Papilloma Virus Disease

PAPILLOMA VIRUS   DISEASE

More than 70 genotypes of human papillomaviruses (HPVs) have been identified in human specimens. Some of the genotypes are antigenically (phenotypically) different, and groups of genotypes are associated with specific lesions. HPVs have been identified in plantar warts; in flat and papillomatous warts of other skin areas; in juvenile laryngeal papillomas; and in a variety of genital hyperplastic epithelial lesions, including cervical, vulvar, and penile warts and papillomas. In addition, they are associated with premalignant (cervical intraepithelial neoplasia) and malignant disease (cervical cancer). Lesions comparable to those occurring in the cervix are now recognized in the anus, especially among men who have sexwith men and are infected by human immunodeficiency virus, or HIV.

EPIDEMIOLOGY

Cutaneous nongenital warts usually occur in children and young adults; presumably immunity to the HPV genotypes causing these lesions develops and appears to provide protection. Twelve HPV genotypes have been identified in genital lesions of humans, and there are many apparently silent infections with these viruses. Cross immunity does not occur, and sequential infection with multiple genotypes does take place. The inci-dence of HPV infections has almost certainly been increasing, and they may now con-stitute the most common sexually transmitted disease. From 20 to 60% of adult women in the United States are infected with one or another of the genotypes. HPV types 6 and 11 are associated most commonly with benign genital warts in males and females and with some cellular dysplasias of the cervical epithelium, but these lesions rarely be-come malignant. They can be perinatally transmitted and cause infantile laryngeal pa-pillomas. Types 16, 18, 31 and 45 may also cause warty lesions of the vulva, cervix, and penis. Infections with these viral types, especially 16, may progress to malignancy. Viral genomes of these four types are found in a proportion of markedly dysplastic uterine cervical cells, in carcinoma in situ, and in cells of frankly malignant lesions. Human papillomavirus infection is now considered to be a cause of the majority of car-cinomas of the cervix. Papillomavirus infection of the anus is a clinical problem in homosexual men, especially those with acquired immunodeficiency syndrome (AIDS), and it appears to be related to the subsequent development of anal neoplasia in these individuals.

PATHOGENESIS

Papillomaviruses have a predilection for infection at the junction of squamous and colum-nar epithelium (eg, in the cervix and anus). Papillomaviruses were the first DNA viruses linked to malignant changes. In the mid-1930s, Shope demonstrated that benign rabbit papillomas were due to filterable agents and could advance to become malignant squa-mous cell carcinomas. External cofactors, such as coal tar, could hasten this process. However, work on the biology and mechanism by which these agents foster malignant transformation has been impeded by the inability to cultivate papillomaviruses in vitro. Molecular probes to detect viral products in vivo indicate that replication and assembly of these viruses take place only in the differentiating layers of squamous epithelia, a situa-tion that has not been reproduced in vitro.

The first evidence that HPVs could be associated with human malignant disease came from observations on epidermodysplasia verruciformis. This disease has a genetic basis that results in unusual susceptibility to HPV types 5 and 8, which produce multiple flat warts. About one third of affected patients develop squamous cell carcinoma from these lesions.

The mechanism of oncogenicity of HPV is less clear. Cells infected with genomes of several papillomaviruses can transform cells and produce tumors when injected into nude (T lymphocyte–deficient) mice. The viral genome exists as multiple copies of a circular episome within the nucleus of transformed cells but is not integrated into the cellular genome. This appears also to be the case with benign human lesions. In malignant tu-mors, part of the viral genome is found integrated into the cellular genome, but integra-tion is not site specific. Both the integrated viral genome and the extrachromosomal form carry their own transforming genes. Host cells normally produce a protein that inhibits expression of papillomavirus transforming genes, but this can be inactivated by products of the virus and possibly by other infecting viruses, thus allowing malignant transforma-tion to occur. HPV DNA is found in more than 95% of cervical carcinoma specimens when tested by polymerase chain reaction (PCR).