Human papillomavirus (HPV) is a DNA virus that causes

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1 Human Papillomavirus Infection of the Skin Patrick Bacaj, MD; David Burch, MD Context. Human papillomavirus is implicated in the pathogenesis of benign and malignant neoplasms of the skin. Objective. To review the role of human papillomavirus in the development of malignancies and their precursor lesions in skin. Data Sources. The study comprised a review of the literature. Conclusions. The use of low-grade squamous intraepithelial lesion and high-grade squamous intraepithelial lesion terminology brings order and simplicity to these lesions, correlates with the current understanding of the biology of human papillomavirus infections, and helps to promote accurate diagnosis of and appropriate treatment for these lesions. (Arch Pathol Lab Med. 2018;142: ; doi: / arpa ra) Human papillomavirus (HPV) is a DNA virus that causes a variety of lesions when it infects the squamous cells of the skin, depending on site, HPV type, and immune status. The terminology of HPV-associated lesions of genital and perianal skin has undergone changes that have been driven by increased understanding of the biology of HPV infections and their clinical and morphologic implications. 1 Traditional terms for HPV-associated lesions of genital and perianal skin include condyloma acuminatum and Bowen disease. Outside of the anogenital region the more common warts include verruca vulgaris, verruca plantaris, and verruca plana. Epidermodysplasia verruciformis reflects a genetic predisposition to certain HPV types not normally found infecting the general population. HPV TYPES AND THE LESIONS THEY PRODUCE Classification of HPV is based on the DNA sequence of the viral L1 gene 2. A simplified association between HPV type and the skin lesion it produces is presented in the Table The HPV types 6 and 11 are found in more than 90% of low-grade squamous intraepithelial lesions (LSILs) of the lower anogenital tract, such as condyloma acuminatum, but HPV types 16, 18, 31, 33, and 51 confer an increased risk of high-grade squamous intraepithelial lesion (HSIL) and carcinoma. Simultaneous dual infection of condyloma acuminatum by low-risk and high-risk HPV is common. 8,9 MECHANISM OF HPV EFFECT ON SQUAMOUS CELLS Following the infection of basal squamous cells, HPV stimulates epidermal proliferation and production of viral Accepted for publication February 2, From the Department of Pathology, West Virginia University School of Medicine, Morgantown. The authors have no relevant financial interest in the products or companies described in this article. Corresponding author: Patrick Bacaj, MD, Pathology Department, West Virginia University Hospital, 1 Medical Center Dr, Morgantown, WV ( pbacaj@hsc.wvu.edu). particles. To stimulate epidermal proliferation, some of the proteins coded for by the virus suppress the cell cycle control mechanisms found in human cells. The E6 viral protein binds to p53, interfering with its normal functions and enhancing its degradation. The normal functions of p53 include cell cycle arrest, facilitation of DNA repair, and apoptosis when DNA damage is beyond repair. The E7 viral protein binds to RB (retinoblastoma protein), removing another check that would ordinarily keep the cell from entering the cell cycle and dividing. 14 For low-risk HPV types, such as HPV 2 (in the skin) and HPV 6 and HPV 11 (in the anogenital region), the affected squamous cells proliferate but mature as they approach the skin surface and the lesions often eventually regress. Not only do the highrisk HPV types, such as HPV 16, induce squamous proliferation, but the affected cells fail to mature, resulting in dysplasia, and the cells eventually may become frankly malignant. The HPV types that readily integrate into the host DNA rather than remaining as episomal DNA have the greatest predilection for causing malignant transformation, in part by causing gene mutations in the process of integration that compound the functional loss of p53 and RB. 15 The tumor suppressor protein p16 is not inhibited directly by HPV proteins and is naturally increased in the absence of RB, but even excess amounts of p16 cannot fully compensate for the loss of p53 and RB in infected cells that have undergone malignant change. TERMINOLOGY OF HPV-ASSOCIATED LESIONS OF GENITAL AND PERIANAL SKIN The terminology of HPV-associated lesions of genital and perianal skin has undergone change driven by increased understanding of the biology of HPV infections and their clinical and morphologic implications. 1 Much of the older terminology of these lesions predates the knowledge that they are virally induced. Older terms for HPV-associated squamous proliferations of the lower anogenital tract (LAT) that are low grade (unlikely to progress to invasive carcinoma) are condyloma acuminatum, flat condyloma, and giant condyloma. The intraepithelial neopla- 700 Arch Pathol Lab Med Vol 142, June 2018 HPV Infection of Skin Bacaj & Burch

2 Human Papillomavirus (HPV) Types of Various Skin Lesions 3 13 Disease Most Common HPV Types Other Types Verruca vulgaris 2 4, 7, 27, 57 Butcher warts 7 2 Verruca plantaris 1 2, 4, 63 Verruca plana 3 10 Epidermodysplasia verruciformis 5, 8 14, 20, 21, 25, 47 Condyloma acuminatum 6, 11, 16 18, 31, 33, 51 Squamous carcinoma 16 18, 33, 5, 8 sia terminology has also been applied to these lesions. Thus, a vulvar condyloma can also be called vulvar intraepithelial neoplasia grade 1 (VIN 1). Similarly, penile condyloma can be called penile intraepithelial neoplasia grade 1 (PeIN 1), and perianal condyloma can be called perianal intraepithelial neoplasia grade 1 (PAIN 1). More recently, the Lower Anogenital Squamous Terminology (LAST) Project for HPV-Associated Lesions has proposed that all of these low-grade lesions be called low-grade squamous intraepithelial lesion. 1 Older terms for HPV-associated lesions of the LAT that are high grade (having significant risk of progression to invasive carcinoma) include erythroplasia of Queyrat for penile lesions, and Bowen disease and Bowenoid papulosis for lesions of the LAT in general. 16 The intraepithelial neoplasia terms for these diseases would be penile, vulvar, or perianal intraepithelial neoplasia grades 2 and 3 (PeIN 2/3, VIN 2/3, or PAIN 2/3, respectively). The LAST Project recommends that these lesions be called high-grade squamous intraepithelial lesions. 1 TYPES OF LSILS OF THE ANOGENITAL TRACT Low-grade squamous intraepithelial lesion of the LAT represents the clinical and morphologic manifestation of productive HPV infection. Low-grade squamous intraepithelial lesions can present as a hyperkeratotic macule that has been called mild dysplasia; VIN 1, PeIN 1, or PAIN 1; or flat condyloma. When the surface of LSIL is undulating, polypoid, papillary, or verrucous the terms condyloma acuminatum or anogenital wart have been employed. The virus that causes LSIL is sexually transmitted, with an estimated 1% prevalence in the sexually active population in the United States. At least 90% to 95% of LSILs are associated with low-risk HPV types 6 or 11, whereas a small minority is associated with high-risk HPV types (16, 18, 31, 33, and 51). 8,9 Most cases resolve spontaneously or are cured by simple excision, 17 but recurrent condyloma acuminatum (large polyps of LSIL) refractory to treatment can be a source of great distress for the patient. The clinical differential diagnosis of LSIL may include seborrheic keratosis or fibroepithelial polyp. A lesion that has the gross morphology of seborrheic keratosis but is positive for HPV infection is best considered to be condyloma acuminatum. 18 The degree of squamous proliferation in LSIL ranges from simple acanthosis to marked papillomatosis. Basal hyperplasia and crowding are found in the lower portion of the epidermis, but the cells gain more cytoplasm as they approach the surface. Mitotic activity is limited to the base of the epithelium, including around dermal papillae. Parakeratosis and hyperkeratosis reflect rapid proliferation of keratinocytes. Cells with large, hyperchromatic nuclei, irregular nuclear contour, and perinuclear clearing, called koilocytes, are a helpful but not mandatory feature of the upper portion of the epidermis (Figure 1). When the LSIL of HPV origin becomes very large, it has been called the giant condyloma of Buschke and Loewenstein. This occurs most commonly in males in the glans and foreskin, but it may occur as a perianal lesion in females. It is a large (5 10 cm) condyloma acuminatum, which may extend into deeper tissues with a pushing border. It is microscopically benign, characterized by cells with a low N/C ratio. Vacuolization of keratinocytes is mild or absent. By immunohistochemistry it is negative for p16. The differential diagnosis is with warty carcinoma and verrucous carcinoma. 19 HSIL OF THE LAT A variety of alternative terms continue to be used for HSIL of the LAT, depending on site of involvement, clinical findings, and personal preference. In 1912 Dr Bowen described 2 cases, 1 on the buttocks and 1 on the lower leg, which microscopically had atypical cells throughout the squamous layer, without maturation. 20 The term Bowen disease has hence been used for squamous carcinoma in situ in sun-exposed skin and what is now called HSIL in the LAT. Bowen disease is typically a circumscribed, erythematous scaly plaque. A distinction has been made between Bowen disease and Bowenoid papulosis based on clinical features. The clinical appearance of Bowenoid papulosis is of multiple, small, red or pigmented papules of the genitalia that may be verrucous. It tends to occur in younger patients than Bowen disease does, in males it mostly occurs on glans or shaft of the penis, and in females it is often vulvar or perineal. The lesions tend to resolve spontaneously but may persist or progress to invasive carcinoma. 16 Plaques and papules of HSIL, sometimes multifocal, have been classified by site using the intraepithelial system. Grades 2 and 3 of VIN, PeIN, and PAIN all can be subsumed under the rubric of HSIL. Erythroplasia of Queyrat is a clinical term applied to HSIL (squamous cell carcinoma [SCC] in situ) of the glans penis. It presents as a circumscribed, red, shiny plaque. Microscopically it is identical to other types of HSIL. High-grade squamous intraepithelial lesion is recognized to carry a risk of developing into invasive SCC if left untreated, 21 but the degree of risk has not been established. Older patients and larger lesions of HSIL are associated with a greater risk of invasion. 17 High-grade squamous intraepithelial lesion microscopically shows full-thickness crowding of atypical keratinocytes, with hyperchromatic nuclei, anisonucleosis, high nuclear to cytoplasmic ratio, and parakeratosis (Figure 2, A). Mitoses are numerous, sometimes atypical, and can be found above the basal layer (Figure 2, B). Koilocytosis may be seen. High-grade squamous intraepithelial lesion may extend into skin appendages and mimic invasive SCC. High-grade squamous intraepithelial lesion is associated with high-risk HPV types (16, 18, 31, 33, and 51). 22 Squamous cell carcinoma in situ arising in sun-damaged skin appears similar, although it may have larger nuclei, a lower nuclear to cytoplasmic ratio, and fewer mitoses. In sun-exposed skin, solar radiation is the major etiologic Arch Pathol Lab Med Vol 142, June 2018 HPV Infection of Skin Bacaj & Burch 701

3 Figure 1. Low-grade squamous intraepithelial lesion (condyloma acuminatum) with acanthosis, papillomatosis, parakeratosis, and koilocytotic atypia (hematoxylin-eosin, original magnification 3200). Figure 2. High-grade squamous intraepithelial lesion (HSIL) arising in condyloma acuminatum. A, At lower magnification, lack of maturation gives the epithelium a darker appearance. Marked parakeratosis is also evident. B, Note the absence of epithelial maturation in HSIL (left half of photograph) (hematoxylin-eosin, original magnifications 3100 [A] and 3200 [B]). factor, although HPV may also be involved, especially in immunocompromised patients SQUAMOUS CELL CARCINOMA Squamous cell carcinoma is defined as an invasive carcinoma composed of squamous cells. The basaloid and warty variants of SCC are associated with HPV infections. The basaloid variant of SCC is composed of immature basaltype cells. The warty variant may have superficial koilocytotic atypia. Both variants are usually positive for HPV 16 and p16. Most verrucous carcinomas, in contrast, are HPV negative and lack koilocytotic atypia. Clinically, SCC of usual type is solitary and forms an ulcer, macule, nodule, or verrucous mass. Microscopically, SCC demonstrates infiltrating islands of malignant squamous cells. The prognosis of SCC depends on depth of invasion and lymph node status. The basaloid variant of SCC is an HPV-related aggressive tumor that presents as a flat, ulcerated, irregular mass with endophytic growth and a solid, tan cut surface. The histopathology shows a downward proliferation of closely packed solid nests of basaloid cells. The nests may have central necrosis and often have foci of abrupt keratinization. The nuclei are of small to medium size, ovoid, and hyperchromatic, with inconspicuous nucleoli and with frequent mitoses. It may mimic neuroendocrine carcinoma. Vascular invasion is common. The tumor is usually deeply invasive, with inguinal metastases in 50% and a mortality rate of 20% to 30%. 26 Warty carcinoma is an exophytic, papillomatous HPVrelated tumor resembling condyloma but with malignant cytologic features. It grows slowly and is moderately differentiated. On gross examination it is cauliflower-like, exophytic, and large, with a granular surface. On cut section it is exo-endophytic. On microscopic examination the warty 702 Arch Pathol Lab Med Vol 142, June 2018 HPV Infection of Skin Bacaj & Burch

4 carcinoma displays long papillae with fibrovascular cores and parakeratosis. It may invade in a burrowing manner with an irregular jagged border. It includes koilocytotic cells with nuclear pleomorphism. The nuclei are of intermediate to large size, hyperchromatic, and wrinkled. In the deeper parts of the papillae, p16 is positive. Multiple HPV types have been found. The mortality rate associated with the tumor is less than 10%. 26 Penile SCC originates on the glans and foreskin; origin on the shaft is rare. About 30% to 50% of penile SCC is HPV related. 27 The incidence of this tumor appears to be increasing in the United States. No consistent molecular prognostic factor has been identified. 26 VERRUCA VULGARIS Verruca vulgaris, or common wart, is found at all ages but is more frequent in children and adolescents. It can be single or multiple and has a predilection for exposed sites, particularly the fingers. Human immunodeficiency virus (HIV) infection and immunosuppression predisposes a person for multiple verruca. Human papillomavirus 2 is the most common type associated with verruca vulgaris, but in patients with HIV other types, such as HPV57, are also found. 12 Common warts appear as hyperkeratotic, domeshaped papules. The surface is typically rough. The filiform variant has slender papillae and is found around the lips, eyelids, or nares. The butcher s wart variant, seen in meat and fish handlers, is more likely to assume a hyperproliferative, cauliflower-like appearance. Black puncta may be seen on the surface of verruca vulgaris, particularly if the surface is scraped, corresponding microscopically to intracorneal hemorrhage or dilated capillary loops within elongated dermal papillae. In the classic histologic presentation, verruca vulgaris has spirelike papillae with highly vascular cores and elongated rete ridges that curve inward (Figure 3). There is parakeratosis over the tips to the papillae and small aggregates of blood or serum in the parakeratosis. In the concavities (valleys) between the papillae the keratin is orthokeratotic, and the granular layer of the epidermis contains large, coarse keratohyalin granules and may additionally have pyknotic nuclei and vacuolated cytoplasm. The surface of verruca vulgaris can be distorted by a prurigo nodule like response to rubbing, with attenuation of the papillae and compact orthokeratosis. The base of verruca vulgaris can be distorted by inflammation, basement membrane disruption, and reactive keratinocytes with large, round nuclei and prominent nucleoli, to the point where it can be difficult to distinguish from SCC arising in verruca vulgaris. VERRUCA PLANTARIS AND VERRUCA PALMARIS Palmoplantar warts are found on the palms of the hands and soles of the feet (acral surfaces), most frequently on the soles of children. Pressure points, such as the mid tarsal area of the sole, are a favored site, and such lesions can be painful. Some verrucae on the soles consist of multiple grouped or fused lesions with a keratinaceous plug and a peripheral, hard keratotic rim; these can be referred to as mosaic warts. As in verruca vulgaris, black puncta can be seen. The soft central core and the presence of punctate bleeding when pared down help to distinguish plantar warts from calluses or corns. A second presentation of verruca plantaris is as a smooth-surfaced, deep, tender, often inflamed papule or plaque. This has been termed myrmecia due to its supposed resemblance to an ant hill (derived from the Greek word for ant). Myrmecia are caused by HPV 1. 5 Similar warts may be found beside or beneath the toenail or fingernail, and can be mistaken for paronychia (nail inflammation) or digital mucinous cyst. A less common variant of plantar wart is the ridged wart, caused mostly by HPV 60, where the dermatoglyphics (fingerprint pattern) is retained over the surface of the nodule. 28 Ridged wart can also result in keratinaceous cyst formation. 29 Verruca plantaris shares many histologic features with verruca vulgaris but is more endophytic and has a greater proportion of the lesion penetrating into the dermis beneath the plane of the epidermis. The appearance of the keratohyalin granules within the superficial squamous cells varies depending on the HPV type. Human papillomavirus 1 is associated with large, eosinophilic keratohyalin granules and prominent cytoplasmic vacuolization (Figure 4). Human papillomavirus 4 is associated with large, vacuolated keratinocytes with few granules and small, peripherally located nuclei. 30 Warts on the feet caused by HPV2 resemble verruca vulgaris microscopically. VERRUCA PLANA Verruca plana, also called flat warts or plane warts, are 2 to 4 mm in size, smooth, flat-topped papules that are frequently multiple and clustered and that generally have little change in color from the adjacent skin other than increased pigmentation. They can extend along sites of trauma (Koebner phenomenon). Flat warts normally arise in children and adolescents but can occasionally be found in adult women and patients with HIV. They have the highest rate of spontaneous remission of HPV skin infections, often regressing in weeks to months, but may persist for years. Human papillomavirus 3 and HPV10 are the types most implicated. Flat warts show acanthosis and hyperkeratosis, but without papillomatosis or parakeratosis. The most striking microscopic features are vacuolization of the cells of the upper stratum spinosum and stratum granulosum with margination of keratohyalin granules (Figure 5). Cases undergoing regression show apoptosis and lymphocyte exocytosis into the epidermis. EPIDERMODYSPLASIA VERRUCIFORMIS A narrow definition of epidermodysplasia verruciformis (EV) requires specific gene abnormalities, susceptibility to b HPV types, and a distinctive clinical appearance. A total of 75% of EV patients have autosomal recessive abnormalities of EVER1/TMC6 at locus 17q25 or EVER2/TMC8 at 2p ,31 X-linked recessive and autosomal dominant cases have also been reported. 32 The nucleotide sequence of the L1 capsid protein gene is used to type HPV, 2 and additionally papillomaviruses are placed into different genera based on the similarity of this gene between various types. 33 The a group contains most of the common HPV types that cause verruca vulgaris (HPVs 2 and 7), verruca plana (HPVs 3 and 10), LSIL (HPVs 6 and 11), and HSIL (HPVs 16 and 18). The l group contains HPV types that cause plantar warts (HPVs 1 and 63). The HPV types of the b family include types 4, 5, 8, 20, 21, 25, and 47. In the general population, b types of HPV can be found on the skin, but no skin lesions are produced. In EV, b HPV types cause numerous skin lesions. HPV5 and HPV8 are the most common, but many other b HPV types are also found. Arch Pathol Lab Med Vol 142, June 2018 HPV Infection of Skin Bacaj & Burch 703

5 Figure 3. Verruca vulgaris. A, Note the inward curvature of the rete ridges. B, Parakeratosis is present over the tips of the papillae in verruca vulgaris, with orthokeratosis and large keratohyalin granules between the papillae (hematoxylin-eosin, original magnifications 320 [A] and 3200 [B]). Figure 4. Verruca plantaris. Verruca plantaris has an endophytic pattern (A) with large, eosinophilic keratohyalin granules and cytoplasmic vacuolization (B) (hematoxylin-eosin, original magnifications 340 [A] and 3200 [B]). The unifying clinical feature of EV is the presence of numerous HPV skin lesions either resembling flat warts or with a plaquelike appearance. Patients with a familial predilection for multiple nonresolving flat warts infected with HPV 3 and HPV 10 (the usual HPV types of flat warts) appear clinically similar to EV patients but are not susceptible to the EV-associated HPV types and do not share the same genetic changes. It is controversial whether the familial flat wart group should be considered a category of EV based on similar clinical features, or a separate entity based on the differing HPV types involved and absence of characteristic genetic defect. The molecular genetic abnormalities associated with EV are thought to impair intrinsic or innate immunity specific for the b HPV types, and are not associated with any other infections. 7 In contrast, patients with primary or acquired immunodeficiencies are susceptible to an EV-like epidermal proliferation caused by b HPV types 34,35 in addition to other infections. In both EV patients and immunosuppressed patients, HPV 5 and HPV 8 carry an increased risk of SCC in sun-exposed areas, possibly due to inhibition of UVBinduced apoptosis. 23 Human papillomavirus 5 or HPV 8 was found in half of SCCs in renal transplantation patients compared with 2.6% in nonimmunosuppressed patients. 24,25 Human papillomavirus 8 has also been found as a coinfection with HPV 16 in erythroplasia of Queyrat type of HSIL. 36 Histologically, the skin lesions of epidermolysis verruciformis in its full expression are acanthotic, with small 704 Arch Pathol Lab Med Vol 142, June 2018 HPV Infection of Skin Bacaj & Burch

6 Figure 5. Verruca plana. Verruca plana shows vacuolization of the cells of the upper stratum spinosum and stratum granulosum with margination of keratohyalin granules (hematoxylin-eosin, original magnification 3400). nests of large cells with pale blue-gray cytoplasm, clear nuclei, and perinuclear halos. Similar features can occasionally be found incidentally or in acanthomas of a normal population. SUMMARY Human papillomavirus causes a variety of proliferative squamous lesions on the skin. The natural history of these lesions depends on site, HPV type, and host factors. In the LAT, these lesions are divided into LSILs and HSILs based on microscopic appearance, to predict risk of progression to SCC and guide treatment. The microscopic appearance generally corresponds to whether the lesion is due to lowrisk or high-risk HPV types. The use of LSIL and HSIL terminology brings order and simplicity to these lesions, correlates with current understanding of the biology of HPV infections, and helps to promote accurate diagnosis of and appropriate treatment for these lesions. Outside of the anogenital region the more common warts include verruca vulgaris, verruca plantaris, and verruca plana, each with a different clinical presentation, histologic appearance, and causative HPV type. Epidermodysplasia verruciformis represents a genetic predisposition to HPV types not normally found in the general population. References 1. Darragh TM, Colgan TJ, Cox JT, et al. The lower anogenital squamous terminology standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Arch Pathol Lab Med. 2012;136(10): Bernard H, Burk RD, Chen Z, van Doorslaer K, zur Hausen H, de Villiers E. 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