High-grade vaginal intraepithelial neoplasia and risk of progression to vaginal cancer. a multicentre study of the Italian Society of Colposcopy and Cervico-Vaginal Pathology (SICPCV)

OBJECTIVE: The aim of this study was to analyse the women with high grade vaginal intraepithelial neoplasia (HG-VaIN), in order to identify a subset of women at higher risk of progression to invasive vaginal cancer. MATERIALS AND METHODS: The medical records of all the women diagnosed with HG-VaIN, and subsequently treated, from January 1995 to December 2013 were analyzed in a multicentre retrospective case series. The rate of progression to invasive vaginal cancer and the potential risk factors were evaluated. RESULTS: 205 women with biopsy diagnosis of HG-VaIN were considered, with a mean follow up of 57 months (range 4-254 months). 12 cases of progression to vaginal squamocellular cancer were observed (5.8%), with a mean time interval from treatment to progression of 54.6 months (range 4-146 months). The rate of progression was significantly higher in women diagnosed with VaIN3 compared with VaIN2 (15.4% vs. 1.4%, p < 0.0001). Women with HG-VaIN and with previous hysterectomy showed a significantly higher rate of progression to invasive vaginal cancer compared to non-hysterectomised women (16.7% vs. 1.4%, p < 0.0001). A higher risk of progression for women with VaIN3 and for women with previous hysterectomy for cervical HPV-related disease was confirmed by multivariable logistic regression analysis. CONCLUSIONS: A higher rate of progression to vaginal cancer was reported in women diagnosed with VaIN3 on biopsy and in women with previous hysterectomy for HPV-related cervical disease. These patients should be considered at higher risk, thus a long lasting and accurate follow up is recommended

Focal Spot, Summer/Fall 2005

https://digitalcommons.wustl.edu/focal_spot_archives/1100/thumbnail.jp

Focal Spot, Summer/Fall 2005

https://digitalcommons.wustl.edu/focal_spot_archives/1100/thumbnail.jp

Concurrent Chemoradiation for Vaginal Cancer

Background: It is not known whether the addition of chemotherapy to radiation therapy improves outcomes in primary vaginal cancer. Here, we review clinical outcomes in patients with primary vaginal cancer treated with radiation therapy (RT) or concurrent chemoradiation therapy (CRT). Methods: Seventy-one patients with primary vaginal cancer treated with definitive RT with or without concurrent chemotherapy at a single institution were identified and their records reviewed. A total of 51 patients were treated with RT alone; 20 patients were treated with CRT. Recurrences were analyzed. Overall survival (OS) and disease-free survival (DFS) rates were estimated using the Kaplan-Meier method. Cox regression analysis was performed. Results: The median age at diagnosis was 61 years (range, 18–92 years) and the median follow-up time among survivors was 3.0 years. Kaplan-Meier estimates for OS and DFS differed significantly between the RT and CRT groups (3-yr OS = 56% vs. 79%, log-rank p = 0.037; 3-yr DFS = 43% vs. 73%, log-rank p = 0.011). Twenty-three patients (45%) in the RT group had a relapse at any site compared to 3 (15%) in the CRT group (p = 0.027). With regard to the sites of first relapse, 10 patients (14%) had local only, 4 (6%) had local and regional, 9 (13%) had regional only, 1 (1%) had regional and distant, and 2 (3%) had distant only relapse. On univariate analysis, the use of concurrent chemotherapy, FIGO stage, tumor size, and date of diagnosis were significant predictors of DFS. On multivariate analysis, the use of concurrent chemotherapy remained a significant predictor of DFS (hazard ratio 0.31 (95% CI, 0.10–0.97; p = 0.04)). Conclusions: Vaginal cancer results in poor outcomes. Adequate radiation dose is essential to ensure curative management. Concurrent chemotherapy should be considered for vaginal cancer patients

Prevalence of oropharynx cancer caused by HPV compared with genital cancer

Introduction: For a long time, the literature has established that HPV may be associated to pharynx cancer. Objective: To verify the number of publications in three different databases on the prevalence of oral, esophageal, penile, and cervical-vaginal cancer associated with HPV. Material and methods: The publications were verified in Pubmed, Lilacs, and Bireme databases; the keywords “mouth cancer”, “esophageal cancer”, “penile cancer”, and “cervical vaginal cancer”were associated with HPV. Data were tabulated in absolute numbers. Results: In all databases, the number of cervical carcinoma was much larger than that of other cancers. Conclusion: The number of cervical cancer was the most found associated with HPV because of the histological and specific functional conditions of this site.Introduction: For a long time, the literature has established that HPV may be associated to pharynx cancer. Objective: To verify the number of publications in three different databases on the prevalence of oral, esophageal, penile, and cervical-vaginal cancer associated with HPV. Material and methods: The publications were verified in Pubmed, Lilacs, and Bireme databases; the keywords “mouth cancer”, “esophageal cancer”, “penile cancer”, and “cervical vaginal cancer”were associated with HPV. Data were tabulated in absolute numbers. Results: In all databases, the number of cervical carcinoma was much larger than that of other cancers. Conclusion: The number of cervical cancer was the most found associated with HPV because of the histological and specific functional conditions of this site

High-dose rate brachytherapy (HDRB) for primary or recurrent cancer in the vagina

PURPOSE: The purpose of this study was to evaluate the efficacy of HDR brachytherapy for primary or recurrent vaginal cancer. METHODS: Between the years 2000 to 2006, 18 patients with primary or recurrent vaginal cancer were treated with brachytherapy (HDRB). Six patients had primary vaginal cancer (stage II to IVA) while 12 were treated for isolated vaginal recurrence (primary cervix = 4, vulva = 1 and endometrium = 7). Five patients had previous pelvic radiation therapy. All except one patient received external beam radiation therapy to a median dose of 45 Gy (range 31.2–55.8 Gy). The HDRB was intracavitary using a vaginal cylinder in 5 patients and interstitial using a modified Syed-Nesblett template in 13 patients. The dose of interstitial brachytherapy was 18.75 Gy in 5 fractions delivered twice daily. The median follow-up was 18 months (range 6–66 months). RESULTS: Complete response (CR) was achieved in all but one patient (94%). Of these 17 patients achieving a CR, 1 had local recurrence and 3 had systemic recurrence at a median time of 6 months (range 6–22 months). The 2-year actuarial local control and cause-specific survival for the entire group were 88% and 82.5%, respectively. In subset analysis, the crude local control was 100% for primary vaginal cancer, 100% for the group with recurrence without any prior radiation and 67% for group with recurrence and prior radiation therapy. Two patients had late grade 3 or higher morbidity (rectovaginal fistula in one patient and chronic vaginal ulcer resulting in bleeding in one patient). Both these patients had prior radiation therapy. CONCLUSION: Our small series suggests that HDRB is efficacious for primary or recurrent vaginal cancer. Patients treated with primary disease and those with recurrent disease without prior irradiation have the greatest benefit from HDRB in this setting. The salvage rate for patients with prior radiation therapy is lower with a higher risk of significant complications. Additional patients and follow-up are ongoing to determine the long-term efficacy of this approach

Risk of progression to vaginal cancer after successful treatment of high-grade cervical intraepithelial neoplasia: a long-term cohort study in a single institution

Background: Studies on the long-term risk of treated cervical intraepithelial neoplasia (CIN), have shown that these women have a higher risk of invasive cancer in the remaining cervix or vagina, when compared to the general population. This risk persists, for at least, ten years after initial treatment. Methods: Retrospective cohort study to evaluate the long-term risk of vaginal cancer after treatment of high-grade cervical intraepithelial neoplasia. Results: The data comprised 460 women with high-grade cervical intraepithelial neoplasia treated at our institution, from January 2012 to December 2020. Three women developed vaginal cancer. The rate of invasive cancer during this period was 181 per 100 000 woman-years. The increased risk of developing cancer was noticed during the first 5 years of follow-up, in women older than 50, and with human papillomavirus (HPV) 16 infections. Conclusions: Women previously treated for high-grade lesions, are at an increased risk of developing invasive vaginal cancer. This risk is higher in older women. Follow-up of these women should be based on risk, by a combination of co-testing and clinical evaluation

Vaginal cancer in patient presenting with advanced pelvic organ prolapse: case report and literature review

Background: Vaginal cancer presenting concurrently with stage 4 uterovaginal prolapse is a rare occurrence, representing less than 1% of all gynecologic malignancies. Case: We review the case of an 82-year-old woman who presented for care of prolapse. Examination demonstrated complete uterovaginal prolapse and a vaginal ulcer, later confirmed to be vaginal cancer. Conclusion: The management of these complicated patients is limited by a lack of data available to guide treatment. This case and the literature review highlight the need for a multi-disciplinary approach to treatment and a high level of clinical suspicion for diagnosis of these very challenging cases

HPV and potential prognostic markers in primary vaginal carcinoma

The overall aim of this PhD thesis is to evaluate HPV status and immunohistochemical expression of different biomarkers, including tumor suppressor p16, proliferation marker Ki67, molecular markers in the LRIG family, WRAP53ß, and dyskerin as well as immune markers CD4+ and CD8+ TILs, and their correlation to clinical manifestations and survival as part of a search for potential prognostic factors in women diagnosed with primary vaginal cancer. Paper I evaluates the presence of HPV in vaginal cancer tumor samples, as well as immunohistochemical expression of p16 and Ki-67. This study includes 68 short-term and long-term survivors diagnosed with vaginal cancer. The results, which have been correlated with both clinical parameters and survival, show presence of HPV in 43% of patients, with HPV16 found in 63% of the HPV-positive cases. HPV-positivity did not correlate with improved survival but did correlate with low histopathological grade. High expression of p16 was found in 54% of cases and correlated with low histopathological grade (p=0.004), HPV-positivity (p=0.032) and long-term survival (p=0.047). High expression of Ki-67, found in only 34% of patients, correlated negatively with histopathological grade (p<0.001) and tumor size (p=0.047). The results suggest that evaluation of p16 and Ki67 may be of value in tumor grading, while expression of p16 may also serve as a possible marker for HPV-positivity. In this study, high p16 expression, in contrast with positive HPV status and presence of Ki-67, was associated with improved survival in the univariate analysis, whereas multivariate analysis indicated that only histopathological grade and tumor size remain as independent prognostic factors. Paper II focuses on the LRIG (leucine-rich repeats and immunoglobulin-like domains) proteins – LRIG1, LRIG2 and LRIG3. Expression of these three proteins is often altered in cancer and has significance for cancer progression. The LRIG1 protein acts as a tumor suppressor, while the function of the remaining two is still unclear. We evaluated immunohistochemical expression of LRIG1, LRIG2, and LRIG3 in tumor samples from a cohort of 70 patients, diagnosed with vaginal cancer between 1975 and 2002, in order to find out whether such expression relates to clinical manifestations and survival. Our results show high (>50% of the cells) expression of LRIG1 and LRIG2 in 72% of tumors, but conversely, little or no expression of LRIG3. The latter two markers did not correlate with any clinical manifestations or survival, while high expression of LRIG1 correlated with HPV positivity and with improved cancer-specific survival (HR 0.35: 95% CI 0.68- 0.73) in vaginal cancer patients. Paper III addresses the molecular factors dyskerin and WRAP53ß in vaginal cancer. These two proteins play a role in the telomerase holoenzyme complex and are upregulated in different cancers. Expression of dyskerin and WRAP53ß was assessed by immunohistochemistry in 68 tumor samples drawn from the same study population as in study II. Most of the tumor samples demonstrated low to moderate expression of dyskerin. This protein is associated with shorter survival time and worse cancer-specific survival (HR 3.701: CI 95% (1.094-12.517). WRAP53ß was also expressed in most cells from the tumor samples, albeit without any association to clinical manifestations or prognosis. Paper IV is concerned with immune response as it relates to presence of CD4+ (Tumor Infiltrating Lymphocyte) TILs and CD8+ TILs in vaginal cancer tumor samples and also addresses the potential association between TILs, p16 expression and HPV status with clinical manifestations and survival. Once again, immunohistochemistry staining was used to evaluate CD4+ and CD8+ TIL infiltration along with p16expression in 69 tumor samples from the same study cohort used for the two previous studies. The results howed higher density CD4+ and CD8+ TIL infiltration in both HPV-positive and p16-positive tumors. High infiltration of CD4+ and CD8+ TILs in tumor samples implies better prognosis. Tumors demonstrating p16 overexpression in addition to high CD8+ TIL infiltration were associated with statistically significant (p=0.033) improvement in prognosis. In contrast, absence of p16 in HPV-negative tumors correlates with a substantially worse prognosis (p= 0.010). In summary, the studies in this thesis, which is concerned with exploring potential prognostic markers in vaginal cancer, identify p16 as a prognostic marker of interest, especially when considered in light of HPV status. Moreover, LRIG1 and dyskerin may be novel prognostic markers of potential interest, while LRIG2, LRIG3, and WRAP53ß appear to fall short in this regard. Furthermore, CD8+ TILs may also be of interest as a prognostic factor, especially when considered together with HPV status and p16 expression. Although this thesis implicates p16 expression together with HPV status as clinically relevant prognostic factors in vaginal cancer, future studies, using larger study cohorts, will be needed to validate these results for improved diagnostics and treatment strategies for women diagnosed with vaginal cancer.