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Vaginal Intraepithelial Neoplasia: a Therapeutical Dilemma

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Vaginal Intraepithelial Neoplasia: a Therapeutical Dilemma ANTICANCER RESEARCH 33: 29-38 (2013) Vaginal Intraepithelial Neoplasia: A Therapeutical Dilemma ANTONIO FREGA1*, FRANCESCO SOPRACORDEVOLE2*, CHIARA ASSORGI1, DANILA LOMBARDI1, VITALIANA DE SANCTIS3, ANGELICA CATALANO1, ELEONORA MATTEUCCI1, GIUSI NATALIA MILAZZO1, ENZO RICCIARDI1 and MASSIMO MOSCARINI1 Departments of 1Gynecological, Obstetric and Urological Sciences, and 3Radiotherapy, Sant’Andrea Hospital, Sapienza University of Rome, Rome, Italy; 2Department of Gynaecological Oncology, National Cancer Institute, Aviano, Italy Abstract. Vaginal intraepithelial neoplasia (VaIN) thirds of the epithelium. Carcinoma in situ, which involves represents a rare and asymptomatic pre-neoplastic lesion. Its the full thickness of the epithelium, is included in VaIN 3. natural history and potential evolution into invasive cancer The natural history of VaIN is thought to be similar to that of are uncertain. VaIN can occur alone or as a synchronous or cervical intraepithelial neoplasia (CIN), although there is metachronous lesion with cervical and vulvar HPV-related little information regarding this. The management of this intra epithelial or invasive neoplasia. Its association with intraepithelial neoplasia should be tailored according to the cervical intraepithelial neoplasia is found in 65% of cases, patient. After early treatment, VaIN frequently regresses, but with vulvar intraepithelial neoplasia in 10% of cases, while patients require careful long-term monitoring after initial for others, the association with concomitant cervical or therapy due to high risk of recurrence and progression. The vulvar intraepithelial neoplasias is found in 30-80% of cases. purpose of this review is to identify the best management of VaIN is often asymptomatic and its diagnosis is suspected in VaIN basing therapy on patients’ characteristics. cases of abnormal cytology, followed by colposcopy and colposcopically-guided biopsy of suspicious areas. In the Epidemiology and Natural History past, high-grade VaIN and multifocal VaIN have been treated by radical surgery, such as total or partial upper vaginectomy In the past, VaIN was rarer than vaginal invasive cancer (1) associated with hysterectomy and radiotherapy. The need to because it was frequently underdiagnosed. Nowadays the maintain the integrity of reproductive capacity has determined incidence of VaIN is expected to rise due to a greater the transition from radical therapies to conservative ones, attention to cervical cytological screening and colposcopy according to the different patients’ characteristics. (2). The age at diagnosis is related to the degree of VaIN, being about 60 years for VaIN 3 and about 45 years for VaIN Vaginal intraepithelial neoplasia (VaIN) is a rare pre- 1 and 2 (3). In our experience, the mean age at diagnosis of malignant lesion characterized by the presence of squamous VaIN was 53 years (range=31-70 years) (4). Other authors cell atypia without invasion. The disease is classified have reported an average age of 35±17 years (5) and the according to the depth of epithelial involvement: VaIN 1 and diagnosis of VaIN 2-3 was also made in patients under 25 2 involve the lower one-third and two-thirds of the years old (6). In the past twenty years, the diagnosis of VaIN epithelium, respectively, and VaIN 3 involves more than two- has been made in younger women, due to the spread of the human papillomavirus (HPV) infection. The incidence of VaIN is 0.2-0.3 per 100,000 women (3, 7, 8). The reported frequencies are 0.5% of all neoplastic lower genital tract *These Authors contributed equally to this work. lesions (9) and 1% of all intraepithelial neoplasias (10). VaIN was associated with CIN in 65% of cases and with vulvar Correspondence to: Professor Antonio Frega, Department of intraepithelial neoplasia (VIN) in 10% of cases (5) in one Gynecological, Obstetric and Urological Sciences, Sant’Andrea study, while for others, the association with concomitant CIN Hospital, Sapienza University of Rome, Via di Grottarossa 1035-1039, or VIN reached 30-80% of cases (1, 5, 8, 10-13). 00189 Rome, Italy. Tel: +39 330885977, Fax +39 0692932259, e- mail: [email protected] Among women hysterectomized due to cervical carcinoma, VaIN was found in approximately 5-10% of cases (14-16). Key Words: Vaginal intraepithelial neoplasia (VaIN), human However, in another study, VaIN was found in 70% of papillomavirus (HPV), review. hysterectomized women for CIN or carcinoma (10). The 0250-7005/2013 $2.00+.40 29 ANTICANCER RESEARCH 33: 29-38 (2013) incidence of VaIN in women with a previous hysterectomy for origin of the upper vagina and cervix was considered in context benign uterine pathologies is about 1.3% in 10 years (17). In of synchronous or metachronous HPV-related cervical lesions. the etiology of VaIN, HPV plays a role similar to that of CIN Clinically, it is possible to recognize four situations: de novo and VIN (18, 19). The presence of HPV in low-grade lesions or found alone; associated with CIN or invasive cervical is found in 98-100% of cases, 90-92.5% in VaIN 2-3 and 65- cancer; associated with VIN or invasive vulvar cancer; 70% for invasive carcinomas (20, 21). VaIN 2-3 are related to associated with CIN or VIN, or their invasive counterparts (39). high-risk (HR) HPV for up to 65% of cases (21, 22): in particular, HPV 16 and 18 were found in 64% of cases (23- Diagnosis 25). The prevalence of HPV 16 and 18 in invasive vaginal cancer is slightly higher, reaching 72% and this confirms that Most patients are asymptomatic or may complain of unusual the affinity of HPV for the vaginal epithelium is similar to that vaginal discharge, thus the diagnosis is often accidental. In for the cervix (26). Among women with any degree of VaIN, order to perform a correct diagnosis, it is fundamental to 21 types of HPV have been found (27). Other risk factors in know if the patients underwent a previous hysterectomy. In addition to HPV include radiotherapy, immunosuppression, non-hysterectomized patients, an abnormal cytology requires prenatal exposure to diethylstilbestrol (DES) and smoking. colposcopy as a second-level examination. Colposcopy should HPV 16 is more frequent in women subjected to external carefully examine not only the cervix, but also the entire irradiation for cervical cancer, while those subjected to vagina. After the application of acetic acid (5%), aceto-white brachytherapy would be more at risk for infection by other areas with a mosaic and punctuation vascular pattern (10, 40, viral types and for developing low-grade lesions (26). In 41) seem to be related to the presence of high-grade lesions women with iatrogenic immunosuppression (28) or affected (41) which are highlighted after the application of Lugol by the human immunodeficiency virus (HIV) infection, VaIN staining. All the suspicious areas should undergo a biopsy for rises to 5% (29), perhaps due to a lower immune control of histological diagnosis. In 2011, the International Federation the HPV infection. Twenty years ago, an increased relative of Cervical Pathology and Colposcopy (IFCPC) agreed on an risk for CIN 2-3 and VaIN 2-3 was noticed in women exposed international revised colposcopic nomenclature of the vagina to DES in utero (30) and this has since been confirmed (31). (Table I). In patients hysterectomized due to CIN, the An association with smoking was found in 41-51% of cases diagnosis of VaIN should be suspected after an abnormal Pap (5, 10): smokers with HR-HPV infection have a significantly test (40) and cytology should be performed regularly once a higher risk of developing VaIN 2-3, compared to non-smokers year (10, 14, 42) for at least 4-10 years (12, 13). Pap test (27). The natural history of the disease is not clearly-defined sensitivity after hysterectomy is more than 80% (41, 43, 44). and the true potential of the lesions is not precisely Colposcopy of the vaginal vault after total hysterectomy is understood. Observational studies have shown that the more difficult than with an intact cervix as VaIN after majority of low-grade VaIN probably regress spontaneously in hysterectomy commonly occurs at the vaginal suture line and 90% of cases (7, 32). VaIN 3 lesions have greater malignant the vaginal angles which are difficult to visualize. In this case, potential and there are no data about the spontaneous histological diagnosis is also necessary. regression of VaIN 2-3. Concerning its progression, an interval of about 15 years between VaIN 1 and VaIN 2-3 lesions has Treatment been reported (2). VaIN 3 biopsies show initial invasion in approximately 10-28% of cases (7, 33-35). The progression to Treatments need individualization according to the patient’s invasive lesions after appropriate treatment ranges from 2% to characteristics, disease extension and previous therapeutic 5% (5, 8, 36, 37) of cases, ten-fold higher than CIN, when procedures. Radical treatment is complex to achieve because properly treated (0.3-0.5%). The scar of the vaginal vault after the vaginal wall is in close relationship with the urethra, hysterectomy may represent a site of progression from high- bladder and rectum. This condition also explains the risk of grade VaIN to invasive cancer (38). complications related to excisional surgery and the morbidity of radiotherapy. Classification and Topography In the literature, the results of different treatments vary. Remission can occur in 70% of cases after a single treatment VaIN (such as CIN and VIN) is classified into low-grade and in another 24% of patients after combined therapy (8). lesions (mild dysplasia or grade 1) and high-grade lesions The various types of treatments are summarized in Table II. [moderate and severe dysplasia, grade 2-3 and carcinoma in situ (CIS)]. In 80% of cases, VaIN involves the upper third of Surgery. The surgical treatments that can be used are CO2 the vagina and it is often multifocal (60%) (2, 3, 5-7, 10, 14), laser, loop electrosurgical excision procedure (LEEP) and mostly in women hysterectomized for CIN 3 or CIS (80%) (2, partial or total vaginectomy.
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