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Surveillance for Recurrent Cancers and Vaginal Epithelial Lesions in Patients With Invasive Cervical Cancer After Hysterectomy
Are Vaginal Cytology and High-Risk Human Papillomavirus Testing Useful?

Zaibo Li MD, PhD, Stacey Barron MD, Wei Hong MD, Arivarasan Karunamurthy MD, Chengquan Zhao MD
DOI: http://dx.doi.org/10.1309/AJCPH4AFSZHU8EKK 708-714 First published online: 1 November 2013

Abstract

Objectives: To examine whether women who have had a hysterectomy for cervical cancer may be at an increased risk of vaginal epithelial lesions.

Methods: We studied 147 patients with invasive cervical carcinoma (76 squamous cell carcinomas [SCCs], 60 adenocarcinomas [ADCs], and 11 adenosquamous cell carcinomas) who were treated by hysterectomy and had vaginal pathologic follow-up for a mean period of 43.3 months.

Results: Of the patients, 15.0% (22/147) developed vaginal intraepithelial neoplasia (VAIN) or recurrence after hysterectomy, including two recurrent carcinomas and eight high-grade VAINs. More important, these high-grade VAINs or recurrent carcinomas were detected only in patients with cervical SCC within the first two years after hysterectomy but not in patients with cervical ADC. Eleven (23.4%) of 47 patients had at least one positive high-risk human papillomavirus (hrHPV) testing result during the follow-up period, and VAIN was detected in 54.5% (6/11) of patients with an hrHPV-positive result compared with 16.7% (6/36) with an hrHPV-negative result.

Conclusions: Our results indicate that women with cervical cancer are at an increased risk of VAIN besides recurrence, and women with cervical SCC are more prone to high-grade VAIN/recurrence, especially within the first two years after hysterectomy. The significantly increased detection rate of VAINs/recurrence in the hrHPV-positive group suggests vaginal cytology and HPV cotesting might be the preferred method for surveillance in these women.

Key Words:
  • Vaginal intraepithelial neoplasia
  • Vaginal carcinoma
  • Hysterectomy
  • Cervical cancer
  • Cytologic follow-up
  • Histologic follow-up

Vaginal carcinoma is an uncommon gynecologic malignancy, with an annual incidence of 0.69 per 100,000 female population,1 and vaginal intraepithelial neoplasias (VAINs) are also rare, with an incidence of 0.2 to 0.3 per 100,000 women.24 For example, abnormal vaginal epithelial cytology was found in only 1.1% to 1.3% of vaginal cuff cytology testing in women hysterectomized for benign disease.5,6 Therefore, abnormal vaginal cytology is rarely of clinical importance for the general population, and new cervical cancer screening guidelines recommend that hysterectomized women at any age who have no history of cervical intraepithelial neoplasia grade 2+ (CIN2+) should not be screened for vaginal cancer using any modality. Evidence of adequate negative prior screening is not required.7

Similar to CINs or carcinomas, VAINs or vaginal carcinomas are also associated with high-risk human papillomavirus (hrHPV).8,9 It has been reported that HPV is present in 98% to 100% of VAIN grade 1 (VAIN1), 90% to 92.5% of VAIN grades 2 to 3 (VAIN2-3), and 65% to 70% of invasive vaginal carcinomas.10,11 HPV types 16 and 18 account for most high-grade VAINs and vaginal carcinomas, as reported in 64% of VAIN2-312,13 and 72% of vaginal carcinomas.14

However, women who have had a hysterectomy for cervical cancer or CINs may be at an increased risk of vaginal cancer based on several reports that found VAINs in approximately 5% to 10% of women hysterectomized due to cervical carcinoma.1520 More than 12,000 women are diagnosed with cervical cancer each year in the United States, and 50% of them have stage I disease.21 The primary treatment options for stage I disease include radical hysterectomy with pelvic lymph node dissection, radiation, and chemotherapy, with the five-year survival rate exceeding 90%. However, local recurrence rates for this group are high, ranging from 10% to 20%.22 Patients with locally recurrent disease can be offered salvage treatments with the potential for cure. Regarding the surveillance for these patients after primary curative treatment, the Society for Gynecologic Oncology (SGO) and the American College of Obstetricians and Gynecologists (ACOG) recommend review of symptoms and physical examination every three to six months for the first two years, as well as a yearly Papanicolaou (Pap) smear to detect local recurrence and preinvasive disease, but Pap smears’ effectiveness is not well studied.2325

Recently, cotesting with both cytology and hrHPV is recommended for cervical screening in women 30 years or older by the American Cancer Society, American Society of Colposcopy and Cervical Pathology, and American Society of Clinical Pathology.7 Although vaginal epithelial lesions are also caused by HPV infection, the role of HPV testing in women with invasive cervical cancer after hysterectomy is not clear. The aims of this study are to investigate the incidence of vaginal intraepithelial lesions in women with invasive cervical cancer after hysterectomy and to explore an effective follow-up testing for these women.

Materials and Methods

Patient Accrual

After obtaining institutional review board approval from the University of Pittsburgh Medical Center (UPMC), a retrospective study was initiated. A computer-based search of the CoPath (Cerner Corporation, Kansas City, MO) laboratory information system (LIS) database at Magee-Womens Hospital (MWH) of UPMC was carried out to retrieve cases with histopathologic biopsy diagnoses of invasive cervical carcinoma rendered between January 2000 and December 2010. The Pap test results, hrHPV DNA test results, and surgical pathology findings, including endocervical curetting, cervical biopsy, loop electrosurgical excision procedure/cone biopsy, and hysterectomy, were recorded from our CoPath database. Other clinical information was also recorded, including age and clinical history available in the LIS.

Cytology Screening Testing

All cytologic tests in this study were performed in the cytology laboratory at the MWH of UPMC. Cytologic testing used ThinPrep Pap tests (TPPTs)26 prepared according to the manufacturer’s specifications from PreservCyt samples using an automated processor (ThinPrep 3000, Hologic, Marlborough, MA). Staining of slides was performed on a Sakura Tissue-Tek Automated Slide Stainer (Sakura Finteck USA, Torrance, CA).

hrHPV DNA Screening Testing

hrHPV DNA detection in TPPT PreservCyt vial fluid was performed using the US Food and Drug Administration–approved Hybrid Capture 2 (HC2) assay method27 (Qiagen, Hinden, Germany), which tests for high-risk and intermediate-risk HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. The results of hrHPV DNA testing were either positive or negative. Women who had equivocal results or residual samples with residual vial fluid volume insufficient for hrHPV DNA testing were excluded from this analysis.

Histopathologic Diagnosis

All histopathologic diagnoses of invasive cervical carcinoma in this study were established by subspecialized staff pathologists at MWH whose practices are largely limited to examination of gynecologic and breast pathology specimens. Cervical/vaginal cytology and histology reports after hysterectomy were recorded.

Statistical Analysis

Pearson’s χ2 test was used for statistical analysis (Fisher exact test for small sample sizes), conducted on the SAS 9.1 system (SAS Institute, Cary, NC). A value of P < .05 was considered statically significant.

Results

The patients who had cervical cancers treated by radiation therapy/chemotherapy and those who had cervical cancers treated by hysterectomy but did not have follow-up results in our database were excluded from this study. In total, 147 patients with invasive cervical carcinoma (76 squamous cell carcinomas [SCCs], 60 adenocarcinomas, and 11 adenosquamous cell carcinomas) treated by hysterectomy were included in this study. Similarly among all three groups, the mean age of these patients was 43 years (range, 29–72 years) at the time of diagnosis of invasive carcinoma, and the mean follow-up period was 43.3 months (range, 1–139 months; median, 40 months) Table 1. High-grade squamous intraepithelial lesion (HSIL) was the most common referral Pap in both cervical SCC and adenosquamous cell carcinoma, but atypical glandular cells and carcinoma were the most common referral Paps in cervical adenocarcinoma. Similarly, among all three groups, most cases in this study had a pathologic stage lower than pT2a.

Of 118 patients identified with cervical SCC and follow-up histology/cytology, 76 had hysterectomy as the primary treatment within six months after diagnosis; the 42 patients who had radiation/chemotherapy only as the primary treatment were excluded from this study. Among 76 patients treated by hysterectomy, 19 had both histologic and cytologic follow-up, and 57 patients had only cytologic follow-up. During the follow-up period, two patients were identified to have local recurrent SCC (one in the vagina and the other in the vulva), eight patients had high-grade VAIN (VAIN2-3/HSIL), and seven patients had low-grade VAIN (VAIN1/low-grade squamous intraepithelial lesion [LSIL]) Figure 1. The overall cure rate for this group was about 97%.

Of 60 patients with cervical adenocarcinoma and follow-up histology/cytology, all were treated by hysterectomy within six months after diagnosis. Thirteen patients had both histologic and cytologic follow-up, and 47 had only cytologic follow-up. During follow-up, four patients were identified to have VAIN1/LSIL, and no high-grade lesion was identified Figure 2. The cure rate for this group was 100%.

Of 20 patients identified with cervical adenosquamous cell carcinoma, nine did not have any pathologic follow-up and were excluded from this study. Among the remaining 11 patients treated by hysterectomy within six months after diagnosis, two had both histologic and cytologic follow-up and nine had only cytologic follow-up. During follow-up, one patient was identified to have VAIN1/LSIL, and no high-grade lesion was identified Figure 3. The cure rate for this group was 100%.

Figure 1

Diagram of study design for squamous cell carcinoma (SCC). Of 118 patients with cervical SCC and follow-up histology/cytology, 76 had hysterectomy as primary treatment within six months after diagnosis. HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion; VAIN1, vaginal intraepithelial neoplasia grade 1; VAIN2-3, vaginal intraepithelial neoplasia grades 2–3.

In summary, VAIN1 and above (VAIN1+) lesions were identified in 15.0% (22/147) of patients with invasive cervical cancer treated by hysterectomy, including two local recurrent SCCs, eight HSILs (seven with histologic diagnosis and one with cytologic diagnosis only), and 10 LSILs Table 2. All 10 cases with high-grade VAIN and above lesions (VAIN2/3+) were identified only in patients with invasive SCC, and the incidence of VAIN2/3+ lesions during follow-up in patients with invasive SCC treated by hysterectomy was about 13%, which was significantly higher than that in patients with cervical adenocarcinoma treated by hysterectomy (no high-grade lesions identified) Figure 4.

View this table:
Table 1
Figure 2

Diagram of study design for cervical adenocarcinoma (ADC). Sixty patients had hysterectomy as primary treatment within six months after diagnosis and had pathologic follow-up results. ASCUS, atypical squamous cells of undetermined significance; VAIN1, vaginal intraepithelial neoplasia grade 1.

We further investigated the detailed history for those 10 cases with VAIN2/3+ in the follow-up term. Two (1.4%) cases of vaginal/vulvar SCC were detected at one and 11 months after the hysterectomy, respectively. Both patients showed clinical symptoms; one underwent biopsy without cytology, and the other one underwent both biopsy and cytology, which showed HSIL Table 3. Eight HSILs were also identified within the first two years of follow-up, including seven cases with histologic diagnosis and one case with cytologic diagnosis. For these nine cases with histologic diagnosis of VAIN2+, seven had cytologic diagnosis before histologic diagnosis, including five HSILs, one with atypical squamous cells (cannot exclude grade), and one LSIL. hrHPV testing result during follow-up was available for four cases. Two had positive results; the other two had negative results after treatment for high-grade VAINs (Table 3).

Figure 3

Diagram of study design for cervical adenosquamous cell carcinoma. Of 20 cases of cervical adenosquamous cell carcinoma, nine without follow-up results were excluded. Of the 11 patients with cervical adenocarcinoma and follow-up histology/cytology, all had hysterectomy as primary treatment within six months after diagnosis. ASCUS, atypical squamous cells of undetermined significance; VAIN1, vaginal intraepithelial neoplasia grade 1.

View this table:
Table 2
Figure 4

The incidence of VAIN1/LSIL and VAIN2-3/HSIL+ during follow-up in patients with different histologic invasive cervical carcinoma. ADC, adenocarcinoma; AdenoSCC, adenosquamous cell carcinoma; HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion; SCC, squamous cell carcinoma; VAIN1, vaginal intraepithelial neoplasia grade 1; VAIN2-3, vaginal intraepithelial neoplasia grades 2–3.

Next we examined hrHPV testing during follow-up in these patients with invasive cervical carcinoma treated by hysterectomy. Eleven (23.4%) of 47 patients had at least one positive hrHPV testing result during the follow-up period. VAIN detection rate was significantly higher in patients with an hrHPV-positive result (54.5%) than in patients with an hrHPV-negative result (16.7%) Table 4. Six patients had both VAIN1+ and negative hrHPV testing during follow-up. Four had VAIN1 and two had VAIN2-3, but the HPV testing occurred after treatment for VAIN2-3, as mentioned above.

Discussion

Since vaginal carcinoma and VAIN are uncommon1,4 and abnormal vaginal cytology is rarely of clinical importance for the general population,5,6 new cervical cancer screening guidelines indicate that women who have undergone hysterectomy and have no history of CIN2+ should not be screened for vaginal cancer.7 However, limited data suggest that women who have had a hysterectomy for cervical cancer or CINs may be at an increased risk of local recurrent cancer or VAIN in up to 5% to 10% of cases.1520 Although the five-year survival rate for stage I cervical cancer exceeds 90%, local recurrence rates are high, ranging from 10% to 20%.21,22 Since patients with locally recurrent disease can be offered salvage treatments with the potential for cure, the SGO and the ACOG recommend review of symptoms and physical examination every three to six months for the first two years and a yearly Pap smear to detect local recurrence and preinvasive disease.2325 Along with clinical symptoms, physical examination will detect most cases of local recurrent cancer. Retrospective studies have shown cytologic evaluation to be low yield for detecting recurrent cancer, with detection rates ranging from 0% to 17%.22

View this table:
Table 3
View this table:
Table 4

Although there is insufficient evidence in cancer surveillance, cytologic evaluation may have value in the detection of preinvasive intraepithelial lesions. A recent study on vaginal cytology in three groups of hysterectomized women due to gynecological malignancy, CIN3, and benign gynecological diseases indicated that VAIN+ lesions occurred in 7.1%, 3.0%, and 0.5%, respectively.28 Consistent with these reports, our finding of VAIN1+ lesions identified in 15.0% (22/147) of patients with invasive cervical cancer treated by hysterectomy indicates an increased risk for vaginal epithelial lesions in these patients. The slightly higher incidence of VAINs in our studies might be due to specifically selected invasive cervical carcinoma cases.

Similar to CIN or cervical carcinoma, VAINs are also caused by HPV, especially hrHPV, since HPV types 16 and 18 account for most cases.2,13,28 The prevalence of HPV in vaginal intraepithelial lesions parallels that of cervical intraepithelial lesions.2932 Our finding of a significantly increased incidence of VAIN1+ lesions in patients with positive hrHPV testing (55%) indicates that VAIN is associated with HPV infection. Of course, a selective bias may be present because hrHPV testing was not performed in all follow-up patients. A negative hrHPV testing result was found in six patients with VAINs (two with VAIN2-3 and four with VAIN1). As mentioned in the Results section, hrHPV testing occurred after treatment for those two patients with high-grade VAIN. The negative hrHPV testing in four patients with low-grade VAIN might be explained by infection of low-risk HPV types (such as HPV 6 or 11), which cannot be identified in HC2 hrHPV testing.

In our studies, all VAIN2+ lesions were identified in patients with invasive cervical SCC, but no high-grade vaginal epithelial lesion was identified in patients with invasive cervical adenocarcinoma or adenosquamous cell carcinoma. These data suggest that cervical SCC is a risk factor for consequent high-grade vaginal epithelial lesions (VAIN2+), but cervical adenocarcinoma might not be a risk factor for high-grade vaginal epithelial lesions (VAIN2+). Although almost all cervical epithelial carcinoma (SCC, adenocarcinoma, and adenosquamous cell carcinoma) are caused by hrHPV infection, our data suggest that there might be a different pathogenic mechanism or genetic vulnerability between SCC and adenocarcinoma, and vaginal intraepithelial lesions might follow the same pathogenic mechanism as cervical SCC instead of just HPV infection. More data are warranted to confirm this observation in the future. Consistent with previous reports,28,33 our data also indicate that in the first two years after hysterectomy, patients are more prone to high-grade vaginal intraepithelial lesions, which suggests that more frequent vaginal cytology tests are necessary in this period.

In summary, our data indicate that women who had invasive cervical cancer are at an increased risk of high-grade VAIN lesions, especially those with cervical SCC. To our knowledge, this is one of the first studies to investigate hrHPV testing during follow-up for women with invasive cervical carcinoma after hysterectomy, and the significantly increased detection rate of VAINs in the hrHPV-positive group suggests that vaginal cytology and HPV cotesting might be an effective detection method for these patients.

CME/SAM

Upon completion of this activity you will be able to:

  • define vaginal cytology’s effectiveness in surveillance for recurrent cancer and vaginal epithelial lesions in patients with invasive cancer after hysterectomy.

  • examine the association between high-risk human papillomavirus testing results and vaginal epithelial lesions in patients with invasive cervical cancer after hysterectomy.

  • discuss appropriate laboratory surveillance methods for patients with invasive cervical cancer treated by hysterectomy.

The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per article. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module.

The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.

Questions appear on p 757. Exam is located at www.ascp.org/ajcpcme.

References

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  16. 16.
  17. 17.
  18. 18.
  19. 19.
  20. 20.
  21. 21.
  22. 22.
  23. 23.
  24. 24.
  25. 25.
  26. 26.
  27. 27.
  28. 28.
  29. 29.
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View Abstract