Prognostic characteristics of surgical stage I endometrial adenocarcinoma

PII: SO360-3016(96)00189-7

ELSEVIER

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Clinical Original Contribution PROGNOSTIC CHARACTERISTICS OF SURGICAL ENDOMETRIAL ADENOCARCINOMA

STAGE I

ANDRE KONSKI, M.D.,* DON DOMENICO, M.D.,’ MICHAEL TYRKUS, PH.D. ,T DOUGLAS IRVING, B.A., M.B.A.,+ JAMES NEISLER, M.D.,’ GARTH PHIBBS, M.D..* STEVEN ZEIDNER, M.D.* AND WILLIAM EGGLESTON, M.D.* *Department of Radiation Oncology, ?Department of Laboratory Medicine, and $Department of Obstetrics and Gynecology, The Toledo Hospital, Toledo, OH 43606 Purpose: To evahtate and correlate the expression of pathologic characteristics, flow cytometric DNA content %iHj?%, and estrogen and progesterone receptor levels with survival in patients with surgical Stage I endometrial carcinoma. Methods and Materials: Hospital tumor registry records were surveyed, and this i&&Bed 232 patientsdiagnosed with endometrial adenocarcinoma between July 1, 1989, and December 30, 1993. DNA content aua#ysis was performed on either paraffin-embedded or fresh tissue samples. Survival was cakulated from the date of diagnosis by the Kaplan-Meier method. Postoperative irradiation (whole pelvis external beam therapy and low dose rate vaginal cufT brachytherapy) was delivered to patients felt to be at high risk for failure. Rest&s: One hundred seventy-one patients had Stage I tumors and were availahle for analysis. Patients with Stage IC! tumors had a statistically significant lower survival rate compared to patients with Stages IA or IB (p = 0.03 and p < 0.01, respectively). Patients with DNA content diploid tumors had a siightly increased (but nonsigni6cantly so) survival compared to patients with non-DNA content dipkvid tumors @ = 0.12). Logistic regression analysis failed to identify an independent prognostic factor that could predict for disease specific survival in patients with Stage I cancers. Condusion: Logistic regression analysis did not identify a single independent prognostic factor in patieuts with Stage I tumors. Pathologic characteristics reported to predict survival advantage correlated with patim&& stage. Additional translational research is needed to identify molecular characteristics of tumors that may indiiate more aggressive treatment for patients at high risk for recurrence. Flow cytometric DNA content analysis, Endometrial carcinoma, Estrogen and progesterone reeeptor analysis, Surgical staging.

these factors are estrogen receptor (ER) and progesterone receptor (PR) steroid receptor analysis, race and Flow Cytometric DNA (FCDNA) content analysis (2-4, 7, 14, 15, 18, 19, 21, 24, 26, 30). Recently, molecular properties of endometrial carcinoma and race of the patient have been reported to have prognostic significance as well (8, 12, 13, 16, 25). We report our experience with endometrial carcinoma by examining pathologic characteristics. Flow Cytometric DNA (FCDNA), and ER/PR steroid receptor analysis as related to disease-free and disease-specific survival in patients with surgical Stage 1 endometrial carcinoma.

INTRODUCTION

The new International Federation of Gynecology and Obstetrics (FIGO) staging system for Endometrial cancer is based upon evaluation of the tumor at the time of surgery (6). Historically, staging of endometrial cancer has been based on the depth of the endometrial cavity at the time of Dilatation and Curettage (D & C) and on other clinically obtained information. The previous staging system ignored important prognostic information such as lymph node involvement and the depth of myometrial invasion, which could have been affected by preoperative irradiation. There have been relatively few reviews reporting institutional experiences with endometrial cancer since the introduction of the new staging system (9). However, a number of recently defined factors of reported prognostic value are not considered in the new FIG0 system. Among

Hospital tumor registry records were surveyed to identify patients diagnosed with endometrial adenocarcinoma

Reprint requests to: Andre Konski, M.D., Department of Radiation Oncology, The Toledo Hospital. N. Cove Boulevard,

Toledo. OH 43606. Accepted for publication 27 March 19%.

METHODS

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Table 1. Distribution of patients by grade and surgical stage Grade I

Grade II

Grade III

Total

31 47 4 82

11 36 11 58

2 15 14 31

44 98 29 171

IA IB IC Total

between July 1, 1989, and December 30, 1993. Patients were eligible for analysis if surgical staging was performed. Cancers were staged in accordance with the 1988 FIG0 guidelines (6). Estrogen and progesterone receptor analysis was performed either from fresh tissue or by immunohistochemical staining of paraffin-embedded tissue. Patients were excluded from the analysis if preoperative radiation had been administered, or if surgical staging had not been performed. A total of 232 patients with endometrial cancer underwent surgical staging during the study period. Of these, 171 patients were found to have Stage I cancers. The mean age of the patients was 63.9 (range: 32-88) years, with a mean time to follow-up of 46.6 (range: 20-78) months. The distribution of patients by substage and grade is shown in Table 1. Flow cytometric DNA content analysis was performed on fresh tissue at the time of pathologic dissection, or (if sufficient fresh tissue was not available) on paraffin-embedded tissue as previously reported (17, 19). Flow cytometric DNA content analysis included determination of DNA content, %G*M, and %S phases. Estrogen and progesterone receptor determination and FCDNA procedures are standardized and reported elsewhere (17-19). Lymph node sampling was performed at the time of surgery if greater than 50% myometrial invasion was identified when the uterus was examined in the operating room. Because this study is retrospective in nature, standard treatment protocols for stage and grade did not exist, though the majority of patients were treated within the following general guidelines: (a) if the patients had less than l/3 myometrial invasion and tumors of Grade I or II, they did not receive adjuvant whole pelvic irradiation; (b)

Volume 35, Number 5, 1996 if the patients had Grade HI tumor differentiation, or greater than l/3 myometrial invasion, adjuvant whole pel-

vic irradiation (45 Gy) with a vaginal cuff boost (20 Gy) with low dose rate brachytherapy was delivered. Statistical analysis was performed with StatView ~4.1 on a PC. ’ Survival was calculated from the date of diagnosis with the Kaplan-Meier method. Intergroup survival differences were determined via the log rank test. Frequency distribution differences between groups were determined by the chi-square test. All analysis was performed on patients with surgical Stage I cancers. Logistic regression analysis was used to evaluate the possible independent prognostic value of the factors studied. RESULTS Depth of myometrial invasion (stage) A statistically significant number of patients with higher pathologic stage received postoperative irradiation (p < 0.01). The distribution of patient treatment by surgical stage is presented in Table 2. Table 3 presents diseasefree status by treatment (whether the patients received postoperative irradiation, either external beam irradiation and/or implant, or no radiation) by stage and grade. Disease-specific survival (DSS) is defined by censoring patients who die of causes other than endometrial cancer, and only counting as “events” patients dying from endometrial cancer. Three patients (1.7%) died in the immediate postoperative period from complications of surgery. Disease-specific survival is shown in Fig. 1 for patients with Stage I cancers. A statistically significant difference in disease specific survival (DSS) is noted between patients with Stages IA and IC (p = 0.03), and between Stages IB and IC (p < 0.01). No statistical difference in survival is noted between patients with Stages IA and IB. Grade A higher proportion of patients with Grade III cancers presented with higher pathologic stage tumors (p < 0.01). Disease-specific survival by grade for patients with Stage I cancers is shown in Fig. 2.

Table 2. Patient treatment by surgical stage

IA IB IC Total

Surgery only

Surgery + RT

Surgery + RT + horm.

Surgery + RT + chemo.

Surgery + brachy

Total

40 64 5 109

3 30 23 56

0 0 1 1

0 1 0 1

1 3 0 4

44 98 29 171

RT-Postoperative external beam radiation therapy plus vaginal brachytherapy; Honn-hormonal Bracy.-vaginal

brachytherapy only.

‘StatView Abacus Concepts Inc. Berkeley, CA

therapy; Chemo.-chemotherapy;

Endometrial prognostic factors l A.

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Table 3. Disease-freestatusby treatment (radiationor no radiation) No radiation IA Grade I

31/31 919

IA GradeII IA Grade III IB Grade I IB Grade 11 IB Grade 111 IC Grade I IC Grade II IC GradeIII

o/o 42142 15/17 414

o/o 212 l/2

-

Radiation

Total

o/o 112 212 5/5 18/19 10/l 1 414 819 9112

31/31 10111 212 47147 33136 1411.5 4/4

0.8-

lO/ll 10/14 0

10

20

30

40

50

80

70

Time (months)

Flow cytometric DNA content analysis One hundred fourteen pathologic specimens contained sufficient pathologic material for DNA content analysis, of which 75 cancers were DNA content diploid (DNAD), 36 cancers were DNA content Aneuploid (DNA-A), one cancer was DNA content Tetraploid (DNA-T), and two cancers were DNA content Hypodiploid (DNA-H). An improvement (not statistically significant) in DSS was noted in patients with DNA-D tumors compared to those with non-DNA-D tumors (p = 0.12). Disease-specific survival for these patients with Stage I cancers is shown in Fig. 3. ER/PR receptor analysis Fifty patients had sufficient pathologic material to undergo progesterone receptor analysis, of which 9 were PR negative, 38 PR positive, and 3 were borderline PR positive. Fifty-one patients had sufficient pathologic material to undergo estrogen receptor analysis, of which 7 were ER negative, 41 were ER positive, and 3 were borderline ER positive. Disease-specific survival is slightly improved in patients with ER positive tumors compared to those with ER negative tumors, but this is not statistically significant

Fig. 2. Disease-specific survival for Stage 1 patient comparing Grade I, II, and III tumors.

(p = 0.28). as is the difference between those with PR positive and negative tumors. Histology One hundred sixty-two cancers were pathologically defined as adenocarcinoma, two as adenosquamous, four as clear cell, and three as uterine papillary serous tumors. A statistically significant difference in DSS was noted in Stage I patients between those patients whose cancers were adenocarcinoma and those patients whose cancers were of the papillary serous variant (p < 0.01). Table 4 shows the distribution of patients by histology and stage. The small number (n = 3) of patients with the papillary serous variant lessens the statistical validity of the effect of histology in our patient population. Three patients not receiving adjuvant irradiation developed recurrent disease. One failure was local, one distant. and one regional and distant. The first two were in patients with Stage 1B and the last in a patient with a Stage 1C cancer.

0.8P 3

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10

20

30 Tlms

40

50

60

70

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0

I 10

I

20

I 30

I

40

q JDtwCaRtwrtllnwplol I I - I 50

80

70

Tlms (months)

Fig. I. Disease-specific survival for patients with Stages IA, IB, and IC tumors. Statistically significant difference in survival is seen between patients with Stage IA and IB and those with Stage IC.

Fig. 3. Disease-specific survival comparing patients with Stage I tumors and DNA content diploid and DNA content aneuploid tumors.

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Table 4. Histologic subtype by pathologic stage

IA IB IC Total

Adenocarcinoma

Adenosquamous

Clear Cell

Papillary serous

Total

42 93 27 162

1 1

1

0

2

2

0 2

1

1

4

3

44 98 29 171

Only one patient receiving adjuvant irradiation experienced a local recurrence. This patient also developed distant disease. Four patients receiving adjuvant irradiation had distant failures and two patients had regional and distant failures. The four patients that received adjuvant irradiation had poor prognostic disease: either deep myometrial invasion or high histologic grade. No isolated vaginal metastases were detected in this group. Because this was not a prospective randomized trial, inferences to the effect of radiation preventing local recurrences cannot be made. Logistic regression analysis for Stage I patients included in the present study did not suggest that grade, stage, histology, age, race, DNA content, or ER, and PR status could function as independent prognostic indicators for DSS potential. DISCUSSION Depth of myometrial invasion (stage) The new FIG0 staging system emphasizes the degree of myometrial invasion apparent at the time of surgery and surgical evaluation of pelvic and paraaortic lymph nodes. Few studies report results on the basis of the new FIG0 staging system (9). The results of treatment for patients with Stage IA disease are excellent, regardless of the treatment employed. Morrow et aZ. reported excellent S-year disease-free survival in patients treated with observation, low dose rate brachytherapy, or external irradiation (27). They reported one failure, a patient with a Grade III tumor. That investigation was, however, a nonrandomized study of over 1,180 women on Gynecologic Oncology Group (GOG) study 33. The majority of studies published to date do not segregate patients according to depth of myometrial invasion at greater or lesser than 50%. The majority of studies placed the separation at a depth of > l/3 myometrial invasion. In our study, no difference was noted in DSS between Stages IA and IB. Patients with Stage IA or IB tumors experienced greater than 90% survival. Or-r et al. reported a failure rate of 3% in patients with Stage IB disease receiving low dose rate brachytherapy (28). Similarly, Calitchi et al. did not find any recurrences in patients treated with low dose rate brachytherapy (5). Toonkel and colleagues observed six recurrences in 29 patients with IB disease treated with external beam irradiation with all of the recurrences occurring in patients with Grade II or III tumors (31).

Survival of patients with Stage IC cancers is significantly worse compared to that of patients with Stages IA and IB disease. This is confirmed in a number of other studies. Aalders et al. reported the results of a randomized trial of low dose rate brachytherapy with or without external beam irradiation (1). All patients received vaginal brachytherapy and were randomized to observation or 40 Gy pelvic irradiation. They reported a 9.8% vaginal and pelvic recurrence rate for patients with Stage IC, Grade I or II tumors and a 19.6% vaginal and pelvic recurrence rate, and a 15.7% distant metastases rate for those with Stage IC, Grade III tumors treated with low dose rate brachytherapy alone. They reported a 9.4% vaginal and pelvic recurrence rate for patients with Stage IC, Grade I or II tumors and a 6.6% vaginal and pelvic recurrence rate and an 11.8% distant metastases rate for those with Stage IC, Grade III tumors treated with external beam irradiation plus low dose rate brachytherapy. A significantly higher recurrence rate as well as a higher frequency of death from cancer and distant metastases was noted in patients with >50% depth of myometrial invasion evident at the time of surgery. Kuipers et al. treated patients with vaginal brachytherapy and added external beam irradiation to the pelvis if >50% myometrial invasion was seen (20). The vaginal treatment was delivered with either low or high dose rate brachytherapy. They reported a 5-year survival rate of 94%. Six patients experienced distant failure, with an increased incidence in patients with higher grade tumors treated with low dose rate brachytherapy and external irradiation to the pelvis. Only one patient had a local failure, once again with a Grade III tumor. They reported six distant failures in 93 patients treated with high dose rate brachytherapy and external irradiation of the pelvis and two patients with some form of local failure as well. Calchiti et al. reported no recurrences in 14 patients with Stage IC lesions treated with external pelvic irradiation only, and Marchetti et al. observed 100% 5-year DFS in patients with Grade I and II tumors and 91% 5year DFS in 11 patients with Stage IC, Grade III tumors (5, 22). Patients in Marchetti’s series were treated with external pelvic irradiation with or without low dose rate brachytherapy. Meerwaldt et al. reported five recurrences in 22 patients with Stage IC, Grade III tumors and three recurrences in 145 patients with Stage IC, Grades I and II tumors treated with external pelvic irradiation with or without low dose rate brachytherapy (23). Toonkel et aE. reported 10 out of 12, 6 out of 7, and 8 out of 8 5-year

Endometrial prognosticfactors0 DFS in patients with Stage IC Grades I, II, and III tumors, respectively, treated with external irradiation alone (31). We suspect that disease-specific and disease-free survival of patients Stage IC Grade III cancers might improve by the addition of postoperative irradiation, but realize that the current sample size is too small to confirm this with any degree of certainty. Our results compare favorably to other reports in the literature for treatment of Stage IA and IB endometrial cancer. Our approximate 60% 5year DSS for patients with Stage IC tumors is based upon only 29 patients. No patients with IC tumors experienced a local failure. Further investigations of adjuvant therapy may be necessary to reduce the number of regional and distant failures seen in this patient population. Grude Grade is another histopathologically defined property that has been used with some success to predict survival. As can be seen from the literature cited above, the majority of failures occur in patients with Grade III tumors. Our results correspond to those reported with lOO%, 88%, and 78% DSS at 40 months for patients with tumors of histologic Grades I, II, and III, respectively. Flow cytometric DNA content analysis DNA content has been reported to be of prognostic benefit in patients with endometrial carcinoma (2, 4, 7, 14, 19, 24, 26, 30). We previously reported a preliminary study of DNA content analysis of patients with endometrial adenocarcinoma (19). Our current study, with larger numbers of surgically staged patients, shows a trend toward improved survival for patients with DNA-D tumors as compared to those with DNA content nondiploid tumors, but the difference did approach statistical significance (p = 0.12). Melchiorri et al. concluded from their study that DNA content was a biologic characteristic firmly associated with tumor aggressiveness (24). Their study, however, used clinical staging and did not attempt to correlate stage and DNA content. Ikeda et aE. reported that tumor DNA content (as defined by flow cytometry) increases with both pathologic stage and depth of myometrial invasion (14). Their multivariate analysis, however, found DNA ploidy to be an independent prognostic factor, a finding that our study does not substantiate. Dyas et al. reported a significant survival advantage for patients with euploid Stage I and II carcinomas compared to those with aneuploid tumors, though they did not specify which staging system they employed (7). Britton et al., Ambros et al., and Rosenberg et al. all found DNA content to be predictive for patient survival (2, 4, 30). ERIPR receptor analysis Cytoplasmic steroid receptors have also been reported to be of prognostic significance in endometrial adenocarcinema. Liao et nl. found a statistically significant survival

A. KONSKI

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039

advantage for patients with ER positive tumors vs. ER negative tumors, PR positive tumors vs. PR negative tumors, and ER-PR positive tumors vs. ER-PR negative tumors (21). Their analysis included all clinical stages. The majority of early stage cancers in our study were ER positive. Although we found a better survival rate for patients with ER positive tumors contrasted to patients with ER negative tumors, the results were not statistically signihcant (p = 0.25). Paradoxically, all patients with PR negative tumors are currently alive compared to 36 out of 39 patients with PR positive tumors. Ingram et al., however. found progesterone receptor levels to be the single most important prognostic indicator of 3-year disease-free survival in patients with clinical Stage I endometrial cancer ( 13). Once again, their analysis included all stages, while that of the present study includes only surgical stage I cases. Histolog?; Uterine papillary serous carcinoma is reported as generally having a worse prognosis compared to adenocarcinema, unspecified type (10, 11,29). Our results confirm other reported studies of the aggressive clinical behavior of uterine papillary serous carcinoma. We did not notice, however, a higher percentage of patients with papillary serous histology with nondiploid DNA content tumors. Our results, however, should be interpreted with caution because of the small number of patients (n = 3) with this histologic variant. Numerous studies have been published attempting to describe tumor “properties” or “factors” that. either separately or in addition to known pathologic characteristics, could be used to identify patients who are at increased risk for tumor recurrence. The tumor properties or factors investigated in the present study did not identify Stage 1 patients at increased risk of recurrence. They did, however, correlate with advanced surgical stage. A higher percentage of high grade tumors were DNA-4 and were ER and PR negative. We are conducting further studies to determine if the combined usage of two or more tumor factors can be used to accurately predict DSS or other pertinent aspects of tumor behavior. In addition, we are attempting to integrate data from molecular biology investigations into ongoing clinical studies.

CONCLUSION Logistic regression analysis failed to reveal a factor that could predict which patients would be at high risk of developing recurrent disease. Unlike most of the reported studies, which state that steroid receptors or DNA content can predict for survival, our series reports data from surgically staged patients. Routine clinical use of ER/PR receptor or DNA content to determine treatment may not be justified at this time outside of clinical trials.

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17. Konski, A.; Domenico, D.; Irving, D.; Tyrkus, M.; Neisler, J.; Phibbs, G.; Bishop, K.; Mah, J.; Eggleston, W. Flow cytometric DNA content analysis of paraffin embedded tissue derived from cervical carcinoma. Int. J. Radiat. Oncol. Biol. Phys. 30:839-843; 1994. 18. Konski, A. A.; Domenico, D.; Irving, D.; Tyrkus, M.; Neisler, J.; Phibbs, G.; Mah, J.; Eggleston, W. Clinicopathologic correlation of DNA flow cytometric content analysis (DFCA), surgical staging, and estrogen/Progestrone receptor status in endometrial adenocarcinoma. Am. J. Clin. Oncol. 19:164-168; 1996. 19. Konski, A. A.; Myles, J. L.; Sawyer, T.; Neisler, J.; Phibbs, G.; Leininger, S.; Kim, K.; Dobelbower, R. R. Flow cytometric DNA content analysis of paraffin block embedded endometrial carcinomas. Int. J. Radiat. Oncol. Biol. Phys. 21:1033-1039; 1991. 20. Kuipers, T. J. The role of radiation therapy in conjunction with surgery in the treatment of endometrial carcinoma. In: Heintz, ed. Surgery in gynecologic oncology. Amsterdam: Martinus Nijhoff; 1984:236-247. 21. Liao, B. S.; Twiggs, L. B.; Leung, B. S.; Yu, W. C. Y.; Potish, R. A.; Prem, K. A. Cytoplasmic estrogen and progesterone receptors as prognostic parameters in primary endometrial carcinoma. Obstet. Gynecol. 67:463-467; 1986. 22. Marchetti, D. L.; Piver, M. S.; Tsukada, Y.; Reese, P. Prevention of vaginal recurrence of stage I endometrial adenocarcinoma with postoperative vaginal radiation. Obstet. Gynecol. 67:399-402; 1986. 23. Meerwaldt, J. H.; Hoekstra, J. M.; Van Putten, W. L. J.; Subandono Tjokrowardojo, A. J.; Koper, P. C. M. Endometrial adenocarcinoma, adjuvant radiotherapy tailored to prognostic factors. Int. J. Radiat. Oncol. Biol. Phys. 18:299304; 1990. 24. Melchiorri, C.; Chieco, P.; Lisignoli, G.; Marabini, A.; Orlandi, C. Ploidy disturbances as an early indicator of intrinsic malignancy in endometrial carcinoma. Cancer 72: 165-172; 1993. 25. Mizuuchi, H.; Nasim, S.; Kudo, R.; Silberberg, S. G.; Greenhouse, S.; Garrett, C. T. Clinical implications of K-ras mutations in malignant epitbelial tumors of the endometrium. Cancer Res. 52:2777-2781; 1992. 26. Moberger, B.; Auer, G.; Forsslund, G.; Moberger, G. The prognostic significance of DNA measurements in endometrial carcinoma. Cytometry 5:430-436; 1984. 27. Morrow, C. P.; Bundy, B. N.; Kurman, R. J.; Creasman, W. T.; Heller, P.; Homesly, H. D.; Graham, J. E. Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: A Gynecologic Oncology Group Study. Gynecol. Oncol. 40:55-65; 1991. 28. Orr, J. W.; Holloway, R. W.; Orr, P. F.; Holimon, J. L. Surgical staging of uterine cancer: An analysis of perioperative morbidity. Gynecol. Oncoi. 42:209-216; 1991. 29. Rosenberg, P.; Boeryd, B.; Simonsen, E. A new aggressive treatment approach to high-grade endometrial cancer of possible benefit to patients with stage I uterine papillary cancer. Gynecol. Oncol. 48:32-37; 1993. 30. Rosenberg, P.; Wingren, S.; Simonsen, E.; Stal, 0.; Risberg, B.; Nordenskjold, B. Flow cytometric measurements of DNA index and S-phase on paraffin-embedded early stage endometrial cancer: An important prognostic indicator. Gynecol. Oncol. 3550-54; 1989. 31. Toonkel, L. M.; Fix, I.; Jacobson, L. H. Myometrial penetration of endometrial carcinoma as a prognostic factor for patients receiving pre- or postoperative radiation therapy. Am. J. Clin. Oncol. 7:669-673; 1984.