Natural History Of Cervical Hpv Infection And Csil

There are more than 100 anogenital HPV types and these are generally divided into oncogenic and nononcogenic types by virtue of the frequency of their association with invasive cervical cancer (see Chapter 14). Of the oncogenic types, HPV-16 is the most important because it is the most common type found in cervical cancer, followed by HPV types 18, 31, and 45. HPV 16 alone counts for about 50% of all cervical cancers worldwide (4). HPV types 18, 31, and 45 are associated with an additional 20% of the cancers. HPV types 33, 52, 58, 35, 39, 56, 59, and 68 account for most of the remaining cancers, but many other HPV types are associated with small percentages of cervical cancers and these vary from country to country. There also exist a group of HPV types in the genital tract that are rarely if ever oncogenic; the most common of these are types 6, 11, 42, 43, and 44. The molecular mechanisms by which HPV contributes to the development of anogenital cancer are reviewed in Chapter 15.

For years there was debate about the modes of acquisition of anogenital HPV infection. There is now a consensus that the great majority of cervical HPV infections are acquired through sexual transmission (5,6). HPV is one of the most common sexually transmitted agents, and estimates are that about 75% of the general population aged 15-49 yr acquires at least one genital HPV type during their lifetimes (7).

Epidemiologic studies of cervical HPV infection suggest that the age-related prevalence of HPV infection, as determined by polymerase chain reaction (PCR), is highest among women in their late teens and early 20s (8). These data suggest that that most women acquire HPV infection relatively early after initiation of sexual activity. The age-related prevalence of cervical HPV infection declines thereafter, probably through development of immunity to HPV. HPV infection in these women has either been cleared or the level of infection may have been reduced to levels that are undetectable using current technology, perhaps with small foci of latent infection. In addition, low prevalence among older women may represent a cohort effect given changes in sexual behaviors that have occurred in the last few decades.

HPV infection is initially established in the basal layer of the anogenital epithelium. In the cervix, this is usually in the transformation zone (TZ), where the squamous epithelium of the exocervix meets the columnar epithelium of the endocervix. This squamocolumnar junction is a relatively thin, highly metabolically active area of epithelium. Most HPV infections occur here and most HPV-related lesions arise from this area, including invasive cancer. The significance of basal layer HPV infection is that this allows the virus to perpetuate itself and persist in the more differentiated cell layers of the epithelium. The basal and parabasal layers constitute the only dividing cell layers in the epithelium under normal circumstances. When the basal cells divide, the HPV genomes replicate as well and are passed to the daughter cells. This allows HPV to persist both in the cells that generate the remainder of the epithelium and in the progeny cells that are derived from the basal cells as they differentiate and rise through the epithelium. It is also possible that HPV may persist for long periods of time, perhaps indefinitely in latent form in the basal cell layers, where it can remain transcrip-

tionally inactive and clinically silent. These clinically normal tissues may later develop into lesions if HPV reactivates. Consequently, treatment and removal of SIL rarely leads to "cure" of HPV infection.

Consistent with a role for HPV in the pathogenesis of anogenital SIL and invasive cancer, the epidemiology of these two diseases tracks closely with risk factors associated with sexual activity. These include a lower frequency of cervical cancer among nuns, higher risk among women whose husbands had more sexual partners, higher risk among second wives if the first wife had a diagnosis of cervical cancer, and higher risk among women whose husbands had penile cancer.

HPV infection of the basal layer may lead to a spectrum of histopathologic changes in the anogenital epithelium. Although HPV infection is established in the basal cell layer, the viral DNA replicates to a much higher level and becomes transcriptionally active in the more differentiated cell layers. Most viral protein expression therefore occurs in the more differentiated cell layers. At the more benign end of the spectrum of disease is condyloma and cervical intraepithelial neoplasia (CIN) grade 1, also known as mild dysplasia (Fig. 1). In the Bethesda system these have been combined into one diagnostic category, known as low-grade SIL (LSIL) for the purpose of grading cytology, and some pathologists combine these categories for histopathologic categorization as well. LSIL is characterized by relatively little basal cell proliferation and atypia, and in the case of condyloma, the presence of koilocytes (cells with an irregular, enlarged nucleus with a clear "halo") (9). Koilocytosis may represent a direct cytopathic effect of HPV infection. Another diagnosis used in the Bethesda system is "atypical squamous cells of undetermined significance" (ASCUS), which describes cells that are neither clearly normal nor clearly dysplastic. In contrast to LSIL, high-grade SIL (HSIL) is characterized by increasingly severe cellular atypia, abnormal mitotic activity in the more superficial cell layers, and replacement of the normal epithelium with immature basaloid cells. In the Bethesda system HSIL includes CIN grades 2 and 3 (moderate and severe dysplasia, respectively) and carcinoma in situ (CIS).

Historically, precancerous lesions of the cervix were considered to be part of a continuum beginning with CIN 1, progressing to CIN 2, CIN 3, CIS, and ultimately invasive cancer. This was based in part on early studies of the natural history of CIN that showed that a high proportion of CIN 1 lesions progressed to higher grades of disease (10). Subsequent studies failed to show a high progression rate, and it is now believed that the result of the Richart study reflected inclusion criteria (three consecutive cytology smears that showed CIN 1) biased toward women who were unlikely to regress spontaneously. Consequently, for most women, current thinking is that CIN 1 has relatively little potential to progress to invasive cancer. Moreover, the schema in which CIN 1 progresses to CIN 2 and CIN 3 has been questioned in light of studies showing not only that these grades of lesion can coexist in the same woman simultaneously, but also that some CIN 3 lesions may arise without going through a CIN 1 intermediate (11). Moreover, CIN 2-3 lesions can develop early after infection with an oncogenic HPV type, with some lesions developing in one cohort study within 6 mo of HPV infection (11). Consistent with the higher risk of progression to cancer from HSIL than LSIL, almost all HSIL lesions contain high- or medium-risk oncogenic HPV types whereas LSIL lesions may contain a wider range of types from low risk to high risk (12).

Cervix Cancer Lsil

Fig. 1. Schematic presentation of different grades of intraepithelial neoplasia. Cervical or anal intraepithelial neoplasia grade 1 are characterized by 20-25% replacement of the epithelium with immature cells with high nucleus/cytoplasm ratios. Intraepithelial neoplasia grade 2 is characterized by approx 50% replacement with immature cells, and grade 3 by complete or nearly complete replacement. Microinvasion, shown at the bottom, occurs when the cells traverse the basement membrane. Although microinvasion can rarely occur in conjunction with intraepithelial neoplasia grade 1, it is likelier to occur in conjunction with intraepithelial neopla-sia grade 3, as indicated schematically. Also depicted are hypothetical mechanisms by which HIV can potentiate development of ASIL. (1) HIV-1 tat can be expressed by cells circulating in the stroma and be taken up by overlying HPV-infected keratinocytes resulting in upregulation of HPV E6 and E7 expression; (2) HIV-1 tat could potentiate migration of HPV-infected keratinocytes; (3) aberrant cytokine expression by locally circulating HIV-infected lymphocytes may modulate local immune response and may modulate HPV gene expression in overlying keratinocytes; and (4) systemic immune response to HPV-infected keratinocytes may be attenuated if HIV infection leads to loss of HPV-specific effector cells.

Fig. 1. Schematic presentation of different grades of intraepithelial neoplasia. Cervical or anal intraepithelial neoplasia grade 1 are characterized by 20-25% replacement of the epithelium with immature cells with high nucleus/cytoplasm ratios. Intraepithelial neoplasia grade 2 is characterized by approx 50% replacement with immature cells, and grade 3 by complete or nearly complete replacement. Microinvasion, shown at the bottom, occurs when the cells traverse the basement membrane. Although microinvasion can rarely occur in conjunction with intraepithelial neoplasia grade 1, it is likelier to occur in conjunction with intraepithelial neopla-sia grade 3, as indicated schematically. Also depicted are hypothetical mechanisms by which HIV can potentiate development of ASIL. (1) HIV-1 tat can be expressed by cells circulating in the stroma and be taken up by overlying HPV-infected keratinocytes resulting in upregulation of HPV E6 and E7 expression; (2) HIV-1 tat could potentiate migration of HPV-infected keratinocytes; (3) aberrant cytokine expression by locally circulating HIV-infected lymphocytes may modulate local immune response and may modulate HPV gene expression in overlying keratinocytes; and (4) systemic immune response to HPV-infected keratinocytes may be attenuated if HIV infection leads to loss of HPV-specific effector cells.

The incidence of CIS among women aged 15-19 yr appears to have been rising in the last few decades compared to similarly aged women, perhaps due to changes in sexual activity during this time and earlier initiation of sexual intercourse (13). The estimated incidence of CIS among women aged 18-24 yr in Washington state was 196/100,000, which was similar to that of women aged 25-34 yr (212/100,000) (14). Although the proportion of CIS cases that progress to invasive cervical cancer remains unknown, some studies report progression in up to 71%. (15). Thus, the clinical significance of distinguishing LSIL from HSIL is that most cases of LSIL will undergo spon taneous regression and do not require treatment to prevent cervical cancer. In contrast, HSIL requires therapy, as these may progress over time to invasive cancer. The time of progression of untreated HSIL to invasive cancer varies from individual to individual, and may take up to several decades. However, because a minority of cases of LSIL can progress to HSIL, women with LSIL require follow-up to ensure that the lesion has regressed. In addition, many clinicians recommend treatment of LSIL if it persists with follow-up as these lesions may be among those that progress to HSIL over time. Some clinicians also treat women with LSIL if compliance with follow-up is uncertain.

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Responses

  • Pearl
    What if lsil persists?
    6 years ago
  • Mewael
    Do all koilocytes develop into hpv?
    5 years ago

Post a comment