Abstract
Objective:
To examine characteristics and survival outcomes of women with surgically-treated cervical cancer exhibiting uterine corpus tumor invasion.
Methods:
We utilized The Surveillance, Epidemiology, and End Results Program to identify cervical cancer patients who underwent hysterectomy between 1973 and 2003. Logistic regression models were used to identify risk factors for uterine corpus tumor invasion on multivariable analysis. Association of uterine corpus tumor invasion and cause-specific survival (CSS) from cervical cancer was examined with Cox proportional hazard regression models on multivariable analysis.
Results:
We identified 837 (4.9%) cases of uterine corpus invasion and 16,237 (95.1%) cases of non-invasion. Median follow-up time was 14.0 years. There were 1642 deaths due to cervical cancer. Uterine corpus invasion was independently associated with older age, non-squamous histology, high-grade tumors, large tumor size, and nodal metastasis on multivariable analysis (all, P < 0.001). On univariable analysis, uterine corpus tumor invasion was significantly associated with decreased CSS compared to the non-invasion (5-year rates, 79.0% versus 94.5%, P < 0.001). After controlling for other significant prognostic factors, uterine corpus tumor invasion remained an independent prognostic factor for decreased CSS (adjusted-hazard ratio 1.45, 95% confidence interval 1.21–1.74). Among stage T1b cases (n = 6730), uterine corpus tumor invasion remained an independent prognostic factor for decreased CSS (adjusted-hazard ratio 1.95, 95%CI 1.47–2.60). Uterine corpus tumor invasion was significantly associated with decreased CSS in stage T1b1 disease (74.5% versus 90.7%, P < 0.001) and in stage T1b2 disease (67.0% versus 79.5%, P = 0.01).
Conclusion:
Uterine corpus tumor invasion is an independent prognostic factor for decreased survival of women with early-stage cervical cancer.
Keywords: Cervical cancer, Uterine corpus, Lymph node metastasis, Survival outcome
Introduction
In 2016, approximately 1 in 160 women are estimated to develop invasive cervical cancer in the United States, and roughly 4100 women will die of cervical cancer in this given year.1 The survival rate of women with cervical cancer has not changed in the past four decades,1 and therefore, understanding the pattern of tumor spread is valuable to improve the prognosis of women with cervical cancer.
Cervical cancers typically spread loco-regionally via direct tumor invasion, laterally into the parametria, distally into the upper vagina, and less often anterior-posteriorly into the bladder or rectum.2 The current staging system for cervical cancer incorporates these anatomical sites of direct tumor extension, and the presence of tumor invasion into these anatomical sites are associated with decreased survival outcome.3
Another potential anatomical direction of direct tumor extension in cervical cancer is into the uterine corpus. One could theorize that uterine corpus tumor invasion is reflective of aggressive tumor behavior associated with decreased survival in women with cervical cancer due to the established association that loco-regional tumor extension of cervical cancer to the adjacent organs with decreased survival outcome.3 However, uterine corpus tumor invasion has not been incorporated into the current cervical cancer staging system.4 Previous studies examining the survival outcome related to uterine corpus tumor invasion had relatively small sample sizes that make the findings difficult to adopt in a general population.5-10
The objective of the study was (i) to identify contributing factors for uterine corpus tumor invasion in surgically-treated cervical cancer, and (ii) to examine survival outcome of women in whom the tumor exhibits uterine corpus invasion by examining a population-based database.
Materials and methods
Data source and eligibility
We utilized The Surveillance, Epidemiology, and End Results Program (SEER) that is the largest population-based tumor registry in the United States.11 The SEER database was launched in 1973, supported and managed by the National Cancer Institute.11 This database covers approximately 27.8% of the US population from 11 States and 7 areas. The SEER database is publicly available and deidentified, and the University of Southern California Institutional Review Board exempted the use of such database. We used The STROBE guidelines to direct the observational study.12
We used SEER*Stat 8.3.2 to extract the dataset for SEER18 Regs Research Data + Hurricane Katrina Impacted Louisiana Cases by using selection codes for “Cervix Uteri”, “malignancy”, and “female sex”. Within the extracted cases, women with cervical cancer who underwent hysterectomy between 1973 and 2003 were included in the study. During this study period, uterine corpus invasion was routinely coded in the 2-digit EOD system (code 70, 74, 77, 79, 80, 84, 87, and 89) between 1973 and 1982, the 4-digit EOD system (code 3) between 1983 and 1987, and the EOD-10 system (code 30, 35, 36, and 37) between 1988 and 2003. After year 2004, the pathology coding system does not include uterine corpus invasion, and therefore, cases were excluded from the study. Cases with uterine sarcomas, metastatic tumors to the uterine cervix, and radiotherapy prior to the hysterectomy were excluded.
Clinical information
Variables abstracted from the SEER database were patient demographics, tumor characteristics, treatment patterns, and survival outcome. Patient demographics included age (<40, 40–49, 50–59, and ≥60), and calendar year at diagnosis (1973–1979, 1980–1989, 1990–1999, and 2000–2003), ethnicity (White, Black, Hispanic, Asian, and others), marital status (single, married, and others), and registered area (East, Central, and West). Tumor characteristics included cancer T stage (T1a, T1b, T2a, and T2b), histologic subtype (squamous, adenocarcinoma, adenosquamous, and others), tumor grade (1, 2, and 3), tumor size (≤2.0, 2.1–4.0, 4.1–6.0, and >6.0 cm), and pelvic lymph node status (metastasis versus non-metastasis). Histologic subtypes were grouped per the ICD-0-3 site/histology validation list and World Health Organization (WHO) histological classification (Table S1). Treatment pattern included type of hysterectomy (simple, radical, and others) and adjuvant radiotherapy (whole pelvic radiotherapy, intracavitary brachytherapy, and others). Survival outcomes were examined for cervical cancer-specific survival and overall survival from all causes. Cause-specific survival was defined as the time interval between the date of cervical cancer diagnosis and date of death due to cervical cancer. Overall survival was defined as the time interval between cervical cancer diagnosis and the data of death from any cause. Patients were censored if alive at the last follow-up.
Statistical analysis
The primary interest of the analysis was to examine characteristics of women with cervical cancer in whom the tumor invaded the uterine corpus. The secondary interest of analysis was to examine survival outcomes of women with cervical cancer whose tumors had uterine corpus invasion. Cases with uterine corpus tumor invasion were compared to cases without uterine corpus tumor invasion. Statistical significance of continuous variables was assessed by the Student t test. Ordinal and categorical variables were assessed with the chi-square test. Binary logistic regression models were used for multivariable analysis to determine independent risk factors for uterine corpus tumor invasion, and magnitude of statistical significance was expressed with adjusted-odds ratio (aOR) with 95% confidence interval (CI). Patient demographics, and tumor characteristics, and treatment patterns were entered in the final model. Model fitting was examined by Hosmer–Lemeshow goodness-of-fit test.
We examined survival outcome with the Kaplan–Meier method to construct survival curves,13 and statistical significance between the curves were assessed with the log-rank test for univariable analysis. Cox proportional hazard regression models were used to identify the independent prognostic factors for Cause-specific survival and overall survival in multivariable analysis,14 and magnitude of statistical significance was expressed with adjusted-hazard ratio (aHR) with 95%CI. Covariates entered in the final model were the significant covariates in univariable analysis with P-value cutoff being less than 0.05. The variance inflation factor was determined among covariates in multivariable analysis, and a value of 2 or greater was defined as multicollinearity in this study (parametrial and vaginal involvements for stage).15 All statistical analyses were twotailed, and a P-value of less than 0.05 was considered statistically significant. Statistical Package for Social Sciences (version 24.0, Chicago, IL, USA) was used for the analysis.
Results
Selection schema is shown in Fig. 1. We identified 52,633 cases of cervical cancer during the study period. Of those, 17,074 women underwent hysterectomy without preoperative radiotherapy with available uterine corpus tumor invasion status. The baseline characteristics of the entire cohort are shown in Table 1. Mean age was 44.6, and the majority were White (63.0%). The majority of tumors was squamous histology (68.4%) and stage T1 disease (98.4%).
Figure 1. Selection criteria.
* Radiation before surgery includes unknown timing of radiation therapy. Abbreviations: CXCA, cervical cancer.
Table 1.
Patient demographics (N = 17,074).
| Characteristic | Number (%) |
|---|---|
| Age | 44.6 (±13.1) |
| ≥60 | 2539 (14.9%) |
| 50–59 | 2494 (14.6%) |
| 40–49 | 5027 (29.4%) |
| <40 | 7014 (41.1%) |
| Race | |
| White | 10,754 (63.0%) |
| Black | 1736 (10.2%) |
| Hispanic | 2834 (16.6%) |
| Asian | 1365 (8.0%) |
| Others | 385 (2.3%) |
| Marital status | |
| Single | 3071 (18.0%) |
| Married | 9598 (56.2%) |
| Others | 4405 (25.8%) |
| Registry area | |
| West | 9883 (57.9%) |
| Central | 4009 (23.5%) |
| East | 3182 (18.6%) |
| Year at diagnosis | |
| 1973–1979 | 1527 (8.9%) |
| 1980–1989 | 2896 (17.0%) |
| 1990–1999 | 7086 (41.5%) |
| 2000–2003 | 5565 (32.6%) |
| Histology | |
| Squamous | 11,673 (68.4%) |
| Adenocarcinoma | 3592 (21.0%) |
| Adenosquamous | 834 (4.9%) |
| Others | 975 (5.7%) |
| Grade | |
| 1 | 1836 (10.8%) |
| 2 | 4070 (23.8%) |
| 3* | 3757 (22.0%) |
| Unknown | 7411 (43.4%) |
| T stage | |
| T1a | 6844 (40.1%) |
| T1b | 6730 (39.4%) |
| T1NOS | 3226 (18.9%) |
| T2a | 34 (0.2%) |
| T2b | 19 (0.1%) |
| T2NOS | 72 (0.4%) |
| Unknown | 149 (0.9%) |
| Uterine corpus invasion | |
| No | 16,237 (95.1%) |
| Yes | 837 (4.9%) |
| Parametrial involvement | |
| No | 16,912 (99.1%) |
| Yes | 19 (0.1%) |
| Unknown | 143 (0.8%) |
| Vaginal involvement | |
| No | 16,892 (98.9%) |
| Yes | 39 (0.2%) |
| Unknown | 143 (0.8%) |
| Lymph node metastasis | |
| No | 13,050 (76.4%) |
| Yes | 1190 (7.0%) |
| Unknown | 2834 (16.6%) |
| Tumor size | |
| ≤2.0 cm | 4623 (27.1%) |
| 2.1–4.0 cm | 2102 (12.3%) |
| 4.1–6.0 cm | 713 (4.2%) |
| >6.0 cm | 211 (1.2%) |
| Unknown | 9425 (55.2%) |
| Surgery type | |
| Total/pan/simple hyst. | 6662 (39.0%) |
| mRH/RH | 8134 (47.6%) |
| Others | 2278 (13.3%) |
| Adjuvant radiation | |
| None | 13,621 (79.8%) |
| WPRT | 3011 (17.6%) |
| ICBT | 105 (0.6%) |
| Other radiation type | 118 (0.7%) |
| Unknown | 219 (1.3%) |
Number (%) per column or mean (±SD) is shown. Abbreviations: hyst, hysterectomy; mRH, modified radical hysterectomy; RH, radical hysterectomy; WPRT, whole pelvic radiotherapy; and ICBT, intracavitary brachytherapy.
Included undifferentiated type.
Uterine corpus tumor invasion was seen in 837 cases (4.9%, 95%CI 4.6–5.2), and non-invasion was seen in 16,237 (95.1%) cases. Women with cervical cancer in whom the tumors extended into the uterine corpus had significantly different patient demographics, tumor factors, and treatment patterns when compared to those without uterine corpus invasion (all, P < 0.05; Table 2). On multivariable analysis (Table 2), uterine corpus tumor invasion was independently associated with older age (≥50 versus <40 years, aOR 3.77; and 40–49 versus <40 years, aOR 1.69), non-squamous histology (aOR 1.69), high-grade tumors (grade 3 versus grade 1, aOR 1.90; and grade 2 versus grade 1, aOR 1.80), large tumor size (>4.0 versus ≤2.0 cm, aOR 4.39; and 2.1–4.0 versus ≤2 cm, aOR 2.29), and nodal metastasis (aOR 2.79) (all, P < 0.001). The final model was in good fit per analysis.
Table 2.
Contributing factors for uterine corpus tumor invasion (N = 17,074).
| Characteristic | Corps invasion (+) | Corps invasion (−) | Adjusted-OR† (95%CI) | P-value |
|---|---|---|---|---|
| Number (%) | 837 (4.9%) | 16,237 (95.1%) | ||
| Age | 51.8 (±13.8) | 44.2 (±12.9) | ||
| ≥50 | 448 (8.9%) | 4585 (91.1%) | 3.77 (3.03–4.70) | <0.001 |
| 40–49 | 209 (4.2%) | 4818 (95.8%) | 1.69 (1.33–2.14) | <0.001 |
| <40 | 180 (2.6%) | 6834 (97.4%) | 1 | |
| Race | ||||
| White | 530 (4.9%) | 10,224 (95.1%) | 1 | |
| Black | 112 (6.5%) | 1624 (93.5%) | 1.16 (0.89–1.51) | 0.29 |
| Hispanic | 110 (3.9%) | 2724 (96.1%) | 0.83 (0.65–1.07) | 0.15 |
| Others | 85 (4.9%) | 1665 (95.1%) | 0.92 (0.70–1.22) | 0.57 |
| Marital status | ||||
| Single | 133 (4.3%) | 2938 (95.7%) | 1 | |
| Married | 416 (4.3%) | 9182 (95.7%) | 0.76 (0.60–0.96) | 0.019 |
| Others | 288 (6.5%) | 4117 (93.5%) | 0.96 (0.75–1.23) | 0.73 |
| Registry area | ||||
| West | 462 (4.7%) | 9421 (95.3%) | 1 | |
| Central | 232 (5.8%) | 3777 (94.2%) | 1.17 (0.94–1.45) | 0.16 |
| East | 143 (4.5%) | 3039 (95.5%) | 0.76 (0.60–0.97) | 0.030 |
| Year at diagnosis | ||||
| 1973–1989 | 275 (6.2%) | 4148 (93.8%) | 1 | |
| 1990–1999 | 320 (4.5%) | 6766 (95.5%) | 2.44 (1.73–3.44) | <0.001 |
| 2000–2003 | 242 (4.3%) | 5323 (95.7%) | 2.06 (1.44–2.95) | <0.001 |
| Histology | ||||
| Squamous | 508 (4.4%) | 11,165 (95.6%) | 1 | |
| Non-squamous | 329 (6.1%) | 5072 (93.9%) | 1.69 (1.42–2.00) | <0.001 |
| Grade | ||||
| 1 | 63 (3.4%) | 1773 (96.6%) | 1 | |
| 2 | 256 (6.3%) | 3814 (93.7%) | 1.80 (1.30–2.48) | <0.001 |
| 3* | 312 (8.3%) | 3445 (91.7%) | 1.90 (1.37–2.62) | <0.001 |
| Unknown | 206 (2.8%) | 7205 (97.2%) | 0.79 (0.56–1.12) | 0.19 |
| T stage | ||||
| T1 | 608 (3.6%) | 16,192 (96.4%) | 1 | |
| T2 | 80 (64.0%) | 45 (36.0%) | 101 (61–167) | <0.001 |
| Unknown | 149 (100%) | 0 | na | 0.99 |
| Parametrial involvement | ||||
| No | 688 (4.1%) | 16,224 (95.9%) | ||
| Yes | 6 (31.6%) | 13 (68.4%) | ||
| Unknown | 143 (100%) | 0 | ||
| Vaginal involvement | ||||
| No | 689 (4.1%) | 16,203 (95.9%) | ||
| Yes | 5 (12.8%) | 34 (87.2%) | ||
| Unknown | 143 (100%) | 0 | ||
| Lymph node involvement | ||||
| No | 493 (3.8%) | 12,557 (96.2%) | 1 | |
| Yes | 171 (14.4%) | 1019 (85.6%) | 2.79 (2.25–3.46) | <0.001 |
| Unknown | 173 (6.1%) | 2661 (93.9%) | 0.59 (0.39–0.88) | 0.010 |
| Tumor size | ||||
| ≤2.0 cm | 104 (2.2%) | 4519 (97.8%) | 1 | |
| 2.1–4.0 cm | 160 (7.6%) | 1942 (92.4%) | 2.29 (1.73–3.04) | <0.001 |
| >4.0 cm | 130 (14.1%) | 794 (85.9%) | 4.39 (3.25–5.94) | <0.001 |
| Unknown | 443 (4.7%) | 8982 (95.3%) | 1.79 (1.39–2.30) | <0.001 |
A binary logistic regression model for multivariable analysis. All listed covariates were entered in the final model.
OR for uterine corpus invasion compared to non-invasion counterpart.
Included undifferentiated type. Significant P-values are emboldened. Abbreviations: OR, odds ratio; and CI, confidence interval; hyst, hysterectomy; mRH, modified radical hysterectomy; and RH, radical hysterectomy. Parametrial involvement and vaginal involvement were not entered in the multivariable model due to multicollinearity to T stage.
Survival analysis was performed. Median follow-up time for the entire cohort was 14.0 years: 11.2 years for the uterine corpus invasion group, and 14.2 years for the non-invasion group. There were 1642 (9.6%) cases of death due to cervical cancer in this cohort: 230 (27.5%) cases in the uterine corpus invasion group, and 1412 (8.7%) cases in the non-invasion group. A total of 4603 (27.0%) women died from any reason during the study period including 458 (54.7%) women in the uterine corpus invasion group and 4145 (25.5%) women in the non-invasion group.
On univariable analysis, women with cervical cancer whose tumors involved the uterine corpus had significantly lower 5-year and 10-year cause-specific survival rates compared to those without uterine corpus invasion (5-year rates 79.0% versus 94.5%; and 10-year rates 72.9% versus 92.4%, P < 0.001; Fig. 2A). On multivariable analysis controlling for age, ethnicity, marital status, histology type, tumor grade, T stage, tumor size, pelvic lymph node status, surgery type, and adjuvant radiotherapy type (Table 3), presence of uterine corpus tumor invasion remained an independent prognostic factor associated with decreased cause-specific survival compared to no uterine corpus tumor invasion (aHR, 1.45, 95%CI 1.21–1.74, P < 0.001). Older age, Black ethnicity, non-squamous histology, higher grade tumor, higher T stage, pelvic lymph node metastasis were also independently associated with decreased CSS (all, P ≤ 0.001). Similar findings were observed for OS (Table S2-3 and Fig. 2B).
Figure 2. Survival curves for women with cervical cancer.
Log-rank test for P-values. Survival curves based on presence of uterine corpus tumor invasion are shown for cause-specific survival (panel A) and overall survival (panel B) for all cases. Cause-specific survival based on uterine corpus tumor invasion is shown for stage T1b1 (panel C) and stage T1b2 (panel D) diseases.
Table 3.
Multivariable analysis for cause-specific survival (N = 17,074).
| Characteristic | No. | Univariable |
Multivariable |
||
|---|---|---|---|---|---|
| HR (95%CI) | P-value | HR (95%CI) | P-value | ||
| Age | <0.001 | ||||
| ≥50 | 5033 | 1.75 (1.56–1.96) | 1.38 (1.22–1.56) | <0.001 | |
| 40–49 | 5027 | 1.20 (1.06–1.35) | 1.08 (0.96–1.23) | 0.21 | |
| <40 | 7014 | 1 | 1 | ||
| Race | <0.001 | ||||
| White | 10,754 | 1 | 1 | ||
| Black | 1736 | 1.43 (1.24–1.65) | 1.26 (1.09–1.46) | 0.002 | |
| Hispanic | 2834 | 1.01 (0.87–1.16) | 0.91 (0.79–1.06) | 0.22 | |
| Others | 1750 | 1.04 (0.88–1.22) | 0.99 (0.84–1.17) | 0.92 | |
| Marital status | 0.001 | ||||
| Single | 3071 | 1 | 1 | ||
| Married | 9598 | 0.90 (0.79–1.02) | 0.86 (0.75–0.99) | 0.034 | |
| Others | 4405 | 1.10 (0.95–1.27) | 0.98 (0.84–1.14) | 0.82 | |
| Histology | <0.001 | ||||
| Squamous | 11,673 | 1 | 1 | ||
| Non-squamous | 5401 | 1.29 (1.17–1.43) | 1.29 (1.16–1.43) | <0.001 | |
| Grade | <0.001 | ||||
| 1 | 1836 | 1 | 1 | ||
| 2 | 4070 | 2.19 (1.76–2.73) | 1.67 (1.34–2.09) | <0.001 | |
| 3* | 3757 | 3.74 (3.03–4.62) | 2.29 (1.84–2.84) | <0.001 | |
| Unknown | 7411 | 0.96 (0.77–1.20) | 1.33 (1.06–1.66) | 0.015 | |
| T stage | <0.001 | ||||
| T1a | 6844 | 1 | 1 | ||
| T1b | 6730 | 4.87 (4.19–5.67) | 2.27 (1.90–2.70) | <0.001 | |
| T1NOS | 3226 | 4.85 (4.12–5.72) | 2.49 (2.07–3.00) | <0.001 | |
| T2a | 34 | 13.0 (7.07–23.8) | 4.08 (2.19–7.62) | <0.001 | |
| T2b | 19 | 41.8 (23.9–73.3) | 12.6 (6.99–22.7) | <0.001 | |
| T2NOS | 72 | 12.0 (7.78–18.4) | 3.74 (2.31–6.07) | <0.001 | |
| Unknown | 149 | 11.0 (7.94–15.2) | 3.25 (2.17–4.88) | <0.001 | |
| Corps invasion | <0.001 | ||||
| No | 16,237 | 1 | 1 | ||
| Yes | 837 | 3.78 (3.29–4.35) | 1.45 (1.21–1.74) | <0.001 | |
| Lymph node involvement | <0.001 | ||||
| No | 13,050 | 1 | 1 | ||
| Yes | 1190 | 5.13 (4.55–5.78) | 1.86 (1.62–2.14) | <0.001 | |
| Unknown | 2834 | 1.13 (0.98–1.29) | 1.27 (1.07–1.50) | 0.006 | |
| Tumor size | <0.001 | ||||
| ≤2.0 cm | 4623 | 1 | 1 | ||
| 2.1–4.0 cm | 2102 | 3.46 (2.96–4.04) | 1.60 (1.36–1.89) | <0.001 | |
| >4.0 cm | 924 | 5.58 (4.69–6.63) | 2.12 (1.77–2.55) | <0.001 | |
| Unknown | 9425 | 1.24 (1.08–1.43) | 1.08 (0.93–1.25) | 0.33 | |
| Surgery type | <0.001 | ||||
| Total/pan/simple hst. | 6662 | 1 | 1 | ||
| mRH/RH | 8134 | 1.87 (1.66–2.10) | 1.08 (0.95–1.22) | 0.23 | |
| Others | 2278 | 1.75 (1.50–2.05) | 1.48 (1.25–1.75) | <0.001 | |
| Adjuvant radiation | <0.001 | ||||
| Performed | 3234 | 1 | 1 | ||
| Not performed | 13,621 | 4.72 (4.28–5.21) | 2.07 (1.84–2.33) | <0.001 | |
| Unknown | 219 | 2.86 (2.01–4.07) | 1.96 (1.37–2.80) | <0.001 | |
Cox proportional hazard regression models for multivariable analysis. All significant covariates in the univariate analysis were entered in the final model for multivariable analysis. Significant P-values are emboldened.
Included undifferentiated type. Abbreviations; HR, hazard ratio; CI, confidence interval; hyst, hysterectomy; mRH, modified radical hysterectomy; and RH, radical hysterectomy.
Sub-analysis was performed for 6730 women with stage T1b disease (T1b1 n = 3,437, T1b2 n = 678, and T1bNOS n = 2615). Median follow-up time for the entire cohort was 12.9 years: 10.1 years for the uterine corpus invasion group and the 13.0 years for the non-invasion group. There were 888 (13.2%) cases of death due to cervical cancer in this cohort: 56 (32.0%) cases in the uterine corpus invasion group, and 832 (12.7%) cases in the non-invasion group. On univariable analysis, uterine corpus tumor invasion was significantly associated with decreased cause-specific survival in stage T1b1 disease (yes versus no, 74.5% versus 90.7%, P < 0.001; Fig. 2C) and in stage T1b2 disease (67.0% versus 79.5%, P = 0.01; Fig. 2D). On multivariable analysis controlling for significant prognostic factors in univariable analysis (Table 4), uterine corpus tumor invasion remained an independent prognostic factor for decreased cause-specific survival in women with stage T1b cervical cancer (aHR 1.95, 95%CI 1.47–2.60, P < 0.001).
Table 4.
Multivariable analysis for cause-specific survival for stage T1b disease (n = 6730).
| Characteristic | No. | Univariable |
Multivariable |
||
|---|---|---|---|---|---|
| HR (95%CI) | P-value | HR (95%CI) | P-value | ||
| Age | 0.007 | ||||
| ≥50 | 1954 | 1.29 (1.10–1.52) | 1.20 (1.02–1.43) | 0.033 | |
| 40–49 | 2100 | 1.14 (0.97–1.34) | 1.09 (0.93–1.28) | 0.30 | |
| <40 | 2676 | 1 | 1 | ||
| Race | 0.001 | ||||
| White | 3959 | 1 | 1 | ||
| Black | 639 | 1.41 (1.15–1.73) | 1.29 (1.05–1.59) | 0.016 | |
| Hispanic | 1364 | 0.87 (0.72–1.04) | 0.82 (0.68–0.99) | 0.036 | |
| Others | 768 | 1.14 (0.93–1.40) | 1.10 (0.89–1.35) | 0.39 | |
| Marital status | 0.004 | ||||
| Single | 1337 | 1 | 1 | ||
| Married | 3777 | 0.79 (0.67–0.93) | 0.78 (0.66–0.93) | 0.006 | |
| Others | 1616 | 0.97 (0.80–1.17) | 0.93 (0.76–1.13) | 0.44 | |
| Year at diagnosis | 0.039 | ||||
| 1973–1989 | 800 | 1 | 1 | ||
| 1990–1999 | 3141 | 1.33 (1.07–1.67) | 0.95 (0.75–1.20) | 0.64 | |
| 2000–2003 | 2789 | 1.24 (0.98–1.57) | 0.72 (0.56–0.93) | 0.011 | |
| Histology | 0.002 | ||||
| Squamous | 4331 | 1 | 1 | ||
| Non-squamous | 2399 | 1.23 (1.08–1.41) | 1.48 (1.29–1.70) | <0.001 | |
| Grade | <0.001 | ||||
| 1 | 734 | 1 | 1 | ||
| 2 | 2313 | 2.13 (1.56–2.92) | 1.98 (1.44–2.73) | <0.001 | |
| 3* | 2390 | 3.37 (2.48–4.58) | 2.79 (2.03–3.82) | <0.001 | |
| Unknown | 1293 | 1.47 (1.04–2.07) | 1.66 (1.17–2.36) | 0.005 | |
| T stage | <0.001 | ||||
| T1b1 | 3437 | 1 | 1 | ||
| T1b2 | 678 | 2.19 (1.83–2.60) | 1.56 (1.30–1.87) | <0.001 | |
| T1bNOS | 2615 | 0.66 (0.57–0.78) | 0.79 (0.67–0.93) | 0.005 | |
| Corps invasion | <0.001 | ||||
| No | 6555 | 1 | 1 | ||
| Yes | 175 | 3.20 (2.44–4.20) | 1.95 (1.47–2.60) | <0.001 | |
| Lymph node involvement | <0.001 | ||||
| No | 5714 | 1 | 1 | ||
| Yes | 885 | 3.40 (2.94–3.93) | 2.00 (1.69–2.37) | <0.001 | |
| Unknown | 131 | 1.60 (1.04–2.48) | 1.39 (0.89–2.15) | 0.15 | |
| Adjuvant radiation | <0.001 | ||||
| Performed | 4634 | 1 | 1 | ||
| Not performed | 1995 | 2.83 (2.47–3.23) | 1.74 (1.48–2.04) | <0.001 | |
| Unknown | 101 | 1.86 (1.11–3.11) | 1.57 (0.93–2.64) | 0.09 | |
Cox proportional hazard regression models for multivariable analysis. All significant covariates in the univariate analysis were entered in the final model for multivariable analysis. Significant P-values are emboldened.
Included undifferentiated type. Abbreviations; HR, hazard ratio; CI, confidence interval; hyst, hysterectomy; mRH, modified radical hysterectomy; and RH, radical hysterectomy. Tumor size was not entered in the model due to multicollinearity to T stage.
Discussion
Salient findings of this study are that (i) uterine corpus tumor invasion was relatively rare in this study population with predominantly early-stage cervical cancer, (ii) uterine corpus tumor invasion represents aggressive tumor behavior in cervical cancer, and (iii) women with cervical cancer in whom the tumors extended to the uterine corpus had significantly worse survival outcome compared to their counterparts without corpus invasion.
In a review of the literature, several studies have reported the significance of uterine corpus invasion in cervical cancer over decades, suggesting it as an indicator of tumor aggressiveness and a predictor of poor survival outcome.5-10 Because these past studies examined somewhat limited numbers of cases of uterine corpus tumor invasion (median 92 cases, range 68–156), our study serves as a large-scale proof-of-concept study of the clinical implications of uterine corpus tumor invasion (837 cases).
We found that non-squamous histology including adenocarcinoma is an independent risk factor for uterine corpus tumor invasion compared to squamous type. While this finding might be partly supporting a hypothesis that squamous type and adenocarcinoma type have different patterns of tumor spread; with lymphatic spread more common in squamous histology and hematogenous spread more frequently seen in adenocarcinoma histology,16 the most likely causality of this association is the anatomical proximity to the uterine corpus. That is, adenocarcinoma of the uterine cervix generally arises in the endocervical gland inside the cervix whereas squamous type generally arises in the extocervix. Because the endocervix has greater anatomical proximity to the uterine corpus as compared to the extocervix, adenocarcinoma is likely to have a higher chance of direct extension to the uterine corpus.
Another possibility of the association between cervical adenocarcinoma and increased risk of uterine corpus tumor invasion is worth discussion. Recent studies have shown that cervical cancer spreads through the embryonic developmental structures within the uterovaginal compartment that includes the uterine corpus, and tumor spread beyond this anatomical barrier is considered a late event given that the compartment borders acts as a tumor suppressor, functioning to contain tumor and preventing extension beyond this barrier.17-19 Therefore, it is speculated that molecular interactions between tumor cells and the tissues bordering this anatomical compartment may be different between squamous carcinomas and adenocarcinomas, resulting in the differing tumor spread patterns. Further study will be warranted to examine if this theory applies to the difference in tumor spreading patterns between the two histology types of the cervical cancer.
We found that there is an independent association between uterine corpus tumor invasion and increased risk of pelvic lymph node metastasis in cervical cancer, thus validating a previous study.5 Not only does increased risk of pelvic lymph node metastasis endorse the hypothesis that uterine corpus invasion is a marker of the aggressive tumor biology, it also suggests that uterine corpus tumor invasion may possibly increase risk of para-aortic lymph node recurrence.20 Because their retrospective study only examined the para-aortic nodal recurrence pattern, it remains undetermined if the uterine corpus tumor invasion is a surrogate marker for para-aortic nodal metastasis at presentation. In the current guideline recommendations for early-stage cervical cancer, routine para-aortic lymphadenectomy is not a part of standard surgical procedure.3 The SEER database between 1973 and 2003 did not have information for para-aortic nodal metastasis so we were not able to examine this association in this study. Taken together, further study will be of interest to examine if uterine corpus tumor invasion, especially lower uterine segment versus uterine fundus, is associated with an increased risk of para-aortic lymph node metastasis in cervical cancer.
Previous studies have shown that presence of uterine corpus tumor invasion is associated with increased risk of ovarian metastasis but the study sizes were somehow limited (odds ratio, 2.2–6.9).6,7 In general, ovarian metastasis is rare in early-stage cervical cancer (<2%).21 Two patterns of ovarian metastasis have been proposed in the literature including hematogenous and lymphatic spread.7,22 Although our study did not have information for ovarian metastasis, it is speculated that anatomical proximity is the key factor for ovarian metastasis from cervical cancer because the uterine corpus is the closer organ to the ovary compared to the uterine cervix, parametrial tissue, and upper vagina. Collectively, it will be paramount to examine whether or not uterine corpus tumor invasion increases the risk of ovarian metastasis.
Uterine corpus tumor invasion is not a part of current cervical cancer staging component in multiple classification schemas such as that defined by the International Federation of Gynecology and Obstetrics (FIGO) or the American Joint Committee on Cancer (AJCC).4,23 Similarly, uterine corpus tumor invasion has not been considered as a surgical-pathological risk factor per the Gynecologic Oncology Group (GOG).24-26 However, our results support others which have suggested that uterine corpus tumor invasion is a possible reliable marker for stratifying prognosis for women with cervical cancer.5-10 Consideration is therefore warranted to examine the significance of uterine corpus tumor invasion in cervical cancer.
Because uterine corpus tumor invasion is a histologic finding in a hysterectomy specimen, women who undergo definitive radiotherapy will have no histologic confirmation on the uterine corpus tumor invasion. Uterine corpus tumor invasion would not be detectable on clinical examination, and therefore, the clinical utility of this tumor factor is limited to the fraction of women with cervical cancer who receive surgical treatment with hysterectomy. However, in a view of the literature, some studies have demonstrated that pre-treatment MRI can detect uterine corpus tumor invasion in locally advanced disease where definitive radiotherapy but not hysterectomy-based surgical treatment is the mainstay of treatment.8,27 Further validation studies are warranted to see if image-detected uterine corpus tumor invasion is indeed correlated to outcome in women with locally advanced cervical cancer.
The main strength of the study is that this is a population-based study that included a large sample size. This methodology was particularly useful to examine this relatively rare clinical entity because uterine corpus tumor invasion was only seen in approximately 5% of early cervical cancer. Long follow-up time strengthened the power of time-dependent analysis for survival outcome. In addition, multivariable analysis enhanced the analytic approach of the study because patient demographics and tumor characteristics were largely different between the uterine corpus invasion group and the non-invasion group.
There are a number of limitations in the study. First, this is a retrospective study and there may be confounding factors not captured in the study. For instance, it was not known if the description of uterine corpus tumor invasion is a part of standardized synoptic pathology report as like other risk factors for nodal metastasis throughout the study period. However, it is likely that pathologists will report such abnormality is present in specimens. Second, we do not know if primary cervical cancer extending into the uterine corpus is misclassified as primary endometrial cancer invading into the uterine cervix. However, in the SEER registry, data entry is performed by trained registrars with vigorous data quality assurance by the program.11 Furthermore, the majority of cervical cancer is squamous cell histology and uterine squamous carcinoma is generally rare. Therefore, such misclassification of the two entities in the database is unlikely. The SEER database doesn’t have information for concurrent use of chemotherapy during radiotherapy. This variable is important in survival analysis because older cases were less likely to receive adjuvant radiotherapy without concurrent chemotherapy as compared to newer cases. Lastly, because all the covariates in the final multivariable model for survival analysis remained statistical significant in our study, independence of the association between the uterine corpus tumor invasion and decreased survival outcome is questionable. The SEER database has a limited amount of variables, and therefore, there might be confounding variables that are missing in the analysis.
Clinical implications of our study include postoperative management. If uterine corpus tumor invasion is proven to be a risk factor for adnexal metastasis, women can be appropriately counseled regarding adnexectomy when ovarian conservation is discussed with patient.28 In addition, administering additional systemic chemotherapy may be considered in women with cervical cancer showing uterine corpus extension. This suggestion is based on a prior study that demonstrated an increased risk of distant recurrence among cervical cancer with uterine corpus tumor invasion.5 Because the SEER database does not have information for recurrence patterns and chemotherapy treatment, this topic merits further investigation.
Supplementary Material
Acknowledgments
Funding source
Ensign Endowment for Gynecologic Cancer Research (K.M.)
Footnotes
Disclosure
The authors did not report any potential conflicts of interest in the study.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejso.2017.01.017.
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