouzon
syndrome with acanthosis nigricans,
thanatophoric dysplasia, severe
achondroplasia with developmental delay,
and acanthosis nigricans [SADDAN]).
Familial cases of isolated acanthosis nigricans
with no other syndromic findings have also been
linked to FGFR mutations. Berk et al.20 and Fu
et al.21 in two independent case reports found
that AN to be caused by a heterozygous
mutation (c.1949A > C, p.K650 T) in fibroblast
growth factor receptor 3 gene (FGFR3).
Sequencing of the FGFR3 gene was suggested a
feasible approach to identify the etiology of AN,
especially for early-onset extensive AN.
Epidemiology
AN is much more common in people with
darker skin pigmentation. AN has no known sex
predilection and the reported incidence is equal
for men and women. AN has been reported at all
ages, including at birth, although it is found
more commonly in the adult population. AN has
been found to be more common in Native
Americans, African Americans, and Hispanics
when compared to Whites or Asian origin
individuals.22-23 The exact prevalence of AN is
not precisely known, but due to the rising
prevalence of obesity and diabetes a high
prevalence of AN has been observed recently.
As such, the prevalence varies widely from 7%
to 74%, depending upon age, race, frequency of
type, degree of obesity and concomitant
endocrinopathy. Stuart CA et al. in 1989
conducted a study in the sixth and eighth grades
of the public schools of Galveston, Texas, USA
and reported a prevalence of 7.1% in the
unselected populations.22 Hud et al. study had
reported 74% in an unselected adult obese
population in Dallas, Texas, USA.23 The
prevalence of AN in an urban population in Sri
Lanka was reported 17.4% in a study conducted
by Dassanayake et al. in 2011.24 The prevalence
of AN in New Mexico adolescents was found to
be 18.9% in a study by Mukhtar et al. that
enrolled 233 middle school students.25 Stoddart
et al. conducted a study on a random sample of
the American Indian diabetic population in
Cherokee Nation members aged 5-40 years.
They found that the overall prevalence rates for
AN and hyperinsulinemia were 34.2 and 47.2%,
respectively.26 In a study conducted in China,
the frequency of AN was reported as 54% in
Chinese obese children.27
Malignant acanthosis nigricans, in contrast to the
benign form, is less common with no racial
predilection and occurs more frequently in
elderly persons; however, cases have been
reported in children with Wilms tumor, gastric
adenocarcinoma, and osteogenic sarcoma.28
Classification of Acanthosis Nigricans
Multiple classifications have been proposed in
literature.29 The commonly cited classifications
by Curth,30 Hernandez-Perez31 and Sinha-
Schwartz28 are shown in Figure 1. Burke et al.7
have developed a scale for AN according to the
severity, on a scale of 0-4 based on how many
areas are affected and the scale is easy to use,
has high interobserver reliability, and correlates
well with fasting insulin and body mass index
(BMI). This scale permits longitudinal and
cross-sectional evaluation of AN and the
evaluation of AN as a trait in genetic studies.
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276
Figure 1 Classification of Acanthosis Nigricans (A)
Curth, (B) Hernandez-Perez (C) Sinha-Schwartz.
Popa et al.32 in 2019, proposed a comprehensive
classification system, as shown in Figure 2. We
have adopted this classification in this review
article for a greater explanation of the variants.
Metabolic disorders
Obesity-associated AN is the most common
form and once termed as pseudoacanthosis
nigricans. Lesions are more common in
adulthood, though it may appear at any age. The
lesion's severity is related to weight excess and
is often slowly reversible after weight loss. It is
more common in obese patients with insulin
resistance.33 In obese women with gestational
diabetes, the lesion may be a reliable marker for
higher insulin needs. Similarly, in paediatric
patients, AN has been shown to be a reliable
early marker for metabolic syndrome.34
In clinical practice, AN may be a useful
morphological marker for early identification of
children and adolescents, prone to insulin-
resistant obese phenotype and metabolic
syndrome, who could benefit from early
interventions.35
Syndromic AN has two types: type A (HAIR-
AN) presents with hyperandrogenemia (HA),
insulin resistance (IR) and AN; type B presents
with diabetes mellitus and ovarian
hyperandrogenemia.
Genetic disorders
Unilateral AN is a rare inherited, autosomal
dominant form that manifests at birth or during
childhood or puberty and is not related to
endocrinopathy. Lesions are unilateral and
appear, especially in the periumbilical area, back
and thighs though rarely face, scalp and chest
may be involved.36-37 The salient features in the
literature include localized distribution, benign
course, lack of systemic and tumor associations,
and occurrence due to somatic mosaicism of
postzygotic gene mutation.38-39
Familial AN is a rare autosomal dominant
disease. The condition is self-limiting and
commonly develops from early childhood to
stabilize or else recede after continuous progress
till puberty. However, it may appear at any
age.40
Benign genetic AN develops from birth or early
childhood, as a rare autosomal dominant form.
Autoimmune disorders
Autoimmune AN is usually determined by anti-
insulin receptor antibodies that appear in
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autoimmune disorders like systemic lupus
erythematosus.41-42 Cases of AN accompanied
by autoimmune manifestations but not type B
insulin resistance, which responded to systemic
immunosuppressive therapy, have been reported.
Kondo et al.41 reported a very rare case of
generalized AN with Sjogren's syndrome- and
systemic lupus erythematosus-like features but
without type B insulin resistance. During a 10
year clinical course, neither any internal
malignancy nor other endocrinological
disorders, including glucose intolerance, were
detected. The lesions regressed with oral
cyclosporine A, accompanied by the lowering of
autoantibody titers.
Sturner et al.43 have speculated that some
unknown autoantibodies other than the insulin-
receptor antibody might generate
mucocutaneous lesions found in AN. Some
patients with AN who are positive for
antinuclear antibodies (ANA), anti-microsomal
antibodies (AMA), or show increased
immunoglobulin levels might associate with
disordered immunoreactivity not fitting any
clinically recognizable syndromes.
Paraneoplastic AN
Paraneoplastic or malignant AN is the most
worrisome of the variants of acanthosis
nigricans because the underlying neoplasm is
often aggressive cancer. The neoplasms usually
have a rapid onset and occur concomitantly in
most cases (61.3%); however, in 17.6% of cases,
the lesions precede the tumor detection and in
21% of cases, appear after the tumor has become
obvious.11
Lesion progression mirrors the development of
malignancy: efficient treatment leads to AN
regression, whereas recrudescence may suggest
recurrence of the malignancy. The vast majority
of cases of malignant AN are secondary to
adenocarcinoma of the stomach,44-46 but cases
have been reported in cancers of other organs
including hepatobiliary tract,47-50 intestine,51
lungs,52 uterus,53-55 ovaries,56 urinary tract,57-58
rectum,59 prostrate,60 soft tissue61 and central
nervous system.62
Iatrogenic disorders
AN may uncommonly appear as an adverse
effect of drugs that promote hyperinsulinemia.
These drugs include nicotinic acid, niacin,
glucocorticoids, fusidic acid, stilbestrol,
methyltestosterone, estrogen, combined oral
contraceptive pill, triazine, pituitary extract,
growth hormone therapy and fibroblast growth
factor receptor ligands such as palifermin.18
Although skin lesions are reversible when
discontinuing offending treatment, the decision
should be made according to the severity of the
disease for which the treatment was
administered.
Nicotinic acid has the most widely recognized
association with acanthosis nigricans,
developing on abdomen and flexor surfaces and
resolving within 4-10 weeks of
discontinuation.63-64 There are reports in the
literature of the development of AN as a local
cutaneous side effect of repetitive same-site
insulin injections.18,65,66 However, it has been
proven that, with the correct insulin type
prescription and proper administration
technique, the development of AN can be
avoided.67
Idiopathic AN
Acral AN occurs in some healthy, dark-skinned
individuals, especially those of African
American or sub-Saharan African descent due to
yet unknown genetic factors. It is most
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prominent over the dorsal surfaces of the hands
and feet.68-69
Mixed-type AN
Mixed-type AN is a term applied to those
situations in which a patient with one of the
above types of acanthosis nigricans develops
new lesions of a different etiology. An example
of this would be paraneoplastic AN lesions
added to older ones in an obese patient with
obesity-associated AN.
Clinical features
Patients usually present with an area of
darkening and thickening of the skin with no
active symptoms or else with mild pruritus. On
physical examination, the lesions appear
symmetrical, hyperpigmented, velvety plaques
that may occur in almost any location though
typically locations include areas of skin folds
like the groin, axilla, or posterior neck (Figures
3-5).
In children, the most common site of acanthosis
nigricans is the posterior neck. Rarely,
acanthosis nigricans may occur on the mucous
membranes of the nose, oral cavity, esophagus
or larynx. Eye involvement, including
papillomatous lesions on the eyelids and
Figure 3 Benign AN in an obese male (Image
courtesy: Prof Uwe Wollina Dresden, Germany).
conjunctiva, has been reported.70
Nail changes, such as leukonychia and
hyperkeratosis, can also occur. Females have
been reported to develop lesions on the nipple.71
In some patients, they may be associated with
skin tags in the same area. Nail changes like
hyperkeratosis and leukonychia may be present.
Clinically, it is not possible to precisely
differentiate the lesions of benign from the
Figure 4 Relapse of AN after successful kidney
cancer treatment on the neck (a), groins, scrotum and
thighs (b), and axillae (c, d). In the axillae, skin tags
are seen (Image courtesy: Prof Uwe Wollina,
Dresden, Germany).
Figure 5 Malignant AN in a woman with
cholangiocarcinoma (Image courtesy: Prof Uwe
Wollina, Dresden, Germany).
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Table 1 Difference between benign and malignant acanthosis nigricans.
Features
Benign
Malignant
Onset
Birth, childhood or puberty
Mostly adulthood
Distribution
Extent of involvement
Lesser
Widespread
Distal extremities
Spared
Affected
Mucous membrane
Rarely affected
Commonly affected
Palms & soles
Rarely affected
Commonly affected
Pigmentation
Less, limited to thickened areas
More, and extends beyond the thickened areas
Skin thickening
Mild
Marked
Skin irritation
None or less
Marked
Additional features
None
i) Tripe palms,
ii) Leser-Trelat sign,
iii) Florid cutaneous papillomatosis (FCP)
i) Tripe palms [46, 72-74]: a cutaneous condition characterized by ridged velvety lesions on the palms resembling
the lining of a cow's stomach (tripe).
ii) Leser-Trelat sign [73-75]: the abrupt appearance of multiple, and sometimes itchy, seborrheic keratoses that
rapidly increase in their number and size.
iii) Florid cutaneous papillomatosis (FCP) [68,75-76]: characterized by the rapid onset of numerous small warty
papules on the trunk and the extremities that morphologically resemble viral warts.
malignant AN, but there are certain features that
should arouse suspicion as depicted in Table 1.
Diagnosis
The diagnosis of AN is mainly based on clinical
assessment. Confirmation is obtained by a skin
biopsy. The histological pattern of the lesion is
common in all forms of AN described above and
comprise of hyperkeratosis, epidermal folding,
the proliferation of melanocytes in the stratum
basale of the epidermis with leukocytic
infiltration.32 The hyperpigmentation seen on
clinical examination is attributed to thickening
and hyperkeratosis rather than the excess of
melanin.77 In malignant AN, the hyperkeratosis
is a dominant feature and due to the proliferation
of keratinocytes, while the hyperpigmentation is
minimal.1
Tristimulus colorimetry and diffuse reflectance
spectroscopy (DRS) are white-light skin
reflectance techniques used to measure the
intensity of skin pigmentation and have been
shown to provide sensitive and specific
diagnosis of AN. Tristimulus colorimetry
quantifies and characterizes the objective colour
change in AN, while DRS may be useful in
characterizing changes in skin melanin content
associated with this skin condition.78-79
Blood tests, endoscopy, or imaging studies may
be required to rule out diabetes or cancer as a
cause of AN. Since a significant majority of
cases are associated with insulin resistance
and/or obesity, screening for diabetes and
measuring glycosylated haemoglobin is
recommended.33,80
Differential Diagnosis
Intertriginous granular parakeratosis Usually
self-resolving, pruritic, red-to-brown, scaly-to-
hyperkeratotic papules or plaques found most
commonly in the axillae or other intertriginous
areas, generally in the middle-aged women.81
Haber’s Syndrome A rare genodermatosis
characterised by an early onset rosacea-like
eruption associated with multiple keratotic
lesions on non-sun-exposed skin of the trunk.82
Confluent and reticulated papillomatosis An
uncommon skin condition affecting the trunk,
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neck and axillae and characterized by
asymptomatic, hyperpigmented papules and
plaques that have a peripheral, net-like
configuration.83
Dowling-Degos disease A rare autosomal
dominant genetic disease that presents in adult
life with multiple small progressive reticular,
reddish-brown to dark-brown, pigmentated
lesions, particularly in the folds of the skin with
soft tissue fibromas and follicular
hyperkeratosis.84
Acropigmentation reticularis of Kitamura A
rare, autosomal dominant disorder characterized
by a slightly atrophic, angulated,
hyperpigmented macules that are arranged in a
reticulate pattern typically on the dorsal aspect
of hands and feet. The lesions usually start in the
first and second decades of life and gradually
darken over time.85
Becker Melanosis A circumscribed
hyperpigmented patch with an irregular outline
and associated hypertrichosis. It usually
develops in the second decade of life over the
upper half of trunk and/or on the proximal upper
extremities.86
Erythrasma An intertriginous infection with
Corynebacterium minutissimum that manifests
as irregular but sharply marginated pink or
brown patches with fine scaling. It is most
common in diabetics and among people living in
warmer climates.87
Seborrhea A common, chronic-recurrent
disorder can affect people of any age, though it’s
most common in infants and adults between the
ages of 30 and 60. It presents most often on the
face and/ or scalp as ill-defined erythematous
patches associated with fine (pityriasiform)
scaling, involving mostly scalp, face and
periauricular region, with the central chest,
axillae and genital region also involved in some
cases.88
Besides, the dermatological manifestations of
various diseases like Addison Disease,
hemochromatosis and pellagra can appear like
AN. There are published reports of the
"neglected nipples" condition, presenting as
bilateral AN-like papules and plaques of the
nipples, due to avoidance of cleansing of the
nipple area, resulting in accumulation of
keratotic cellular debris.89
Complications
AN does not cause any serious complications
per se. The appearance of acanthosis nigricans
during childhood usually is associated with a
benign condition, though in the adult-onset AN,
the underlying malignancy must be ruled out.
However, most cases of adult-onset acanthosis
nigricans are benign and often are associated
with insulin resistance.
Patient Education
There is a need to educate the patients that AN
may not solely be a skin condition and hence
ought to be evaluated further by multiple
specialties, especially if it occurs in middle-aged
to elderly patients. Patients need to be educated
on identifying the risk factors and common
features of the malignant conditions associated
with AN. They are to be encouraged that AN per
se can resolve or improve with adequate
treatment of the skin condition or treatment of
the underlying condition, lifestyle adjustments,
including losing some weight. Depression and
low self-esteem may occur in patients with AN
and counselling with psychological treatment
should be started early in these patients.90-91
Treatment
AN is not a disease per se, but a sign of various
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causes and hence, treatment of AN should focus
on proper identification and correction of the
underlying disease process. Simple measures
like weight reduction in obesity-related AN may
resolve the hyperkeratotic lesions, while
correction of hyperinsulinemia can reduce the
burden of AN lesions.77 Cessation of the
causative agent in idiopathic AN often results in
the resolution of AN, and surgical removal of
the malignant tumors is the mainstay of
treatment in malignant AN.92
Besides focussing on the primary goal of therapy
for AN by managing the underlying cause,
cosmetic resolution of AN lesions can be
significant for improving the quality of life. A
wide range of oral and topical treatment options
have been reported.93
Topical treatments
Topical retinoids Topical retinoids are one of
the first-line treatment options for AN,
particularly for the unilateral nevoid AN.37 They
act as epidermopoietic and cause a reduction of
the stratum corneum replacement time, thereby
leading to correction of hyperkeratosis and near-
complete reversion to the normal state. Lahiri
and Malakar, in their study of 30 patients, found
that clinical improvement of treatment-resistant
AN was seen in all patients after 14 days of
0.05% tretinoin application with 24 patients
(80%) showing total clearance at 16 weeks.
However, intermittent tretinoin was needed to
maintain an improvement as relapse was noted
within a period of 4 weeks after discontinuation
of treatment.94 There are reports of
improvement, even with the use of lower
concentration topical 0.1% tretinoin.95 Studies
have shown significant minimization of skin
darkening by application of 0.1% adapalene gel
for childhood AN.96-97 Treesirichod et al. in one
study compared 0.1% adapalene gel and 0.025%
tretinoin cream in the treatment of AN-
associated hyperpigmentation and they found
that there was no statistically significant
difference in the outcomes.98
In another recent study, Treesirichod et al.
compared the effects of 0.025% tretinoin and
10% urea. They found that both the medications
significantly improved AN though the efficacy
of 0.025% tretinoin was significantly better than
10% urea.99
Combination therapy may also be used to treat
AN successfully. In one case report by
Blobstein, the combination of 0.05% tretinoin
cream and 12% ammonium lactate cream led to
the resolution of AN associated with obesity.100
In another case report by Adigun and Pandya, a
triple-combination depigmenting cream
composed of 0.05% tretinoin, 4% hydroquinone,
and 0.01% fluocinolone acetonide was applied
for AN at night along with daily sunscreen and it
showed successful results after one month of
use.101
Topical vitamin D analogs Topical Vitamin D
analogs like Calcipotriene and calcipotriol are
believed to inhibit keratinocyte proliferation and
promote differentiation by increasing
keratinocyte intracellular calcium and cyclic
GMP levels, thereby reducing the number of
keratinocytes resulting in minimization of the
cutaneous effects of insulin 102. Bom et al.
demonstrated improvement of a mixed-type AN
in the flexural areas of an obese man after 3
months of 0.005% calcipotriol cream application
twice daily.103
Lee H W et al. also demonstrated improvement
in the lesions of an obese patient who used
calcipotriol ointment twice daily for a period of
3 months.104 Gregoriou et al. also reported
calcipotriol to be a safe, effective, and well-
tolerated treatment for AN, particularly in cases
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where definite etiological treatment is not
possible due to any reason.105
Chemical peels Superficial chemical peels have
been reported to be a relatively safe and
effective treatment option for AN.
Trichloroacetic acid (TCA) is a caustic chemical
substance and causes coagulation and
precipitation of skin proteins, leading to necrosis
of epidermis. This destruction is followed by
inflammation and the activation of wound repair,
resulting in re-epithelialization with smoother
skin.106 Zayed et al. in a pilot study, documented
improvement in AN in six female patients who
used TCA peels. Improvement was seen with
regards to hyperpigmentation, thickening, and
overall appearance.107 TCA is safe, easily
accessible, inexpensive, and can be easily
prepared and since it is a stable compound with
known precipitation, absorption, and peel depth,
judging its endpoint exfoliation is relatively
simple.106
Oral treatment
Oral retinoids (isotretinoin and acitretin) Large
doses and extended courses of oral retinoids
such as isotretinoin and acitretin have been
found to be effective in the treatment of
AN.95,108 The proposed mechanism of action for
these drugs is the normalization of epithelial
growth and differentiation. Katz reported
successful treatment of an extensive AN
associated with obesity with isotretinoin (3
mg/kg/day).108 However, discontinuation of the
treatment resulted in relapse. Walling et al.
reported a 90% improvement of palmar AN and
50% improvement of axillary AN within 2
months of taking isotretinoin 80 mg/day.
However, after gradually tapering this dose over
more than a year and receiving over a total of 30
g, the patient experienced recurrence of his skin
lesions that improved on taking 1000 mg
metformin twice daily.109 For the treatment of
AN with acitretin, some reports point towards
success in cases of syndromic and benign
AN.106 Ozdemir et al. reported complete
recovery of an 18-year-old male with
generalized idiopathic AN experienced after 45
days of acitretin 0.8 mg/kg (50 mg) divided into
two daily doses. After starting maintenance
therapy of 25 mg acitretin daily for 2 months,
lesions recurred that subsequently resolved with
topical application of 0.1% retinoic acid
110. Because of acitretin’s longer terminal
elimination half-life and fewer lipophilic
properties, its use may, however, be limited with
greater potential for early recurrence after
discontinuation.
Metformin and rosiglitazone Metformin and
rosiglitazone are useful in AN characterized by
insulin resistance (IR). They are believed to
increase peripheral insulin responsiveness,
resulting in a reduction of glucose production,
hyperinsulinemia, body weight, and fat mass, as
well as an increase in insulin sensitivity in
patients with insulin resistance and AN.110
Giri et al. reported an adolescent Caucasian boy
with IR and extensive AN who showed complete
resolution of AN after two years of metformin,
despite the persistence of IR, whereas
Wasniewska reported recovery of acanthosis
nigricans under prolonged metformin treatment
in an adolescent with normal weight 112-113.
Bellot-Rojas et al. observed a reduction in
fasting insulin levels with rosiglitazone when
compared to metformin and modest
improvement of skin texture with both.114
Miscellaneous treatment
Other beneficial therapies (case reports) include
fish oil,115 20% podophyllin in alcohol (for
benign AN),116 topical cholecalciferol and
surgical excision.117 Urea, salicylic acid and
triple-combination depigmenting cream
Journal of Pakistan Association of Dermatologists. 2021;31(2):273-288.
283
(tretinoin 0.05%, hydroquinone 4%,
fluocinolone acetonide 0.01%) with sunscreens
are other options 77.
Conclusion
Though mainly a disease of cosmetic concern by
itself and most often asymptomatic without a
significant impairment, AN can be of great
importance to identify a wide range of
underlying pathologies, including metabolic
syndrome and malignancy. A thorough
investigation and treatment are, therefore,
warranted to prevent long term consequences.
Acknowledgments
The authors acknowledge with thanks the help
provided by Prof Uwe Wollina, Department of
Dermatology and Allergology, Teaching
Hospital Dresden - Friedrichstadt, Dresden,
Germany. E-mail: uwollina@gmail.com by
granting permission for the usage of images
from their open-access article with the citation:
Acanthosis NigricansA Two-Sided Coin:
Consider Metabolic Syndrome and
Malignancies! Open Access Maced J Med Sci.
2019 Sep 30; 7(18):3081-3084.
https://doi.org/10.3889/oamjms.2019.258 . The
permission was granted through email on 13
July 2020.
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