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Does Today’s Vaginal Surgery Still Have a Specific Role in the Treatment of Endometrial Cancer? L. CARENZA, C. VILLANI, F. NOBILI, M . G. PORPORA, A. LUKIC, AND L. FALQUI Department of Obstetrics and Gynecology University of Rome, “La Sapienza” Vide del Policlinico, 155 00161 Rome, Italy Because of some assumptions which caused delays and confusion in acquiring a more specific knowledge of its natural history, for many years endometrial carcinoma has been considered as a low malignancy neoplasm. Four so-called “myths”’ have been dispelled over the years: Endometrial cancer is a benign disease. Since hysterectomy is the cornerstone of management and in some institutions the only treatment used, this approach suggested that endometrial cancer, along with many other benign gynecologic diseases, should be considered a “milder” tumor among the gynecologic ones. Moreover, since in some reports the 5-year survival rates were particularly high (90-95%), many investigators have suggested that little could be done to improve treatment results in early endometrial cancer. This reinforced the idea that this tumor was a low malignancy neoplasm. Contemporary gynecologic impressions suggested that endometrial cancer had a better prognosis than cervical cancer. The overall corpus cancer salvage rate is indeed better than that of cervical cancer, but the data analyzed reflect the fact that stage I endometrial cancer was diagnosed considerably more frequently (approx. 75% of the cases) than stage I cervical cancer. The best way to treat endometrial cancer has been defined. The standard treatment consisted, and still consists of an extrafascial hysterectomy and upper colpectomy, with or without pre- or post-operative radiotherapy (radium or external beam). Although surgery was the first major modality to significantly control endometrial cancer, its general applicability, especially as a single procedure, was very restricted until the 1950s, when adequate blood banking, improved anesthesia, antibiotics and other supportive measures changed the picture. When intracavitary radiation was introduced in 1919, it was apparent that surgery alone could not deal with all problems, and that another treatment modality needed to be involved. Radiation therapy from the early 1920s on has grown to play a major role: indeed, in many institutions it reduced surgery’s role to little more than diagnosis and application of intracavitary radioactive sources. 411
478
ANNALS NEW YORK ACADEMY OF SCIENCES
By the mid 1950s, chemotherapy and hormonal therapy had come into the picture, thus further reducing the role of surgery. The interaction of 90 years of development for both radiation and surgery (even radical hysterectomy) led to the appearance of quite a number of programs involving single or multimodality approaches. There were those who supported the simplest of procedures and those who supported the fairly complex evaluation. The Mayo Clinic’s advocacy of vaginal hysterectomy (with at least half the patients having adnexal removal by the vaginal route) was supported by excellent results (overall 5-year survival rate: 84%). A more extensive surgery was not required, since less than 20%of the patients (lesions with low-grade malignancy, cervical involvement and large palpable lymph-nodes) would benefit, and even if malignancy were found in nodes, their removal and subsequent modification of therapy probably would not lead to better results than those achieved by less radical surgery.2 Vaginal hysterectomy has been used by a number of physicians whose results have supported the Mayo Clinic’s work. The other extreme was represented by stall worth^,^ who stressed the importance of thorough exploration including the evaluation of pelvic and para-aortic nodes. He noted that deep myometrial penetration could mean higher incidence of positive nodes and metastases to other structures. He removed nodes whenever the inspection of the opened specimen indicated deep muscle penetration. More recently, considerable data have been collected on the treatment of endometrial cancer. Jones4 extensively reviewed the literature of the 1950s, 1960s and 1970s and noted that the 5-year survival rate for patients treated with surgery alone was essentially the same as for those who were treated with radiation plus surgery. Unfortunately, the vast majority of those reports were not evaluated in regard to the grade of the tumor or myometrial involvement. It is anticipated that many of the patients who were found to have poorly differentiated lesions were more likely to be treated in the combined group and, as a result, would bias the overall survival rate in the combined therapy category. Furthermore, comparing the 5-year survival rates of the patients with FIGO stage I endometrial carcinoma, it is clear that over the years the differences are not statistically ~ignificant.~fi This is also confirmed in the overall survival rates: 60%*vs. 67.7.6 In a recent FIGO Annual Report’ the 5-year survival rate (all stages) referring to the years 1979-1981 is 72.3%,showing once again that, in spite of the knowledge of its natural history, endometrial carcinoma cannot always be considered as a low malignancy neoplasm. Thus, surgery should be intended: a) to “cure” the patient, b) to outline diagnosis, and c) to delineate prognosis. Although the last two items have undoubtedly improved over the years, it seems that, concerning early stage endometrial carcinoma, nothing has changed in terms of cure from the results of 15years ago. The prognostic factors have been su@ciently elucidated. In 1962 Gusberg anticipated that “studies of the biology of this tumor have afforded us greater insight into its histogenesis, vitality and spread, but lack of agreement about coding these facts into an acceptable pattern of classification has deprived gynecologists of the clinical benefits of this knowledge.”8 Over the years this fact caused delays in the comparison of various treatment modalities and a tendency to treat all patients with this disease in a standard manner, rather than selecting the most effective treatment with possible diminution in complication rate, thereby improving the recovery state. There was a widespread illusion that treatment of endometrial cancer conferred good results almost universally, but
CARENZA et al.: SURGERY AND ENDOMETRIAL CANCER
419
this fallacy is demonstrated when analyzing data from a sufficiently large series of unselected cases. Over the years great emphasis has been placed on the correlation between the different biologic tumoral parameters and prognosis. These are now considered as real "markers" of aggressiveness and tumor spread. A large amount of data on this subject9 clearly shows the importance of pathologic features for a better definition of the tumor extent and possible clues for improving therapy. It is well-established that surgery, besides representing in most instances an adequate therapy (according to Boronow about 75% of cases are at low prognostic risk after surgical staging), allows intensive pathological staging. Indeed all tumoral parameters (TABLE1) necessary for an accurate prognosis and for a rational use of therapeutic integrations can be obtained through surgery. Staging criteria recommended by FIGO and universally accepted as methods of evaluation represented an international language for the exchange of data and results, but because of some limitations (i.e.,clinical staging instead of a pathological one) they could not select patients in risk categories and did not lead to targeted and individualized treatment programs. Subjective evaluations and inaccurate clinical staging (this was modified in 51% of the patients after surgery in the study by CowlesIo) undermine the meaning of such a system. In effect the tumor extension, the only parameter taken into consideration, could not fully identify the biologic complexity of the tumor. During the 1970s and 1980s the growing knowledge of the natural history of endometrial cancer and understanding of the propensity of certain sub-groups for a more aggressive clinical course led to improved pre-surgical diagnostic procedures and therapeutic results. This influenced the staging system adopted so far. In 1988 such important factors as myometrial invasion, cervical involvement, peritoneal cytology and lymph-node metastases have been introduced in the staging system recommended by FIGO. Pelvic and aortic nodes are of little or no consequence in endometrial cancer. It is now well-established that about 10%of patients with stage 1 disease show pelvic lymph-node metastases.9 This incidence, however, is highly affected, both positively or negatively by other prognostic factors (TABLES2-4). Because of this important observation, lymph-node involvement can be predicted by the assessment of other tumoral parameters such as grade of differentiation, depth of myometrial invasion and less significantly by the stage of the tumor. The therapeutic role of lymphadenectomy has always been very controversial: it did not improve survival rates and the incidence of relapses, it was of little applicability and entailed a high morbidity, especially in obese patients. A para-aortic lymphadenectomy-a very high risk procedure in obese
TABLE 1. Prognostic Factors in Endometrial Carcinoma Age Histologic type Grade Myometrial invasion Stage Lymph-node metastases Hormonal receptors
Capillary-like spaces Tumor size Adnexal metastases Peritoneal cytology Tumor ploidy Growth factors
ANNALS NEW YORK ACADEMY OF SCIENCES
480
TABLE 2. Grade versus Positive Pelvic and Aortic Nodes: Stage Ia Grade
Pelvic
Aortic
3% 9% 18%
2%
~
G1 G2 G3
5% 11%
a Based on Creasman.13
TABLE 3. Myometrial Invasion versus Positive Pelvic and Aortic Nodes: Stage Ia Myometrial Invasion
Pelvic
Aortic
MO M1 M2 M3
1%
5% 6% 25 %
1% 3% 1% 17%
a
Based on Creasman.13
TABLE 4. Stage versus Positive Pelvic and Aortic Nodesa ~~
Stage IA IB
Pelvic
Aortic
7% 13%
3% 8%
a Based on Creasman.13
patients-is recommended only when poor prognostic factors are found: in fact, paraaortic lymph-node metastases in early stages are restricted to poorly differentiated tumors with deep invasion of the myometrium, with a respective incidence of 11% and 17%. Moreover, other parameters are well correlated to lymph-node involvement: tumor size, capillary-like spaces involvement, and peritoneal cytology. Schink et al. found that the incidence of lymph-node metastases in patients with tumor size 2 cm in diameter, there were nodal metastases in 21% of cases. If the entire endometrium was involved, the incidence was 40%. Hanson ef al. found capillary-like spaces involvement in patients with poorly differentiated tumors with deep invasion. The incidence of pelvic and para-aortic node metastases, was 27% and 75% respectively. This compares with a 19% occurrence of pelvic node metastases, and 3% occurrence of periaortic node metastases when there is no capillary-like spaces involvement. Therefore, on the strength of all these data, we think that in order to evaluate the real applicability of vaginal surgery in the treatment of stage I endometrial carcinoma we cannot fail to take into consideration the following elements: 0
0
Endometrial carcinoma is not always a benign disease. The best way to treat it has not been completely defined for each individual case.
CARENZA et a/.: SURGERY AND ENDOMETRIAL CANCER
48 1
Prognostic factors represent the major indicators for planning therapy. Pelvic and para-aortic lymph-nodes can be of great consequence in particular high-risk categories.
THE AUTHORS’ EXPERIENCE In the light of recently acquired information on prognostic risk factors, we present a review of our personal experience using the vaginal approach with the purpose of establishing the exact role of vaginal hysterectomy in the management of endometrial carcinoma. Between 1968 and 1985 we performed vaginal hysterectomy in 160 patients with stage I endometrial carcinoma. However, over the years greater selectivity of patients to be treated brought us to use this surgical procedure less frequently. Obesity or major medical problems, such as hypertension, placed these patients at high morbidity risk from an abdominal surgery operation (TABLE5 ) . Patients underwent a standard pre-treatment evaluation and were staged according to FIG0 staging criteria. All histologic specimens were evaluated, before and after surgery, by a pathologist experienced in gynecologic pathology. We performed a simple vaginal hysterectomy with salpingo-oophorectomy and dissection of the upper third of the vagina. The Schuchardt incision was used in most cases and the margins of the vaginal cuff clamped together with Chrobak clamps in order to envelop the cervix and avoid further neoplastic contamination during hysterectomy. Vaginal hysterectomy was the only therapeutic modality in about half of the patients (TABLE6). Adjuvant hormonal or radiation therapy followed in almost half of the other patients, depending on prognostic factors. The 5-year survival rate as a function of age (TABLE7) can be explained by the finding that younger women tend to have well-differentiated cancer more frequently than older women, and when corrected for grade, age does not seem to be an independent prognostic factor. Histologic subtypes were: adenocarcinoma (81.25%), papillary adenocarcinoma (12.5%) and adenoacanthoma (6.25%). Grade provides one of the major prognostic
TABLE 5. Endometrial Carcinoma: Patients Treated by Vaginal Surgery (1%8-1985Ia 160 Patients Obesity 62.34% (1
Data from the I1 Dept. Ob/Gyn, Rome.
TABLE 6. Endometrial Carcinoma: Vaginal Surgery and Combined Treatmenta Treatment
Number of Patients (X)
Vaginal hysterectomy only + hormonal therapy + radiotherapy + chemotherapy
81 (50.6) 50 (31.25) 25 (15.6) 4 (2.5)
a
Data from the I1 Dept. Ob/Gyn, Rome.
482
ANNALS NEW YORK ACADEMY OF SCIENCES
TABLE 7. Endometrial Carcinoma Vaginal Surgery -Survival Rate and Prognostic Factors0 Prognostic Factors
5-Year Survival Rate (%)
Age
Does Today’s Vaginal Surgery Still Have a Specific Role in the Treatment of Endometrial Cancer? L. CARENZA, C. VILLANI, F. NOBILI, M . G. PORPORA, A. LUKIC, AND L. FALQUI Department of Obstetrics and Gynecology University of Rome, “La Sapienza” Vide del Policlinico, 155 00161 Rome, Italy Because of some assumptions which caused delays and confusion in acquiring a more specific knowledge of its natural history, for many years endometrial carcinoma has been considered as a low malignancy neoplasm. Four so-called “myths”’ have been dispelled over the years: Endometrial cancer is a benign disease. Since hysterectomy is the cornerstone of management and in some institutions the only treatment used, this approach suggested that endometrial cancer, along with many other benign gynecologic diseases, should be considered a “milder” tumor among the gynecologic ones. Moreover, since in some reports the 5-year survival rates were particularly high (90-95%), many investigators have suggested that little could be done to improve treatment results in early endometrial cancer. This reinforced the idea that this tumor was a low malignancy neoplasm. Contemporary gynecologic impressions suggested that endometrial cancer had a better prognosis than cervical cancer. The overall corpus cancer salvage rate is indeed better than that of cervical cancer, but the data analyzed reflect the fact that stage I endometrial cancer was diagnosed considerably more frequently (approx. 75% of the cases) than stage I cervical cancer. The best way to treat endometrial cancer has been defined. The standard treatment consisted, and still consists of an extrafascial hysterectomy and upper colpectomy, with or without pre- or post-operative radiotherapy (radium or external beam). Although surgery was the first major modality to significantly control endometrial cancer, its general applicability, especially as a single procedure, was very restricted until the 1950s, when adequate blood banking, improved anesthesia, antibiotics and other supportive measures changed the picture. When intracavitary radiation was introduced in 1919, it was apparent that surgery alone could not deal with all problems, and that another treatment modality needed to be involved. Radiation therapy from the early 1920s on has grown to play a major role: indeed, in many institutions it reduced surgery’s role to little more than diagnosis and application of intracavitary radioactive sources. 411
478
ANNALS NEW YORK ACADEMY OF SCIENCES
By the mid 1950s, chemotherapy and hormonal therapy had come into the picture, thus further reducing the role of surgery. The interaction of 90 years of development for both radiation and surgery (even radical hysterectomy) led to the appearance of quite a number of programs involving single or multimodality approaches. There were those who supported the simplest of procedures and those who supported the fairly complex evaluation. The Mayo Clinic’s advocacy of vaginal hysterectomy (with at least half the patients having adnexal removal by the vaginal route) was supported by excellent results (overall 5-year survival rate: 84%). A more extensive surgery was not required, since less than 20%of the patients (lesions with low-grade malignancy, cervical involvement and large palpable lymph-nodes) would benefit, and even if malignancy were found in nodes, their removal and subsequent modification of therapy probably would not lead to better results than those achieved by less radical surgery.2 Vaginal hysterectomy has been used by a number of physicians whose results have supported the Mayo Clinic’s work. The other extreme was represented by stall worth^,^ who stressed the importance of thorough exploration including the evaluation of pelvic and para-aortic nodes. He noted that deep myometrial penetration could mean higher incidence of positive nodes and metastases to other structures. He removed nodes whenever the inspection of the opened specimen indicated deep muscle penetration. More recently, considerable data have been collected on the treatment of endometrial cancer. Jones4 extensively reviewed the literature of the 1950s, 1960s and 1970s and noted that the 5-year survival rate for patients treated with surgery alone was essentially the same as for those who were treated with radiation plus surgery. Unfortunately, the vast majority of those reports were not evaluated in regard to the grade of the tumor or myometrial involvement. It is anticipated that many of the patients who were found to have poorly differentiated lesions were more likely to be treated in the combined group and, as a result, would bias the overall survival rate in the combined therapy category. Furthermore, comparing the 5-year survival rates of the patients with FIGO stage I endometrial carcinoma, it is clear that over the years the differences are not statistically ~ignificant.~fi This is also confirmed in the overall survival rates: 60%*vs. 67.7.6 In a recent FIGO Annual Report’ the 5-year survival rate (all stages) referring to the years 1979-1981 is 72.3%,showing once again that, in spite of the knowledge of its natural history, endometrial carcinoma cannot always be considered as a low malignancy neoplasm. Thus, surgery should be intended: a) to “cure” the patient, b) to outline diagnosis, and c) to delineate prognosis. Although the last two items have undoubtedly improved over the years, it seems that, concerning early stage endometrial carcinoma, nothing has changed in terms of cure from the results of 15years ago. The prognostic factors have been su@ciently elucidated. In 1962 Gusberg anticipated that “studies of the biology of this tumor have afforded us greater insight into its histogenesis, vitality and spread, but lack of agreement about coding these facts into an acceptable pattern of classification has deprived gynecologists of the clinical benefits of this knowledge.”8 Over the years this fact caused delays in the comparison of various treatment modalities and a tendency to treat all patients with this disease in a standard manner, rather than selecting the most effective treatment with possible diminution in complication rate, thereby improving the recovery state. There was a widespread illusion that treatment of endometrial cancer conferred good results almost universally, but
CARENZA et al.: SURGERY AND ENDOMETRIAL CANCER
419
this fallacy is demonstrated when analyzing data from a sufficiently large series of unselected cases. Over the years great emphasis has been placed on the correlation between the different biologic tumoral parameters and prognosis. These are now considered as real "markers" of aggressiveness and tumor spread. A large amount of data on this subject9 clearly shows the importance of pathologic features for a better definition of the tumor extent and possible clues for improving therapy. It is well-established that surgery, besides representing in most instances an adequate therapy (according to Boronow about 75% of cases are at low prognostic risk after surgical staging), allows intensive pathological staging. Indeed all tumoral parameters (TABLE1) necessary for an accurate prognosis and for a rational use of therapeutic integrations can be obtained through surgery. Staging criteria recommended by FIGO and universally accepted as methods of evaluation represented an international language for the exchange of data and results, but because of some limitations (i.e.,clinical staging instead of a pathological one) they could not select patients in risk categories and did not lead to targeted and individualized treatment programs. Subjective evaluations and inaccurate clinical staging (this was modified in 51% of the patients after surgery in the study by CowlesIo) undermine the meaning of such a system. In effect the tumor extension, the only parameter taken into consideration, could not fully identify the biologic complexity of the tumor. During the 1970s and 1980s the growing knowledge of the natural history of endometrial cancer and understanding of the propensity of certain sub-groups for a more aggressive clinical course led to improved pre-surgical diagnostic procedures and therapeutic results. This influenced the staging system adopted so far. In 1988 such important factors as myometrial invasion, cervical involvement, peritoneal cytology and lymph-node metastases have been introduced in the staging system recommended by FIGO. Pelvic and aortic nodes are of little or no consequence in endometrial cancer. It is now well-established that about 10%of patients with stage 1 disease show pelvic lymph-node metastases.9 This incidence, however, is highly affected, both positively or negatively by other prognostic factors (TABLES2-4). Because of this important observation, lymph-node involvement can be predicted by the assessment of other tumoral parameters such as grade of differentiation, depth of myometrial invasion and less significantly by the stage of the tumor. The therapeutic role of lymphadenectomy has always been very controversial: it did not improve survival rates and the incidence of relapses, it was of little applicability and entailed a high morbidity, especially in obese patients. A para-aortic lymphadenectomy-a very high risk procedure in obese
TABLE 1. Prognostic Factors in Endometrial Carcinoma Age Histologic type Grade Myometrial invasion Stage Lymph-node metastases Hormonal receptors
Capillary-like spaces Tumor size Adnexal metastases Peritoneal cytology Tumor ploidy Growth factors
ANNALS NEW YORK ACADEMY OF SCIENCES
480
TABLE 2. Grade versus Positive Pelvic and Aortic Nodes: Stage Ia Grade
Pelvic
Aortic
3% 9% 18%
2%
~
G1 G2 G3
5% 11%
a Based on Creasman.13
TABLE 3. Myometrial Invasion versus Positive Pelvic and Aortic Nodes: Stage Ia Myometrial Invasion
Pelvic
Aortic
MO M1 M2 M3
1%
5% 6% 25 %
1% 3% 1% 17%
a
Based on Creasman.13
TABLE 4. Stage versus Positive Pelvic and Aortic Nodesa ~~
Stage IA IB
Pelvic
Aortic
7% 13%
3% 8%
a Based on Creasman.13
patients-is recommended only when poor prognostic factors are found: in fact, paraaortic lymph-node metastases in early stages are restricted to poorly differentiated tumors with deep invasion of the myometrium, with a respective incidence of 11% and 17%. Moreover, other parameters are well correlated to lymph-node involvement: tumor size, capillary-like spaces involvement, and peritoneal cytology. Schink et al. found that the incidence of lymph-node metastases in patients with tumor size 2 cm in diameter, there were nodal metastases in 21% of cases. If the entire endometrium was involved, the incidence was 40%. Hanson ef al. found capillary-like spaces involvement in patients with poorly differentiated tumors with deep invasion. The incidence of pelvic and para-aortic node metastases, was 27% and 75% respectively. This compares with a 19% occurrence of pelvic node metastases, and 3% occurrence of periaortic node metastases when there is no capillary-like spaces involvement. Therefore, on the strength of all these data, we think that in order to evaluate the real applicability of vaginal surgery in the treatment of stage I endometrial carcinoma we cannot fail to take into consideration the following elements: 0
0
Endometrial carcinoma is not always a benign disease. The best way to treat it has not been completely defined for each individual case.
CARENZA et a/.: SURGERY AND ENDOMETRIAL CANCER
48 1
Prognostic factors represent the major indicators for planning therapy. Pelvic and para-aortic lymph-nodes can be of great consequence in particular high-risk categories.
THE AUTHORS’ EXPERIENCE In the light of recently acquired information on prognostic risk factors, we present a review of our personal experience using the vaginal approach with the purpose of establishing the exact role of vaginal hysterectomy in the management of endometrial carcinoma. Between 1968 and 1985 we performed vaginal hysterectomy in 160 patients with stage I endometrial carcinoma. However, over the years greater selectivity of patients to be treated brought us to use this surgical procedure less frequently. Obesity or major medical problems, such as hypertension, placed these patients at high morbidity risk from an abdominal surgery operation (TABLE5 ) . Patients underwent a standard pre-treatment evaluation and were staged according to FIG0 staging criteria. All histologic specimens were evaluated, before and after surgery, by a pathologist experienced in gynecologic pathology. We performed a simple vaginal hysterectomy with salpingo-oophorectomy and dissection of the upper third of the vagina. The Schuchardt incision was used in most cases and the margins of the vaginal cuff clamped together with Chrobak clamps in order to envelop the cervix and avoid further neoplastic contamination during hysterectomy. Vaginal hysterectomy was the only therapeutic modality in about half of the patients (TABLE6). Adjuvant hormonal or radiation therapy followed in almost half of the other patients, depending on prognostic factors. The 5-year survival rate as a function of age (TABLE7) can be explained by the finding that younger women tend to have well-differentiated cancer more frequently than older women, and when corrected for grade, age does not seem to be an independent prognostic factor. Histologic subtypes were: adenocarcinoma (81.25%), papillary adenocarcinoma (12.5%) and adenoacanthoma (6.25%). Grade provides one of the major prognostic
TABLE 5. Endometrial Carcinoma: Patients Treated by Vaginal Surgery (1%8-1985Ia 160 Patients Obesity 62.34% (1
Data from the I1 Dept. Ob/Gyn, Rome.
TABLE 6. Endometrial Carcinoma: Vaginal Surgery and Combined Treatmenta Treatment
Number of Patients (X)
Vaginal hysterectomy only + hormonal therapy + radiotherapy + chemotherapy
81 (50.6) 50 (31.25) 25 (15.6) 4 (2.5)
a
Data from the I1 Dept. Ob/Gyn, Rome.
482
ANNALS NEW YORK ACADEMY OF SCIENCES
TABLE 7. Endometrial Carcinoma Vaginal Surgery -Survival Rate and Prognostic Factors0 Prognostic Factors
5-Year Survival Rate (%)
Age
