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SHORT COMMUNICATION
Human Papillomavirus Type 16 Induced Squamous Cell Carcinoma (In situ) of the Toes
Alexander KREUTER 1 , Georgios MITRAKOS 1 , Bijan KOUSHK-JALALI 1 , Thomas KUNTZ 1 , Frank OELLIG 2 , Christian TIGGES 1 ,
Steffi SILLING 3 and Ulrike WIELAND 3
Department of Dermatology, Venereology, and Allergology, HELIOS St Elisabeth Hospital Oberhausen, University Witten-Herdecke, DE-46045
Oberhausen, 2 Institute of Pathology, Mülheim an der Ruhr, Mülheim, and 3 Institute of Virology, National Reference Center for Papilloma-
and Polyomaviruses, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Germany. E-mail: [email protected]
1
Accepted Jul 9, 2019; E-published Jul 10, 2019
Human papillomaviruses (HPV) are amongst the most
common sexually transmitted infections. Phylogenetically,
HPVs are classified into 5 different genera, called alpha,
beta, gamma, mu and nu (1). Approximately 40 HPV-types
of the genus alpha predominantly infect the anogenital
region and, depending on their oncogenic potential, are
divided into low- and high-risk HPV types (1, 2). Alpha-
HPV infections can cause a broad spectrum of diseases,
ranging from benign genital warts to (pre-)invasive can-
cer. In contrast to HPV-induced anogenital disease, the
association of alpha-HPV infection with squamous cell
carcinoma (SCC) of the non-genital skin is a very rare
event. Certain digital (particularly periungual) SCCs and
SCCs in situ are associated with alpha-HPV infections,
especially with HPV16 (3–5). Anogenital–digital spread
of high-risk HPV has been suggested to play a role in the
pathogenesis of these lesions (6). To date, the association
of HPV with SCC or SCC in situ located on the feet has
only been reported rarely. We describe here 2 patients
with HPV16-induced SCC and SCC in situ of the toes,
with significant delay between first clinical appearance
and correct diagnosis in both cases.
CASE REPORTS
Patient 1. A 78-year-old Caucasian woman presented with a
slowly enlarging verrucous plaque located in the 4 th interdigital
space of the right foot (Fig. 1A). She reported that she had first
noticed the asymptomatic lesion 18 years previously. She had
undergone several treatments with topical antifungal and anti-
bacterial creams, without clinical improvement. The patient had
no history of trauma, previous HPV-related disease, no exposi-
tion to tar, and no previous arsenic or radiation therapy. Besides
arterial hypertension and hypothyroidism, her medical history was
unremarkable. Inspection of the entire skin, including the anoge-
nital region, revealed no further abnormalities. HIV testing was
negative and lymphocyte subpopulations were within the normal
range. The patient was a non-smoker. A lesional punch biopsy
revealed typical histological features of SCC in situ with focal
areas of invasive SCC (Fig. 1B). Maximal depth of penetration of
the SCC was 1.2 mm. Immunohistochemical staining for p16 INK4a ,
an indirect marker of high-risk HPV E7-oncogene expression,
showed strong nuclear and cytoplasmatic p16 INK4a -expression
(Fig. 1C). HPV-DNA detection and typing from lesional tissue
biopsies were performed with an alpha-HPV group-specific PCR
and bead-based multiplex hybridization (7, 8). HPV-DNA load
was determined with real-time PCR using type-specific primers
and probes (8). The assays revealed infection with HPV16 and a
high viral load of 1,893 HPV16 DNA copies per beta-globin gene
copy. Surgical excision of the lesion, with a margin of 5 mm, was
performed, followed by coverage with a split-thickness skin graft.
Patient 2. A 31-year-old Caucasian woman presented with
complete destruction of the nail apparatus of the right hallux is
presented in Appendix S1 1 .
DISCUSSION
Almost all cervical cancers, the vast majority of anal
cancers, and approximately half of all vulvar and penile
carcinomas, are induced by high-risk alpha-HPV-types.
Specific alpha-HPV-types, especially HPV16, are invol-
ved in the pathogenesis of periungual SCCs (3, 4). It has
been hypothesized that the periungual skin is particularly
susceptible to HPV acquisition due to the propensity of the
nail unit to abrasion and microtrauma (4). In the largest
https://www.medicaljournals.se/acta/content/abstract/10.2340/00015555-3260
1
Fig. 1. Patient 1. (A) Clinical findings at first presentation in our department. A verrucous hyperkeratotic plaque with brownish adherent crusts is
located in the interdigital space of the right foot, enlarging to the dorsal part of both toes. (B) Histopathological findings of a lesional biopsy. Atypical
keratinocytes are present in the entire epidermis, with focal areas of microinvasion into the dermis and moderate accompanying inflammatory infiltrates.
These findings are consistent with microinvasive squamous cell carcinoma. The maximal depth of penetration is 1.2 mm (original magnification 100×).
(C) Immunohistochemical staining with p16 INK4a . Strong nuclear and cytoplasmic p16 INK4a -expression is present in the entire epithelium (called p16 INK4a -
block-staining) and in areas of invasive squamous cell carcinoma. p16 INK4a is an indirect marker of high-risk human papillomavirus E7 oncogene expression
(original magnification 100×).
This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta
Journal Compilation © 2019 Acta Dermato-Venereologica.
doi: 10.2340/00015555-3260
Acta Derm Venereol 2019; 99: 927–928