- Email: [email protected]
Surgical management of endometrial cancer: How much is enough?
Available online at www.sciencedirect.com
Gynecologic Oncology 109 (2008) 1 – 3 www.elsevier.com/locate/ygyno
Editorial
Surgical management of endometrial cancer: How much is enough? Endometrial cancer, typically characterized as a “single” diagnosis, undeniably represents many diverse diseases managed with a variety of treatment schemes. Although some disagreement exists as to the most effective management plan, most would agree to four largely uncontested observations, namely: • The foundation of primary treatment is hysterectomy, during which nodal assessment and surgical staging offer the opportunity for the most accurate assessment/detection of occult extrauterine malignancy in all women whose disease appears clinically confined to the uterus. • The likelihood of nodal metastasis increases with the clinical extent of disease. • The risk and pattern of recurrence and long-term survival differ between women with node-positive and node negative-disease. • The probability and patterns of treatment failure as well as survival differ in comparisons of outcomes of women with endometrioid and those with non-endometrioid histology. Although these tenets are universally accepted, the integration and implementation of these concepts when performing the “proper or appropriate” surgical procedure(s) remain contested. The debate continues over which individuals will benefit from extensive surgical staging and subsequent adjuvant therapy. Importantly, it appears that perioperative risks are not clinically increased when surgery is performed by those with appropriate surgical expertise, and the preponderance of evidence suggests that “routine” surgical staging is an economically effective strategy [1]. Dr. Mariani and colleagues from the Mayo Clinic have extensively analyzed and published their surgical experience with women with endometrial cancer. Their current article, described as a paradigm shift, tenders four conclusions [2]: • Adoption of a standardized institutional surgical guideline with internal quality controls can be effective in standardizing the care provided by a diverse group of surgeons. • Women with endometrial cancer can be readily segregated intraoperatively into “low-risk” and “high-risk” groups to better identify those women who will most likely benefit from thorough lymphadenectomy. • Lymphadenectomy does not benefit groups of women with low-risk disease, defined as Grade 1 or 2 disease and b50% 0090-8258/$ - see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.ygyno.2008.02.013
myoinvasion (MI) and a primary tumor diameter (PTD) b2 cm. • The high rate of lymphatic metastasis above the inferior mesenteric artery (IMA) in those with high-risk disease lends further support to the recommendation for systematic pelvic and para-aortic lymphadenectomy (vs sampling) with a dissection extending to the renal veins and should include the consideration of excision of the gonadal veins. The authors are to be heartily congratulated for instituting predefined surgical guidelines and developing a strategy and initiatives for improving surgical quality and compliance for assessing disease status in women with endometrial cancer. Standardization and quality control must be considered crucial elements of all surgical clinical trials. The details of their article clearly illuminate the difficulty in ensuring adherence and a uniform application of such guidelines, even in one of the most highly respected and structured medical institutions, staffed with experienced and highly motivated surgeons and pathologists. Using lymph node count as a surrogate for quality, they report a gradual improved performance during the study period as all surgeons submitted “similar” mean numbers of pelvic (36.5 ± 13.4) and para-aortic (17.4 ± 8.1) lymph nodes. However, review of their 95% confidence levels still suggests a very wide intra-surgeon variation of mean numbers of nodes submitted at the 21-month interval for all nodal basins. Additionally, there was substantial variance from the predetermined guidelines, as 8% of women underwent Type II or III hysterectomy, 20% of those with low-risk disease had a lymphadenectomy, and 9% of those with high-risk lesions had lymphadenectomy omitted. At the conclusion of the study period, 12% of the para-aortic nodal specimens were not separated to facilitate study of nodal involvement above or below the IMA. These and other variations will very likely be amplified in larger multi-institutional studies and stress the importance of disciplined quality control measures similar to those employed by Mariani et al. to ensure high-quality and reliable data in cooperative studies otherwise subject to some skepticism. A number of widely validated and broadly accepted histological parameters used to define patients at risk for occult nodal metastasis have typically been established retrospectively based on the results from the study of permanent section
2
Editorial
material. In contrast, these authors have found that intraoperative frozen section examination can be effectively used to prospectively relegate women into low- or high-risk groups for nodal metastasis. Furthermore, they maintain that the pertinent pathologic parameters for so doing are “readily distinguishable,” “accurate and readily assessable.” On the basis of these frozen section data, 27% of their entire patient population were deemed low risk for lymphatic dissemination and the majority of this group did not undergo lymphadenectomy. The article offers no recurrence or survival data. In contrast, published reports from other learned institutions have found this frozen section approach to be more challenging and less reliable [1,3,4]. In fact, one recent, and perhaps the only, randomized prospective trial reported a frozen sectionfinal pathology correlation of only 67% for MI and 58% for tumor grade with a “clinically relevant” upstaging in 18% of patients [4]. This prospective report confirms the results from numerous prior retrospective publications that related the difficulty-discordance in correlating frozen section-permanent section results in this patient subgroup [1,3,4]. Additionally, while not addressed in the current report, Dr. Mariani and colleagues have previously stressed the importance and significant adverse impact of a fourth factor, lymph vascular space involvement (LVI), on the risk of lymphatic failure [RR = 4.27] [5]. This important adverse risk factor is present in as many as 25% of patients [1,6] and is associated with an increased incidence of nodal disease even when controlling for grade and MI [6]. Previously, Dr. Mariani has reported that LVI adversely influenced “5 year cancer-related survival, recurrence free survival and presence of recurrence with a distal component” [5]. We are unaware of any reports evaluating the accuracy of determining LVI on frozen section and would ask if LVI is unimportant or not considered to be predictive in their proposed model. Given this information, these readers have great reservation whether their proposed surgical management plan, predicated upon highly specialized intraoperative frozen section analysis, can be generalized or replicated in the hundreds of other hospitals and pathology laboratories across the country—where most women receive their surgical care. In support of the third conclusion, the authors cite their previous report [7] and add 22 low-risk, node-negative patients following off-guideline lymphadenectomy. Thus they report an overall nodal risk of 4.3% (9/209 with combined data). Interestingly, this 4.3% incidence of nodal metastasis is nearly identical to the previously reported risk of nodal disease of 4% in women with no MI [8] or in those with PTD b 2 cm [9]. Notably, the risk of nodal disease has been reported to be as high as 8.6% in patients with no MI [10]. The question looms: what level of risk of undetected metastatic nodal disease is acceptable? The author's previous conclusions regarding their reported cancer related (97%) and recurrence free (96%) survival must be viewed conditionally, recognizing that adjuvant radiation was administered to 20% of their patients and the majority had lymphadenectomy for putative low-risk lesions [7]. Furthermore, recurrence rates as high as 9.8% have been previously
reported in this subset of women with no MI [8] and 7% in those with PTD b 2 cm [9]. The absence of clinical staging assignment coupled with the pooling and inclusion of data from patients with Stage I–IV disease with low- and high-risk histology is very confusing. One cannot simply ascertain how many of the 422 patients had disease “clinically” confined to the uterus at exploration, how many were undergoing staging lymphadenectomy, or how many were undergoing resection of clinically evident extrauterine disease. The importance of the assessment of nodes in the pre-caval and para-aortic basins has been the subject of multiple studies, often performed in patients with clinically advanced disease, endometrioid Grade 3 and non-endometrioid histology. A table illustrating clinical staging and the number of nodes (±) in all of the nodal basins would facilitate interpretation of the data and clarify its relevance as a component of a true staging procedure. Support for their recommendation for routinely extending the staging nodal dissection bilaterally to the renal veins must be tempered without such clinical correlation. Although para-aortic nodal involvement is more common in the presence of pelvic nodal disease, the concept of involved para-aortic nodes in the absence of involved pelvic nodes is not a novel observation. Review of the results of GOG 33 finds that 35% of para-aortic nodal metastases occur with negative pelvic nodes [11]. Hirahatake [12] reported that 11% of para-aortic node metastases occurred with negative pelvic nodes and that 45% were positive above and below the IMA; only 18% were positive above the IMA. Dr. Mariani’s article relates an overall incidence of isolated para-aortic node metastasis of 3% (9+/28 1ymphadenectomies) with a 2.9% risk with endometrioid histology and a 4.2% incidence with high-risk histology. The location as it relates to the IMA of involved para-aortic nodes was available in 66%. Thus 12 patients had involved nodes above the IMA with ipsilateral negative nodes below. Unfortunately, the article does not allow identification of the pelvic nodal status or the status of specific nodal basins in this subgroup of women. This is of clinical importance, as Dr. Mariani has previously reported that the incidence of para-aortic nodal involvement was significantly associated with obturator lymph node status [13]. In summary, the information provided by Dr. Mariani and colleagues challenges us to carefully review the surgical approach to all patients with endometrial cancer and focuses attention on the potential importance of the oft-neglected nodal basin inferior to each renal vein. We believe that the relative sophistication of the intraoperative frozen section-based algorithm the authors prospectively employ to forego surgical nodal assessment on almost 1/3 women requires validation by multiple other hospitals and groups. The many unknowns, including but not limited to recurrence and survival data, render it difficult for these readers to urge adoption of this proposal based solely on this highly selected and site-specific data set. The absence of clinical staging assessment and the comingling of patients with Stage I–IV disease of different histologic types render it challenging to place Dr. Mariani’s
Editorial
recommendation for revised surgical staging in a proper perspective. Before every hysterectomy, each surgeon and patient together must strive to balance the risks and benefits of performing or foregoing lymphadenectomy. Only after those discussions can the ceiling of risk for undetected nodal metastasis be determined and the question whether a 2%, 4%, 8%, 12%, or greater threshold risk of nodal disease is acceptable or ‘too high’ for comfort or safety be answered The relative safety and value of the procedure when performed by gynecologic oncologists, surgeons trained to complete the procedures, are such that foregoing lymphadenectomy in any women with invasive endometrial cancer, or conversely extending the scope of staging lymphadenectomy, even in those with Grade 3 or non-endometrioid histology, requires serious deliberation. We enthusiastically support efforts by the authors and others dedicated to the care of women with endometrial cancer to continue investigating methods and seeking opportunities to improve the risk/benefit ratio of surgical staging. However, we conclude that the data as presented in this article do not provide either the evidence for or the direction of a “paradigm” shift in the surgical assessment and treatment of women whose endometrial cancer appears confined to the uterus at exploration. References [1] Orr JW, Naumann WR, Escobar P. “Attitude is a little thing that makes a big difference” Winston Churchill. Gynecol Oncol 2008;109:147–51. [2] Mariani A, Dowdy SC, Cliby WA, Gostout BS, Jones MB, Wilson TO, Podratz KC. Prospective assessment of lymphatic dissemination in endometrial cancer: A paradigm shift in surgical staging. Gynecol Oncol 2008;109:11–8. [3] Orr JW. Surgical staging of endometrial cancer: does the patient benefit? Gynecol Oncol 1998;71:335–9. [4] Case AS, Rocconi RP, Straughn Jr JM, Conner M, Novak L, Wang W, Huh WK. Prospective blinded evaluation of the accuracy of frozen section for
[5] [6]
[7]
[8]
[9] [10]
[11]
[12]
[13]
3 the surgical management of endometrial cancer. Obstet Gynecol 2006;108:1375–9. Mariani A, Webb MJ, Keeney GL, Aletti G, Podratz KC. Predictors of lymphatic failure in endometrial cancer. Gynecol Oncol 2002;84:437–42. Cohn DE, Horowitz NS, Mutch DG, Kim SM, Manolitsas T, Fowler JM. Should the presence of lymphvascular space involvement be used to assign patients to adjuvant therapy following hysterectomy for unstaged endometrial cancer? Gynecol Oncol 2002;87:243–6. Mariani A, Webb MJ, Keeney GL, Haddock MG, Calori G, Podratz KC. Low risk corpus cancer: is lymphadenectomy or radiotherapy necessary? Am J Obstet Gynecol 2000;182:1506–19. Lurain JR, Rice BL, Rademaker AW, Poggensee LE, Schink JC, Miller DS. Prognostic factors associated with recurrence in clinical stage I adenocarcinoma of the endometrium. Obstet Gynecol 1991;78:63–9. Schink JC, Rademaker AW, Miller DS, Lurain JR. Tumor size in endometrial cancer. Cancer 1991;67:2791–4. Takeshima N, Hirai Y, Tanaka N, Yamawaki T, Yamauchi K, Hasumi K. Pelvic lymph node metastasis in endometrial cancer with no myometrial invasion. Obstet Gynecol 1996;88:280–2. Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer 1987, Oct 15;60(8 Suppl): 2035–41. Hirahatake K, Hareyama H, Sakuragi N, Nishiya M, Makinoda S, Fujimoto S. Clinical and pathologic study on para-aortic lymph node metastasis in endometrial carcinoma. J Surg Oncol 1997;65:82–7. Mariani A, Webb MJ, Keeney GL, Podratz KC. Routes of lymphatic spread: a study of 112 consecutive patients with endometrial cancer. Gynecol Oncol 2001;81:100–4.
James W. Orr, Jr. Florida Gynecologic Oncology and Lee Cancer Care, Fort Myers, FL 33919, USA E-mail address: [email protected]. Corresponding author. Peyton T. Taylor, Jr. University of Virginia, Charlottesville, VA 22908, USA 18 February 2008
Gynecologic Oncology 109 (2008) 1 – 3 www.elsevier.com/locate/ygyno
Editorial
Surgical management of endometrial cancer: How much is enough? Endometrial cancer, typically characterized as a “single” diagnosis, undeniably represents many diverse diseases managed with a variety of treatment schemes. Although some disagreement exists as to the most effective management plan, most would agree to four largely uncontested observations, namely: • The foundation of primary treatment is hysterectomy, during which nodal assessment and surgical staging offer the opportunity for the most accurate assessment/detection of occult extrauterine malignancy in all women whose disease appears clinically confined to the uterus. • The likelihood of nodal metastasis increases with the clinical extent of disease. • The risk and pattern of recurrence and long-term survival differ between women with node-positive and node negative-disease. • The probability and patterns of treatment failure as well as survival differ in comparisons of outcomes of women with endometrioid and those with non-endometrioid histology. Although these tenets are universally accepted, the integration and implementation of these concepts when performing the “proper or appropriate” surgical procedure(s) remain contested. The debate continues over which individuals will benefit from extensive surgical staging and subsequent adjuvant therapy. Importantly, it appears that perioperative risks are not clinically increased when surgery is performed by those with appropriate surgical expertise, and the preponderance of evidence suggests that “routine” surgical staging is an economically effective strategy [1]. Dr. Mariani and colleagues from the Mayo Clinic have extensively analyzed and published their surgical experience with women with endometrial cancer. Their current article, described as a paradigm shift, tenders four conclusions [2]: • Adoption of a standardized institutional surgical guideline with internal quality controls can be effective in standardizing the care provided by a diverse group of surgeons. • Women with endometrial cancer can be readily segregated intraoperatively into “low-risk” and “high-risk” groups to better identify those women who will most likely benefit from thorough lymphadenectomy. • Lymphadenectomy does not benefit groups of women with low-risk disease, defined as Grade 1 or 2 disease and b50% 0090-8258/$ - see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.ygyno.2008.02.013
myoinvasion (MI) and a primary tumor diameter (PTD) b2 cm. • The high rate of lymphatic metastasis above the inferior mesenteric artery (IMA) in those with high-risk disease lends further support to the recommendation for systematic pelvic and para-aortic lymphadenectomy (vs sampling) with a dissection extending to the renal veins and should include the consideration of excision of the gonadal veins. The authors are to be heartily congratulated for instituting predefined surgical guidelines and developing a strategy and initiatives for improving surgical quality and compliance for assessing disease status in women with endometrial cancer. Standardization and quality control must be considered crucial elements of all surgical clinical trials. The details of their article clearly illuminate the difficulty in ensuring adherence and a uniform application of such guidelines, even in one of the most highly respected and structured medical institutions, staffed with experienced and highly motivated surgeons and pathologists. Using lymph node count as a surrogate for quality, they report a gradual improved performance during the study period as all surgeons submitted “similar” mean numbers of pelvic (36.5 ± 13.4) and para-aortic (17.4 ± 8.1) lymph nodes. However, review of their 95% confidence levels still suggests a very wide intra-surgeon variation of mean numbers of nodes submitted at the 21-month interval for all nodal basins. Additionally, there was substantial variance from the predetermined guidelines, as 8% of women underwent Type II or III hysterectomy, 20% of those with low-risk disease had a lymphadenectomy, and 9% of those with high-risk lesions had lymphadenectomy omitted. At the conclusion of the study period, 12% of the para-aortic nodal specimens were not separated to facilitate study of nodal involvement above or below the IMA. These and other variations will very likely be amplified in larger multi-institutional studies and stress the importance of disciplined quality control measures similar to those employed by Mariani et al. to ensure high-quality and reliable data in cooperative studies otherwise subject to some skepticism. A number of widely validated and broadly accepted histological parameters used to define patients at risk for occult nodal metastasis have typically been established retrospectively based on the results from the study of permanent section
2
Editorial
material. In contrast, these authors have found that intraoperative frozen section examination can be effectively used to prospectively relegate women into low- or high-risk groups for nodal metastasis. Furthermore, they maintain that the pertinent pathologic parameters for so doing are “readily distinguishable,” “accurate and readily assessable.” On the basis of these frozen section data, 27% of their entire patient population were deemed low risk for lymphatic dissemination and the majority of this group did not undergo lymphadenectomy. The article offers no recurrence or survival data. In contrast, published reports from other learned institutions have found this frozen section approach to be more challenging and less reliable [1,3,4]. In fact, one recent, and perhaps the only, randomized prospective trial reported a frozen sectionfinal pathology correlation of only 67% for MI and 58% for tumor grade with a “clinically relevant” upstaging in 18% of patients [4]. This prospective report confirms the results from numerous prior retrospective publications that related the difficulty-discordance in correlating frozen section-permanent section results in this patient subgroup [1,3,4]. Additionally, while not addressed in the current report, Dr. Mariani and colleagues have previously stressed the importance and significant adverse impact of a fourth factor, lymph vascular space involvement (LVI), on the risk of lymphatic failure [RR = 4.27] [5]. This important adverse risk factor is present in as many as 25% of patients [1,6] and is associated with an increased incidence of nodal disease even when controlling for grade and MI [6]. Previously, Dr. Mariani has reported that LVI adversely influenced “5 year cancer-related survival, recurrence free survival and presence of recurrence with a distal component” [5]. We are unaware of any reports evaluating the accuracy of determining LVI on frozen section and would ask if LVI is unimportant or not considered to be predictive in their proposed model. Given this information, these readers have great reservation whether their proposed surgical management plan, predicated upon highly specialized intraoperative frozen section analysis, can be generalized or replicated in the hundreds of other hospitals and pathology laboratories across the country—where most women receive their surgical care. In support of the third conclusion, the authors cite their previous report [7] and add 22 low-risk, node-negative patients following off-guideline lymphadenectomy. Thus they report an overall nodal risk of 4.3% (9/209 with combined data). Interestingly, this 4.3% incidence of nodal metastasis is nearly identical to the previously reported risk of nodal disease of 4% in women with no MI [8] or in those with PTD b 2 cm [9]. Notably, the risk of nodal disease has been reported to be as high as 8.6% in patients with no MI [10]. The question looms: what level of risk of undetected metastatic nodal disease is acceptable? The author's previous conclusions regarding their reported cancer related (97%) and recurrence free (96%) survival must be viewed conditionally, recognizing that adjuvant radiation was administered to 20% of their patients and the majority had lymphadenectomy for putative low-risk lesions [7]. Furthermore, recurrence rates as high as 9.8% have been previously
reported in this subset of women with no MI [8] and 7% in those with PTD b 2 cm [9]. The absence of clinical staging assignment coupled with the pooling and inclusion of data from patients with Stage I–IV disease with low- and high-risk histology is very confusing. One cannot simply ascertain how many of the 422 patients had disease “clinically” confined to the uterus at exploration, how many were undergoing staging lymphadenectomy, or how many were undergoing resection of clinically evident extrauterine disease. The importance of the assessment of nodes in the pre-caval and para-aortic basins has been the subject of multiple studies, often performed in patients with clinically advanced disease, endometrioid Grade 3 and non-endometrioid histology. A table illustrating clinical staging and the number of nodes (±) in all of the nodal basins would facilitate interpretation of the data and clarify its relevance as a component of a true staging procedure. Support for their recommendation for routinely extending the staging nodal dissection bilaterally to the renal veins must be tempered without such clinical correlation. Although para-aortic nodal involvement is more common in the presence of pelvic nodal disease, the concept of involved para-aortic nodes in the absence of involved pelvic nodes is not a novel observation. Review of the results of GOG 33 finds that 35% of para-aortic nodal metastases occur with negative pelvic nodes [11]. Hirahatake [12] reported that 11% of para-aortic node metastases occurred with negative pelvic nodes and that 45% were positive above and below the IMA; only 18% were positive above the IMA. Dr. Mariani’s article relates an overall incidence of isolated para-aortic node metastasis of 3% (9+/28 1ymphadenectomies) with a 2.9% risk with endometrioid histology and a 4.2% incidence with high-risk histology. The location as it relates to the IMA of involved para-aortic nodes was available in 66%. Thus 12 patients had involved nodes above the IMA with ipsilateral negative nodes below. Unfortunately, the article does not allow identification of the pelvic nodal status or the status of specific nodal basins in this subgroup of women. This is of clinical importance, as Dr. Mariani has previously reported that the incidence of para-aortic nodal involvement was significantly associated with obturator lymph node status [13]. In summary, the information provided by Dr. Mariani and colleagues challenges us to carefully review the surgical approach to all patients with endometrial cancer and focuses attention on the potential importance of the oft-neglected nodal basin inferior to each renal vein. We believe that the relative sophistication of the intraoperative frozen section-based algorithm the authors prospectively employ to forego surgical nodal assessment on almost 1/3 women requires validation by multiple other hospitals and groups. The many unknowns, including but not limited to recurrence and survival data, render it difficult for these readers to urge adoption of this proposal based solely on this highly selected and site-specific data set. The absence of clinical staging assessment and the comingling of patients with Stage I–IV disease of different histologic types render it challenging to place Dr. Mariani’s
Editorial
recommendation for revised surgical staging in a proper perspective. Before every hysterectomy, each surgeon and patient together must strive to balance the risks and benefits of performing or foregoing lymphadenectomy. Only after those discussions can the ceiling of risk for undetected nodal metastasis be determined and the question whether a 2%, 4%, 8%, 12%, or greater threshold risk of nodal disease is acceptable or ‘too high’ for comfort or safety be answered The relative safety and value of the procedure when performed by gynecologic oncologists, surgeons trained to complete the procedures, are such that foregoing lymphadenectomy in any women with invasive endometrial cancer, or conversely extending the scope of staging lymphadenectomy, even in those with Grade 3 or non-endometrioid histology, requires serious deliberation. We enthusiastically support efforts by the authors and others dedicated to the care of women with endometrial cancer to continue investigating methods and seeking opportunities to improve the risk/benefit ratio of surgical staging. However, we conclude that the data as presented in this article do not provide either the evidence for or the direction of a “paradigm” shift in the surgical assessment and treatment of women whose endometrial cancer appears confined to the uterus at exploration. References [1] Orr JW, Naumann WR, Escobar P. “Attitude is a little thing that makes a big difference” Winston Churchill. Gynecol Oncol 2008;109:147–51. [2] Mariani A, Dowdy SC, Cliby WA, Gostout BS, Jones MB, Wilson TO, Podratz KC. Prospective assessment of lymphatic dissemination in endometrial cancer: A paradigm shift in surgical staging. Gynecol Oncol 2008;109:11–8. [3] Orr JW. Surgical staging of endometrial cancer: does the patient benefit? Gynecol Oncol 1998;71:335–9. [4] Case AS, Rocconi RP, Straughn Jr JM, Conner M, Novak L, Wang W, Huh WK. Prospective blinded evaluation of the accuracy of frozen section for
[5] [6]
[7]
[8]
[9] [10]
[11]
[12]
[13]
3 the surgical management of endometrial cancer. Obstet Gynecol 2006;108:1375–9. Mariani A, Webb MJ, Keeney GL, Aletti G, Podratz KC. Predictors of lymphatic failure in endometrial cancer. Gynecol Oncol 2002;84:437–42. Cohn DE, Horowitz NS, Mutch DG, Kim SM, Manolitsas T, Fowler JM. Should the presence of lymphvascular space involvement be used to assign patients to adjuvant therapy following hysterectomy for unstaged endometrial cancer? Gynecol Oncol 2002;87:243–6. Mariani A, Webb MJ, Keeney GL, Haddock MG, Calori G, Podratz KC. Low risk corpus cancer: is lymphadenectomy or radiotherapy necessary? Am J Obstet Gynecol 2000;182:1506–19. Lurain JR, Rice BL, Rademaker AW, Poggensee LE, Schink JC, Miller DS. Prognostic factors associated with recurrence in clinical stage I adenocarcinoma of the endometrium. Obstet Gynecol 1991;78:63–9. Schink JC, Rademaker AW, Miller DS, Lurain JR. Tumor size in endometrial cancer. Cancer 1991;67:2791–4. Takeshima N, Hirai Y, Tanaka N, Yamawaki T, Yamauchi K, Hasumi K. Pelvic lymph node metastasis in endometrial cancer with no myometrial invasion. Obstet Gynecol 1996;88:280–2. Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer 1987, Oct 15;60(8 Suppl): 2035–41. Hirahatake K, Hareyama H, Sakuragi N, Nishiya M, Makinoda S, Fujimoto S. Clinical and pathologic study on para-aortic lymph node metastasis in endometrial carcinoma. J Surg Oncol 1997;65:82–7. Mariani A, Webb MJ, Keeney GL, Podratz KC. Routes of lymphatic spread: a study of 112 consecutive patients with endometrial cancer. Gynecol Oncol 2001;81:100–4.
James W. Orr, Jr. Florida Gynecologic Oncology and Lee Cancer Care, Fort Myers, FL 33919, USA E-mail address: [email protected]. Corresponding author. Peyton T. Taylor, Jr. University of Virginia, Charlottesville, VA 22908, USA 18 February 2008