Gefitinib: A Cause of Pyogenic

Granulomalike Lesions of the Nail

G eftinib (Iressa; AstraZeneca Pharmaceuticals LP,

Wilmington, Del) is an epidermal growth fac-
tor receptor (EGFR) tyrosine kinase inhibitor
used to treat non–small cell lung cancer (NSCLC). Re-
cently, this agent has been a point of controversy. In pa-
tients who demonstrate a response, the results are often
dramatic; however, such a response has occurred in as
few as 10% of treated patients.1
In June 2005, using data from a phase 3 trial that failed
to demonstrate prolonged survival, the US Food and Drug
Administration revised the labeling to indicate contin-
ued use only in those with a prior response to gefitinib
or in further clinical trials.2 Similar related monoclonal
antibodies include cetuximab, panitumumab, or erlo-
tinib. Despite recognized cutaneous manifestations at-
tributed to this entire class of EGFR inhibitors, there is
a paucity of discussion regarding such events within the
major American dermatology journals.
Report of a Case. A 78-year-old woman with NSCLC pre-
sented to our clinic with the complaint of exquisitely pain-
ful erythematous papules erupting from the proximal nail
fold of both thumbs (Figure). The tissue was friable and
bled easily. For this reason, she kept the lesions covered
with bandages most of the time. She had consulted her
oncologist and had also been examined by 2 dermatolo-
gists. Concern had focused on trauma-induced pyo-
genic granulomas or possibly metastases from her can-
cer. There was no history of trauma. Interestingly, she
also reported tender erythema surrounding the nail folds
of her great toes and had a faint, follicularly centered, ery-
thematous and papular eruption on the face, neck, and
upper chest. A review of her medications revealed that
she had begun gefitinib treatment 2 months prior to the
development of the lesions.
Cutaneous adverse effects of EGFR inhibitors in-
clude acneiform eruptions, xerosis, trichomegaly, telan-
giectasias, dyspigmentation, painful paronychia, nail
cracking, and pyogenic granulomalike lesions of the nail
fold.3 An acneiform rash is identified in 50% to 100% of
patients taking EGFR inhibitors, and it appears to be dose
dependent.3 Nail changes are seen in 10% to 15% of pa-
tients and are typically a later event, beginning 4 to 8 weeks
after initiation of therapy.4 The mechanism underlying
these cutaneous manifestations is unknown.3,4 Our pa-
tient demonstrated not only the acneiform rash but also
bilateral nail splitting with pyogenic granulomalike le-
sions of the thumbs after 8 weeks of gefitinib use.
Discontinuance of gefitinib therapy yielded slow but
complete resolution. The rash cleared in several weeks,
and the lesions of the nails resolved over 6 weeks. It is
unclear whether other therapy, such as debridement or
laser treatment, would have hastened resolution. Dis-
continuance alone was satisfactory to her, and was ac-
ceptable to her oncologist.
Comment. Pyogenic granulomalike lesions are a well-
recognized occurrence following treatment with certain
Figure. A 78-year-old woman presented with friable papules erupting from
the proximal nail fold of each thumb following 8 weeks of gefitinib use for
non–small cell lung cancer.
medications, including systemic retinoids, antiretrovi-
ral agents such as indinavir, and capecitabine, a novel fluo-
ropyrimidine used in the treatment of advanced breast
and colorectal cancers.5 While underappreciated within
much of the dermatology literature, gefitinib and other
EGFR inhibitors should be recognized as a cause of such
an occurrence, and further study might yield other rel-
evant cutaneous manifestations as well. Familiarity with
these cutaneous reaction patterns may improve patient
care, particularly with the expanding use of such agents.
Whitney A. High, MD
Correspondence: Dr High, Department of Dermatol-
ogy, University of Colorado Health Sciences Center Can-
cer Pavilion, PO Box 6510, Mail Stop F.703, Denver, CO
80045-0510 (whitney.high@uchsc.edu).
Financial Disclosure: None reported.
1. Frantz S. Drug discovery: playing dirty. Nature. 2005;437:942-943.
2. United States Food and Drug Administration. FDA Alert: Gefitinib (mar-
keted as Iressa) Information. http://www.fda.gov/cder/drug/infopage/ gefitinib
/default.htm. Accessed October 30, 2005.
3. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management
of skin toxicity during therapy with epidermal growth factor receptor inhibitors.
Ann Oncol. 2005;16:1425-1433.
4. Lee MW, Seo CW, Kim SW, et al. Cutaneous side effects in non-small cell
lung cancer patients treated with Iressa (ZD1839), an inhibitor of epidermal
growth factor. Acta Derm Venereol. 2004;84:23-26.
5. Piguet V, Borradori L. Pyogenic granuloma-like lesions during capecitabine
therapy. Br J Dermatol. 2002;147:1270-1272.
Acrokeratoelastoidosis With Nail Dystrophy:
A Coincidence or a New Entity?
A crokeratoelastoidosis (AKE) was first de-
scribed in 1954.1 This dominant disorder is char-
acterized by the presence of small, skin-
colored to yellowish, round to polygonal papules on the
thenar and hypothenar eminences of the palms and on
the plantar surfaces of the feet. Histologic examination
typically shows broadening of the granular layer, with
circumscribed hyperkeratosis in a cup-shaped depres-
sion of the epidermis. Fragmentation of elastic fibers is
also found.2 Histologic studies are needed to differenti-
ate AKE from similar disorders such as focal acral hy-
perkeratosis, acrokeratosis verruciformis of Hopf, and

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Figure 1. Nail dystrophy with pterygium formation (inset).
B
Figure 2. A,Translucent polygonal papules on the thenar eminence;
B, hyperkeratosis with papules on the plantar surface.
punctate palmoplantar keratoderma.3,4 To our knowl-
edge, no other skin abnormalities have been described
in conjunction with AKE to date,4 but we recently saw a
patient with AKE that was accompanied by pitted kera-
tolysis and nail dystrophy.
Report of a Case. A 47-year-old Dutch woman sought
help for abnormal nails. She had also noted thickening
of the skin on the soles of her feet, which had an un-
pleasant smell. “Bumps” had been present on the pal-
mar surface of her hands for a long time, but she had paid
no particular attention to them. Other family members
were not affected. Her general health was good. Physi-
cal examination revealed dystrophic nails with longitu-
dinal ridging, onychorrhexis, and distal onycholysis. Some
nails showed pterygia (Figure 1). Multiple polygonal
to round, translucent, skin-colored papules of varying size
were present on the thenar and hypothenar eminences
of both hands. The soles of the feet demonstrated a yel-
low hyperkeratosis with grayish pits on the balls of the
feet and polygonal papules along the edges of the soles
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Figure 3. Typical histopathologic appearance, with hyperkeratosis overlying a
cup-shaped depression (hematoxylin-eosin, original magnification ⫻50). Inset,
Fragmentation of elastic fibrils (elastic van Gieson, original magnification ⫻100).
(Figure 2). A pronounced fetor was noted, prompting
an examination with a Wood light, which showed a coral-
red fluorescence between the toes, extending onto the
plantar surface of the feet (not shown). Histologic ex-
amination of a papule revealed broadening of the granu-
lar layer, with a circumscribed hyperkeratosis project-
ing into a cup-shaped depression of the epidermis. The
underlying dermis contained fragmented elastic fibers
(Figure 3). Based on these results, a diagnosis of AKE
with pitted keratolysis was made. Treatment with topi-
cal antibiotics resulted in clearance of the pits and dis-
appearance of the fetor.
Comment. The present case is unusual. The patient had
pitted keratolysis, also referred to as keratoma sulcatum.
We consider it unlikely that there is a direct association
between pitted keratolysis and AKE, but in this case, the
pitted keratolysis obscured the plantar keratoderma that
can be part of AKE5 and resulted in a delay in diagnosis.
Nail dystrophy has not been previously described in AKE,
but subtle changes may well have escaped attention. The
lifelong presence of the nail dystrophy, the fact that all nails
were affected, and the absence of skin changes, as seen in
psoriasis or lichen planus, suggest that the nail abnormali-
ties in our patient are part of the phenotype. Careful ex-
amination for nail dystrophy in patients with AKE will help
to delineate the extent of nail disease in AKE.
Maurice A. M. van Steensel, MD, PhD
Valerie L. R. M. Verstraeten, MD
Jorge Frank, MD, PhD
Correspondence: Dr van Steensel, Department of Derma-
tology, University Hospital Maastricht, PO Box 5800, 6202
AZ Maastricht, the Netherlands (mvst@sder.azm.nl).
WWW.ARCHDERMATOL.COM
Financial Disclosure: None reported.
Funding/Support: Dr van Steensel’s research is sup-
ported by Barrier Therapeutics NV, Geel, Belgium, and
by the International Pachyonychia Congenita Founda-
tion. Dr Verstraeten is supported by funds from the
University Hospital Maastricht. Dr Frank is a member
of the Network for Ichthyoses and Related Keratiniza-
tion Disorders (NIRK), which is supported by the Ger-
man Federal Ministry of Education and Research
(BMBF).
1. Costa OG. Acrokeratoelastoidosis. AMA Arch Derm Syphilol. 1954;70:228-231.
2. Fiallo P, Pesce C, Brusasco A, Nunzi E. Acrokeratoelastoidosis of Costa: a pri-
mary disease of the elastic tissue? J Cutan Pathol. 1998;25:580-582.
3. Korc A, Hansen RC, Lynch PJ. Acrokeratoelastoidosis of Costa in North America:
a report of two cases. J Am Acad Dermatol. 1985;12:832-836.
4. Lewis KG, Bercovitch L, Dill SW, Robinson-Bostom L. Acquired disorders of
elastic tissue, II: decreased elastic tissue. J Am Acad Dermatol. 2004;51:165-
188.
5. Highet AS, Rook A, Anderson JR. Acrokeratoelastoidosis. Br J Dermatol. 1982;
106:337-344.
Comment. Trigeminal trophic syndrome is a rare com-
plication after peripheral or central damage to the tri-
geminal nerve.3 There are approximately 125 cases re-
ported in the literature, and of those, only 2 cases have
been reported in children with associated Herpes sim-
plex trigeminal neuritis and trigeminal neuralgia.1,2 The
ulcers usually present 2 to 30 weeks after injury to the
trigeminal ganglion.4 The lesions are characterized by cres-
cent-shaped erosions occurring in the dermatomal dis-
tribution of the trigeminal nerve, typically involving the
nasal ala, but they can also involve other areas such as
the scalp, forehead, ear, palate, and jaw. Trigeminal tro-
phic syndrome may also involve the mucous mem-
branes, as was seen in this patient. Interestingly, our pa-
tient also went on to develop neurotrophic keratitis of

Trigeminal Trophic Syndrome:

A Pediatric Case

T rigeminal trophic syndrome (TTS) is a rare con-

dition characterized by unilateral facial ulcer-
ation, usually involving the nasal ala, resulting
from damage to the trigeminal nerve or its central sen-
sory root. To our knowledge, there are only 2 previ-
ously reported1,2 pediatric cases of TTS.

Report of a Case. An 8-year-old girl presented with a

2-month history of multiple ulcerations involving the left
side of her face. Significant medical history included a
possible pilocytic astrocytoma of the lower brainstem par-
tially resected at age 7 years. During a second resection,
the residual tumor was reclassified as a ganglioglioma.
Several months later, she presented to her primary care
physician with a crusted erosion on the left side of her
nose. Despite multiple courses of antibiotics for sus-
pected impetigo, the ulcerated lesions enlarged. Subse-
quently, the patient was referred to the dermatology and Figure 1. Crescent-shaped ulcerations involving the left medial infraorbital
otolaryngology departments for evaluation. region, chin, and cheek extending into the internal lateral nasal ala.
On initial examination, she was noted to have ery-
thematous, crescent-shaped ulcerations with crust on the
left medial infraorbital region, chin, cheek, and internal
left lateral nasal ala (Figure 1). An eroded white plaque
on the lateral left side of the tongue was also noted
(Figure 2). Superficial sensation did not seem to be de-
creased on the left side of her face. Vasculitis was not found
on serologic evaluation, and indirect immunofluores-
cence findings were negative. Histopathologic findings
revealed nonspecific necrosis and acute inflammation of
the involved skin and nasal mucosa. Viral, fungal, and
acid-fast bacilli tissue culture findings were negative. A
bacterial tissue culture was positive for methicillin-
resistant Staphylococcus aureus. Despite wound care and
antibiotic coverage for methicillin-resistant S aureus, the
ulcerations continued to worsen. A second opinion from
another pediatric dermatologist was therefore obtained,
and a clinical diagnosis of trigeminal trophic syndrome
was made. Figure 2. Eroded white plaque of the lateral left side of the tongue.

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