Initial identifications of human papillomaviruses in human cancers were made in squamous cell carcinomas of the skin of patients with a rare hereditary disorder, epi-dermodysplasia verruciformis (38). Jablonska and co-workers considered this condition already in 1972 (11) as a model to study the role of papovaviruses in human cancers.
A very common human cancer presently known to be caused by specific papillo-mavirus types is cancer of the cervix. The link of this cancer to HPV infections was proposed between 1974 and 1976 (15,16). The first virus isolates from this tumor type, HPV-16 and HPV-18, were published in 1983 and 1984 (19,20). Today > 95%
Genotypes of HPV Detected in Benign and Neoplastic Lesions of the Cervix
Lesion HPV genotypes2
Condyloma acuminata 6,11,42, 44, 51, 53, 83
Intraepithelial neoplasia 6, 11, 16, 18, 26, 30, 31, 33, 34, 35, 39, 40, 42, 43,
45, 51, 52, 56, 57, 58, 59, 61, 62, 64, 67, 68, 69, 70, 71,74, 79,81,82
Cervical and other anogenical cancers 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 54, 56, 58,
a Large font indicates most common genotypes; small font indicates least common genotypes.
of cervical cancer biopsies contain HPV sequences. Although HPV-16 represents by far the most frequently identified virus, a number of additional genotypes has been identified in this tumor. Table 1 lists HPV genotypes found in cervical cancer biopsies.
Besides cervical cancer other anogenital cancers (anal, perianal, vulval, penile, and vaginal) have been linked to the same infections. Whereas anal and perianal cancers reveal a similar distribution of high-risk HPV infections, as found in cervical cancer, only about 50% of the other cancers turn out to contain high-risk HPV DNA. It is presently unknown whether the negative biopsies are indeed HPV-negative or contain other, possibly cutaneous, HPV types. In view of the scarcity of biopsies from such tumors no careful studies have been conducted to analyze the presence of cutaneous HPV in these conditions.
Besides anogenital cancers, approx 20% of oropharyngeal cancers have been found to contain anogenital high-risk HPV types (39). Particularly frequent are HPV findings in cancers of the tonsils (40,41) and the tongue (42). Occasional HPV positivity has also been reported for other cancers, such as cancer of the larynx (43,44), hypopharynx (45), nasal cavity (46), palatine, buccal mucosa, lips (45), and even for a few lung cancer biopsies (47). Since HPV-positive oral cancers, to the extent they have been investigated, express the viral oncoproteins E6 and E7 (48,49), it is likely that the virus plays a causal role in these tumors.
HPV infections have also been suspected to play a role in cancer of the esophagus (50). The available data are not fully convincing, and vary substantially between individual laboratories and different geographic regions from zero to 67% (reviewed in 51). A recent report finds a relatively high rate (34.9%) of HPV-positive biopsies in samples obtained from China and in 26.4% of samples obtained from cancer cases in South Africa (52). Only a small fraction of the latter tumors contained anogenital HPVs; the others contained HPV types also found in cutaneous lesions. Three of the identified types represented putative novel HPV genomes.
Squamous cell carcinomas developing in patients with epidermodysplasia verruci-formis (EV) have been shown in 1979 to contain members of a specific subgroup of HPVs (38). The development of broad-spectrum PCRs permitting the detection of a wide variety of HPV types resulted in the demonstration of a high percentage of squa-
mous cell carcinomas in immunosuppressed as well as in immunocompetent individuals containing in part novel HPV sequences (53-57). At present more than 80% of these tumors are HPV positive. A recent report describes a higher prevalence of some types in these lesions with HPVs 20, 23, 38 and two putative novel types accounting for 73% of the virus-positive biopsies (58). The significance of these findings is difficult to assess. Problems arise from the high rate of HPV prevalence in plucked hair follicles and in biopsies from normal skin (30,31), where up to 50% of the analyzed materials were found to be HPV-positive. In these materials a broad spectrum of different HPV genotypes has been detected, leading in addition to the identification of several putative novel genotypes.
It is possible that, in contrast to high risk anogenital HPV infections, cutaneous HPV infections contribute by an indirect mode to squamous cell carcinoma development: their presence may protect against apoptosis after genetic damage due to solar exposure (Storey, personal communication), thus resulting in increased survival of the genetically modified cells. On the other hand, the development of papillomas in immunosuppressed patients specifically at sun-exposed sites points also to an involvement of genetic damage in wart development caused by these viruses. Further studies will have to clarify the picture.
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