Endometrial carcinoma is the most common cancer of the female genital tract in the western world. Worldwide 287,000 new cases are diagnosed annually with this disease. Endometrial carcinomas are generally thought to have a favorable prognosis due to early detection, and the majority of tumors are detected in early stages. However, in fact this is not fully true, and there are important subgroups within this diagnosis with poor prognosis and outcome of treatment. Therefore, the first step to improve the situation has been to find predictive and prognostic factors, then to define clinically relevant risk groups, and finally to design clinical trials and treatment options for these risk groups.
Unfortunately, no consensus exists on which predictive or prognostic factors that should be used and how to combine them in the definition of suitable-risk groups. As a result of this, the randomized phase III trials presented during the last decades are difficult to compare since these definitions have varied, more or less, in most of them.
Another problem has been the small size and low power of most studies in the literature dealing with prognostic and predictive factors. Despite more or less sophisticated statistical methods with multivariate technique, the results are not reliable enough for definitive conclusions from such small series analyzing multiple variables. A few exceptions do exist but then with data from large registry studies, but then with other problems of selection and bias built in.
Six prospective randomized studies have been presented since 1980 to elucidate the value of external beam pelvic radiotherapy after surgery in early-stage endometrial carcinoma (Aalders, PORTEC-1, GOG#99, ASTEC/EN.5, PORTEC-2, and Sorbe) [
Three prospective randomized trials of low-risk, medium-risk, and high-risk cancers have been performed in Sweden and some other European countries. Vaginal brachytherapy, external beam pelvic radiation, and adjuvant chemotherapy were addressed in these studies. These three studies are now published [
In the present retrospective study a large, comprehensive, and consecutive series of more than 4,500 endometrial carcinomas in FIGO stages I–IV were analyzed with regard to predictive and prognostic factors and definition of the risk groups used in the above mentioned three prospective randomized studies. Special emphasis will be made on the prognostic value of DNA ploidy and the importance of this factor in the risk group definitions.
One Swedish Cancer Center (Örebro) for gynecological oncology recruited patients with all stages (FIGO I–IV) of endometrial carcinomas in an observation study. The period of recruitment was from January 1975 to December 2009. In all, 4,543 patients were included. Postoperative external pelvic irradiation and/or vaginal brachytherapy were administered to the majority of the patients. No further treatment-related details were analyzed in this study. The median age of the patients was 67 years (range 23–99 years). Tumor characteristics are presented in Tables
Tumor stage (clinical and surgical) distributions of the complete series.
FIGO stage (clinical)
IA | 1 388 |
IB | 865 |
II | 185 |
III | 108 |
IV | 97 |
None | 1 900 |
| |
Total | 4 543 |
1 840 patients were staged both clinically and surgically.
FIGO stage (surgical)
I* | 899 |
IA | 91 |
IB | 1 453 |
IC | 625 |
II* | 130 |
IIA | 50 |
IIB | 100 |
III* | 82 |
IIIA | 84 |
IIIB | 11 |
IIIC | 68 |
IVA | 3 |
IVB | 144 |
None | 803 |
| |
Total | 4543 |
*No further substage.
Tumor characteristics of the complete series.
Histology | ||
Endometrioid | 3 971 | 87.4% |
Nonendometrioid | 323 | 7.1% |
Unspecified | 249 | 5.5% |
| ||
Nuclear grade | ||
1 | 538 | 11.8% |
2 | 746 | 16.4% |
3 | 433 | 9.5% |
Unknown | 2 866 | 62.2% |
| ||
P53 status | ||
Positive | 249 | 5.5% |
Negative | 258 | 5.7% |
Unknown | 4 036 | 88.8% |
| ||
Myometrial infiltration | ||
Endometrium alone | 95 | 2.1% |
≤50% | 1 562 | 34.4% |
>50% | 848 | 18.7% |
Unknown | 2 038 | 44.9% |
| ||
FIGO grade | ||
1 | 1 433 | 31.5% |
2 | 1 808 | 39.8% |
3 | 850 | 18.7% |
Unknown | 452 | 9.9% |
| ||
DNA ploidy | ||
Diploid | 1 231 | 27.1% |
Nondiploid | 382 | 8.4% |
Unknown | 2 930 | 64.5% |
The definition of high-risk carcinomas was as follows: (1) FIGO stage I, (2) nonendometrioid histological type, (3) presence of two of the following risk factors: FIGO grade 3 (poorly differentiated), deep (≥50%) myometrial infiltration, DNA aneuploidy (FCM), (4) nuclear grade 3, (5) pathologically negative lymph nodes, and (6) negative abdominal cytology. Points 5-6 were optional in this study, and data are not available for all cases.
The definition of medium-risk carcinomas was as follows: (1) FIGO stage I, (2) endometrioid histological type, (3) presence of one of the following risk factors: FIGO grade 3 (poorly differentiated), deep (≥50%) myometrial infiltration, DNA aneuploidy (FCM), (4) nuclear grade 1-2, (5) pathologically negative lymph nodes, and (6) negative abdominal cytology. Points 5-6 were optional in this study, and data are not available for all cases. Lymph vascular space invasion (LVSI) was not regularly included in the pathology reports at the participating centers and was not included in the definition of the medium-risk group.
The definition of low-risk carcinomas was as follows: (1) FIGO stage I, (2) endometrioid histological type, (3) presence of none of the following risk factors: FIGO grade 3 (poorly differentiated), deep (≥50%) myometrial infiltration, DNA aneuploidy (FCM), or (4) nuclear grade 3. All pathology reports were reviewed by one experienced pathologist at the regional referral center.
The primary surgery was total abdominal hysterectomy, bilateral salpingo-oophorectomy, appendectomy, node sampling of enlarged lymph nodes, and peritoneal washing with cytology. Lymphadenectomy (pelvic ± paraaortic) was not performed as a routine at the centers referring patients to the regional clinic. The surgery was performed at five departments of Gynecology and Obstetrics, but all patients were then referred to a Gynecologic Oncology Department for postoperative evaluation and treatment. The time interval between surgery and brachytherapy ± external pelvic irradiation was 4–8 weeks. All patients were then planned for a 10-year follow-up program. The median follow-up period at the time of analysis was 115 months (range 1–362 months) for patients alive. During all visits, symptoms and signs related to the therapy were recorded, but in this study treatment-related side effects are not presented.
For
External beam therapy was given to patients with high-risk tumors and to many with medium-risk tumors. The target volume was the previous site of the uterus and adnexa, the parametria, the proximal two-thirds of the vagina, and the lymphatic drainage regions along the iliac vessels up to the promontory. The superior field border was set at the L5-S1 disk. The total dose to be delivered to this volume was 46 Gy (median dose 46.0 Gy, range 6–50 Gy) and daily fractions of 1.8–2.0 Gy (Table
Techniques used for the external beam pelvic radiotherapy.
Parameter | Specification |
---|---|
Type of field | 4-field box technique |
Radiation quality | 6–50 MV (linear accelerators) |
Dose per fraction | 1.8–2.0 Gy |
Number of fractions | 23 (median) (range 5–26) |
Total dose | 46.0 Gy (median) (range 6–50 Gy) |
Fractionation | Daily fractions, 5 fractions per week |
Superior field border | L5-S1 disk |
Inferior field border | Lower margin of the fossa obturatoria |
Lateral borders | 1 cm lateral of the linea terminals |
All data were collected in a computerized database at the Regional Oncology Center, Örebro, Sweden.
In the statistical analyses, survival curves were generated using the Kaplan-Meier technique, and differences were tested with the log-rank test. The Pearson chi-square test was used for comparison of proportions and the independent
The overall recurrence rate of the complete series was 519 out of 4,543 cases or 11.4%. Eighty-seven vaginal recurrences (1.9%) were diagnosed in the complete series. The regional pelvic (excluding vaginal recurrence) recurrence rate was 2.3% (103 cases), and the locoregional (vaginal or pelvic, or both) recurrence rate was 4.2% (190 cases). Of 190 locoregional recurrences, 87 (46%) occurred at the vaginal site. The 5-year actuarial locoregional relapse rate was 3.6%. Distant recurrences (outside the pelvic area) were noted in 329 cases (7.2%), and the 5-year actuarial relapse rate was 6.6%. The median time to relapse in the complete series was 19.7 months (range 1–248 months). In the complete series, 370 out of 519 recurrences (71%) occurred within 3 years and 445 recurrences (86%) within 5 years. The median age of all patients was 67.0 years (23–99 years), for those with recurrences was 68.4 years, and those without recurrences was 66.4 years.
At least 12 prognostic factors are described in endometrial carcinoma (Table
Prognostic factors in endometrial carcinoma.
(1) FIGO stage (clinical, surgical)* | |
(2) Tumor size (>2 cm) | |
(3) Histology (endometrioid, nonendometrioid)* | |
(4) Myometrial infiltration (>50%)* | |
(5) FIGO grade (grade 3 versus 1-2)* | |
(6) Nuclear grade (grades 1–3)* | |
(7) DNA ploidy (diploid, nondiploid)* | |
(8) S-phase fraction | |
(9) P53 expression (positive versus negative)* | |
(10) ER and PgR expression | |
(11) Lymphovascular space invasion (LVSI) | |
(12) Age of the patient (>60 years)* |
*Factors analysed in the present study.
Multivariate logistic regression analyses of factors predicting recurrences.
Factor | Odds ratio | 95% CI |
|
---|---|---|---|
Overall tumor recurrences | |||
Age (>60 years) | 1.300 | 0.619–2.729 | 0.489 |
Histology* | 1.092 | 0.556–2.147 | 0.798 |
FIGO grade (3 versus 1-2) | 3.726 | 1.957–7.095 | 0.00006 |
Nuclear grade (3 versus 1-2) | 1.713 | 0.878–3.341 | 0.114 |
DNA ploidy** | 1.669 | 1.071–2.602 | 0.024 |
Myometrial infiltration*** | 2.077 | 1.392–3.098 | 0.0003 |
| |||
Distant tumor recurrences | |||
Age (>60 years) | 0.844 | 0.377–1.889 | 0.680 |
Histology* | 1.155 | 0.572–2.330 | 0.689 |
FIGO grade (3 versus 1-2) | 4.750 | 2.319–9.729 | 0.00002 |
Nuclear grade (3 versus 1-2) | 1.686 | 0.809–3.515 | 0.163 |
DNA ploidy** | 1.805 | 1.101–2.957 | 0.019 |
Myometrial infiltration*** | 2.853 | 1.784–4.565 | 0.00001 |
*Nonendometrioid versus endometrioid. **Nondiploid versus diploid. ***>50% versus <50%.
At the last followup (March 2010), the number of patients alive was 2,764 (61%), dead of disease 819 (18%), and dead of intercurrent disease 960 (21%). Death from intercurrent disease was more common than death from the cancer disease. The five-year actuarial overall survival rate was 73% and the cancer-specific survival rate was 83%. Five-year overall survival after any relapse was 30%. The salvage rate was 44% (38/87) after isolated vaginal recurrences, 20% (21/103) after pelvic recurrences, and 6% (19/329) after distant recurrences.
Eight prognostic factors were analyzed with Cox proportional multivariate regression analyses and with overall and cancer-specific survival rate as the dependent variable. Seven of these factors were independent and statistically highly significant (Table
Multivariate Cox proportional regression analyses of prognostic factors.
Factor | Risk ratio | 95% CI |
|
---|---|---|---|
Overall survival rate | |||
Age (>60 years) | 2.951 | 2.467–3.531 | <0.00001 |
FIGO stage (III-IV versus I-II) | 2.489 | 2.169–2.855 | <0.00001 |
Histology* | 1.569 | 1.340–1.836 | <0.00001 |
FIGO grade (3 versus 1-2) | 1.814 | 1.590–2.069 | <0.00001 |
Nuclear grade (3 versus 1-2) | 1.558 | 1.286–1.888 | <0.00001 |
DNA ploidy** | 1.456 | 1.215–1.744 | <0.0001 |
Myometrial infiltration*** | 1.322 | 1.164–1.501 | <0.0001 |
P53 expression**** | 0.955 | 0.715–1.276 | 0.755 |
| |||
Cancer-specific survival rate | |||
Age (>60 years) | 1.925 | 1.509–2.456 | <0.00001 |
FIGO stage (III-IV versus I-II) | 4.205 | 3.542–4.993 | <0.00001 |
Histology* | 1.717 | 1.410–2.090 | <0.00001 |
FIGO grade (3 versus 1-2) | 2.524 | 2.099–3.035 | <0.00001 |
Nuclear grade (3 versus 1-2) | 1.635 | 1.279–2.090 | <0.0001 |
DNA ploidy** | 1.591 | 1.267–1.999 | <0.0001 |
Myometrial infiltration*** | 1.292 | 1.069–1.561 | 0.008 |
P53 expression**** | 1.089 | 0.747–1.587 | 0.657 |
*Nonendometrioid versus endometrioid. **Nondiploid versus diploid. ***>50% versus <50%. ****Positive (>30% staining) versus negative (<30% staining).
The risk group definitions presented under Material and Methods were used in the complete series and for all stages together and for stage I alone. In the complete series, 54% of the cases fulfilled low-risk criteria, 23% medium-risk criteria, and 22% high-risk criteria. In stage I, the corresponding figures were 57%, 25%, and 17%, respectively. The discriminating power (chi-square = 471.8;
Cancer-specific survival rate versus three postoperative risk groups.
If instead only two risk groups are used, which are proposed for preoperative risk group definitions, a 30% difference was noted in cancer-specific survival at 5 years, which was also highly statistically significant (Z = 22.948;
Cancer-specific survival rate versus two preoperative risk groups.
The optimal treatment of endometrial carcinoma patients have been vividly discussed and also studied in a number of randomized trials during the last decades [
The aim of the present study was to evaluate the prognostic value of the various clinical and histopathological factors commonly discussed in endometrial cancer and how to combine them into risk group definitions. Proposals of pre- and postoperative risk groups are presented and tested in a large series of endometrial carcinomas comprising more than 4,500 patients. The only large study published before analyzing prognostic factors in endometrial cancer was the registry SEER study, where 41,120 cases were included. FIGO stage, type of histology, FIGO grade, lymph node status, age at diagnosis, and race were found to be prognostic factors in that study [
The 5-year actuarial locoregional recurrence rate was 3.6%, and the distant recurrence rate was 6.6% in our series. Eight of twelve commonly used prognostic and predictive factors were analyzed in this study. With regard to recurrences FIGO grade, DNA ploidy, and depth of myometrial infiltration were independent and significant predictive factors in a multivariate logistic regression analysis. A best subset analysis also confirmed that these three factors were the most important ones, and addition of further factors only marginally improved the predictive value of the model. The single most important factor was the FIGO grade, but it is important to point out that the DNA ploidy, not so commonly used in the international literature, was one of the three most important predictive factors together with myometrial invasion to predict the risk of tumor recurrences, and especially distant recurrences. A number of studies from Sweden [
The 5-year actuarial overall survival rate in this series of patients was 73%, and the cancer-specific survival rate was 83%. The study covers a long time period, but in fact the overall survival did not change during the last three decades. Changes in the treatment technique during these years seem to have had no impact on survival. Cox proportional multivariate regression analysis was used to find out the most important prognostic factors with regard to the cancer-specific survival probability. Eight factors were included in the model, and seven were found to be independent and significant. Of the included factors only p53 expression was nonsignificant in these analyses. Advanced versus early tumor stage was the single most important factor with a risk ratio of 4.2, and FIGO grade was the second most important with a risk ratio of 2.5. Interesting findings were that the nuclear grade [
Tumor size and lymphovascular space invasion (LVSI) were not included in the present analyses, since these variables were not regularly reported by the departments of pathology during the extensive study period. Tumor size with a cutoff level of 2 cm has been reported to be an important predictive factor in preoperative risk classification to define a low-risk group where lymph node dissection is not required [
Three risk groups were analyzed with the definitions used in our country during the last 20 years and also in three published randomized multicenter studies [
For preoperative risk group classification it is more convenient to use two risk groups. The aim of this classification is to sort out those patients requiring lymph node dissection from those who do not. Myometrial invasion is an important predictive and prognostic factor but difficult to assess preoperatively in a reliable way. Our multivariate analyses of this large series of patients have shown that myometrial invasion can be replaced by other prognostic factors without losing to much of prognostic information. The results from our analysis showed that histology (nonendometrioid versus endometrioid), FIGO grade (grade 3 versus grade 1-2), and DNA ploidy (nondiploid versus diploid) could be used to define two preoperative risk groups. These two risk groups discriminated well (
The importance of DNA ploidy as a predictive and prognostic factor in endometrial carcinoma [
Risk group definitions are important in the design of randomized studies in endometrial carcinomas. Up to now some confusion exists in these definitions in published randomized studies making firm conclusions and comparisons difficult. Three risk groups seem reasonable to use in the postoperative setting, but probably only two in the preoperative classification. Our study has shown that DNA ploidy is an important predictive and prognostic factor and if used in combination with the FIGO grade and type of histopathology can replace myometrial invasion in definition of preoperative high-risk cases needing more extensive surgery.
The author declares that there is no conflict of interests.
The author forwards great thanks to Peter Jansson, IT Coordinator at the Department of Oncology, Örebro University Hospital, for his work with the data base and retrieval of the patient data included in this study.