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Role of Human Papillomavirus Genotype in Prognosis of Early-Stage Cervical Cancer Undergoing Primary Surgery

Chyong-Huey Lai, Chee-Jen Chang, Huei-Jean Huang, Swei Hsueh, Angel Chao, Jung-Erh Yang, Cheng-Tao Lin, Shang-Lang Huang, Ji-Hong Hong, Hung-Hsueh Chou, Tzu-I Wu, Kuan-Gen Huang, Chun-Chieh Wang, Ting-Chang Chang

From the Departments of Obstetrics and Gynecology, Pathology, and Radiation Oncology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine; and Graduate Institutes of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan

Address reprint requests to Chyong-Huey Lai, MD, Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, 5 Fu-Shin St, Kueishan, Taoyuan 333, Taiwan; e-mail: sh46erry{at}ms6.hinet.net

	ABSTRACT

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Purpose Our aim was to evaluate the prognostic significance of human papillomavirus (HPV) genotype in early-stage cervical carcinoma primarily treated with surgery in a large tertiary referral medical center.

Patients and Methods Consecutive patients who underwent primary surgery for invasive cervical carcinoma of International Federation of Gynecology and Obstetrics (FIGO) stage I to IIA between 1993 and 2000 were retrospectively reviewed. Polymerase chain reaction (PCR) using a general primer set followed by reverse-blot detection of 38 types of HPV DNA in a single reaction was performed for genotyping. E6 type-specific PCR was performed to validate multiple types.

Results A total of 1,067 eligible patients were analyzed. HPV DNA sequences were detected in 95.1% of the specimens, among which 9.6% contained multiple types. HPV 16 was detected in 63.8% of the samples, and HPV 18 was detected in 16.5% of the samples. The median follow-up time of surviving patients was 77 months. By multivariate analysis, FIGO stage, lymph node metastasis, depth of cervical stromal invasion, grade of differentiation, and HPV 18 positivity were significantly related to cancer relapse. FIGO stage II, deep stromal invasion, parametrial extension, HPV 18 positivity, and age older than 45 years were significant predictors for death. Using the seven selected variables from either recurrence-free or overall survival analysis, death-predicting (P < .0001) and relapse-predicting (P < .0001) models classifying three risk groups (low, intermediate, and high risk) were constructed and endorsed by internal validation.

Conclusion The independent prognostic value of HPV genotype is confirmed in this study. The prognostic models could be useful in counseling patients and stratifying patients in future clinical trials.

	INTRODUCTION

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Cervical cancer remains the second most prevalent female malignancy in the world.¹ Optimal management of cervical cancer consists of precisely evaluating tumor extent and implementing treatment followed by deliberate post-therapy surveillance, early detection of recurrence, and appropriate salvage therapy. For early-stage invasive cervical cancer, either radical surgery or radiotherapy (RT) provides equal efficacy.^1-3 Selecting appropriate candidates for primary surgery and providing well-defined high-risk patients with postoperative adjuvant therapy is crucial.

Clinicopathologic factors for cervical cancer, including International Federation of Gynecology and Obstetrics (FIGO) stage, lymph node metastasis, parametrial or vaginal extension, nonsquamous histology, grade of differentiation, lymphovascular space invasion, and depth of cervical stromal invasion, have been noted to be associated with prognosis. Most studies are concordant regarding the former two variables (stage and lymph node metastasis); however, selected significant prognostic covariates vary between studies according to the patient population and methods of analysis.^1-5

Although the molecular mechanisms of human papillomavirus (HPV) in cervical carcinogenesis have not been fully elucidated, HPV infection has been established as a necessary cause for cervical intraepithelial lesions and invasive carcinoma. With adequately sensitive methods, the HPV DNA detection rates approach 95% to 100% in cervical carcinoma tissue.^6-9 The relationship of HPV genotype to prognosis of invasive cervical cancer has been controversial.^9-23 Many reports found that HPV 18–positive tumors were associated with poorer prognosis.^10-15 Some reported that serum antibody to HPV 16 E7 peptide,¹⁶ HPV 16 DNA positivity,¹⁷ and HPV 16/18 DNA positivity¹⁸ were associated with poor outcome, whereas HPV 16 DNA positivity was related to better survival in another report.¹⁹ One report found that HPV 58–related types were associated with better prognosis,²⁰ whereas another study noted that HPV 31–related types predicted better survival.²¹ In contrast, no prognostic value for HPV status or HPV genotype was found by other studies.^9,22,23

There are at least three reasons for the controversy. First, the previous reports investigating the prognostic role of HPV genotype are mostly small series (n < 150).^{10,11,15,18,19,21,22} Usually, only case-control or univariate analyses were performed.^{9,10,18,19,23} Second, series able to perform multivariate analysis usually included cervical cancer stages I to IV, where other variables could not compete with the powerful factor of stage^12,14,16,21 or lymph node metastasis.¹⁵ Third, various methods of different sensitivity of detecting HPV were used. Further studies with sufficient sample size and sensitivity in detecting HPV DNA are necessary to draw conclusion.

The purpose of this retrospective study was to evaluate the prognostic significance of HPV genotype in FIGO stage I to IIA cervical carcinoma primarily treated with surgery in a large tertiary referral medical center. The target sample size was more than 1,000 patients.

	PATIENTS AND METHODS

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Study Population
A list of consecutive patients who underwent primary definitive surgery or RT for invasive cervical carcinoma of FIGO stage I to IV between 1993 and 2000 at Chang Gung Memorial Hospital was retrieved from the hospital database initially.²⁴ Medical records were retrospectively reviewed. The institutional review board approved the study. Formalin-fixed paraffin-embedded tissue specimens were used for DNA analysis. Patients who had a wrong diagnosis or incomplete medical records, missing paraffin blocks, or specimens with inadequate DNA quality were excluded; the remaining patients were eligible for the HPV genotype study.²⁴ For prognosis analysis, only patients with stage I to IIA disease receiving primary surgery were included in the current report.

DNA Extraction, SPF1/GP6+ Polymerase Chain Reaction, and E6 Type-Specific Polymerase Chain Reaction
The procedures of DNA extraction and polymerase chain reaction (PCR) have been detailed previously.^24-26 Briefly, short PCR fragment 1 (SPF1)/general primer 6 (GP6)+^9,25 PCR was performed for 40 cycles. E6 type-specific PCR was performed for 50 cycles. The 25 sets of primer sequences and procedures of type-specific PCR were detailed in previous reports.²⁴ Routine precaution procedures were applied to avoid carrying over or contamination.^24-26

HPV Genotyping by Genechip
Fifteen microliters of the resultant PCR products were hybridized with an Easychip HPV Blot (King Car, I-Lan, Taiwan; hereafter referred to as HPV Blot) membrane in a single reaction. HPV Blot contains 38 types of HPV (6, 11, 16, 18, 26, 31, 32, 33, 35, 37, 39, 42, 43, 44, 45, 51, 52, 53, 54, 55, 56, 58, 59, 61, 62, 66, 67, 68, 69, 70, 71 [CP8061], 72, 74, 81 [CP8304], 82 [MM4], 83 [MM7], 84 [MM8], L1AE5) oligonucleotide probes of 20- to 30-mer on a nylon membrane. The hybridization and detection procedures were described previously.^24-26

Validation of HPV-Negative Results and Multiple Types
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) PCR was performed when HPV-negative results were obtained at the first round. If GAPDH PCR was also negative, another block was used when appropriate. In case of GAPDH positivity and HPV negativity by both type-specific PCR of the leading eight types (determined by the preliminary data) and a repeat of HPV Blot, the final result was designated as HPV negative.²⁴

E6 type-specific PCRs (25 types) were performed to validate multiple types on HPV Blot. In case of discordance between the type-specific PCR and HPV Blot results, a repeat of HPV Blot was performed to resolve the discordance.²⁴

Postoperative Adjuvant Therapy
Our policy of selecting patients for adjuvant therapy after primary surgery has evolved with time according to ongoing clinical trials. In general, patients with positive vaginal margin, parametrial extension, and full thickness of cervical stromal invasion would be offered adjuvant RT. For pelvic lymph node–positive patients, adjuvant chemotherapy, RT, or concurrent chemoradiotherapy (CCRT) was prescribed within or out of a clinical trial.²⁷ The regimen of chemotherapy and method of adjuvant RT have been described previously.^27,28 HPV genotype was not available for the decision of adjuvant therapy during the study period.

Post-Therapy Surveillance
Our protocol of post-therapy surveillance consisted of follow-up visits every 3 months for 2 years, every 4 months for the third year, every 6 months between years 3 and 5, and yearly after 5 years. Clinical history, physical and pelvic examination, Pap smear, and serum tumor markers were checked on every visit. Yearly chest x-ray studies were advised in asymptomatic patients, whereas computed tomography or magnetic resonance imaging scans were performed yearly for the first 3 consecutive years for high-risk groups or when clinically indicated.²⁹

Statistical Analysis
The data were analyzed using the SPSS version 11.0 statistical package (SPSS Inc, Chicago, IL). Pearson's ² test was used to evaluate the association between covariates. Survival curves were generated using the Kaplan-Meier method. Multivariate analysis by Cox stepwise forward regression was used for those covariates selected in univariate analyses of survival by log-rank test with a P < .05. Their hazard ratios (HRs) and 95% CIs were calculated using the Wald test. Using the selected independent prognostic variables, outcome-predicting models were formulated. Continuous variables (such as age) were determined by the recursive partitioning method for optimal cut point analysis. Bootstrap resampling using R software (http://www.r-project.org) was performed randomly to construct new data sets (events per variable > 10, n = 1,067) followed by Cox regression analysis, which was repeated 1,000 times, and the counts of selection as significant were recorded for each variable.³⁰ All tests were two sided, and P < .05 was considered statistically significant.

	RESULTS

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The hospital database identified 2,446 patients with FIGO stage I to IV cervical cancer primarily treated with surgery or definitive RT/CCRT between 1993 and 2000. Of the 2,446 patients, 161 with a wrong diagnosis or incomplete medical records, 154 with missing paraffin blocks, and 13 with GAPDH-negative specimens were excluded. A total of 2,118 patients (1,072 receiving primary surgery and 1,046 receiving primary RT/CCRT) were analyzed for genotype distribution, the results of which were reported elsewhere.²⁴ Of the 1,072 patients, five patients were subsequently excluded because of receiving neoadjuvant chemotherapy (n = 1) and primary RT (n = 4) before surgery; therefore, the remaining 1,067 patients were eligible for the current study. The clinicopathologic characteristics of the study patients are listed in Table 1.

HPV DNA Analysis
Of the 1,067 eligible patients, HPV DNA sequences were detected in 1,015 of the specimens (95.1%; 95% CI, 93.8% to 97.4%), among which 90.4% harbored single-type and 9.6% contained multiple-type HPV sequences. A total of 28 types of HPV were detectable in this study. The leading 10 types were HPV 16 (63.8%), HPV 18 (16.5%), HPV 58 (6.8%), HPV 52 (5.3%), HPV 33 (4.3%), HPV 45 (2.4%), HPV 31 (1.1%), HPV 39 (0.8%), HPV 59 (0.6%), and HPV 53 (0.5%). The other 18 types in order of decreasing frequency were HPV 67, 11, 43, 35, 82 (MM4), 51, 42, L1AE5, 70, 68, 37, 26, 81, 71, 72, 69, 62, and 54. HPV 16 or 18 comprised 77% of specimens (822 of 1,067 specimens), and HPV 58, 33, or 52 was detected in 16.5% of specimens (176 of 1,067 specimens). Of the 1,015 HPV-positive specimens, 78 (7.7%) contained double types, 18 (1.8%) contained triple types, and one (0.1%) contained quadruple types.

Associations of HPV Parameters With Various Clinicopathologic Characteristics
Associations of HPV parameters with various clinicopathologic characteristics are listed in Appendix Table A1 (online only). By Pearson's ² analysis, age, tumor size, FIGO stage, depth of cervical stromal invasion, lymph node metastasis, and parametrial extension were unrelated to HPV 18 positivity. HPV 18 positivity was significantly more common in adeno-adenosquamous (43%) than squamous carcinoma (11%; P < .001) and presence of lymphatic permeation was also significantly associated with HPV 18 positivity (P = .04). No variable was significantly related to HPV status (positive or negative). HPV 58, 33, or 52 positivity was significantly associated with age ( 35 v > 35 years: 7% v 17%, P = .01; 45 v > 45 years: 10% v 21%, P < .001; 50 v > 50 years: 11% v 23%, P < .001) and histologic type (squamous v adeno-adenosquamous: 18% v 7%, P < .001).

Univariate and Multivariate Analyses of Prognostic Factors
The median follow-up time of surviving patients was 77 months (range, 0.1 to 161 months). Up to the date of analysis (December 30, 2006), there were 137 cancer recurrences and 152 deaths. Of the 137 patients who experienced a relapse, 94 died of disease, whereas the remaining 43 were alive either without disease after salvage treatment or alive with cancer. Of the 152 deaths, four patients who died of intercurrent disease unrelated to cancer were censored at the date of death for the calculation of cancer-specific overall survival (OS). The other 40 patients whose cause of death on death certificates was cervical cancer without a definite recurrence record were counted as having cancer-specific events. The remaining 14 patients with unknown cause of death were censored.

Univariate analyses were performed using the log-rank test. Age, stage, tumor size, grade, depth of cervical stromal invasion, lymphatic permeation, lymph node metastasis, and HPV 18 positivity were significantly associated with both recurrence-free survival (RFS) and OS rates, whereas histologic type, HPV status (positive or negative), and HPV pattern (single type or multiple type) were unrelated to survival (Table 2). Using an age cut point of 50 years, only FIGO stage II, deep cervical stromal invasion, parametrial extension, and HPV 18 positivity were significant by multivariate analysis (Appendix Table A2, online only), whereas age was selected in addition to the former four variables as independent predictors for OS using an age cut point of 45 years (Table 3). By multivariate analysis, FIGO stage, lymph node metastasis, depth of cervical stromal invasion, grade of differentiation, and HPV 18 positivity (P = .009) were significantly related to RFS, despite using different age cut points (Appendix Table A2 and Table 3).

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. (A) Kaplan-Meier overall survival curves according to risk groups in early-stage cervical cancer patients undergoing primary surgery (n = 1,067). (B) Kaplan-Meier recurrence-free survival curves according to risk groups in early-stage cervical cancer patients undergoing primary surgery (n = 1,067).

	DISCUSSION

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The independent prognostic significance of HPV 18 positivity in early-stage cervical cancer is confirmed in this sufficiently sized study. HPV 18 positivity was significantly more common in adeno-adenosquamous carcinoma and lymphatic permeation but was unrelated to age, tumor size, FIGO stage, depth of cervical stromal invasion, lymph node metastasis, and parametrial extension.

In this series, FIGO stage, lymph node metastasis, depth of cervical stromal invasion more than one third, grade 2 to 3 differentiation, and HPV 18 positivity were significant predictors of relapse, and FIGO stage II, depth of cervical stromal invasion more than one third, parametrial extension, HPV 18 positivity, and age older than 45 years were significant predictors for death by multivariate analysis. The prognostic models including HPV 18 positivity are powerful in predicting death (P < .0001) and relapse (P < .0001).

Burger et al¹² also identified HPV 18 positivity as a significant poor prognostic factor in FIGO stage I and II patients (n = 171) undergoing RH-PLND, whereas in the analysis of the whole series of patients with stage I to IV disease (n = 291), only stage was significant. Schwartz et al¹⁴ noted that HPV 18–related tumors were significantly related to poor outcome for patients with FIGO stage IB and IIA but not prognostic for stage IB to IV. Viladiu et al¹⁶ also identified clinical stage as the only independent prognostic factor, and HPV 16 E7 antibody predicted mortality only limited to stage I and II.

Lombard et al¹³ confirmed the adverse prognostic significance of HPV 18 positivity in 399 patients with stage I to IV disease; however, the variables included in the multivariate analysis were limited to those obtainable without RH-PLND. Conversely, Plich et al¹⁷ identified HPV 16 positivity, not HPV 18 positivity, as a poor prognostic factor in 204 patients undergoing primary RH-PLND.

In this series, HPV 58, 33, or 52 was associated with older age and squamous carcinoma. The 5-year RFS rate of patients positive for HPV 58, 33, or 52 (n = 165) was marginally higher than the rate for patients negative for HPV 58, 33, or 52 (P = .07) by univariate analysis. In this study, HPV 58, 33, or 52 positivity was detected in 16.5% and multiple-type HPV was detected in 9.6% of early-stage primarily surgically treated patients compared with 44.5% and 26.5% of patients, respectively, receiving RT/CCRT in our previous study.²⁴

Regarding the prognostic impact of multiple infections, few data are available in the literature. Moreover, multiple infections cannot be identified using direct sequencing; therefore, those using only direct sequencing tend to severely underestimate the frequency of multiple-type HPV.^24,26,31,32 Bachtiary et al³³ reported a study of 106 cervical cancer patients receiving RT, in which multiple-type HPV was an independent poor prognostic factor. In the current study, there was no correlation of multiple-type HPV with RFS or OS in patients receiving primary surgery. The prognostic significance of multiple HPV types in RT/CCRT patients will be answered in our next report.

Limitations of our study include that we did not test the predicting models using an external validation data set. Statistical inference was weakened despite bootstrap resampling to reduce bias. In addition, we gave equal weight to each predictor that had a different HR (1.7 to 3.2) to facilitate clinical use. We attempted to use a sample of patients (n = 274) treated between 2001 and 2003 for external validation; however, the number of events was small (20 recurrences and 14 deaths), and the median follow-up time was relatively short, which made it invalid.

Among the seven selected risk factors, only grade, FIGO stage, HPV genotype, and age can be accurately assessed at preoperative period, whereas clinical occult lymph node and/or parametrial metastasis or depth of cervical stromal invasion cannot be reliably determined by imaging technology.^34,35 In this series, for patients who have three risk factors (n = 80), additional HPV genotyping can help to exclude HPV 18–positive patients from primary radical surgery because four risk factors would predict a high probability of postoperative RT/CCRT. We should avoid using both modalities in early-stage cervical cancer. Moreover, for patients who have three risk factors other than HPV genotype after primary surgery (n = 318), adjuvant therapy can be offered to patients with HPV 18–positive tumors.

In conclusion, HPV genotyping is worthwhile to perform because of its independent prognostic value in early-stage cervical cancer, and the predicting models for death and relapse could be useful for counseling the individual patient and stratifying study patients in future clinical trials.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Chyong-Huey Lai, Chee-Jen Chang, Huei-Jean Huang

Provision of study materials or patients: Chyong-Huey Lai, Huei-Jean Huang, Swei Hsueh, Angel Chao, Cheng-Tao Lin, Ji-Hong Hong, Hung-Hsueh Chou, Tzu-I Wu, Kuan-Gen Huang, Chun-Chieh Wang, Ting-Chang Chang

Collection and assembly of data: Chyong-Huey Lai, Huei-Jean Huang, Swei Hsueh, Angel Chao, Jung-Erh Yang, Cheng-Tao Lin, Shang-Lang Huang, Ji-Hong Hong, Hung-Hsueh Chou, Tzu-I Wu, Kuan-Gen Huang, Chun-Chieh Wang, Ting-Chang Chang

Data analysis and interpretation: Chyong-Huey Lai, Chee-Jen Chang, Huei-Jean Huang

Manuscript writing: Chyong-Huey Lai, Chee-Jen Chang, Huei-Jean Huang

Final approval of manuscript: Chyong-Huey Lai, Chee-Jen Chang, Huei-Jean Huang, Swei Hsueh, Angel Chao, Jung-Erh Yang, Cheng-Tao Lin, Shang-Lang Huang, Ji-Hong Hong, Hung-Hsueh Chou, Tzu-I Wu, Kuan-Gen Huang, Chun-Chieh Wang, Ting-Chang Chang

	Appendix

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	NOTES

 
Supported by Grants No. NSC93-2314-B-182-036 and NSC94-2314-B-182-011 from the National Science Council–Taiwan.

Presented in part at the 38th Annual Meeting on Women's Cancer, March 3-7, 2007, San Diego, CA.

C.-H.L., C.-J.C., and H.-J.H. contributed equally to this work.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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Submitted February 16, 2007; accepted May 21, 2007.

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