Malignant acanthosis nigricans (AN) is a rare paraneoplastic syndrome seen primarily in adults with an underlying diagnosis of gastrointestinal adenocarcinoma. Malignant AN is characterized by hyperpigmentation and velvety hyperplasia of the epidermis. This condition is generally not associated with tumors in pediatric populations or in the adrenal gland. We present a case of malignant AN in a pediatric patient with a nonmalignant, functional adrenocortical tumor

Bruce Pawel

Elizabeth Isaacoff

Filippina Filia Dimitriadi

Frank Barrows

Kane

M Capella

M P Islam

N Demura

Peter Mattei

Sogol Mostoufi-Moab

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Case Reports in Endocrinology
Volume 2013, Article ID 174593, 4 pages
http://dx.doi.org/10.1155/2013/174593
Case Report
Acanthosis Nigricans Associated with an Adrenocortical
Tumor in a Pediatric Patient
Elizabeth Isaacoff,1 Filippina Filia Dimitriadi,2 Frank Barrows,3
Bruce Pawel,4 Peter Mattei,5 and Sogol Mostoufi-Moab1
1 Department of Pediatrics, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard,
3535 Market Street, Room 1562, Philadelphia, PA 19104, USA
2Division of Pediatric Endocrinology, St. Christopher’s Hospital for Children, 3601 A. Street, Philadelphia, PA 19134, USA
3Division of Pediatric Endocrinology, Monmouth Medical Children’s Hospital, 180 Avenue at the Commons, Suite 7B,
Shrewsbury, NJ 07702, USA
4Department of Pathology, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard,
Philadelphia, PA 19104, USA
5Department of General Surgery, The Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard,
Philadelphia, PA 19104, USA
Correspondence should be addressed to Elizabeth Isaacoff; isaacoffe@email.chop.edu
Received 13 March 2013; Accepted 19 May 2013
Academic Editors: C. Capella, M. Demura, N. Islam, and M. P. Kane
Copyright © 2013 Elizabeth Isaacoff et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
cited.
Malignant acanthosis nigricans (AN) is a rare paraneoplastic syndrome seen primarily in adults with an underlying diagnosis of
gastrointestinal adenocarcinoma. Malignant AN is characterized by hyperpigmentation and velvety hyperplasia of the epidermis.
This condition is generally not associated with tumors in pediatric populations or in the adrenal gland. We present a case of
malignant AN in a pediatric patient with a nonmalignant, functional adrenocortical tumor.
1. Introduction
Childhood adrenocortical tumors (ACTs) generally present
during the first 5 years of life, with a second, smaller peak
noted during adolescence [1–4]. Majority of these tumors
come to medical attention subsequent to overproduction of
adrenal cortical hormones. Virilization is the most common
presenting sign (84.3%), either alone (55.1%) or in com-
bination with overproduction of other adrenal hormones
including aldosterone or glucocorticoids (29.2%), followed
by 5.5% with isolated Cushing’s syndrome, and 10.2% with
nonfunctional tumors [4].
The diagnosis of ACTs in pediatric patients is generally
made within 5–8 months of the first presenting signs and
symptoms [2, 4, 5]; however, one-third of pediatric patients
have either unresectable or metastatic disease at the time of
diagnosis.The remaining two-thirds have disease confined to
the adrenals [4]. An elevated blood or urine concentration
of adrenocortical hormones and a suprarenal mass generally
suggest a preoperative diagnosis of ACT. Imaging studies
are necessary for sufficient staging and surgery planning [6].
Surgery is the best treatment plan for those with ACTs, and
cisplatin-based chemotherapy with mitotane is indicated for
metastatic disease or when complete resection is not possible
at presentation [6]. In children with localized ACTs, tumor
weight ≤200 g, virilization alone, stage I disease, absence
of spillage during surgery, and age ≤3 years are considered
important favorable prognostic indicators [4].
Malignant acanthosis nigricans (AN) is a rare paraneo-
plastic syndrome seen mainly in adults with adenocarcino-
mas, primarily of gastric origin [7, 8]. Malignant AN appears
concurrently at the time of tumor diagnosis in 61.3%, butmay
also appear before (17.6%) or after (21.1%) cancer diagnosis
[9]. Malignant AN is usually not a recognized paraneoplastic
2 Case Reports in Endocrinology
Table 1: Pre- and postoperative endocrine laboratory values.
Hormone
Preoperative
hormone level Postoperative hormone level Normal range
4/19/2010 5/11/2010 6/30/2010 4/20/2011 9/26/2012
Glucose (mg/dL) 88 71 127 83 78 74–127
Nonfasting insulin (uU/mL) 43.7 — 30.7 — — —
Hemoglobin A1C (%) 4.9 — — 4.7 4.7 3.8–5.9
Testosterone (ng/dL) 150 <3.0 <3.0 <2.5 <2.5 Tanner 1 range <3–10Tanner 2 range 18–150
Androstenedione (ng/dL) 72 <10 — <10 <10 Tanner 1 range <10–17Tanner 2 range 31–65
Dehydroepiandrosterone sulfate
(ug/dL) 73 <10 — — —
Range for 1–5 years of age
<5–57
Tanner 2 range 42–109
IGF-1/Somatomedin-C serum
(ng/mL) 325 — 143 101 111
Range for 3-4 years of age
54–178
FSH (mIU/mL) 0.143 — — — — Tanner 1 range 0.1–3.0
Luteinizing hormone (mIU/mL) 0.010 — — — — Tanner 1 range 0.01–0.3
finding associated with pediatric tumors. Here, we report the
first case of malignant AN in a pediatric patient with a non-
malignant, functional ACT at the time of tumor diagnosis.
2. Case Presentation
A previously healthy 33-month-old Caucasian male pre-
sented with a three-month history of rapid virilization and a
neck rash. Height and weight remained unchanged over the
precedingmonths at the 50th percentile. Blood pressure at the
time of diagnosis was 123/65mmHg and heart rate 112 bpm.
Physical examination was notable for coarse facial features,
facial acne, anterior and posterior cervical acanthosis
nigricans, Tanner 2 pubic hair, and pubertal phallus (8 cm in
length and 2 cm in diameter), but prepubertal testes at 3mL
volume bilaterally. Laboratory evaluation revealed an ele-
vated nonfasting insulin level with normal values for glucose,
random cortisol 19.6mcg/dL (normal range 9–22mcg/dL),
ACTH 8.35 pg/mL (normal range 5–46 pg/mL), and
hemoglobin A1C 4.7% (normal range 3.8–5.9%). Abnormal
laboratory findings for age included elevated testosterone,
androstenedione, dehydroepiandrosterone sulfate (DHEAS),
all within Tanner 2-3 range. IGF-I level was increased for age.
Gonadotropins were Tanner stage 1, confirming a peripheral
source for androgen production. Serum electrolytes, beta-
HCG, and alpha-fetoprotein levels were all within normal
limits. Table 1 is a summary of pertinent laboratory results.
MRI of the abdomen revealed a 2.3× 3 cmmasswithin the
right adrenal cortex, absent retroperitoneal lymphadenopa-
thy, and lack of tumor thrombus within the IVC. The
patient underwent a successful right adrenalectomy and
retroperitoneal lymph node dissection without any compli-
cations. Postoperative screening morning cortisol was unde-
tectable (<1.0mcg/dL), indicating suppression of contralat-
eral unaffected adrenal gland. He was treated with stress-
dose hydrocortisone and subsequently transitioned to and
slowlyweaned off of physiologic replacement postoperatively.
Follow-up random cortisol level one year postoperatively was
normal at 7.1mcg/dL (normal range 1.5–9.0mcg/dL). Pathol-
ogy review revealed a 12.5-gram encapsulated tumor without
hemorrhage, necrosis, or capsular invasion (Figure 1). Tumor
cells exhibited rare mitotic figures, favoring the diagnosis of
a non-malignant adrenal cortical tumor. He demonstrated
marked clinical improvement of all symptoms, including
normalization of all laboratory values three weeks after
surgery and complete resolution of the acanthosis nigricans
three months postoperatively.
3. Discussion
ACT peaks during the first and fourth decades of life [10].
The incidence of ACT varies internationally, with particularly
high rates noted in southern Brazil, where the incidence is
approximately 10–15 times that observed in the USA [6].
Predisposing genetic factors may be responsible for this
increased incidence [6]. ACT in children is exceptionally
rare, composing only 0.2% of pediatric cancers [11]. Only 25
new cases are expected to occur annually in the USA, for an
estimated annual incidence of 0.2–0.3 cases per million [11].
Acanthosis nigricans (AN), a common cutaneous finding,
is characterized by hyperpigmentation and velvety hyperpla-
sia of the epidermis [12]. In general, it affects flexural areas
including the neck, antecubital, and, the popliteal fossa [12].
Benign AN usually presents between birth and puberty and
can have a possible genetic component [8]. Benign AN often
occurs in individuals exhibiting insulin resistance, such as
patients with a diagnosis of diabetes mellitus, obesity, and
polycystic ovarian syndrome [12]. Although benign forms of
AN are relatively common, malignant AN can occur as a rare
paraneoplastic syndrome with approximately 1,000 reported
worldwide cases [13]. It is most often seen in adults with
an underlying diagnosis of gastrointestinal adenocarcinoma
[7, 8]. Malignant AN tends to worsen with progression of
the neoplasm, lessen with treatment, and return with tumor
Case Reports in Endocrinology 3
2 3 4 5 6 7
(a)
(b)
(c)
Figure 1: (a) Gross photograph of resected adrenal mass. (b) Low
power photomicrograph of adrenocortical tumor. The tumor is
encapsulated (arrow) and has a pushing border, with compressed
normal adrenal cortex on the right. (H&E, 20x). (c) High power
photomicrograph of adrenocortical tumor. Arrow is pointing to a
thin fibrous capsule. The tumor has similar cytologic features to the
normal adrenal seen on the right. Features that have been associated
with malignancy (capsular invasion, necrosis, and increased mitotic
activity) are not present (H&E, 200x).
recurrence and/or metastases [8]. Malignant AN is extremely
uncommon in pediatric tumors [14, 15] with only one report-
ed pediatric case of malignant AN associated with a malig-
nant adrenal tumor [16].
The pathophysiology of malignant AN is not well under-
stood. Elevated levels of growth factors released from tumors,
such as transforming growth factor alpha (TGF-alpha), can
bind to epidermal growth factor receptors (EGFR) in the
epidermis and stimulate keratinocyte growth [7, 12, 17].
Malignant AN can be associated with the sign of Leser-
Trélat (LT), a rare and sudden onset of multiple benign skin
growths originating in keratinocytes (seborrheic keratoses)
and associated with an internal malignancy [7, 12]. Biopsy
specimens of seborrheic keratoses in a patient with LT,malig-
nant AN, and melanoma revealed elevated levels of urinary
TGF-alpha and increased epidermal staining of EGFRs, with
decreased levels of both after treatment of the melanoma
[17]. Hereditary diseases associated with AN demonstrate
activating germ line mutations in the fibroblast growth factor
receptor 3 (FGFR3) gene, which increase keratinocyte growth
[18–21]. A positive association of FGFR3 expression has been
reported in two cases of malignant AN, with expression
throughout the acanthotic lesions [22].
Our patient’s AN likely resulted from excess glucocorti-
coid production by the adrenal tumor, albeit not captured
in preoperative laboratory studies. His elevated IGF-1 driven
by increased adrenal androgens may have also played a
role. Contralateral adrenal cortical suppression with unde-
tectable cortisol and suppressed ACTH after surgery points
to excess glucocorticoid hormone secretion by the adrenal
mass in addition to the noted elevated adrenal androgens.
The excess glucocorticoid production likely contributed to
glucocorticoid-induced insulin resistance, resulting in AN.
This case represents the first reported association of malig-
nant AN with a nonmalignant, functional cortical adrenal
mass in a pediatric patient and an important clue to a possible
underlying cortical adrenal tumor as a contributing cause for
this unusual phenomenon.
Conflict of Interests
No real or perceived conflict of interests exists for the listed
authors.
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Case Report Acanthosis Nigricans Associated with an Adrenocortical Tumor in a Pediatric Patient

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Case Report Acanthosis Nigricans Associated with an Adrenocortical Tumor in a Pediatric Patient

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