The role of lymphadenectomy in endometrial cancer, Part 1

Endometrial cancer is the most common gynecologic malignancy in the United States. Fortunately, most endometrial cancers present at an early stage with excellent overall survival – approximately 85% – in clinical stage I disease. Since 1988, the International Federation of Gynecology and Obstetrics (FIGO) staging of endometrial cancer has required surgical staging reflecting increasing data on the prognostic significance of lymph node metastasis and the treatment implications for node positive cancers.

Indeed, lymph nodes represent the most common location for extrauterine spread in endometrial cancer. The lymphatic drainage from the uterus is to both the pelvic and the para-aortic lymph nodes. Lymphatic channels from the uterus can drain directly from the fundus via the infundibulopelvic ligament to the aortic lymph node chain, thereby bypassing the pelvic lymph nodes. As a result, there is a 2%-3% risk of isolated aortic metastasis with negative pelvic lymph nodes.

The extent of lymph node evaluation required for staging is debatable. The National Comprehensive Cancer Network (NCCN) guidelines recommend complete hysterectomy with bilateral salpingo-oophorectomy and additional procedures based on preoperative and intraoperative findings. During surgery, the surgeon should evaluate all peritoneal surfaces and the retroperitoneal lymphatic chains for abnormalities. All suspicious lymph nodes should be removed, but the extent of lymphadenectomy should be based on the NCCN guidelines.¹ The NCCN offers the option for use of sentinel lymph node evaluation with adherence to specific staging algorithms for this technology.

Proponents of lymphadenectomy cite the need for accurate staging to guide adjuvant therapies, to provide prognostic information, and to eradicate metastatic lymph nodes with possible therapeutic benefit. However, criticisms of lymphadenectomy include a lack of randomized studies demonstrating a therapeutic benefit and the morbidity of lymphedema with its corresponding quality of life and cost implications. As a result, practices regarding lymph node evaluation vary widely.

There is conflicting data on whether there is a therapeutic benefit to performing lymphadenectomy. Retrospective studies have shown a benefit, but this was not seen in two prospective trials. There appears to be clear benefit for debulking of clinically enlarged nodal metastasis,^2,3 and likely benefit to resection of microscopic metastasis, particularly with combined pelvic and aortic lymphadenectomy in high-risk endometrial cancers.^4,5,6,7,8

The ASTEC trial by Kitchener et al and an Italian collaborative trial by Benedetti et al, however, both evaluated the role of lymph node dissection in predominantly low-risk endometrial cancer and found no benefit.^9,10 Both studies documented no difference in overall survival, but increased morbidity with lymphadenectomy. No prospective trials have evaluated the role of lymphadenectomy in high-risk endometrial cancers.

Universal use of complete lymphadenectomy in all patients with endometrial cancer would subject a large percent of low risk patients to undo surgical risk. The two most commonly utilized strategies are risk factor based lymphadenectomy and sentinel lymph node evaluation.

Tumors are considered low risk if they are less than 2cm in size, grade 1 or 2, and superficially invasive (less than 50% myometrial invasion).¹¹ The risk of lymph node metastasis in these patients was exceedingly low with no lymph node metastasis detect in more than 400 women who prospectively underwent this evaluation, thus lymphadenectomy can be safely avoided. Utilizing risk factor based lymphadenectomy does require the availability of reliable frozen section pathology evaluation, which may be a limitation for some institutions.

A key argument against routine use of systematic lymphadenectomy is the concern for postoperative complications and lymphedema. The estimated incidence of lymphedema following lymphadenectomy is 20%-30%.¹² However, there are challenges in studying lymphedema that likely limit our understanding of the true incidence. The ASTEC trial and Italian cooperative trial have demonstrated that there is an eight-fold increased risk of lymphedema in women who undergo lymphadenectomy, compared with those who do not.¹³ The development of lymphedema requires ongoing treatment with associated costs of care. Thus, the selective lymphadenectomy or sentinel nodes have the ability to reduce healthcare costs.¹⁴ Sentinel lymph nodes will be covered in Part Two of this article.

References

1. J Natl Compr Canc Netw. 2014 Feb;12(2):248-80.

2. Gynecol Oncol. 2005 Dec;99(3):689-95.

3. Int J Gynecol Cancer. 2003 Sep-Oct;13(5):664-72.

4. Gynecol Oncol. 1995 Jan;56(1):29-33.

5. J Clin Oncol. 2005 Jun 1;23(16):3668-75.

6. Lancet. 2010 Apr 3;375(9721):1165-72.

7. Gynecol Oncol. 1998 Dec;71(3):340-3.

8. Cancer. 2006 Oct 15;107(8):1823-30.

9. Lancet. 2009 Jan 10;373(9658):125-36.

10. J Natl Cancer Inst. 2008 Dec 3;100(23):1707-16.

11. Gynecol Oncol. 2008 Apr;109(1):11-8.

12. Obstet Gynecol. 2014 Aug;124(2 Pt 1):307-15.

13. Cochrane Database Syst Rev. 2015 Sep 21;(9):CD007585.

14. Gynecol Oncol. 2014 Dec;135(3):518-24.

Dr. Gehrig is professor and director of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Clark is a fellow in the division of gynecologic oncology, department of obstetrics and gynecology at the university. They reported having no financial disclosures relevant to this column. Email them at [email protected].

Endometrial cancer is the most common gynecologic malignancy in the United States. Fortunately, most endometrial cancers present at an early stage with excellent overall survival – approximately 85% – in clinical stage I disease. Since 1988, the International Federation of Gynecology and Obstetrics (FIGO) staging of endometrial cancer has required surgical staging reflecting increasing data on the prognostic significance of lymph node metastasis and the treatment implications for node positive cancers.

Indeed, lymph nodes represent the most common location for extrauterine spread in endometrial cancer. The lymphatic drainage from the uterus is to both the pelvic and the para-aortic lymph nodes. Lymphatic channels from the uterus can drain directly from the fundus via the infundibulopelvic ligament to the aortic lymph node chain, thereby bypassing the pelvic lymph nodes. As a result, there is a 2%-3% risk of isolated aortic metastasis with negative pelvic lymph nodes.

The extent of lymph node evaluation required for staging is debatable. The National Comprehensive Cancer Network (NCCN) guidelines recommend complete hysterectomy with bilateral salpingo-oophorectomy and additional procedures based on preoperative and intraoperative findings. During surgery, the surgeon should evaluate all peritoneal surfaces and the retroperitoneal lymphatic chains for abnormalities. All suspicious lymph nodes should be removed, but the extent of lymphadenectomy should be based on the NCCN guidelines.¹ The NCCN offers the option for use of sentinel lymph node evaluation with adherence to specific staging algorithms for this technology.

Proponents of lymphadenectomy cite the need for accurate staging to guide adjuvant therapies, to provide prognostic information, and to eradicate metastatic lymph nodes with possible therapeutic benefit. However, criticisms of lymphadenectomy include a lack of randomized studies demonstrating a therapeutic benefit and the morbidity of lymphedema with its corresponding quality of life and cost implications. As a result, practices regarding lymph node evaluation vary widely.

There is conflicting data on whether there is a therapeutic benefit to performing lymphadenectomy. Retrospective studies have shown a benefit, but this was not seen in two prospective trials. There appears to be clear benefit for debulking of clinically enlarged nodal metastasis,^2,3 and likely benefit to resection of microscopic metastasis, particularly with combined pelvic and aortic lymphadenectomy in high-risk endometrial cancers.^4,5,6,7,8

The ASTEC trial by Kitchener et al and an Italian collaborative trial by Benedetti et al, however, both evaluated the role of lymph node dissection in predominantly low-risk endometrial cancer and found no benefit.^9,10 Both studies documented no difference in overall survival, but increased morbidity with lymphadenectomy. No prospective trials have evaluated the role of lymphadenectomy in high-risk endometrial cancers.

Universal use of complete lymphadenectomy in all patients with endometrial cancer would subject a large percent of low risk patients to undo surgical risk. The two most commonly utilized strategies are risk factor based lymphadenectomy and sentinel lymph node evaluation.

Tumors are considered low risk if they are less than 2cm in size, grade 1 or 2, and superficially invasive (less than 50% myometrial invasion).¹¹ The risk of lymph node metastasis in these patients was exceedingly low with no lymph node metastasis detect in more than 400 women who prospectively underwent this evaluation, thus lymphadenectomy can be safely avoided. Utilizing risk factor based lymphadenectomy does require the availability of reliable frozen section pathology evaluation, which may be a limitation for some institutions.

A key argument against routine use of systematic lymphadenectomy is the concern for postoperative complications and lymphedema. The estimated incidence of lymphedema following lymphadenectomy is 20%-30%.¹² However, there are challenges in studying lymphedema that likely limit our understanding of the true incidence. The ASTEC trial and Italian cooperative trial have demonstrated that there is an eight-fold increased risk of lymphedema in women who undergo lymphadenectomy, compared with those who do not.¹³ The development of lymphedema requires ongoing treatment with associated costs of care. Thus, the selective lymphadenectomy or sentinel nodes have the ability to reduce healthcare costs.¹⁴ Sentinel lymph nodes will be covered in Part Two of this article.

References

1. J Natl Compr Canc Netw. 2014 Feb;12(2):248-80.

2. Gynecol Oncol. 2005 Dec;99(3):689-95.

3. Int J Gynecol Cancer. 2003 Sep-Oct;13(5):664-72.

4. Gynecol Oncol. 1995 Jan;56(1):29-33.

5. J Clin Oncol. 2005 Jun 1;23(16):3668-75.

6. Lancet. 2010 Apr 3;375(9721):1165-72.

7. Gynecol Oncol. 1998 Dec;71(3):340-3.

8. Cancer. 2006 Oct 15;107(8):1823-30.

9. Lancet. 2009 Jan 10;373(9658):125-36.

10. J Natl Cancer Inst. 2008 Dec 3;100(23):1707-16.

11. Gynecol Oncol. 2008 Apr;109(1):11-8.

12. Obstet Gynecol. 2014 Aug;124(2 Pt 1):307-15.

13. Cochrane Database Syst Rev. 2015 Sep 21;(9):CD007585.

14. Gynecol Oncol. 2014 Dec;135(3):518-24.

Dr. Gehrig is professor and director of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Clark is a fellow in the division of gynecologic oncology, department of obstetrics and gynecology at the university. They reported having no financial disclosures relevant to this column. Email them at [email protected].

Endometrial cancer is the most common gynecologic malignancy in the United States. Fortunately, most endometrial cancers present at an early stage with excellent overall survival – approximately 85% – in clinical stage I disease. Since 1988, the International Federation of Gynecology and Obstetrics (FIGO) staging of endometrial cancer has required surgical staging reflecting increasing data on the prognostic significance of lymph node metastasis and the treatment implications for node positive cancers.

Indeed, lymph nodes represent the most common location for extrauterine spread in endometrial cancer. The lymphatic drainage from the uterus is to both the pelvic and the para-aortic lymph nodes. Lymphatic channels from the uterus can drain directly from the fundus via the infundibulopelvic ligament to the aortic lymph node chain, thereby bypassing the pelvic lymph nodes. As a result, there is a 2%-3% risk of isolated aortic metastasis with negative pelvic lymph nodes.

The extent of lymph node evaluation required for staging is debatable. The National Comprehensive Cancer Network (NCCN) guidelines recommend complete hysterectomy with bilateral salpingo-oophorectomy and additional procedures based on preoperative and intraoperative findings. During surgery, the surgeon should evaluate all peritoneal surfaces and the retroperitoneal lymphatic chains for abnormalities. All suspicious lymph nodes should be removed, but the extent of lymphadenectomy should be based on the NCCN guidelines.¹ The NCCN offers the option for use of sentinel lymph node evaluation with adherence to specific staging algorithms for this technology.

Proponents of lymphadenectomy cite the need for accurate staging to guide adjuvant therapies, to provide prognostic information, and to eradicate metastatic lymph nodes with possible therapeutic benefit. However, criticisms of lymphadenectomy include a lack of randomized studies demonstrating a therapeutic benefit and the morbidity of lymphedema with its corresponding quality of life and cost implications. As a result, practices regarding lymph node evaluation vary widely.

There is conflicting data on whether there is a therapeutic benefit to performing lymphadenectomy. Retrospective studies have shown a benefit, but this was not seen in two prospective trials. There appears to be clear benefit for debulking of clinically enlarged nodal metastasis,^2,3 and likely benefit to resection of microscopic metastasis, particularly with combined pelvic and aortic lymphadenectomy in high-risk endometrial cancers.^4,5,6,7,8

The ASTEC trial by Kitchener et al and an Italian collaborative trial by Benedetti et al, however, both evaluated the role of lymph node dissection in predominantly low-risk endometrial cancer and found no benefit.^9,10 Both studies documented no difference in overall survival, but increased morbidity with lymphadenectomy. No prospective trials have evaluated the role of lymphadenectomy in high-risk endometrial cancers.

Universal use of complete lymphadenectomy in all patients with endometrial cancer would subject a large percent of low risk patients to undo surgical risk. The two most commonly utilized strategies are risk factor based lymphadenectomy and sentinel lymph node evaluation.

Tumors are considered low risk if they are less than 2cm in size, grade 1 or 2, and superficially invasive (less than 50% myometrial invasion).¹¹ The risk of lymph node metastasis in these patients was exceedingly low with no lymph node metastasis detect in more than 400 women who prospectively underwent this evaluation, thus lymphadenectomy can be safely avoided. Utilizing risk factor based lymphadenectomy does require the availability of reliable frozen section pathology evaluation, which may be a limitation for some institutions.

A key argument against routine use of systematic lymphadenectomy is the concern for postoperative complications and lymphedema. The estimated incidence of lymphedema following lymphadenectomy is 20%-30%.¹² However, there are challenges in studying lymphedema that likely limit our understanding of the true incidence. The ASTEC trial and Italian cooperative trial have demonstrated that there is an eight-fold increased risk of lymphedema in women who undergo lymphadenectomy, compared with those who do not.¹³ The development of lymphedema requires ongoing treatment with associated costs of care. Thus, the selective lymphadenectomy or sentinel nodes have the ability to reduce healthcare costs.¹⁴ Sentinel lymph nodes will be covered in Part Two of this article.

References

1. J Natl Compr Canc Netw. 2014 Feb;12(2):248-80.

2. Gynecol Oncol. 2005 Dec;99(3):689-95.

3. Int J Gynecol Cancer. 2003 Sep-Oct;13(5):664-72.

4. Gynecol Oncol. 1995 Jan;56(1):29-33.

5. J Clin Oncol. 2005 Jun 1;23(16):3668-75.

6. Lancet. 2010 Apr 3;375(9721):1165-72.

7. Gynecol Oncol. 1998 Dec;71(3):340-3.

8. Cancer. 2006 Oct 15;107(8):1823-30.

9. Lancet. 2009 Jan 10;373(9658):125-36.

10. J Natl Cancer Inst. 2008 Dec 3;100(23):1707-16.

11. Gynecol Oncol. 2008 Apr;109(1):11-8.

12. Obstet Gynecol. 2014 Aug;124(2 Pt 1):307-15.

13. Cochrane Database Syst Rev. 2015 Sep 21;(9):CD007585.

14. Gynecol Oncol. 2014 Dec;135(3):518-24.

Dr. Gehrig is professor and director of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Clark is a fellow in the division of gynecologic oncology, department of obstetrics and gynecology at the university. They reported having no financial disclosures relevant to this column. Email them at [email protected].