What is the evidence based surgical approach for lymphadenectomy in low and high risk apparent early stage endometrial cancer

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What is the evidence based surgical approach for lymphadenectomy in low and high risk apparent early stage endometrial cancer?

A lymphadenectomy encompassing a pelvic lymphadenectomy (with or without a paraaortic lymph node dissection) may be performed in patients with clinical early stage endometrial cancer to:

  1. Perform full surgical staging[1][2]
  2. Remove bulky lymph node disease
  3. Help tailor postoperative adjuvant therapy.

Lymphadenectomy can be performed as part of an open or minimally invasive procedure.

Practice point(s)

While lymphadenectomy is part of the current FIGO 2009 surgical staging for endometrial cancer, it is important for clinicians to consider the benefits, limitations and morbidity of the procedure in the absence of compelling evidence for any survival advantage related to full surgical staging. This is of particular importance in patients who are at lower risk of nodal metastasis.

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Background

Several issues require consideration when determining the place of lymphadenectomy in clinical practice in any individual case. These are outlined below:

Prediction of lymph node metastasis

Some patients with apparent “early” disease are at higher risk of having more advanced surgical stage based on the presence of metastatic nodal disease and this can be predicted pre-, intra- and postoperatively based on histopathological factors and surgical findings.

Pre-operative imaging where indicated (see related section on Pre-operative imaging) may also predict the presence of enlarged and possibly involved nodes.

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Pelvic nodal involvement

The most important histopathologic risk factors to predict pelvic nodal involvement in patients with “early” endometrial cancer are high grade of tumour, deep myometrial invasion, large tumour size and the presence of cervical stromal involvement.[3]

Unfortunately, pre-operative tumour grade has been shown to correlate poorly with final postoperative histopathology findings, with only 67% of patients having their depth of invasion accurately predicted and only 58% of patients having grade of tumour accurately assessed[4] (see section on Intra-operative assessment). Intraoperative frozen section ( where available) is better at predicting high grade rather than grade 1 and 2 disease which further hampers its use in patients with grade 1 and 2 disease who are less likely to benefit from lymphadenectomy.[4][5][6]

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Para-aortic nodal involvement

The risk of positive paraaortic nodes is related to the presence of positive pelvic nodes, adnexal disease and involvement of the cervix. Less than 2% of patients have isolated paraaortic nodes in the absence of positive pelvic nodes.[7] Thirty eight to fifty two (38-52) percent of patients with positive pelvic nodes and 20-57% with adnexal disease will have positive paraaortic lymph nodes[3][7][8][9] The incidence of positive paraaortic nodes directly correlates with the number of positive pelvic nodes.[10][11]

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Intraoperative assessment of lymph node status

Nodal palpation and frozen section are used intraoperatively to detect metastatic nodal disease. Immunoscintigraphy has also been used, but only be used in the context of research.

Intraoperative lymph node detection has a 26-36% false negative rate as more than a third of all nodal metastases are smaller than 2mm in diameter and only 7% of metastases in early cancer are larger than 2cm.[12][13][14]

Intraoperative frozen section has been proposed as a method of assessing nodal disease, however, this may underestimate the risk of nodal involvement and using this to tailor lymphadenectomy had a sensitivity of 41% and a false negative rate of 59%.[15][16] Intra-operative frozen section may be helpful in cases of clinically suspicious nodes, as a definite positive would allow the surgeon to abandon a full lymph node dissection in favour of a nodal debulking.

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Extent of nodal resection

The extent of lymphadenectomy has previously been standardized by the GOG (Gynecologic Oncology Group). The limits of node dissection includes the circumflex iliac vein caudally, the genito-femoral nerve on the psoas muscle laterally, the obliterated umbilical artery medially, the obturator nerve deeply and either the common iliac vessels in the case of a pelvic lymphadenectomy or the inferior mesenteric artery for a paraaortic lymphadenectomy cranially.[1]

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Number of nodes

Retrospective series of patients undergoing pelvic lymphadenectomy have shown that removal of ≥11 nodes in patients with high-risk histology is an independent prognostic factor for improved overall survival.[17][18]

The likelihood of detecting metastatic nodes also depends on the number of nodes removed and the superior extent of the nodal dissection.[19][20] Large series where 21 to 25 lymph nodes were removed[19] and where the superior limit of dissection went even higher than the inferior mesenteric artery to the level of the renal veins significantly increased the risk of detecting metastatic paraaortic nodal disease.[20]

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Laparoscopy or laparotomy for lymphadenectomy

The LAP 2 study comparing open hysterectomy and laparoscopic hysterectomy demonstrated that when compared to open lymphadenectomy, a laparoscopic approach could be performed with equivalent completeness, detection of metastatic disease, and complication rates.[21] While there was a longer operative time, the postoperative hospital stay was significantly shorter in the laparoscopic arm. Due to patient factors, a paraaortic lymphadenectomy was less likely to be performed in the open group as opposed to the laparoscopic group. A laparoscopic approach to pelvic lymphadenectomy is equivalent to laparotomy in regard to nodal number and extent of pelvic node dissection.[21]

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Complications of lymphadenectomy

Two large randomised clinical trials have reported the complication rate of patients undergoing open lymphadenectomy when compared to no lymph nodal dissection. Lymphadenectomy has been shown to be associated with an increased operating time, postoperative ileus, deep venous thrombosis, wound dehiscence and length of hospital stay. Not surprisingly, the incidence of postoperative lower limb lymphoedema and pelvic lymphocyst formation was significantly higher in the lymphadenectomy group.[2][22]

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Role of lymphadenectomy in surgical staging

Two recent randomised studies have revealed conflicting results on the ability of systematic lymphadenectomy to increase the detection rate of metastatic disease in patients with endometrial cancer. The ASTEC study noted that the incidence of nodal disease in the lymphadenectomy group (9%) was not statistically different to that observed in patients who had selective sampling of nodes.[22]

An Italian randomised controlled trial has demonstrated that lymphadenectomy is the most effective way of detecting metastatic disease with 13.3% of patients in the lymphadenectomy group having metastatic disease versus 3% in the no lymphadenectomy group[2]

One of the possible explanations for these conflicting results is the fact that mean nodal counts in the MRC ASTEC trial was low, while in the Italian study, patients were recruited only if they had more than 20 lymph nodes removed. In addition, post-operative adjuvant therapy differed between the studies.

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Role of lymphadenectomy in tailoring adjuvant treatment

Adjuvant treatment of endometrial cancer has traditionally consisted of pelvic radiotherapy and/or brachytherapy. A number of trials have shown that adjuvant radiation improved local recurrence rates with no effect on overall survival.[23][24][25][26][27] (see section on Adjuvant Radiotherapy) In addition, there is some evidence to suggest that adjuvant chemotherapy may be of some value.[28] However this remains controversial, with toxicities of combined therapies an ongoing concern (see section on Adjuvant Chemotherapy).

In patients with apparent early stage disease and poor prognostic factors the detection of lymph node metastases will ‘upstage’ the disease and may indicate the need for adjuvant treatment (see related sections on Adjuvant Radiotherapy and Adjuvant Chemotherapy) in accordance with current institutional treatment protocols.

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Impact on survival

Pelvic Lymphadenectomy

Two recent randomised trials have both failed to demonstrate a survival advantage in patients undergoing pelvic lymphadenectomy for apparent early stage endometrial cancer. The MRC ASTEC trial accrued 1408 patients prospectively and no survival advantage was noted after a median follow-up period of 37 months. The validity of these data has been questioned based on adequacy of nodal dissection, patient selection, indications for adjuvant therapy and significant recruitment bias in selecting patients for adjuvant treatment.[22]

An Italian randomised trial recruited patients with early stage endometrial cancer and while this study also showed no difference in progression free and overall survival, a significantly higher proportion of patients in the no lymphadenectomy group had better histologic prognostic factors.[2] The detection of metastatic disease and therefore the ability to provide prognostic information was significantly higher in patients who had lymphadenectomy.[2]

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Para-aortic Lymphadenectomy

Retrospective series have suggested that paraaortic nodal dissection may increase survival in patients with high-risk early stage endometrial cancer.[29][30] However, there are no randomised trials on this subject and studies are required.

Lymphadenectomy in patients with non- endometrioid endometrial cancer

Non-endometrioid histologic types make up 5-10% of all patients with endometrial cancers and these tumours have a significantly higher incidence of extrauterine and nodal disease and a poorer prognosis. The presence of extrauterine disease in these patients is independent of tumour size or depth of uterine invasion.[31][32][33] However, the management of these patients is limited by the absence of effective adjuvant therapies in patients with extrauterine disease.

There is currently insufficient evidence to recommend full surgical staging in patients with non-endometrioid uterine cancer. All patients with these histological subtypes should be recruited into randomised clinical trials where available.

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Conclusion

There is conflicting randomised trial based evidence on the role of lymphadenectomy in the management of women with early stage endometrial cancer. While lymphadenectomy may assist in the tailoring of adjuvant treatment in identified ‘high-risk’ patients there is no demonstrated long term disease specific survival advantage. More research is needed before lymphadenectomy can be strongly recommended in the management of endometrial cancer patients.

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Evidence summary and recommendations

Evidence summary Level References
Pelvic lymphadenectomy with or without paraaortic lymphadenectomy in patients with grade 1 or grade 2 endometrioid adenocarcinoma confined to the inner half of the myometrium, does not help tailor adjuvant treatment and is associated with an increased complication rate without prolonging progression free survival or overall survival. II [2]
Recommendation Grade
A simple hysterectomy and bilateral salpingo-oophorectomy may be considered optimal surgery for patients with apparent stage 1A Grade 1 or Grade 2 endometrioid adenocarcinoma of the uterus.
B

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Evidence summary Level References
Pelvic lymphadenectomy in patients with high-risk endometrial cancer confined to the uterus allows accurate staging and appropriate planning of adjuvant therapy. There is, however, no evidence that this offers a long term disease specific survival advantage. II [2], [22]
Recommendation Grade
Pelvic lymphadenectomy may be carried out in surgically fit patients with grade 3 endometrioid adenocarcinoma, deeply invasive (more than 50% myoinvasion) grade 1 and grade 2 tumours, cervical involvement, palpably enlarged nodes, or endometrioid tumours greater than 2cm, for accurate staging and appropriate planning and tailoring of adjuvant therapy.
B

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Evidence summary Level References
Isolated paraaortic nodal involvement is uncommon.

The paraaortic nodal spread of endometrial endometrioid cancer can be predicted by the presence of multiple involved pelvic lymph nodes, involvement of the uterine cervix, and adnexal involvement.

The impact of a para-aortic lymphadenectomy on overall survival in patients with high-risk early stage disease without the above risk factors is not clear.

III-3 [3], [9], [7]
Recommendation Grade
A para-aortic lymphadenectomy may be considered in selected groups of patients with positive pelvic nodes, palpably enlarged para-aortic nodes, tumour involvement of the cervix, or adnexal disease for accurate staging and appropriate planning and tailoring of adjuvant therapy.
C

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References

  1. 1.0 1.1 American College of Obstetricians and Gynecologists. Management of Endometrial Cancer. ACOG Practice Bulletin No. 65. Obstet Gynecol 2005;106(2):413-425 [Abstract available at http://journals.lww.com/greenjournal/Citation/2005/08000/ACOG_Practice_Bulletin__65__Management_of.50.aspx].
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Benedetti Panici P, Basile S, Maneschi F, Alberto Lissoni A, Signorelli M, Scambia G, et al. Systematic pelvic lymphadenectomy vs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst 2008 Dec 3;100(23):1707-16 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19033573].
  3. 3.0 3.1 3.2 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 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/3652025].
  4. 4.0 4.1 Case AS, Rocconi RP, Straughn JM Jr, Conner M, Novak L, Wang W, et al. A prospective blinded evaluation of the accuracy of frozen section for the surgical management of endometrial cancer. Obstet Gynecol 2006 Dec;108(6):1375-9 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17138769].
  5. Frumovitz M, Slomovitz BM, Singh DK, Broaddus RR, Abrams J, Sun CC, et al. Frozen section analyses as predictors of lymphatic spread in patients with early-stage uterine cancer. J Am Coll Surg 2004 Sep;199(3):388-93 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15325608].
  6. Petersen RW, Quinlivan JA, Casper GR, Nicklin JL. Endometrial adenocarcinoma--presenting pathology is a poor guide to surgical management. Aust N Z J Obstet Gynaecol 2000 May;40(2):191-4 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10925908].
  7. 7.0 7.1 7.2 Mariani A, Keeney GL, Aletti G, Webb MJ, Haddock MG, Podratz KC. Endometrial carcinoma: paraaortic dissemination. Gynecol Oncol 2004 Mar;92(3):833-8 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14984949].
  8. Benedetti-Panici P, Maneschi F, Cutillo G, D'Andrea G, Manci N, Rabitti C, et al. Anatomical and pathological study of retroperitoneal nodes in endometrial cancer. Int J Gynecol Cancer 1998;8:322-7.
  9. 9.0 9.1 Fujimoto T, Fukuda J, Tanaka T. Role of complete para-aortic lymphadenectomy in endometrial cancer. Curr Opin Obstet Gynecol 2009 Feb;21(1):10-4 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19124998].
  10. Bristow RE, Zahurak ML, Alexander CJ, Zellars RC, Montz FJ. FIGO stage IIIC endometrial carcinoma: resection of macroscopic nodal disease and other determinants of survival. Int J Gynecol Cancer 2003;13(5):664-72 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14675352].
  11. Havrilesky LJ, Cragun JM, Calingaert B, Synan I, Secord AA, Soper JT, et al. Resection of lymph node metastases influences survival in stage IIIC endometrial cancer. Gynecol Oncol 2005 Dec;99(3):689-95 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16126261].
  12. Arango HA, Hoffman MS, Roberts WS, DeCesare SL, Fiorica JV, Drake J. Accuracy of lymph node palpation to determine need for lymphadenectomy in gynecologic malignancies. Obstet Gynecol 2000 Apr;95(4):553-6 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10725488].
  13. Eltabbakh GH. Intraoperative clinical evaluation of lymph nodes in women with gynecologic cancer. Am J Obstet Gynecol 2001 May;184(6):1177-81 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11349185].
  14. Girardi F, Petru E, Heydarfadai M, Haas J, Winter R. Pelvic lymphadenectomy in the surgical treatment of endometrial cancer. Gynecol Oncol 1993 May;49(2):177-80 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/8504985].
  15. Papadia A, Azioni G, Brusacà B, Fulcheri E, Nishida K, Menoni S, et al. Frozen section underestimates the need for surgical staging in endometrial cancer patients. Int J Gynecol Cancer 2009 Dec;19(9):1570-3 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19955939].
  16. Pristauz G, Bader AA, Regitnig P, Haas J, Winter R, Tamussino K. How accurate is frozen section histology of pelvic lymph nodes in patients with endometrial cancer?. Gynecol Oncol 2009 Oct;115(1):12-7 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19654070].
  17. Cragun JM, Havrilesky LJ, Calingaert B, Synan I, Secord AA, Soper JT, et al. Retrospective analysis of selective lymphadenectomy in apparent early-stage endometrial cancer. J Clin Oncol 2005 Jun 1;23(16):3668-75 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15738538].
  18. Lutman CV, Havrilesky LJ, Cragun JM, Secord AA, Calingaert B, Berchuck A, et al. Pelvic lymph node count is an important prognostic variable for FIGO stage I and II endometrial carcinoma with high-risk histology. Gynecol Oncol 2006 Jul;102(1):92-7 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16406063].
  19. 19.0 19.1 Chan JK, Wu H, Cheung MK, Shin JY, Osann K, Kapp DS. The outcomes of 27,063 women with unstaged endometrioid uterine cancer. Gynecol Oncol 2007 Aug;106(2):282-8 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17662377].
  20. 20.0 20.1 Mariani A, Dowdy SC, Cliby WA, Gostout BS, Jones MB, Wilson TO, et al. Prospective assessment of lymphatic dissemination in endometrial cancer: a paradigm shift in surgical staging. Gynecol Oncol 2008 Apr;109(1):11-8 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18304622].
  21. 21.0 21.1 Walker JL, Piedmonte MR, Spirtos NM, Eisenkop SM, Schlaerth JB, Mannel RS, et al. Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. J Clin Oncol 2009 Nov 10;27(32):5331-6 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19805679].
  22. 22.0 22.1 22.2 22.3 Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK, ASTEC study group. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet 2009 Jan 10;373(9658):125-36 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19070889].
  23. Aalders J, Abeler V, Kolstad P, Onsrud M. Postoperative external irradiation and prognostic parameters in stage I endometrial carcinoma: clinical and histopathologic study of 540 patients. Obstet Gynecol 1980 Oct;56(4):419-27 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/6999399].
  24. Creutzberg CL, van Putten WL, Koper PC, Lybeert ML, Jobsen JJ, Wárlám-Rodenhuis CC, et al. Surgery and postoperative radiotherapy versus surgery alone for patients with stage-1 endometrial carcinoma: multicentre randomised trial. PORTEC Study Group. Post Operative Radiation Therapy in Endometrial Carcinoma. Lancet 2000 Apr 22;355(9213):1404-11 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10791524].
  25. Blake P, Swart AM, Orton J, Kitchener H, Whelan T, Lukka H, et al. Adjuvant external beam radiotherapy in the treatment of endometrial cancer (MRC ASTEC and NCIC CTG EN.5 randomised trials): pooled trial results, systematic review, and meta-analysis. Lancet 2009 Jan 10;373(9658):137-46 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19070891].
  26. Keys HM, Roberts JA, Brunetto VL, Zaino RJ, Spirtos NM, Bloss JD, et al. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2004 Mar;92(3):744-51 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/14984936].
  27. Randall ME, Filiaci VL, Muss H, Spirtos NM, Mannel RS, Fowler J, et al. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 2006 Jan 1;24(1):36-44 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/16330675].
  28. Randall ME, Spirtos NM, Dvoretsky P. Whole abdominal radiotherapy versus combination chemotherapy with doxorubicin and cisplatin in advanced endometrial carcinoma (phase III): Gynecologic Oncology Group Study No. 122. J Natl Cancer Inst Monogr 1995;(19):13-5 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/7577198].
  29. Mariani A, Webb MJ, Galli L, Podratz KC. Potential therapeutic role of para-aortic lymphadenectomy in node-positive endometrial cancer. Gynecol Oncol 2000 Mar;76(3):348-56 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10684709].
  30. Todo Y, Kato H, Kaneuchi M, Watari H, Takeda M, Sakuragi N. Survival effect of para-aortic lymphadenectomy in endometrial cancer (SEPAL study): a retrospective cohort analysis. Lancet 2010 Apr 3;375(9721):1165-72 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20188410].
  31. Cirisano FD Jr, Robboy SJ, Dodge RK, Bentley RC, Krigman HR, Synan IS, et al. The outcome of stage I-II clinically and surgically staged papillary serous and clear cell endometrial cancers when compared with endometrioid carcinoma. Gynecol Oncol 2000 Apr;77(1):55-65 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/10739691].
  32. Havrilesky LJ, Secord AA, Bae-Jump V, Ayeni T, Calingaert B, Clarke-Pearson DL, et al. Outcomes in surgical stage I uterine papillary serous carcinoma. Gynecol Oncol 2007 Jun;105(3):677-82 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17355889].
  33. Matthews RP, Hutchinson-Colas J, Maiman M, Fruchter RG, Gates EJ, Gibbon D, et al. Papillary serous and clear cell type lead to poor prognosis of endometrial carcinoma in black women. Gynecol Oncol 1997 May;65(2):206-12 [Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/9159326].

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Supporting material

Initial literature search

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