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Anthony Amoroso, Section Editor
A Patient With Ulcerated Nodules on His Face
(See page 839 for the Photo Quiz.)
Figure 2. Histologic section from right mandibular region skin biopsy
(hematoxylin-eosin stain, ×100 magnification), demonstrating squamous
cell carcinoma. The image shows a dermal proliferation with nuclear
atypia and numerous mitotic figures (small arrow). The cells have abundant eosinophilic cytoplasm with intracellular bridging confirming the squamous lineage (large arrow).
Figure 1. Skin lesions on the right side of the face; diffuse nontender,
hard, ulcerated nodules with necrosis that oozed serous fluid.
Diagnosis: Cutaneous squamous cell carcinoma (SCC) likely
due to the long-term use of voriconazole.
In some clinical settings, ulcerated nodular skin lesions can be
concerning for a cutaneous nontuberculosis mycobacterial or
fungal infection (Figure 1). However, in our patient, the histological sections of skin from the right mandibular region demonstrated dermal proliferation with nuclear atypia and numerous
mitotic figures typical of SCC (Figure 2). In addition, the cells
had abundant eosinophilic cytoplasm with intracellular bridging
confirming the squamous lineage. The overlying surface epithelium was relatively unremarkable and all fungal and nontuberculosis mycobacterial specific stains and cultures were negative.
A computed tomographic (CT) scan of the head and neck
revealed periauricular skin thickening compatible with SCC
with focal dermal lesions along the face in addition to necrotic
lymphadenopathy with apparent invasion into the floor of the
mouth.
Based on the biopsy and CT findings, the patient was diagnosed with stage IV cutaneous SCC (T4N1M0, with various bilateral cervical lymph nodes). He underwent his initial
treatment with local radiotherapy (40 Gy in 16 fractions),
which was complicated by hemoptysis. His chronic fungal
infection, decreased pulmonary function, and overall poor performance status prohibited the use of systemic myelosuppressive chemotherapy; therefore, a palliative course of cetuximab
(epidermal growth factor receptor inhibitor) was administered.
Unfortunately, despite these interventions, his SCC progressed
over a period of several months and eventually led to airway
compromise and death.
Voriconazole is a broad-spectrum second-generation azole
that exerts its antifungal activity by inhibiting ergosterol synthesis [1]. It has activity against all Candida species, most Aspergillus species, Fusarium species, the endemic mycoses, and
Scedosporium apiospermum [1].
Voriconazole is generally well tolerated, but side effects can
include self-limiting visual disturbances ( photophobia, altered
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CID 2014:58 (15 March)
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901
color discrimination, and blurred vision) and elevations in
hepatic enzymes [1].
Of note, this antifungal agent can also cause a generalized
rash in up to 8% of patients, and more specifically, voriconazole
has been associated with a phototoxicity-related rash that manifests as a sunburn-like erythema in 2% of patients [2, 3].
The mechanism of action for voriconazole-associated phototoxicity is largely unknown. One theory is that voriconazole
inhibits all-trans retinol metabolism and leads to the accumulation of phototoxic retinoid compounds [3]. Another explanation is that the principal metabolite of voriconazole, voriconazole
N-oxide, absorbs the ultraviolet A wavelength (the action spectrum for most phototoxic reactions) and induces this phenomenon [4].
It is hypothesized that voriconazole-induced phototoxicity
may account for the recent reports linking the long-term use of
this antifungal agent to the development of cutaneous SCC and
melanoma [5–12].
In the largest case series, Clancy et al reported 36 patients with
skin cancer following the long-term use of voriconazole [5]. All
patients reported were white, the majority were men, the median
length of voriconazole use ranged from 2 to 60 months, and 3
died as a result of their skin cancer [5].
The use of immunosuppressive therapies, underlying human
immunodeficiency virus (HIV) infection, and residing in
regions of the United States with high sun exposure appear to
be risk factors for the development of voriconazole-associated
SCC [6–8, 10]. Our patient was not infected with HIV or on immunosuppressive medications. However, we suspect that his
residence in Virginia (a region of the United States with higher
levels of sun exposure and ultraviolet index compared to northwestern states such as Washington and Oregon) in addition to
his severely decreased pulmonary function and chronic fungal infection may have been put him at risk for this malignancy [13].
Although further studies are needed to define the causal relationship between voriconazole use and SCC, when prescribing
this antifungal agent, physicians should advise patients to limit
sunlight exposure and have new skin lesions evaluated promptly.
Notes
Acknowledgments. In fond memory of J. A. M., who reminded us that
medicine is still an art, and that every day is a blessing.
Disclaimer. The views expressed in this article are those of the authors
and do not necessarily reflect the official policy or position of the Department of the Navy, Department of the Army, Uniformed Services University,
Department of Defense, or the US government. This work was prepared as
part of D. C. D., J. D. M., E. H., J. M., and T. J. W. official duties. Title 17
U.S.C. 101 defines a US government work as a work prepared by a military
service member or employee of the US government as part of that person’s
official duties. Reviewed by the WRNNMC public affairs office in September 2013.
Potential conflicts of interest. All authors: No reported conflicts.
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CID 2014:58 (15 March)
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ANSWER TO THE PHOTO QUIZ
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
Dennis C. Drinkwater,1 Jan Davidson-Moncada,2 Emily Heckendorn,3
Janet Myers,4 and Timothy J. Whitman5
1
Department of Internal Medicine, Walter Reed National Military Medical Center
(WRNMMC), 2Department of Hematology/Oncology, National Institutes of Health,
and 3Department of Pathology, WRNMMC, Bethesda, Maryland; 4Department of
Pulmonary Medicine, United States Naval Hospital Okinawa, Japan; and
5
Department of Infectious Diseases, WRNMMC, Bethesda, Maryland
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agent. Clin Infect Dis 2003; 36:630–7.
2. Rubenstein M, Levy ML, Metry D. Voriconazole-induced retinoid-like
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facial erythema related to the novel triazole antifungal agent voriconazole. Clin Exp Dermatol 2001; 26:648–53.
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Biochem Pharmacol 2007; 73:2020–6.
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there cause for concern? Curr Infect Dis Rep 2011; 13:536–43.
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therapy. AIDS 2008; 22:905–6.
11. Vanacker A, Fabre G, Van Dorpe J, et al. Aggressive cutaneous squamous cell carcinoma associated with prolonged voriconazole therapy in
a renal transplant patient. Am J Transplant 2008; 8:877–80.
12. McCarthy KL, Playford EG, Looke DF, et al. Severe photosensitivity
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voriconazole therapy. Clin Infect Dis 2007; 44:e55–6.
13. National Oceanic and Atmospheric Administration. National Weather
Service Climate Prediction Center. Available at: http://www.cpc.ncep.
noaa.gov/products/stratosphere/uv_index/uv_current_map.shtml. Accessed 27 September 2013.
Correspondence: Timothy J. Whitman, DO, Department of Infectious Diseases, Walter Reed
National Military Medical Center, 8901 Wisconsin Ave, Bethesda, MD 20889 (timothy.j.
[email protected]).
Clinical Infectious Diseases 2014;58(6):901–2
Published by Oxford University Press on behalf of the Infectious Diseases Society of America
2014. This work is written by (a) US Government employee(s) and is in the public domain in the
US.
DOI: 10.1093/cid/cit713