Postgraduate Training Course in Reproductive Health/Chronic Disease

The impact of positive peritoneal cytology on survival of patients treated for endometrial cancer

Review prepared for the 12th Postgraduate Course in Reproductive Medicine and Biology, Geneva, Switzerland

Dr P.M. Tebeu
Department of Obstetrics and Gynecology
Faculty of Medicine and Biomedical Sciences
University of Yaounde - Cameroon
Supervisors: A. Major, F. Lüdicke, Y. Popovski, C. Bouchardy, M Usel, HM Verkooijen

See also presentation

Summary

BACKGROUND: Cancer of the endometrium is the most common genital tract malignancy in developed countries, and the third most common one in developing countries. The long-term survival of patients with endometrial cancer is clearly related to the stage at diagnosis. Stage IIIA includes both, patients with only positive peritoneal washing cytology and patients with macroscopic/histological invasion of serosa or adnexal tissues. Nowadays, the value of peritoneal cytology as a prognostic factor in patients with endometrial carcinoma is very controversial. The purpose of this study is to establish the impact of positive peritoneal cytology on the survival of patients operated for endometrial cancer and treated with adjuvant radiotherapy.
PATIENTS AND METHODS: The current study included all women who received adjuvant radiotherapy after surgery for endometrial cancer between 1980 and 1993 at the Division of radio-oncology, Geneva University Hospital. Endometrial cancer specific survival rates by stage were calculated using the Kaplan Meier curve and different stages were compared using log-rank test. Stage lllA cancers were categorised into two distinct categories: cytological stage lllA is defined as having only positive peritoneal cytology and histological stage lllA is defined as having histological or macroscopic infiltration of the serosa or adnexal tissues. The effect of peritoneal cytology on endometrial cancer mortality was analysed by using Cox-proportional hazards model accounting for other variables significantly linked to survival.
RESULTS: Of the 170 patients included in this study, 112 were diagnosed as stage I, 14 as stage II, 17 as stage IIIA based on positive peritoneal cytology (cytological stage IIIA), 18 as stage IIIA based on histological involvement of adnexal or serosa (histological stage IIIA) and 9 as stage IIIB or more.
The disease specific 5-years survival of patients with cytological stage IIIA tumours was not statistically significantly different from that of patients with stage I tumours (94% versus 88% respectively, p=0.5). In contrast, the 5-years disease specific survival of patients with cytological stage IIIA tumours was significantly better than that of patients with histological stage IIIA tumours (94% versus 51% respectively, p=0.008). The risk of death from endometrial cancer was not significantly different in patients with cytological stage IIIA endometrial cancer compared to patients with stage I cancer (HR 0.3, 95% CI: 0.3-2.0). However, patients with histological stage IIIA tumours were 2.7 times more likely (95% CI: 1.0-7.7) to die from endometrial cancer.
CONCLUSION: This study shows that women with cytological stage lllA endometrial cancer have a similar prognosis as women with stage l cancer and a better prognosis than women with histological stage IIIA cancer. Therefore, staging codification should be reviewed to permit a distinction of this group in order to optimise the management of these patients.

Introduction

With an incidence of 15 to 20 cases per 100 000 women, endometrial cancer is the most common genital tract malignancy in Western countries (1-4). Endometrial cancer is also the third genital tract malignancy in developing countries, where the incidence is reported to be 3 to 25 new cases per 100 000 women (5). More than 75% of women diagnosed with endometrial cancer have early stage disease, i.e. cancer limited to the uterus (6-9).
The long-term survival of patients with endometrial cancer is clearly related to the stage at diagnosis. The specific survival for tumour localised at the corpus uteri is over 80%, but it decreases to approximately 40% for tumours invading the serosa, the fallopian tube or the ovary (10).
Before 1988, endometrial cancer was staged clinically (International Federation of Gynaecology & Obstetrics, FIGO 1971). This staging system was based on the fractional biopsy of the endometrium, the depth of the uterine cavity, and physical examination. Stage I tumour was limited to the corpus uteri, stage ll extended to the cervix, stage lll spread to the adjacent pelvic structures, and stage lV included bulky pelvic disease, tumours extending to the bladder, rectum or outside the pelvic cavity, or tumours presenting with distant metastases. The clinical system was abandoned because the accumulated data from surgical staging reports were more accurate and allowed stratification of similar risk groups for adjuvant therapy trials. Consequently, the surgical staging system was approved at the 1988 FIGO meeting (2;4;10;11). In addition to pathological extension, the result of cytology obtained by peritoneal washings became an important determinant of staging. Thus, if a patient with an endometrial cancer confined to the uterus presents with positive peritoneal washing, the stage changes from l to IIIA (12). Stage IIIA therefore includes both patients with only positive peritoneal washing cytology and patients with macroscopic/histological invasion of serosa or adnexal tissues. The value of peritoneal cytology as a prognostic factor in patients with endometrial carcinoma is controversial (13). In the study of the Gynaecologist Oncology Group reported by Morrow et al. on 567 patients with stage I carcinoma, disease free 5-year survival was 65% in patients with positive cytology compared with 96% in cytology-negative patients (14). Similar findings were reported in 2001 by Obermair et al. on stage I tumours: 3 year disease-free survival of 67% for patients with positive peritoneal cytology compared with 96% in patients with negative peritoneal cytology (15). These findings were not confirmed by other studies, which found no significant differences in the prognosis between patients with positive or negative cytology (16;17). In a recent study from Japan, based on a cohort of 280 patients with endometrial cancer, Kasamatsu et al. concluded that the presence of positive peritoneal cytology is not an independent prognostic factor in patients with tumours confined to the uterus (18). In 2002, Preyer et al. reported in a retrospective study that patients with stage IIIA endometrial carcinoma constitute, in fact, a very heterogeneous group (19). Patient with endometrioid adenocarcinoma with invasion of adnexe and serosa had worse prognosis when compared to women presenting only positive peritoneal washing.
Accordingly, there is controversy concerning the indication for and efficacy of adjuvant treatment in case of peritoneal cytology. In general, surgery alone is a curative treatment for most stage I cancers, whereas additive radiation therapy is required for patients with stage IIIA carcinoma. Therefore, women with localised disease, but with positive cytology, are theoretical candidates for adjuvant radiotherapy. In the Landoni et al. trial on surgery and radiation therapy versus surgery alone for the treatment of localised cervical cancer, the same outcome in terms of survival and recurrence was found, but the radiotherapy group was associated with significant higher morbidity (20). In a trial comparing surgery only, or surgery and radiotherapy for stage I endometrial cancer, Creutzberg et al. did not find any advantages in terms of survival for either group, but radiotherapy was associated with increased morbidity (21). More recently, Ayhan et al. published a study on adjuvant radiotherapy in high risk stage I endometrial cancer (22). They found that none of the modalities had an advantage on survival when compared to each other.
Radiotherapy is associated with increased morbidity and stage I endometrial cancers. Therefore, it is important to find an adequate staging system that is capable to better define the prognosis in order to minimise the adverse effects of radiotherapy without diminishing the chance of cure. In particular, the impact of positive peritoneal cytology on the survival of patients with endometrial cancer requires further investigation.

Objective

The purpose of this study is to establish the impact of positive peritoneal cytology on the survival of patients operated for endometrial carcinoma and treated with adjuvant radiotherapy.

Methods

Patients

The current study included women who received adjuvant radiotherapy after surgery for endometrial cancer between 1980 and 1993 at the Division of radio-oncology, Geneva University Hospitals (n=295). All women had hysterectomy and oophorsalpingectomy with or without lymph node dissection followed by external radiotherapy or brachytherapy. We excluded patients with no peritoneal cytology assessment (n=111), with previous malignancy occurring within five years prior to the diagnosis of endometrial cancer (n=2), or patients who were not resident in the canton (n=12). The final study population included 170 patients. According to the Geneva cancer registry, these women represented approximately 50% of all endometrial cancer patients treated in the public sector during the period considered.
Histological type and differentiation were coded according to the International Classification of Diseases for Oncology (23). Stages were coded according to the FIGO staging system (1988). A patient was considered to have positive peritoneal cytology if adenocarcinoma cells were detected, regardless of the number of cancer cells.

Variables

Stage lllA cancers were categorised into two distinct categories: cytological stage lllA defined as cases with only positive peritoneal cytology and histological stage lllA defined as cases with histological or macroscopic infiltration of serosa or adnexal tissues. Stages were named as stage l, ll, cytological lllA, histological lllA, and lllB or more.
The other variables considered were: age at diagnosis (<50, 50-69, ≥70 years), civil status (single, married, widowed, separated), period of diagnosis (1980-87, 1988-93), differentiation (good, moderate, poor, unknown), degree of myometrial invasion (<50%, ≥50%), type of surgery (hysterectomy and oophorsalpingectomy with and without lymphadenectomy), and type of radiotherapy (external with brachytherapy, external only, brachytherapy only).
Data on follow-up were derived from the Geneva cancer registry, which regularly assesses vital status from the Cantonal Population Office, and actively collects information on the cause of death from medical files. Variables were vital status, date and cause of death, or date of departure from the canton of Geneva.

Statistical analyses

Specific survival was calculated considering only death from endometrial cancer. Survival curves were obtained by the Kaplan Meier method and were compared by non parametric survival analyses using log-rank test. The effect of peritoneal cytology on endometrial cancer mortality was analysed in multivariate analysis based on Cox-proportional hazards model after accounting for other variables significantly linked to survival. These analyses were performed using SPSS24. Differences were considered statistically significant at p<0.05.

Results

Between 1980 and 1993, 295 patients were treated for endometrial cancer at the Geneva University Hospital. Of those, 170 (58%) patients met the inclusion criteria. Among them, 112 were diagnosed as stage I (confined to uterus), 14 as stage II (tumour invading cervix), 17 as stage IIIA based on positive peritoneal cytology (cytological stage IIIA), 18 as stage IIIA based on histological involvement of adnexe or serosa (histological stage IIIA), 9 were diagnosed as stage IIIB or more advanced stages (stage IIIB+, involvement of vagina, mucosa of bladder/bowel, regional lymph node or distant metastases). If peritoneal cytology would not have been incorporated in the staging of the endometrial cancers, 15 of the 17 cytological stage IIIA tumours would have been classified as stage I and two as stage II.
Table 1 presents the characteristics of these 170 patients according to the stage of the endometrial cancer. The mean age of the patients was around 65 years and relatively similar for the different stages. Compared to histological stage IIIA tumours, cytological stage IIIA tumours less often invaded the myometrium, more than 50%, were more often well differentiated and were treated less often with both external and internal radiotherapy. Almost all endometrial cancers were treated by hysterectomy with unilateral or bilateral adnexectomy, except for 3 patients with stage I cancer that were treated with hysterectomy only.
The mean duration of follow-up was 3612 days ranging from 313 to 7574 days and 14 patients (8%) were lost to follow-up. Table 2 presents the overall and disease specific 5-year survival rates per stage. Figure 1 graphically presents the disease specific survival curves per stage. The disease specific 5-year survival of patients with cytological stage IIIA tumours was not significantly different from that of patients with stage I tumours (94 versus 88% respectively, log-rank test: p=0.5). In contrast, the 5-year disease specific survival of patients with cytological stage IIIA tumours was significantly better than that of patients with histological stage IIIA tumours (94 versus 51% respectively, log-rank test: p=0.008). A similar pattern was observed when considering the overall survival rates accounting for all deaths, including death from other causes than endometrial cancer.
After adjustment for factors significantly linked to survival from endometrial cancer (i.e. age, tumour differentiation and type of radiotherapy), the risk to die from endometrial cancer was not significantly different in patients with cytological stage IIIA endometrial cancer compared with patients with stage I cancer (HR 0.3, 95% CI 0.3-2.0). Patients with stage II endometrial cancer had a 3.2-fold (95% CI 1.2-8.6) increased risk of death from endometrial cancer compared to stage I patients. Similarly, patients with histological stage IIIA and patients with stage IIIB were at 2.7-fold (95% CI 1.0-7.7) and 3.5-fold (95% CI 1.2-10.4) increased risk of death from endometrial cancer, respectively.
Excluding the 2 patients in the cytological stage IIIA category who, without the incorporation of peritoneal cytology, would have been staged as stage II, did not alter the results significantly.

Discussion

In the past 20 years, over 50 reports on the significance of positive peritoneal cytology in endometrial carcinoma have been published, and many conflicting results have appeared in the literature (25). Based on the studies that found that positive cytology is an important adverse prognostic factor, postoperative radiotherapy was recommended for patients with positive peritoneal cytology. On the contrary, investigators who did not find that malignant positive cytology was a significant prognostic factor were not in favour of adjuvant therapy and highlighted adverse effects of radiotherapy. This retrospective study based on cancer patients recorded at the Geneva cancer registry found that positive peritoneal cytology is not an independent prognostic factor in patients with endometrial cancer. Women with only positive cytology (cytological stage IIIA) had the same prognosis as women who have endometrial cancer confined to uterus (stage I). The lack of significant difference between these two groups allows us to suggest that the presence of positive peritoneal cytology, which transforms stage I to stage lllA probably upstages these patients.
On the other hand, this study clearly shows that woman with only cytological disease (cytological stage IIIA) present a much better prognosis than those with macroscopic invasion of the serosa or adnexal tissues (histological stage IIIA). Patients staged as cytological lllA had a specific survival of 94% at 5 years, compared with 51% for patients staged as lllA based on adnexal or serosa involvement. In multivariate analysis, cytological based stage lllA patients were less likely to die from endometrial cancer after accounting for other prognostic factors such as age, differentiation and type of surgery or radiotherapy. Regrouping these women in stage IIIA disease, as it is actually the case in the FIGO classification, is debateable. As previously shown by Preyer et al., 1988 FIGO stage lllA uterine cancer constitutes a very heterogeneous group (26).
Despite the absence of strong scientific data to support its use, adjuvant radiotherapy has been a key component in the treatment of endometrial cancer, even for early stages. However, no improvement in survival has been documented in patients with early stage (27-29). This study included only patients treated with adjuvant therapy and the effect of radiotherapy itself could not be studied. We can only conclude that prognosis of cytological stage IIIA women with radiotherapy was different from that of histological stage IIIA women with radiotherapy.
Another current question remaining is to know whether adjuvant radiotherapy should be omitted for this stage lllA category of patients. When adjuvant radiotherapy is given after surgical staging with lymph node dissection in stage I endometrial cancer, the overall survival is between 97% to 100%, and is comparable to that without radiotherapy (30). The incidence of bowel complications (usually about 4% of patient with lymph node dissection is increased by adjuvant radiotherapy (31). For patients with more limited operative procedures, after additional radiotherapy, the 5-year overall survival is 97% to 100% and is then similar to that of patients with major surgery only (32;33).
However, despite the reduction of recurrences by radiotherapy from 7-14% to 2-4%, radiotherapy is associated with numerous adverse effects (34-36). Patients who receive radiotherapy and who develop extra vaginal pelvic relapse, have a lower chance to cure from their relapse, i.e. 5% compared to 20-30% for those who were never irradiated (37-39). As reported by Creutzberg et al. 20% of patients have long-term symptoms, mainly urinary problems, frequent bowel movements, abdominal cramps, and occasional bouts of diarrhoea. These symptoms are usually rated as mild morbidity but do influence quality of life (40).
For patients treated by simple hysterectomy, even for high-risk cases, the overall survival is between 94% and 96% (41;42). It appears that the effect of the additional radiation or lymph node dissection might influence only the additional overall survival of about 4-6% in patients with stage I endometrial cancer.
Considering the state of knowledge, specific recommendations whether to give adjuvant radiotherapy to women with cytological stage IIIA cancer is not possible. Only randomised clinical trials testing the benefice and adverse effect of radiotherapy among women with positive cytology localised disease cancer could answer this delicate question.
Like previous studies, the present study shows that prognosis of endometrial cancer is good. This good prognosis is due to the fact that most women are diagnosed with early stage disease (2;4). In the present study, 66% of women had stage I cancer and 10% had cytological stage lllA disease. This observation is similar to that of other studies where stage I endometrial cancer was reported to be more than 75% of the cases.
This study also shows that endometrial cancer is a disease of elderly women with most cases occurring after menopause, with a mean age at diagnosis of 65 years. In many other studies, the mean age at diagnosis of endometrial cancer ranged from 64 to 66 years (43;44). The late occurrence of this pathology in postmenopausal women can explain its importance in ageing industrial population and its relative rarity in developing countries where the life expectancy is usually about 50 years.

Conclusion

This study shows that women with cytological stage lllA endometrial cancer have a similar prognosis as women with stage l cancer and a better prognosis than women with histological stage IIIA cancer. Therefore, staging codification should be reviewed to permit a distinction of this group in order to optimise the management of these patients. Additional research is needed for better assessment of the impact of cytology on the outcome of patients with endometrial cancer.

References

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Table 1. Characteristics of 170 endometrial cancer patients according to stage

Stage I: tumour confined to uterus; stage II: tumour invading cervix; stage IIIA cyt: positive peritoneal cytology; Stage IIIA hist: histological involvement of serosa or adnexa; stage IIIB + : tumour invading vagina, mucosa of bladder/bowel, regional lymph node or distant metastases.

 

Table 2. Observed and disease specific 5-years survival after endometrial cancer according to stage

Stage I: tumour confined to uterus; stage II: tumour invading cervix; stage IIIA cyt: positive peritoneal cytology; Stage IIIA hist: histological involvement of serosa or adnexa; stage IIIB + : tumour invading vagina, mucosa of bladder/bowel, regional lymph node or distant metastases.

 

Table 3. Hazard ratio of death from endometrial cancer according to stage

	HRa	95% CI
Stage I	1b
Stage II	3.2*	1.2-8.6
Stage IIIA cytological	0.3	0.3-2.0
Stage IIIA histological	2.7c	1.0-7.7
Stage IIIB and more	3.5*	1.2-10.4

^a Hazard ratio are derived from Cox model adjusted for age, tumour differentiation and type of radiotherapy (external radiation therapy, brachytherapy or both);
^b reference category;
^c p borderline significant (0.057);
* p < 0.05.
Stage I: tumour confined to uterus; stage II: tumour invading cervix; stage IIIA cyt: positive peritoneal cytology; Stage IIIA hist: histological involvement of serosa or adnexa; stage IIIB + : tumour invading vagina, mucosa of bladder/bowel, regional lymph node or distant metastases.