5, 8, 9, 12, 14, 15, 17, 19-25, 36, 46, 47
" Common types in bold type Types 5, 8, and less commonly 17, 20, and 47 are the principal types so far associated with malignant change in epidermodysplasia verruciformis
" Common types in bold type Types 5, 8, and less commonly 17, 20, and 47 are the principal types so far associated with malignant change in epidermodysplasia verruciformis cences of soft papillomas found on the external genitalia, perineum, vaginal introitus, penis, or anus, caused commonly by HPV types 6 and 11 (Fig. 18-3). Condyloma planum (fitif wart) is the more usual presentation in the cervix, with types 6 and 11 again being the commonest. Cervical carcinoma may develop 20-50 years after infection with certain mucosal HPV types. There is a slow progression through three stages of lesions variously called cervical dysplasia or ceri'ical intraepithelial neoplasia (C1N). The flat condyloma is sometimes classified as CIN-1; CIN-3 is often designated carcinoma in situ. The fully malignant, invasive carcinoma is usually but not always of the squamous type. Over 90% of all cancers of the cervix contain HPV DNA, usually of type 16 or 18. The same types are associated with carcinomas of the vulva, vagina, penis, and anus
Much more rarely the genital HPV types infect the respiratory tract, usually in young children but also sometimes in young adults. Classically, the lesions begin in the larynx, but they grow copiously, obstructing the airway, and tend to spread also to other parts ol the respiratory tract. Malignant change occurred occasionally in the days when children with laryngeal papillomatosis were treated with irradiation. Papillomas caused by these genital types are also seen occasionally on the conjunctiva.
Focal epithelial hyperplasia, associated almost exclusively with HPV types 13 and 32, is a condition characterized by multiple nodular lesions in the mouth and is particularly prevalent in Eskimos and in South and Central American Indians. Oral papillomas of the more conventional kind can be caused by the
sexually transmitted types 6, 11, and 16. Common warts on the lips are usually type 2 HPV-16 DNA has also been reported in a minority of oral carcinomas.
Perhaps 10% of all schoolchildren and young adults experience a crop of warts on the skin, probably acquired in the course of body-contact recreational activities. Generally, warts regress within 2 years. Common warts, seen on prominent regions subject to abrasion such as hands and knees, are raised papillomas with a rough surface, often caused by type 2 or 4. Type 7 is the agent of "butchers' warts," an occupational disease of meat-handlers. Flat warts, sometimes called plane warts, are smaller, flatter, smoother, and more numerous, seen especially on the arms, face, and knees of youngsters. Types 3 and 10 are often involved. Plantar warts are painful deep endophytic warts found on the weight-bearing regions of the heel and sole of the foot; palmar warts are similar. Type 1 is the major etiological agent.
Epidermodysplasia verruciformis is a rare condition seen in people with a particular autosomal recessive hereditary cell-mediated immunodeficiency which has not yet been fully defined. The infection, acquired in childhood but persisting for life, is characterized by numerous warts widely disseminated over the skin. The lesions are of two varieties: (1) flat warts, commonly caused by types 3 and 10, as in normal children and (2) reddish-brown macular scaly patches from which can be isolated any of nearly 20 rare HPV types found almost exclusively in these patients (presumably they must cause subclinical infections in normal people). Squamous cell carcinoma (SCC) arises in about one-third of all epidermodysplasia verruciformis patients, after many years, in one or often several of the macular lesions situated on areas of the skin exposed to sunlight, which is obviously therefore a critical cofactor in the genesis of this malignancy. The tumors, usually carrying the genome of HPV type 5 or 8, are often slow-growing in situ carcinomas but may be invasive SCCs which metastasize. HPV-5 or HPV-8 DNA has also been detected in SCCs on exposed areas of the skin of a small number of chronically immu-nosuppressed recipients of renal allografts as well as from some apparently immunocompetent individuals, but an etiologic association has yet to be proved.
Clinically, the diagnosis of skin warts and condyloma acuminata on the external genitalia generally poses no great problems, but histology is required whenever malignancy is a possibility. Cervical condylomas, visualized by colposcopy, are often flat and indistinguishable from cervical intraepithelial neoplasia The Papanicolaou smear is widely used for routine screening'of women for premalignant and malignant changes in the cervix.
Although human papillomavirus has recently been successfully grown in organ cultures of floating rafts of infected skin treated with the phorbol ester TPA to increase keratinocyte differentiation, isolation of virus is not an appropriate approach to laboratory diagnosis of papillomavirus infections. Because only terminally differentiated nonreplicating cells of squamous epithelium are fully permissive for viral replication, virions and capsid proteins are demonstrable only in the outer keratinized layers of skin warts. However, the HPV genome can persist for years in basal cells, as an episome in benign papillomas or premalignant cervical dysplasia, or integrated in cancer cells Thus, to be confident of not overlooking HPV infections, the only generally applicable diagnostic approach is to probe for viral DNA or for particular viral genes (see Chapter 12 for detailed discussion). Nucleic acid hybridization is currently employed mainly for the investigation of condyloma and cervical carcinoma.
The DNAs of most HPV types have been cloned and can be labeled with a radioactive isotope, such as 32P, 35S, or H, or with a nonradioactive label such as biotin. Furthermore, exon-specific probes can be constructed to search for individual HPV genes or for the corresponding mRNAs, for example, DNA probes specific for the LI ORF (encoding the major capsid protein) of the common HPV types, or for the oncogenes E6 and E7. Often, the first approach will be to screen for conserved papillomavirus DNA sequences by using as a probe either a single type or an appropriate cocktail of a few distantly related types, under "relaxed" (low stringency) conditions. Determination of the type requires the use of particular HPV probes, at high stringency.
Southern blot hybridization has served as the gold standard for identification of HPV DNA in human tissue; it offers the advantages of high specificity and high sensitivity, being capable of detecting one copy of the HPV genome per cell under conditions of high stringency (see Fig. 12-7). Dot-blot hybridization is simpler, but its sensitivity is lower. In situ hybridization has been widely employed by pathologists to screen numbers of gynecologic specimens, including cervical "touch smears," frozen sections, or even formalin-fixed sections, on slides; sensitivity is low, but the method presents the advantage that the autoradiograph (or immunoperoxidase cytochemistry) reveals the topographic location of the viral genome in particular layers of the epidermis or the tumor.
Gene amplification by the polymerase chain reaction (PCR) has emerged as by far the most sensitive method of detecting low numbers of genome copies and can detect low-level latent infection in clinically and histologically normal tissue, as well as the larger copy numbers present in papillomas, dysplasias, and carcinomas, with a sensitivity several orders of magnitude higher than Southern blotting. However, false positives resulting from contamination or the use of unsuitable primers plagued many ol the early PCR studies of genital HPV infections, flooding the literature with misleading results. The PCR amplification should be conducted by experts and interpreted with caution. We need to discover the implications ol asymptomatic persistence of HPV DNA in low copy number in healthy tissue. Although identification of a carcinogenic HPV type has prognostic value, it is important to remember that the great majority of women infected with HPV types 16 or 18 will never develop cervical cancer. Telltale histologic change in a Papanicolaou smear is still a better indicator of impending malignant change than is identification of a highly oncogenic type of HPV.
Transmission of skin warts occurs mainly in school-age children via direct contact through abrasions, with the possibility of subsequent spread by scratching (autoinoculation) Plantar warts are readily picked up from the wet floors of public swimming pools and bathrooms. Genital warts, on the other hand, are spread by sexual intercourse; not surprisingly their incidence skyrocketed in parallel with the sexual revolution of the late 1960s and 1970s. Some cases of oral or respiratory papillomatosis may also be sexual in origin, but most such infections in young children are assumed to be acquired during passage of the baby through an infected birth canal. Fortunately, the efficiency of transmission in this manner must be very low, considering the rarity of laryngeal papillomatosis vis-a-vis the high frequency of cervical infection.
The fact that skin warts regress spontaneously encourages the perpetuation of mythical cures ranging from hypnosis to Tom Sawyer's infallible dead-cat-in-the-cemetery-at-midnight cure. A comparable rate of success can be assured by letting nature take its course. However, skin warts can be removed by cryotherapy or caustic chemicals, laryngeal papillomas by laser, external genital warts by cryotherapy, podophyllin, laser, or diathermy, and cervical dysplasia by laser or diathermy; invasive carcinoma requires surgery. As discussed in Chapter 16, it has been reported that interferon a or 0 injected intramuscularly and/or into the lesion itself, may be effective in causing genital or laryngeal papillomas to regress temporarily, but recent studies do not support these claims.
Experimental vaccines have been produced by recombinant DNA technology. For example, infection with live vaccinia recombinants incorporating the genes for the HPV-16 capsid proteins LI and L2 yields particles resembling empty HPV capsids, which might be expected to induce synthesis of neutralizing antibodies. Similar vaccinia recombinants incorporating the HPV-16 E6/E7 genes are undergoing human trials in the hope that they may be used therapeutically to boost the cytotoxic T-cell response to E6/E7 peptides presented on the surlace of cervical intraepithelial neoplasia or invasive carcinoma cells.
The prototype after which the genus Polyomavirus was named is the polyoma virus of mice. Though causing only harmless inapparent infections in mice when spread by natural routes, the virus induces many different types of malignant tumors ("polyomas") when artificially injected into infant rodents, such as hamsters. Another Polyomavirtis, simian virus 40 (SV40), infects monkeys subclinically but also induces tumors after inoculation into baby rodents. During the 1960s and 1970s these two viruses became the principal models lor the biochemical investigation of virus-induced malignancy. The newly discovered techniques of molecular biology were brought to bear on the expression of the integrated viral genome and associated cellular changes m cultured fibroblasts transformed by these viruses in vitro (sec Chapters 3 and I i, and Figs. 3-6 and 11-1). Subsequently two human polyomaviruses, designated BK and JC, were discovered. BK virus was recovered from the urine of a renal transplant recipient, and JC virus from the brain of a patient i.ith a rare demyelinating condition, progressive multifocal leukoencephalopathy (PML). Like SV40, BK and JC are oncogenic in newborn hamsters and transform mammalian cells in vitro, but there is no evidence that they cause human cancer. Both are ubiquitous in humans, producing inapparent infections that persist for many years in the urinary tract, and may be reactivated by immunosuppression.
BK virus infects most children before the age of 10, often subclinically but sometimes associated with mild upper respiratory symptoms, suggesting that transmission may occur via the respiratory route. The viral genome persists for life in the kidney without any apparent ill effects. Reactivation occurs during the last trimester of about 3% of pregnancies, causing asymptomatic shedding of virus intermittently in urine. Following immunosuppression, for example, in kidney transplantation, reactivation is demonstrable in about a third of all patients, and urinary shedding continues for days to months, with no detectable loss of renal function.
JC virus has a similar natural history, although primary infection may occur somewhat later in childhood and only about 75% of the population has antibody. Again, lifelong persistence is established in the kidney, and virus is shed in urine sporadically throughout life and more frequently during pregnancy or immunosuppression. Unlike BK virus, however, JC virus causes a lethal disease, progressive multifocal leukoencephalopathy (PML). PML is a rare subacute demyelinating disease of the CNS which is seen mainly as a complication of advanced disseminated malignant conditions such as Hodg-* kin's disease or chronic lymphocytic leukemia, but also in primary or secondary immunodeficiency syndromes, especially AIDS, or following immunosuppression for organ transplantation (Fig. 18-4). The target cell is the oligodendrocyte, in which the virus undergoes a lytic productive infection; neurons are unaffected. Histologically, the disease is characterized by multiple foci of demyelination in the brain, accompanied by proliferation of giant bizarre astrocytes. The surrounding oligodendrocytes are enlarged, with swollen nuclei occupied by a prominent inclusion body, which in fact contains a crystalline aggregate of thousands of virions.
The disease PML represents a reactivation of long-standing persistent infection of the kidney, and perhaps also of the brain Previously rare and confined largely to the elderly, it is now seen principally in AIDS patients. Indeed, the HIV-1 Tat protein has been shown to fransactivate transcription of the late JC viral genes.
Two types of JC virus have recently been defined. JC virus isolated from
the brain of PML patients usually differs from the "archetype" found in the urine of asymptomatic carriers by extensive deletions and duplications in the nucleotide sequences within the promoter/enhancer region of the genome.
BK virus can be isolated from urine in cultured human diploid fibroblasts, or JC virus from urine or brain in human fetal glial cells, and the two viruses can be distinguished by hemagglutination inhibition. Much simpler, however, is direct detection of antigen in urine by enzyme immunoassay, or direct detection of the viral genome by PCR and nucleic acid hybridization (e.g., Southern blotting). Following brain biopsy or autopsy, JC viral DNA can be demonstrated by in situ hybridization, JC. antigens by immunofluorescence, and virions by electron microscopy.
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