STAGE I WELL DIFFERENTIATED ADENOCARCINOMA OF THE ENDOMETRIUM*

VOL. 123, No. 3 STAGE I WELL DIFFERENTIATED ADENOCARCINOMA OF THE ENDOMETRIUM* By NATHAN GREEN, M.D.,t ROY WILBUR MELBYE, M.D.,t and JULES KERNEN, M.D4 LOS ANGELES, CALIFORNIA T HE treatment of well differentiated adenocarcinoma of the endometrium Stage I disease continues to be controversial. Total hysterectomy alone has given very good cure rates. However, some patients are at risk for treatment failure. The risk has been related to the degree of muscle invasion and the presence of metastases. 4 Adjunct irradiation has been used to minimize the risk for treatment failure. The indications for radiotherapy and the proper method of delivery are in doubt.2 6 4 Proper treatment should encompass all the extent of tumor spread. The method of treatment is initially determined by the clinical stage. We assessed whether the clinical Stage could be used to determine proper treatment by comparing the clinical stage to the pathologic stage. The effectiveness of surgical treatment alone and surgical treatment with adjunct irradiation was assessed with special regard to tumor recurrence and cause of death. MATERIAL AND METHOD Between 1966 and 1972, 112 patients with well differentiated adenocarcinoma of the endometrium Stage I disease were treated by total hysterectomy. The study group consisted of 88 patients initially staged I clinically and 24 patients staged I post hysterectomy. One hundred and eight patients had a total abdominal hysterectomy and bilateral salpingo-oophorectomy and 4 patients had a vaginal hysterectomy. Nine patients had preoperative irradiation delivering a minimum of 5,ooo milligram hours with vaginal and intrauterine radium ; 4 patients had postoperative irradiation with cobalt 6o teletherapy, delivering a minimum of4,ooo rads to the total pelvis. The reliability of the histologic grading was assessed. One hundred and two patients had curettage and hysterectomy slides for review. The original histologic interpretations were atypical endometrial hyperplasia, adenocarcinoma in situ and well differentiated The review histologic intepretations were: atypical endometrial hyperplasia; well differentiated adenocarcinoma; and moderate differenti#{227}tedadenocarcinoma.3 We feel that the term adenocarcinoma in situ was mappropriate when used for the curettage specimens as many of the hysterectomy specimens had muscle invasion. A comparison of the clinical stage with the anatomic extent of disease was made in the 88 patients staged i clinically. Excluded were patients with curettage findings of tumor extension into the endocervix and patients with pelvic findings suggesting node or ovarian metastases. Since preoperative irradiation can affect the anatomic findings, the 79 patients treated by hysterectomv alone were Studied separately from 9 patients treated with preoperative irradiaflon. Of the 24 patients staged i post hysterectomy, I 5 patients had curettage specimens originally interpreted as atypical endometrial hyperplasia; 4 patients had only abnormal Papanicolaou smears and 5 patients had a hysterectomy without prior suspicion for carcinoma. All patients proved to have carcinoma limited to the corpus. These patients were included in the study * Presented at the Seventy-fifth Annual Meeting of the American Roentgen Ray Society, San Francisco, California, September 24-27, 1974. t Division of Radiation Therapy, Hospital of the Good Samaritan. Department of Pathology, Hospital of the Good Samaritan. 563

564 N. Green, R. W. Melbye and J. Kernen MARCH, 1975 I COMPARISON OF ORIGiNAL AND REVIEW HISTOPATHOLOGY Original Well Differentiated Adenocarci noma COMPARISON OF CURETTAGE TO HYSTERECTOMY FINDINGS FOR PATIENTS WITH CLINICAL STAGE I TREATED BY TOTAL HYSTERECTOMY Hysterectomy Review Well Atypical Moderately Differentiated Endometri al Differentiated Adenocarcinoma H yperplasia Adenocarcinoma 102 94 3 5 in order to enhance the number of patients that could be evaluated for treatment response. Treatment response was assessed from the recorded observations of tumor recurrence, metastases and cause of death. RESULTS The age range was 38 years to 84 years, with the median age 8 years. Ninety-one patients had abnormal uterine bleeding; 95 patients had the weight and length of the uterus recorded; 42 patients had leiomyomata; 68 patients used estrogens. Histologic review showed 9 patients to have had well differentiated adenocarcinoma and patients less well differentiated adenocarcinoma. Three patients had curettage and hysterectomy specimens that failed to show adenocarcinoma (Table i). The clinical Stage i compared favorably to the surgical and hysterectomy findings. No patient was observed to have gross pelvic lymph node or abdominal metastases (Tables n; III; and Iv). Most patients had noninvasive carcinoma or carcinoma invasive to less than one-third of the muscle thickness. Deeper invasion was infrequent. There was no relationship of the weight or Curettage l indings 1ABLE length of the uterus to the extent of tumor invasion. The incidence and degree of muscle invasion was the same for patients with small and large uteri either with or without leiomyomata. Thirty patients had curettage specimens originally interpreted as adenocarcinoma in situ. Thirteen of these patients had invasive carcinoma. Fifteen patients had curettage specimens interpreted as atypical endometrial hyperplasia; 6 patients had noninvasive carcinoma, and 6 patients had invasive carcinoma; 3 hysterectomy specimens failed to show carcinoma. A total of io8 patients was followed for I to 7 years; 4 patients were lost to followup. Seventy-nine patients were followed for a minimum of3 years-the high risk period for recurrence (Table iv).4 7 No patient managed by either surgery alone or surgery with adjunct irradiation developed vaginal or pelvic recurrence, distant metastases or death from carcinoma. Findings DISCUSSION Eighty per cent of our patients with well differentiated adenocarcinoma of the endometnium, Stage I disease presented with abnormal uterine bleeding. More than half II Well Differentiated Adenocarcinoma No Residual Cancer No Muscle Superficial Muscle Deep Muscle 79 17 31 28 3

VOL. 123, No. 3 Adenocarcinoma of the Endometrium III COMPARISON OF CURETTAGE TO HYSTERECTOMY FINDINGS FOR PATIENTS WITH CLINICAL STAGE I TREATED BY PREOPERATIVE IRRADIATION AND TOTAL HYSTERECTOMY Curettage Findings Hysterectomy Findings Well Differentiated Adenocarcinoma No Residual No Muscle Superficial Muscle Deep Muscle Cancer 9 3 4 2 0 of the patients had used estrogens. Unopposed estrogen use can act as a stimulant to endometrial hyperplasia and may predispose to the development of malignancy. 6 7 Surgery alone and surgery with adjunct irradiation have been advocated for well differentiated adenocarcinoma Stage I disease. 8 However, up to I 5 per cent of patients managed by surgery alone have been reported to develop vaginal recurrence and up to I 2 per cent death caused by cancer.9 8 Adjunct irradiation has been advocated to prevent local recurrence and improve survival. The value of adjunct irradiation has been questioned. The basis for conflicting reports may have been due to the assessment of patients with differences in socioeconomic status or in extent of disease4 9 13 7 8 We limited our study almost exclusively to patients with curettage specimens interpreted as suspicious or diagnostic of well differentiated adenocarcinoma. Patients with tumor extension into the endocervix or patients with a pelvic examination suggestive of lymph node or ovarian metastases were excluded. The histologic interpretation of well differentiated adeno- HYSTERECTOMY FINDINGS AND TREATMENT Hysterectomy Findings No Muscle Muscle IV FOR PATIENTS FOLLOWED 3 YEARS Surgery 3 31 Treatment Surgery Irradiation 5 4 and carcinoma was corroborated in the hysterectomy specimen of most patients. The corroboration was important as the clinical stage does not accurately predict the true extent of disease for patients with less well differentiated adenocarcinoma. Also, the prognosis is worse.7 4 None ofour patients with well differentiated adenocarcinoma Stage I clinically proved to have carcinoma beyond the corpus. The carcinoma was usually noninvasive or invasive to less than one-third of the myometrium. Although approximately 4 per cent of patients with well differentiated adenocarcinoma Stage I disease have been reported to have pelvic node metastases, no gross pelvic lymph node metastases were observed in our pa- 14 The favorable clinical course of our patients suggests that the presence of occult pelvic lymph node metastases was unlikely. Most of our patients were treated solely by a total hysterectomy and bilateral salpingo-oophorectomy. Seventy per cent of our patients were followed for a minimum of 3 years-the high risk period for tumor recurrence.4 7 No tumor recurrences or deaths caused by cancer were observed. The excellent results may be unique to our Medical Center where patients are followed closely and operated upon early. Our patients did not have extensive disease. We are still uncertain whether adjunct irradiation is necessary. We have not excluded its value in preventing late treatment failures. Therefore, at present we continue to use adjunct irradiation in patients with a predictable long life cx-

66 N. Green, R. W. Melbye and J. Kernen MARCH, 1975 pectancy. We use vaginal and intrauterine preoperative irradiation, as this almost always encompasses the known and suspected extent of disease. Rarely would the operative findings show tumor spread that would require total pelvic irradiation. Postoperative irradiation can be used for patients when adenocarcinoma is found unexpectedly in the hysterectomy specimen.6 8 SUMMARY The experience of I i 2 patients with well differentiated adenocarcinoma of the endometrium Stage i disease was reviewed. All patients had a total hysterectomy and bilateral salpingo_oophorectomy ; I 3 patients had adjuvant radiotherapy. The clinical stage correlated well with the pathologic stage and could be used with confidence to determine proper treatment. Almost all patients had noninvasive or minimally invasive carcinoma. No patient had tumor extension beyond the corpus. Total hysterectomy alone gave excellent results. No patient developed vaginal or pelvic recurrence, distant metastases or death caused by endometnial cancer. The possibility of late recurrence and metastases could not be excluded. Nathan Green, M.D. Division of Radiation Therapy Hospital of the Good Samaritan 1212 Shatto Street Los Angeles, California 90017 \Ve wish to thank Dns. John Bach, Betty Gorman, E. Henniksen, F. Holmes, P. Horn, Joe McDaniel, James McNulty, Kenneth Morgan, Morgan Morgan, R. Newman, W. Schumann, and Grace Waldrop for the case material. \Ve would also like to express our appreciation to Laura Eppers and Betty Imbach, tumor registrars. REFERENCES I. AUSTIN, J. H., and MACMAHON, B. Indicators of prognosis in carcinoma of corpus uteri. Surg., Gnec. & O6st., 1969, 128, 1247-1252. 2. B0R0N0W, R. C. Fresh look at corpus cancer management. Obst. & Gynec. 1973, 42, 448-45 I. 3. BRODERS, A. C. Microscopic grading of cancer. In: l reatment of Cancer and Allied Diseases. Volume I. Edited by G. 17. Pack and E. M. Livingston. Paul B. Hoeber, Inc., New York, 1941. 4. CARMICHAEL, J. A., and BEAN, H. A. Carcinoma of endometrium in Saskatchewan. Am. 7. 06sf. & Gynec., i 954, 88, I 57-I 6 I. 5. COPENHOvER, E. H. Cervical occlusion in treatment of endomettial carcinoma. Obst. & Gynec., 1973, 42, 68-66o. 6. GRAHAM, J. Value of preoperative or postoperative treatment by radium for carcinoma of Liten ne bod y. Surg., Gy nec. & Obst., I 97 I, 132, 7. GUSBERG, J. B. Problem of staging endometrial cancer. Obst. & Gynec., 1966, 28, 305-308. 8. GUSBERG, S. B., and KAPLAN, A. L. Precursors of corpus carcinoma or Stage o carcinoma ofendometrium. Am. :i. Obst. & Gynec., 1963, 87, 662-678. 9. GUSBERG, S. B., and YANNOPOULOS, 0. Therapeutic decisions in corpus cancer. Am. 7. Obst. &Gynec., 1964,88, 157-161. 10. HENRIKSEN, E. Lymphatic spread of carcinoma ofcervix and ofbody ofuterus. AM. J. ROENT- GENOL. & RAD. IHERAPY, 1949,58, 924. II. KELLER, D., KEMPSON, R., LEVINE, G., and MCLENNAN, C. Management of patient with early endonietrial carcinoma. Cancer, 1947, 33, 1108-1110. I 2. LEWIS, B. J., STOLLWORLKY, J. B., and CODWELL, R. Adenocarcinoma of body of uterus. 7. Obst. & Gynaec. Brit. Emp., 1970, 77, 343-348. 13. LOTTMEIER, H. L. Individualization of therapy in carcinoma of corpus. In: Cancer of the Uterus and Ovary. Year Book Medical Publishers, Inc., Chicago, 1969, p. 102. 14. MoRRow, C. P., DISAIA, P. J., and I OWNSEND, D. E. Current management of endometrial carcinoma. Obsi. & Gvnec., 1967, 9/, 294-304. Is. NOLAN, J. if., BOROUGH, M. E., and ANSON, J. L. Value of preoperative radiation therapy in Stage I carcinoma of uterine corpus. Am. 7. Obst. & Gynec., I 967, 98, 663-674. i6. NovAK, E. K., JONES, G. S., and JONES, H. W. l extbook of Gynecology. Williams & Wilkins Company, Baltimore, 1970. 17. SHAK, C. A., and GREEN, 1. H. Evaluation of current management of endometrial carcinoma. Obst. &Gynec., 1971,39, 500-508. i8. SHAPIRO, R. 1., KUROHARA, S. S., and GEORGE, 1.W., Ill. Clinical decision in management of Stage I endometrial carcinoma. AM. J. ROENTGENOL., RAD. LHERAI\ & NUClEAR MED., 1973, 117, 623-628.

This article has been cited by: 1. Herwig Kucera, Norbert Vavra, Karl Weghaupt. 1990. Benefit of external irradiation in pathologic stage I endometrial carcinoma: A prospective clinical trial of 605 patients who received postoperative vaginal irradiation and additional pelvic irradiation in the presence of unfavorable prognostic factors. Gynecologic Oncology 38:1, 99-104. [CrossRef] 2. Maria Aida Tavares, Maria Brites Patricio, Mario Vilhena, J. Neves da Silva. 1977. Management and results of endometrial carcinoma treated at instituto portuguěs de oncologia de francisco gentil. Cancer 39:2, 675-680. [CrossRef]