Dermatology Online Journal

Multiple human papillomavirus-16 associated digital squamous-cell carcinomas in an immunocompetent woman with prior human papillomavirus-related genital carcinoma
Raegan Hunt MD PhD, Charlotte Hwa BA, Julia Tzu MD, Rishi Patel MD, Peter Rady MD PhD, Stephen K Tyring MD PhD, Jennifer Stein MD PhD
Dermatology Online Journal 17 (10): 20

Department of Dermatology, New York University, New York, New York

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Abstract

High-risk subtype human papillomavirus (HPV) infection, which is known to contribute to the oncogenesis of anogenital squamous-cell carcinoma (SCC), is detected in the majority of digital SCCs. Evidence suggests a genital-digital route of transmission of high-risk HPV, and most HPV-related digital SCCs occur near the nail unit in immunocompetent adults. As early HPV-related SCC commonly appears as a verrucous periungual papule, a biopsy should be considered if such a lesion persists or occurs in an individual who is likely to inoculate their digits with high-risk HPV from digital-genital contact with themselves or sexual partners. We present a 60-year-old woman, who has a personal history of vulvar and cervical SCC and an appreciable disease burden from SCCs that involved five digits of her hands.

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History

A 60-year-old woman presented to the Charles C. Harris Skin and Cancer Unit for evaluation of gradually expanding verrucous plaques on five digits of the hands. The affected digits were painful and intermittently bled, and were without loss of sensation or paresthesia. She denied a history of trauma to her fingers as well as any occupational or environmental exposure to carcinogens. She reported minimal exposure to well water in Puerto Rico and no known arsenic ingestion. Past medical history included genital warts, vulvar squamous-cell carcinoma, and invasive cervical cancer, which required wide local vulvar excision, skin grafting, and hysterectomy. She reported that the growths on her fingers developed approximately ten years after the genital warts appeared. They had been treated with cryotherapy without resolution. There was no history of susceptibility to infectious organisms. She reports one lifetime male sexual partner, who also was infected with genital warts. No family members have a similar skin condition. Review of symptoms was negative.

Physical examination

Figure 1

Verrucous, pink-tan plaques extended from the distal phalanx to past the distal interphalangeal joint in a partially-circumferential manner on the first and second digits of the right hand and the second through fourth digits of the left hand. A 1 mm to 2 mm band of brown hyperpigmentation accentuated the proximal edges of several plaques. On three of the five affected digits, the nailplate was lost or dystrophic. The toes were normal. No verrucous, flat papules or erythematous macules were found elsewhere on the body.

Laboratory data

Radiographs of the affected fingers were unremarkable with no bony invasion. A complete blood count was normal. An ELISA test was negative for antibodies to the human immunodeficiency virus-1. Human papillomavirus (HPV) testing of the digital lesions demonstrated infection with HPV-16 [1].

Histopathology

Figure 2

There is a papillated, acanthotic epidermis with orthokeratosis and parakeratosis, full-thickness keratinocytic atypia, suprabasal mitoses, and dyskeratosis.

Discussion

Although the exact incidence is unknown, digital squamous-cell carcinoma (SCC) represents a small subset of SCC. Digital SCC can present a diagnostic challenge by mimicking benign conditions, such as verruca vulgaris and chronic paronychia. Risk factors for the development of SCC include exposure of the hands to ionizing radiation or carcinogenic chemicals, arsenic ingestion, trauma, burns, genetic predisposition from specific genodermatoses, immunosuppression, and infection with human papillomavirus (HPV) [2-7].

High-risk HPV strains (most frequently HPV-16, -18, -31, and -35) are known to contribute to oncogenesis in anogenital and cervical SCC [8]. Apart from genital SCCs, HPV-associated cutaneous SCC in the immunocompetent host has been limited to the fingers with a predilection for the periungual and subungual areas [9, 10]. Over a 15-year period, one group found that 90 percent of all digital SCCs encountered were HPV-associated. However, they noted that HPV positive and negative digital SCCs affected the same demographic population and were clinically indistinguishable [10]. The most frequent clinical presentation of HPV-related digital SCC is a persistent, periungual, verrucous papule or plaque, but also it may manifest as a subungual tumor, onycholysis, or melanonychia [11].

The most commonly associated HPV type in digital SCC is HPV-16, which accounts for 74 percent of examined cases although HPV-2, -11, -18, -26, -31, -34, -35, -56, -58, and -73 also have been detected [12]. HPV-11, which is the only associated low-risk HPV type reported, always co-existed with a high-risk HPV subtype. In some patients, the same HPV type has been identified in both digital SCCs and samples from genital dysplasia, which suggests a genital-digital transmission route [10]. A literature review of 120 HPV-associated digital SCCs found that approximately one-third of the patients had a history of HPV-related genital disease in themselves or a sexual partner, and only 6.8 percent of patients were immunocompromised. In this series, multiple HPV-related digital SCCs occurred in only thirteen patients (12.6%), among whom one patient was female [11].

HPV-related and HPV-negative digital SCCs share the same 2 percent to 3 percent risk of metastasis; however, HPV-related digital SCCs are more likely to be locally aggressive and to recur after excision [13]. In comparison to HPV-negative digital SCCs, HPV-related digital SCCs exhibit higher levels of p16^INK4a and Ki67 expression, which suggests that an increased cellular proliferation rate may contribute to the biologic behavior of these tumors [9]. The majority of digital SCCs are surgically excised using the Mohs micrographic technique. HPV-related digital SCC recurrence after Mohs micrographic surgery is reported to be as high as 20 percent in contrast with an average recurrence rate of 3 percent for all cutaneous SCC after Mohs micrographic surgery [11, 14]. Residual oncogenic HPV harbored in cells beyond the tumor margin, which was observed in two cases at the periphery of the specimen, may in part account for this high recurrence risk [10]. Radiation therapy has been described as an alternative treatment modality for those unable or unwilling to undergo surgical excision [11].

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