Emerging Infections and the Skin

Journal of Investigative Dermatology Symposium Proceedings (2001) 6, 203–206; doi:10.1046/j.0022-202x.2001.00044.x

Human Papillomavirus and Skin Cancer

Alfred B Jenson, Stanley Geyer*, John P Sundberg† and Shin-je Ghim

  1. Cervical Cancer Research Institute, The Western Pennsylvania Hospital Foundation, Pittsburgh, Pennsylvania, U.S.A.
  2. *Department of Pathology, The Western Pennsylvania Hospital, Pittsburgh, Pennsylvania, U.S.A.
  3. †The Jackson Laboratory, Bar Harbor, Maine, U.S.A.

Correspondence: Dr J. P. Sundberg, The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609-1500. Email: jps@jax.org

Received 31 January 2001; Accepted 19 February 2001.

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Abstract

Human papillomavirus (HPV) appears to be the most ubiquitous of the human viruses. Over 100 HPV types have been identified. A minority of HPV cause cutaneous warts and mucosal condylomata. The HPV that cause mucosal condylomata put the patient at various degrees of risk for developing cancers, particularly cervical cancer. The majority of HPV infect the skin of normal and immunocompromised individuals. In normal people, most of these HPV appear to establish a latent infection of the skin, most likely as normal flora residing in hair follicles; however, in patients with various systemic and localized depressions of cell-mediated immunity, some HPV infections appear to be involved in the development of nonmelanotic skin cancer and its precursor lesions in skin, usually in sunlight-exposed areas. Circumstantial evidence suggests that these HPV may have a role in promoting proliferative lesions of the skin, although their sites of active infection and mode of transmission to susceptible individuals remain unknown.

Keywords:

condylomata, human papillomavirus, papillomas, skin cancer, squamous carcinoma

Human papillomaviruses (HPV) are small DNA tumor viruses that cause cutaneous warts and mucosal condylomata (Schlegel, 1990;Shah and Howley, 1990;Jenson and Lancaster, 1991;Pfister and Fuchs, 1994;zur Hausen and de Villiers, 1994;Tyring, 2000). HPV infect basal cells of susceptible squamous epithelium. Type-specific infections are restricted by the biologic function of the squamous epithelium at different anatomic sites. Although active infections by HPV are associated with the development of familiar, benign cutaneous warts and mucosal condylomata, latent infections appear to occur most frequently on mucosal surfaces (Ferenczy et al, 1985;Steinberg et al, 1983) and in hair follicles (Boxman et al,1997,1999a,b,2000;Schenkel et al, 1999). Only HPV capable of establishing latent infections appear to impart various degrees of malignant potential to susceptible individuals. Over 100 HPV genotypes have been identified by molecular analysis of the viral genome, which is subdivided into three functionally distinct regions: the long control region (LCR), the early region, and the late region (Baker, 1987). Most genotypes are represented clinically by serotypes that reflect the antibody response to neutralizing, conformational epitopes formed by tertiary folding of the variable domains of the major capsid (L1) protein (Cowsert et al, 1987;Ghim et al, 1992;Christensen et al, 1994;Hines et al, 1994). The L1 gene constant domains are highly conserved and their translation into similar amino acid sequences provides the basis for the infrastructure of the viral capsid (Chen et al, 1998).

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Cutaneotropic and mucosotropic hpv and their malignant potential

Of the known HPV types, at least 75% are cutaneotropic. Only a few cutaneotropic HPV actually induce cutaneous warts (common warts, plantar warts, and flat juvenile warts) in immunocompetent individuals. The remaining cutaneotropic HPV appear to inhabit healthy skin as normal flora, presumably by latently infecting hair follicles (Pfister, personal communication). Only after suppression of systemic cell-mediated immunity or downregulation of the local immune response of the skin will some of the latent HPV infections become clinically apparent, frequently as disseminated or localized pityriasiform-like lesions (Jablonska et al, 1997;Favre et al, 1998). Patients with epidermodysplasia verruciformis (EV), an autosomal recessive disease characterized by various degrees of depressed cell-mediated immunity, develop carcinomas associated with several HPV (HPV-5 and -8 in particular). The other EV HPV and the more recently discovered novel HPV have not been directly associated with malignancies; however, the recent identification of these HPV by polymerase chain reaction (PCR) and neutralizing antibodies against these HPV in kidney transplant patients with nonmelanotic cutaneous carcinomas and in normal individuals with squamous carcinoma and precursor lesion and solar keratosis, has focused attention on the malignant potential of the HPV that appear to constitute normal flora (de Villiers et al, 1997,1999;Berkhout et al, 2000).

The mucosotropic HPV have various degrees of carcinogenic potential that are fairly well defined for each virus type. Some, such as HPV-16 and -18, are high-risk viruses that cause 50% and 25% of cervical cancers, respectively (Lorincz et al, 1992;Bosch et al, 1995). HPV-31, -33, and -35 put the patient at intermediate risk. The remainder of the mucosotropic HPV (HPV-6 and -11) appear to impart little if any risk to most patients. All carcinogenic HPV appear to require cofactors to develop into cancers (zur Hausen, 1999). The highest-risk types require less clinically obvious cofactors. One of the low-risk types, HPV-11, causes cancer of the respiratory tract, particularly the larynx (Abramson et al, 1987), after irradiation.

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Hpv infection

Warts and condylomata produce the HPV virions responsible for horizontal or vertical transmission or reinoculation (Jenson and Lancaster, 1991). Reinoculation of adjacent squamous epithelium by productively infected warts and condylomata may be a much more common cause of persistent HPV-induced lesions than previously realized. Prophylactic vaccines may be able to eradicate genital condylomata (Schiller and Lowy, 1996;Breitburd and Coursaget, 1999), something that could not be accomplished if the lesions were being regenerated by latent infections (Jenson, unpublished data). Virions are formed when the viral genome is encapsidated by structural viral proteins in the nuclei of terminally differentiated keratinocytes (Jenson and Lancaster, 1991). Virions appear to become embedded in desiccated cellular debris before being shed either directly or indirectly to areas of similar squamous epithelium on susceptible individuals. The keratinaceous debris may protect encased virions from the external environment for long periods. It may also allow virions to penetrate cracks and crevices of susceptible squamous epithelium to infect basal keratinocytes. HPV virus particles appear to be capable of attaching to, binding with, and entering into almost any living cell (Roden et al, 1994;Muller et al, 1995); however, replication of the virus depends on the interaction between the virus LCR and the intracellular milieu of site-restricted basal keratinocytes.

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Hpv transmission

HPV are transmitted either directly or indirectly from warts and condylomata to susceptible human hosts. Transmission of HPV by direct contact includes horizontally transmitted mucosotropic HPV, the most common sexually transmitted disease (Ferenczy and Jenson, 1996). Vertically transmitted laryngeal papillomatosis occurs in susceptible infants exposed to HPV-11-induced venereal warts (Steinberg, 1988;Kashima et al, 1996). Although never proven epidemiologically, there appears to be an age distribution for indirect transmission that reflects shared activities in different age groups (Jenson and Lancaster, 1991); e.g., crawling and transmission of HPV-3-induced verruca plana from the scraped surface of one child's knees to those of another, the occurrence of HPV-2-induced verruca vulgaris in adolescents who share bracelets, and the appearance of HPV-1-induced verruca plantaris in young adults walking barefoot around swimming pools and on diving boards or sharing communal shower stalls.

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Immunologic response to hpv infection

Effective immunologic responses to HPV infection appear to be induced systemically and include (i) HPV type-specific, neutralizing antibody responses against the conformational epitopes of the major capsid (L1) protein (Ghim et al, 1991;Frazer, 1996;Schiller and Lowy, 1996), and (ii) cell-mediated immune responses against viral antigenic determinants presented in the context of the major histocompatibility complex-1 molecules (Chen et al, 1992;Nakagawa et al, 1997). The latter appears to be responsible for the spontaneous regression of HPV type-specific warts and condylomata. Reactivity of a patient's serum with recombinant virus-like particles has been reported in approximately 55%-70% of patients with mucosal lesions that contain specific virus DNA (Carter et al, 2000). A positive reaction probably results from previous or concurrent HPV infections or spontaneous regression of HPV-induced warts or condylomata. The significance of a negative reaction is unknown.

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Reservoirs of hpv infection

The mucosotropic, novel, and EV HPV all appear capable of establishing a latent state. The mucosotropic HPV establish a latent infection in the basal cells of mucosal squamous epithelium (Steinberg et al, 1983;Ferenczy et al, 1985). The novel and EV viruses appear to establish a latent state in either the basal cells of skin or another site in the hair follicle, either the bulge or the infundibulum. The latter has been demonstrated in animal models (Schmitt et al, 1996). The discovery of mucosotropic HPV in an apparent latent state in plucked hair from the hair follicles that define cutaneous secondary sex characteristics, suggests that hormonally responsive squamous epithelium of the skin may also provide sites of latency for mucosotropic HPV (Boxman et al, 1999a). Latently infected squamous epithelium appears clinically and histologically as normal tissue (Stubenrauch and Laimins, 1999).

Cutaneotropic, novel, and EV HPV

Latent virus infections are important because they represent a reservoir of viruses that appear to establish a privileged state with respect to the immune system. A competent immune system can prevent latent HPV infections from becoming a wart or papilloma. Various cofactors, many of which may be related to either transient or permanent alterations in cell-mediated immunity, appear to reactivate these viruses to produce a mucosal papilloma or, in the case of EV, a flat macule. In EV the flat macules may become disseminated as the degree of immunosuppression worsens with age, with those exposed to sunlight having a 30% chance of developing into a cancer. HPV-5 or -8 appear to be carcinogenic in EV patients (Orth, 1986;Pfister, 1992), although the skin surrounding the lesion appears to be teeming with large numbers of other HPV EV types (Gassenmaier et al, 1984;Wieland et al, 1998;de Villiers et al, 1999). Because EV patients live in a small area in Eastern Europe and only a few EV patients have been seen worldwide, the EV viruses have been considered by many to be very interesting but unique and out of the mainstream of clinical lesions caused by the other HPV types.

Until recently (Astori et al, 1998;Boxman et al, 1997,2000;Harwood et al, 1999), attempts to identify the cutaneotropic novel and EV viruses as putative latent infections in immunocompetent individuals by molecular cloning techniques were largely unsuccessful, evoking questions about the sites of infection and reservoirs for these viruses. The only clinical evidence that these HPV are present in normal individuals has been the presence of circulating antibodies against the major capsid protein of patients with nonmelanotic skin cancers, burns, and other lesions of the skin characterized by proliferation of squamous epithelium (Jablonska et al, 1978;Orth, 1986;Majewski and Jablonska, 1997).

Mucosotropic HPV

Latent infections with the various mucosotropic HPV infections appear to extend contiguously outside the margin of active infection (Ferenczy et al, 1985). Persistence of the latent infection, particularly in the larynx of individuals who have had laryngeal papillomatosis, has been well established (Steinberg et al, 1983;Maran et al, 1995). Deformed largyngeal tissue, surgically removed years after the disease burned out, has been shown to harbor latent HPV-11 infections.

Approximately 20% of all cutaneous warts and mucosal condylomata do not undergo spontaneous natural regression and are refractory to treatment (Bunney, 1982). The most effective treatment appears to be treatment that causes inflammation at the site of the wart or condylomata. Lesions that recur within 1 wk to 1 mo after treatment probably represent activation of a latent infection such as recurrent laryngeal papillomatosis. Lesions that recur after 6 wk of treatment most likely represent reinoculation. If the lesion has not recurred by 6 mo, the patient is most likely cured.

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Detection of novel and ev-like hpv in latent and active infection

Cloning and sequencing of papillomavirus (PV) genomes directly from infectious lesions have established a site specificity and the malignant potential for many of the known PV genotypes that infect the anogenital and oropharyngeal tracts and cutaneous epithelium of immunocompetent individuals. The novel and EV viruses are difficult to identify in normal and abnormal skin for two reasons (Harwood et al, 1999,2000). First, only a few of the cells of the hair follicle, skin, or dermatologic lesion appear to be infected, most likely latently. As few as 1 in 100 cells from a particular site have been estimated to harbor one copy of a particular HPV genome. Second, although there are highly conserved regions of the L1 protein, conservation occurs among the amino acid sequences and not the codons that are necessary to encode each amino acid. In fact, many silent nucleic acid mutations allow the fidelity of highly conserved amino acid sequences to be maintained according to the genetic code; However, amplification by PCR depends highly on matching the base pairs of synthetic primers to those of the viral DNA. A low copy number of HPV genome equivalents (characteristic of latent infections) combined with the most highly conserved amino acid regions of the L1 protein with silent mutations, have made it difficult to design PCR primers sensitive enough to identify the HPV type by PCR amplification. The reported findings of significantly increased prevalence of antibodies against HPV-8 virus-like particles in patients with squamous carcinoma and its precursor lesion, solar keratosis, suggest that skin surgically removed from these areas should maintain lesions productively infected by novel or EV-like HPV.

We previously screened different warty lesions of the skin and mucosa for productive HPV infections by using polyclonal antibodies produced against disrupted PV particles that recognize PV genus-specific antigenic determinants. Positive intranuclear staining in the granular cells of the squamous epithelium by immunohistochemistry using this antibody is interpreted as being positive for PV structural antigens and a productive HPV infection.

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Experiments

To determine whether we could identify productive HPV infections in hyperplastic and neoplastic tissue from sun-exposed areas of patients, we retrieved paraffin blocks from the archival files of the pathology department at Georgetown University. The specimens were from the patients who had been diagnosed as having squamous carcinoma and solar keratosis or seborrheic keratosis. We included the latter because seborrehic keratosis-like lesions in cats, large (leopards, panthers, etc.) and small (domestic), are associated with productive infections by the feline PV (Sundberg et al, 2000). Multiple step sections were cut from each of 45 blocks that represented at least 15 squamous carcinomas, 15 basal carcinomas, and 15 lesions diagnosed as seborrheic keratosis. Each section was stained with a cocktail of antibodies from three rabbits immunized with disrupted bovine PV-1, disrupted canine PV (CPV), and disrupted HPV-8 virus-like particles. Control sections were cervical dysplasias previously shown to be positive for HPV-6 productive infection, flat warts positive for HPV-3 productive infection, and canine oral papillomas positive for CPV productive infection.

None of the cutaneous lesions exposed to ultraviolet light was positive for PV structural viral antigens. All positive controls stained positively. These results suggested that productive infection of the skin by novel and EV viruses are sporadic, random, and not easily detectable. We also concluded that most novel and EV infections of the skin are latent. In situ hybridization may be more successful in localizing HPV lesions that may be associated with nonmelanotic skin cancers and their precursor lesions.

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