Affiliation of authors: Department of Pathology, University of Washington, Seattle
Correspondence to: Nancy B. Kiviat, MD, Department of Pathology, Box 358050, University of Washington, 815 Mercer St., Seattle, WA 98109 (e-mail: nbk{at}u.washington.edu).
Infection with high-risk types of human papillomavirus (HR-HPV) is extremely common in the cervix, vagina, and vulva; and women with persistent HR-HPV infections at these sites have been shown to be at increased risk for the development of invasive squamous cell cancers at these locations (13). Prior to the establishment of routine cervical cancer screening, invasive cervical cancer was among the most common causes of cancer mortality in women. Compared with cervical cancer, vaginal and vulvar cancers develop infrequently (current age-adjusted incidences of cervical, vaginal, and vulvar cancers = 8.9/100 000 women per year, 0.7/100 000 women per year, and 2.3/100 000 women per year, respectively) (4). Previous studies (e.g., [5,6]) have shown that a history of a prior cervical neoplasm (cervical intraepithelial neoplasia grade 3 [CIN 3] or invasive cervical cancer) is an important risk factor for the development of vaginal and vulvar cancers. The most likely explanation for this association is that women who develop cervical neoplasia frequently are infected with HR-HPV both at the cervix and in the vagina and vulva, and they occasionally develop a second independent neoplasm at the last two sites. Other explanations for this association between a history of a prior cervical neoplasm and the later development of a vaginal or vulvar cancer include recurrence of the original cervical cancer at the surgical margin after hysterectomy and development of a second primary neoplasm in the vagina or vulva as a result of radiation therapy for treatment of the original cervical neoplasm.
In this issue of the Journal, Vinokurova et al. (7) examine the relationship between a history of a prior cervical CIN 3/invasive cervical cancer and subsequent pathogenesis of vaginal and vulvar cancers, with intriguing results. By using the site of HPV DNA integration as a marker of clonality, these researchers detected identical HPV DNA integration loci in tissue from the initial cervical cancer or CIN 3 lesion and in the subsequent vaginal or vulvar cancers. Thus, the metachronic, multicentric lesions they examined appear to share a common (i.e., cervical) clonal origin.
Relatively little is known about the molecular pathogenesis of multiple synchronous or metachronous squamous lesions on the cervix or in the vagina and vulva. Some (810), but not all (11), studies suggest that invasive cervical cancers as well as CIN 3 lesions are monoclonal in origin. However, there is disagreement as to whether multicentric CIN 3/carcinoma in situ (CIS) lesions arise independently or share a common origin (1116). The study by Vinokurova et al. is unique in its examination of the clonality of multicentric cancers and high-grade lesions located on the cervix, vagina, and vulva. Two of the women described in this study initially underwent hysterectomy as treatment for a stage 2 invasive cervical cancer (i.e., one that extends to the upper two-thirds of the vagina) and were later diagnosed with squamous cancers in the vagina and neovagina (vulva). The fact that the original cervical cancers and the subsequently diagnosed cancers (in the neovagina and the remaining vaginal epithelium) were clonal is not surprising, because the vaginalneovaginal cancers most likely arose from undetected, microscopic foci of malignant cells, left at, or seeded to, the vaginal margin during surgery. However, Vinokurova et al. also examined neoplastic tissue from four women with CIN 3 lesions, one of whom was treated by cold-knife conization and three of whom were treated by hysterectomy. All four women were later diagnosed with vaginal cancers, and in all cases the vaginal cancers appear to have arisen from cells derived from the previously treated CIN 3 lesions. Exactly how these premalignant cells (CIN 3) have migrated to other sites (vagina) is unclear. The authors hypothesize that these vaginal cancers were derived from quiescent dysplastic HPV-transformed cells that were disseminated early during carcinogenesis and thus undetectable by conventional histopathology. Another more likely possibility is that the trauma inflicted on the vaginal epithelium during surgery predisposes it to accept implantation of transformed cells derived from the original CIN 3 lesion. Dissemination and implantation of cancer cells during biopsy or treatment has been described for many other cancers. For example, breast cancer cells have been detected at the sites of fine-needle or stereotactic core-needle biopsies, and such cells are known to give rise to local recurrence of breast cancers (17).
The findings reported by Vinokurova et al. raise several interesting questions. Clearly not all vaginal or vulvar cancers arise in this fashion, given that many women who develop vaginal cancer never had a previous cervical disease. Nevertheless, further examination of the pathogenesis of vaginal cancers among those women with prior cervical disease is of interest. For example, it may be of clinical interest to determine whether surgical procedures (i.e., hysterectomy) are associated with longer periods of trauma to the vaginal epithelium or perhaps whether the size of the original cervical lesion predisposes a women to develop "clonal" vaginal or vulvar cancers that appear to originate from a cervical neoplasia. Although some studies among women with and without vaginal cancer have reported finding an increased risk of vaginal neoplasia associated with prior hysterectomy (5,6,18), this increased risk most likely reflects the fact that anogenital neoplasias are often treated by hysterectomy. It is not known whether women who have CIN 3 lesions and are treated with a hysterectomy are more likely to develop vaginal neoplasia than those who are treated by less invasive procedures, such as the loop electrosurgical excision procedure. However, given that hundreds of thousands of women are diagnosed and treated each year for CIN 3 or CIS, and that the incidence of vaginal and vulvar cancers is extremely low, it appears that the development of a vaginal or vulvar cancer from cells derived from a previous cervical lesion must be exceedingly rare. (Unfortunately, the true incidence of vaginal or vulvar cancers among women with CIN 3 lesions or invasive cervical cancer is not known because data on the incidence of CIN 3 are no longer collected by tumor registries.)
What are the clinical implications of these findings and of findings from previous studies demonstrating the increased risk of vaginal cancer associated with prior anogenital neoplasia? Current screening recommendations by the American College of Obstetricians and Gynecologists are that women who have a history of cervical carcinoma should continue having annual vaginal Pap screening indefinitely. Women who have had a hysterectomy for treatment of CIN 3 or CIS are recommended to undergo follow-up cervical cytology every 46 months until three documented, consecutive, and technically satisfactory normal or negative vaginal cytology tests, and no abnormal or positive cytology tests within a 36-month period following hysterectomy, are obtained before they discontinue cytology screening. However, among the small number of patients included in the Vinokurova et al. study, some women developed vaginal or vulvar cancers later after hysterectomy (38143 months after treatment of the cervical lesion). If such late development of vaginal cancer among women treated for CIN 3 by hysterectomy is observed in other studies, continued vaginal cytologic screening of this population may need to be considered.
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