Abstract
OBJECTIVE
: The aim of this study was to determine the lymph node status in a large cohort of women with endometrial cancer from the public health system who were referred to an oncology reference center in Brazil to identify candidates for the omission of lymphadenectomy based on clinicopathological parameters.
METHODS
: We retrospectively analyzed a cohort of 310 women with endometrial cancer (255 endometrioid, 40 serous, and 15 clear cell tumors) treated between 2009 and 2014. We evaluated the histological type, grade (low vs. high), tumor size (cm), depth of myometrial invasion (≤50%, >50%) and lymphovascular space invasion to determine which factors were correlated with the presence of lymph node metastasis.
RESULTS
: The factors related to lymph node involvement were tumor size (p=0.03), myometrial invasion (p<0.01), tumor grade (p<0.01), and lymphovascular space invasion (p<0.01). The histological type was not associated with the nodal status (p=0.52). Only twelve of 176 patients (6.8%) had low-grade endometrioid carcinoma, tumor size ≤2 cm and <50% myometrial infiltration.
CONCLUSIONS
: The omission of lymphadenectomy based on the histological type, grade, tumor size and depth of myometrial invasion is not likely to have a large impact on the surgical treatment of endometrial cancer in our population because most patients present with large and advanced tumors. New strategies are proposed that prioritize hysterectomy performed in a general hospital as soon as possible after diagnosis, followed by an evaluation of the need for lymph node dissection at a reference center.
Endometrial cancer; Lymph node dissection; Myometrial invasion; Lymphovascular space invasion; Surgery
INTRODUCTION
Endometrial cancer is among the most frequently diagnosed malignancies of the female
genital tract in industrialized nations (11. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA
Cancer J Clin 2013;63(1):11-30,10.3322/caac.v63.1
http://dx.doi.org/10.3322/caac.v63.1...
).
Although this disease is 10 times more common in developed countries than in the
developing world, the incidence of and the mortality related to endometrial cancer
have increased dramatically in underprivileged regions in past decades, and this
neoplasm will certainly constitute a major health care problem in the near future
(22. INCA. Instituto Nacional do Câncer. Incidência de
câncer no Brasil. Available at: http://www.inca.gov.br/estimativa/2014/sintese-de-resultados-comentarios.asp.
Accessed August 2014.
http://www.inca.gov.br/estimativa/2014/s...
).
Since 1988, the international scientific agenda regarding endometrial cancer has been
dominated by a debate about nodal dissection. Although there have been technical
discussions about the most appropriate surgical approach for treating endometrial
cancer, regional disparities in access to proper oncologic therapies have rarely
been discussed in the literature (33. Maggino T, Romagnolo C, Zola P, Sartori E, Landoni F, Gadducci A.
An analysis of approaches to the treatment of endometrial cancer in Western
Europe: a CTF study. Eur J Cancer.
1995;31A(12):1993-7,10.1016/0959-8049(95)00316-9
http://dx.doi.org/10.1016/0959-8049(95)0...
,44. Maggino T, Romagnolo C, Landoni F, Sartori E, Zola P, Gadducci A.
An analysis of approaches to the management of endometrial cancer in North
America: a CTF study. Gynecol Oncol.
1998;68(3):274-9,10.1006/gyno.1998.4951
http://dx.doi.org/10.1006/gyno.1998.4951...
). Intuitively, one may assume that
insufficient human resources and medical technology are available in the developing
world. The lack of professionals with advanced surgical expertise and the ability to
perform retroperitoneal lymphadenectomy is evident. In addition, many cancer
institutions in the developing world cannot offer adequate operative treatments to
meet patient demand. This situation poses major difficulties in implementing
standard oncologic therapies and results in unacceptable treatment delays that may
lead to tumor progression and can negatively impact survival (55. Goss PE, Lee BL, Badovinac-Crnjevic T, Strasser-Weippl K,
Chavarri-Guerra Y, St Louis J, et al. Planning cancer control in Latin America
and the Caribbean. Lancet Oncol. 2013;14(5):391-436,
10.1016/S1470-2045(13)70048-2
http://dx.doi.org/10.1016/S1470-2045(13)...
). Thus, the scientific discussion of lymphadenectomy in the
developed world may be considered distant from the realities of the great number of
women in developing countries who are affected by the disease (55. Goss PE, Lee BL, Badovinac-Crnjevic T, Strasser-Weippl K,
Chavarri-Guerra Y, St Louis J, et al. Planning cancer control in Latin America
and the Caribbean. Lancet Oncol. 2013;14(5):391-436,
10.1016/S1470-2045(13)70048-2
http://dx.doi.org/10.1016/S1470-2045(13)...
).
Several algorithms have been designed to guide the selective omission of nodal
dissection in patients with endometrial cancer (66. Falcone F, Balbi G, Di Martino L, Grauso F, Salzillo ME, Messalli
EM. Surgical Management of Early Endometrial Cancer: An Update and Proposal of a
Therapeutic Algorithm. Med Sci Monit.
2014;20:1298-313,10.12659/MSM.890478
http://dx.doi.org/10.12659/MSM.890478...
–1111. Mariani A, Dowdy SC, Podratz KC. New surgical staging of
endometrial cancer: 20 years later. Int J Gynaecol Obstet.
2009;105(2):110-1,10.1016/j.ijgo.2009.02.008
http://dx.doi.org/10.1016/j.ijgo.2009.02...
). The Mayo Clinic
criteria (1212. 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;109(1):11-8,10.1016/j.ygyno.2008.01.023
http://dx.doi.org/10.1016/j.ygyno.2008.0...
), which are based on
histological type, differentiation grade, tumor size, and myometrial invasion, are
the most commonly applied. The presence of lymphovascular space invasion (LVSI) has
also been used to predict lymph node (LN) metastasis (1313. Kumar S, Mariani A, Bakkum-Gamez JN, Weaver AL, McGree ME,
Keeney GL, et al. Risk factors that mitigate the role of paraaortic
lymphadenectomy in uterine endometrioid cancer. Gynecol Oncol.
2013;130(3):441-5,10.1016/j.ygyno.2013.05.035
http://dx.doi.org/10.1016/j.ygyno.2013.0...
). Although this algorithm was independently validated (1010. Dowdy SC, Borah BJ, Bakkum-Gamez JN, Weaver AL, McGree ME, Haas
LR, Keeney GL, et al. Prospective assessment of survival, morbidity, and cost
associated with lymphadenectomy in low-risk endometrial cancer. Gynecol Oncol.
2012;127(1):5-10, 10.1016/j.ygyno.2012.06.035
http://dx.doi.org/10.1016/j.ygyno.2012.0...
), it has never been tested in a large cohort
of women in Brazil.
Following the 2009 release of guidelines for the surgical staging of endometrial
cancer by the International Federation of Gynecology and Obstetrics (FIGO) (1414. Pecorelli S. Revised FIGO staging for carcinoma of the vulva,
cervix, and endometrium. Int J Gynaecol Obstet.
2009;105(2):103-4,10.1016/j.ijgo.2009.02.012
http://dx.doi.org/10.1016/j.ijgo.2009.02...
) and because of the current lack of
consensus regarding the importance of retroperitoneal lymphadenectomy (99. 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(6):1506-19,10.1067/mob.2000.107335
http://dx.doi.org/10.1067/mob.2000.10733...
,1515. Coronado PJ, Fasero M, Baquedano L, Martinez-Maestre MA, Casado
A, Vidart JA, et al. Impact of the lymphadenectomy in high-risk histologic types
of endometrial cancer: a matched-pair study. Int J Gynecol Cancer.
2014;24(4):703-12, 10.1097/IGC.0000000000000120
http://dx.doi.org/10.1097/IGC.0000000000...
,1616. May K, Bryant A, Dickinson HO, Kehoe S, Morrison J.
Lymphadenectomy for the management of endometrial cancer. Cochrane Database Syst
Rev 2010:CD007585.), our institution initiated
a protocol in 2009 in which all patients with clinical disease are considered
candidates for complete surgical staging with pelvic and para-aortic nodal
dissection, independent of prognostic risk factors.
The primary study objective was to use the Mayo Clinic algorithm to determine the
percentage of patients in our institution for whom LN dissection could be avoided.
The secondary objective was to determine whether these criteria are as useful in
Brazil as they were found to be in the previous validation study (1010. Dowdy SC, Borah BJ, Bakkum-Gamez JN, Weaver AL, McGree ME, Haas
LR, Keeney GL, et al. Prospective assessment of survival, morbidity, and cost
associated with lymphadenectomy in low-risk endometrial cancer. Gynecol Oncol.
2012;127(1):5-10, 10.1016/j.ygyno.2012.06.035
http://dx.doi.org/10.1016/j.ygyno.2012.0...
).
PATIENTS AND METHODS
After receiving ethics review board approval (ICESP no. 394/13), we conducted a retrospective study of patients with endometrial cancer who underwent primary surgical treatment at the Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, Brazil, between January 2009 and February 2014. We included all patients with histologically confirmed endometrial carcinoma (FIGO stages Ia-IIIc2) and no evidence of extrapelvic disease on initial imaging staging (computed tomography or magnetic resonance imaging) who underwent primary operative therapy that included total hysterectomy with bilateral salpingo-oophorectomy. We excluded patients who had received neoadjuvant therapies and those who did not undergo a total hysterectomy with bilateral salpingo-oophorectomy.
The medical records of all patients were reviewed, and the following epidemiologic
and operative information was collected: age at diagnosis, surgical route
(laparoscopic, laparotomic, or vaginal), and the magnitude of the procedure
(complete staging with pelvic and para-aortic LN dissection, incomplete staging with
only pelvic or para-aortic LN dissection, or lack of nodal dissection). Pathological
analyses were performed at the institution’s central laboratory. Tumors were
classified according to the World Health Organization criteria as endometrioid
(endometrioid or mucinous) or non-endometrioid (serous or clear cells). Endometrioid
tumors were classified according to FIGO criteria (1414. Pecorelli S. Revised FIGO staging for carcinoma of the vulva,
cervix, and endometrium. Int J Gynaecol Obstet.
2009;105(2):103-4,10.1016/j.ijgo.2009.02.012
http://dx.doi.org/10.1016/j.ijgo.2009.02...
) as low grade (1 or 2) or high grade (3). Non-endometrioid histology
was considered high grade. Data on tumor size (≤ or >2 cm), the depth of
myometrial invasion (≤50% or >50%), and LVSI were obtained from the
pathological descriptions.
The final tumor staging was established according to the FIGO 2009 classification
(1414. Pecorelli S. Revised FIGO staging for carcinoma of the vulva,
cervix, and endometrium. Int J Gynaecol Obstet.
2009;105(2):103-4,10.1016/j.ijgo.2009.02.012
http://dx.doi.org/10.1016/j.ijgo.2009.02...
). The patients included in the study
were divided into two major groups according to their surgical staging. Group 1
comprised women for whom lymphadenectomy was omitted or who underwent incomplete
nodal dissection for diverse reasons, including poor clinical condition, massive LN
involvement, or intraoperative complications. Group 2 comprised women who underwent
pelvic and para-aortic lymphadenectomy and who were categorized as LN positive
(LN+) or LN negative (LN-).
Statistical analysis
The associations between LN metastasis and histological parameters, tumor size, myometrial invasion, tumor grade, and LVSI were assessed using chi-squared tests. The statistical analyses were performed using MedCalc for Windows (version 11.5.0.0; MedCalc Software, Mariakerke, Belgium), and p-values <0.05 were considered significant.
RESULTS
The cohort comprised 310 patients (134 [43%] in group 1 and 176 [57%] in group 2). The mean patient age was 64±10.2 (range, 32-86) years. In group 1, no LN dissection was performed in 119 (38%) patients, and only pelvic or para-aortic LN dissection was performed in 15 (5%) patients. Most (n=192 [62%]) of the surgeries were laparoscopic, and laparotomy was performed in 138 (38%) patients.
According to the histological analysis, 255 (82.3%) tumors were endometrioid, 40 (12.9%) were serous, and 15 (4.8%) were clear cell tumors. Table 1 summarizes the pathological characteristics of the patients in groups 1 and 2. No differences in age, histology, grade, tumor size, myometrial infiltration, or LVSI were observed between the groups (Table 1).
Among the patients in group 2, the median numbers of pelvic and para-aortic LNs dissected were 14 (range, 1-47) and 9 (range, 1-41), respectively. Table 2 shows the pathological features of the surgical specimens according to the participant’s LN status. The risk of LN involvement was related to the tumor size (p=0.03; OR 0.13 [0.01-0.90]), depth of myometrial invasion (p<0.01; OR 0.18 [0.07-0.44]), LVSI (p<0.01; OR 0.14 [0.06-0.33]), and grade (p=0.01; OR 0.39 [0.18-0,85]) but not to histological type (p=0.52; OR 0.77 [0.32-1.99]). Twelve of the 176 (6.8%) patients in group 2 fulfilled the Mayo Clinic criteria for the omission of LN dissection (endometrioid carcinoma with tumor size ≤2 cm, ≤50% depth of myometrial infiltration, and low grade).
DISCUSSION
Surgeons have not reached a consensus regarding the advantages of LN dissection for
all patients with endometrial cancer. Almost three decades after FIGO recommended
including lymphadenectomy in the surgical treatment of endometrial cancer, much
doubt remains about the extension and benefits of this procedure (1515. Coronado PJ, Fasero M, Baquedano L, Martinez-Maestre MA, Casado
A, Vidart JA, et al. Impact of the lymphadenectomy in high-risk histologic types
of endometrial cancer: a matched-pair study. Int J Gynecol Cancer.
2014;24(4):703-12, 10.1097/IGC.0000000000000120
http://dx.doi.org/10.1097/IGC.0000000000...
,1717. Dogan NU, Gungor T, Karsli F, Ozgu E, Besli M. To what extent
should para-aortic lymphadenectomy be carried out for surgically staged
endometrial cancer? Int J Gynecol Cancer.
2012;22(4):607-10,10.1097/IGC.0b013e3182434adb
http://dx.doi.org/10.1097/IGC.0b013e3182...
,2121. Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK, group As.
Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC
trial): a randomised study. Lancet. 2009;373 (9658):125-36.). Even in reference
centers, complete LN dissection increases morbidity, operative time, and treatment
costs (2222. Kodama J, Seki N, Ojima Y, Nakamura K, Hongo A, Hiramatsu Y.
Risk factors for early and late postoperative complications of patients with
endometrial cancer. Eur J Obstet Gynecol Reprod Biol.
2006;124(2):222-6,10.1016/j.ejogrb.2005.06.027
http://dx.doi.org/10.1016/j.ejogrb.2005....
,2323. Franchi M, Ghezzi F, Riva C, Miglierina M, Buttarelli M, Bolis
P. Postoperative complications after pelvic lymphadenectomy for the surgical
staging of endometrial cancer. J Surg Oncol. 2001;78(4):232-7;discussion
37-40.). Many algorithms have been proposed to predict LN involvement and to
stratify patients according to their need for a lymphadenectomy (1212. 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;109(1):11-8,10.1016/j.ygyno.2008.01.023
http://dx.doi.org/10.1016/j.ygyno.2008.0...
,2424. Han SS, Lee SH, Kim DH, et al. Evaluation of preoperative
criteria used to predict lymph node metastasis in endometrial cancer. Acta
Obstet Gynecol Scand. 2010;89(2):168-74,
10.3109/00016340903370114
http://dx.doi.org/10.3109/00016340903370...
).
The most commonly used parameters are histological type, grade, tumor size,
myometrial invasion (99. 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(6):1506-19,10.1067/mob.2000.107335
http://dx.doi.org/10.1067/mob.2000.10733...
), tumor markers (2525. Saarelainen SK, Peltonen N, Lehtimäki T, Perheentupa A,
Vuento MH, Mäenpää JU. Predictive value of serum human epididymis
protein 4 and cancer antigen 125 concentrations in endometrial carcinoma. Am J
Obstet Gynecol. 2013;209(2):142.e1-6,10.1016/j.ajog.2013.04.014
http://dx.doi.org/10.1016/j.ajog.2013.04...
), LVSI (1313. Kumar S, Mariani A, Bakkum-Gamez JN, Weaver AL, McGree ME,
Keeney GL, et al. Risk factors that mitigate the role of paraaortic
lymphadenectomy in uterine endometrioid cancer. Gynecol Oncol.
2013;130(3):441-5,10.1016/j.ygyno.2013.05.035
http://dx.doi.org/10.1016/j.ygyno.2013.0...
), and imaging characteristics (2626. Luomaranta A, Lohi J, Bützow R, Leminen A, Loukovaara M.
Prediction of para-aortic spread by gross pelvic lymph node findings in patients
with endometrial carcinoma. Int J Gynecol Cancer. 2014
;24(4):697-702,10.1097/IGC.0000000000000113
http://dx.doi.org/10.1097/IGC.0000000000...
).
Mariani et al. (1212. 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;109(1):11-8,10.1016/j.ygyno.2008.01.023
http://dx.doi.org/10.1016/j.ygyno.2008.0...
) proposed the use of the
Mayo Clinic algorithm to predict LN involvement in endometrial cancer. Patients with
low-grade endometrioid carcinoma, tumor size <2 cm, and ≤50% myometrial
invasion are considered to be at low risk of LN involvement and are thus candidates
for lymphadenectomy omission. These criteria indicated that lymphadenectomy was not
required for 27% of patients (all low risk) and 33% of endometrioid cases (1212. 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;109(1):11-8,10.1016/j.ygyno.2008.01.023
http://dx.doi.org/10.1016/j.ygyno.2008.0...
). Despite the omission of lymphadenectomy,
the 5-year cause-specific survival rate was 99.0%. This intraoperative algorithm has
been validated in two independent studies (1212. 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;109(1):11-8,10.1016/j.ygyno.2008.01.023
http://dx.doi.org/10.1016/j.ygyno.2008.0...
,2424. Han SS, Lee SH, Kim DH, et al. Evaluation of preoperative
criteria used to predict lymph node metastasis in endometrial cancer. Acta
Obstet Gynecol Scand. 2010;89(2):168-74,
10.3109/00016340903370114
http://dx.doi.org/10.3109/00016340903370...
)
Comparing our population to that examined by Mariani et al. (1212. 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;109(1):11-8,10.1016/j.ygyno.2008.01.023
http://dx.doi.org/10.1016/j.ygyno.2008.0...
), we found that 20% vs. 18% of cases were
classified as the non-endometrioid histological subtype, 72% vs.
68% of tumors were low grade, and 77% vs. 46% of tumors had
≤50% myometrial invasion. In addition, only 11% of our patients presented a
tumor size ≤2 cm. Mariani et al. (1212. 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;109(1):11-8,10.1016/j.ygyno.2008.01.023
http://dx.doi.org/10.1016/j.ygyno.2008.0...
)
determined that 27% of all patients and 33% of patients with endometrioid tumors
fulfilled the criteria for lymphadenectomy omission; in contrast, only 6.8% of the
patients in our population fulfilled these criteria. Most of our patients presented
with deep myometrial invasion and large tumors; thus, the use of the Mayo Clinic
criteria is unlikely to have a large impact on surgical treatment in a population
such as ours.
LVSI is another strong predictor of LN metastasis (1313. Kumar S, Mariani A, Bakkum-Gamez JN, Weaver AL, McGree ME,
Keeney GL, et al. Risk factors that mitigate the role of paraaortic
lymphadenectomy in uterine endometrioid cancer. Gynecol Oncol.
2013;130(3):441-5,10.1016/j.ygyno.2013.05.035
http://dx.doi.org/10.1016/j.ygyno.2013.0...
). In the presence of LVSI, an overall recurrence rate of 17% has been
reported (2727. Weinberg LE, Kunos CA, Zanotti KM. Lymphovascular space invasion
(LVSI) is an isolated poor prognostic factor for recurrence and survival among
women with intermediate- to high-risk early-stage endometrioid endometrial
cancer. Int J Gynecol Cancer. 2013
;23(8):1438-45,10.1097/IGC.0b013e3182a16c93
http://dx.doi.org/10.1097/IGC.0b013e3182...
), along with a hazard ratio of
4.9 (p=0.000) that increased to 8.8 (p=0.004) when
the LNs were positive (2828. Narayan K, Khaw P, Bernshaw D, Mileshkin L,
Kondalsamy-Chennakesavan S. Prognostic significance of lymphovascular space
invasion and nodal involvement in intermediate- and high-risk endometrial cancer
patients treated with curative intent using surgery and adjuvant radiotherapy.
Int J Gynecol Cancer.
2012;22(2):260-6,10.1097/IGC.0b013e318230c264
http://dx.doi.org/10.1097/IGC.0b013e3182...
). The estimated
5-year survival rates of patients with stage IIIc endometrial cancer with and
without LVSI are 50.9% and 93.3%, respectively (p=0.0024) (2929. Watari H, Todo Y, Takeda M, Ebina Y, Yamamoto R, Sakuragi N.
Lymph-vascular space invasion and number of positive para-aortic node groups
predict survival in node-positive patients with endometrial cancer. Gynecol
Oncol. 2005;96(3):651-7,10.1016/j.ygyno.2004.11.026
http://dx.doi.org/10.1016/j.ygyno.2004.1...
). Thus, LVSI is associated with a high risk
of recurrence and poor overall survival, even in the early stages of endometrial
cancer (3030. Loizzi V, Cormio G, Lorusso M, Latorre D, Falagario M, Demitri
P, et al. The impact of lymph vascular space invasion on recurrence and survival
in patients with early stage endometrial cancer. Eur J Cancer Care (Engl).
2014;23(3):380-4.).
The main characteristics of endometrial cancer in our Brazilian population were large tumors, deep myometrial invasion, and a high rate of LVSI. This presentation of more advanced disease may be associated with difficulties in providing timely oncologic treatment for all cases within the public health system. New strategies are thus needed to address the challenge of providing adequate treatment. We believe that it is most important to consider offering early hysterectomy with bilateral salpingo-oophorectomy to all patients as soon as possible after diagnosis. LN dissection should be postponed until patients have been evaluated at a reference center.
Developing countries lack sufficient numbers of reference centers that perform oncologic surgery. In Brazil, and likely in many other countries, patients with endometrial cancer have two options: (1) undergoing a simple hysterectomy and salpingo-oophorectomy at a general hospital, in discordance with the protocol proposed by FIGO, or (2) waiting for several months until treatment can be provided at one of the few reference centers. General obstetricians and gynecologists are discouraged from surgically treating endometrial cancer, even in cases of clinical suspicion, because they are not sufficiently trained in LN dissection. When patients finally arrive at reference centers, the disease is often advanced, and tumors are large; in such scenarios, discussions about whether to perform LN dissection are not relevant. In our opinion, the main issue is determining how to reduce the interval between diagnosis and surgical treatment at existing general hospitals.
The delayed diagnosis of endometrial cancer has been demonstrated to impact survival
rates. In a retrospective study of 190 postmenopausal patients with symptomatic
endometrial cancer and 123 asymptomatic patients with suspicious endometria detected
with transvaginal ultrasound, the 5-year disease-free survival rates were 74% and
62% in patients with ≤8 weeks and >16 weeks of bleeding, respectively
(3131. Gerber B, Krause A, Müller H, Reimer T, Külz T, Kundt
G, et al. Ultrasonographic detection of asymptomatic endometrial cancer in
postmenopausal patients offers no prognostic advantage over symptomatic disease
discovered by uterine bleeding. Eur J Cancer.
2001;37(1):64-71,10.1016/S0959-8049(00)00356-7
http://dx.doi.org/10.1016/S0959-8049(00)...
). Delayed surgical treatment can
reasonably be considered to have the greatest impact on patients with cancer
diagnoses compared with other patient groups. We believe that efforts should be made
to perform a hysterectomy while the disease is still in an early stage with a low
probability of LN metastasis. For patients with early-stage disease, LN dissection
has no benefit; in fact, it increases morbidity and mortality. Previous studies have
shown that LN dissection with customized adjuvant treatment has a potential
advantage only in patients with LN positivity (3232. 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;375(9721):1165-72,10.1016/S0140-6736(09)62002-X
http://dx.doi.org/10.1016/S0140-6736(09)...
,3333. Todo Y, Watari H, Kang S, Sakuragi N. Tailoring lymphadenectomy
according to the risk of lymph node metastasis in endometrial cancer. J Obstet
Gynaecol Res. 2014;40(2):317-21,10.1111/jog.12309
http://dx.doi.org/10.1111/jog.12309...
); even among these
patients, the benefits of systematic LN dissection are questionable (1515. Coronado PJ, Fasero M, Baquedano L, Martinez-Maestre MA, Casado
A, Vidart JA, et al. Impact of the lymphadenectomy in high-risk histologic types
of endometrial cancer: a matched-pair study. Int J Gynecol Cancer.
2014;24(4):703-12, 10.1097/IGC.0000000000000120
http://dx.doi.org/10.1097/IGC.0000000000...
).
To overcome current obstacles to the surgical treatment of endometrial cancer in
Brazil, we recently proposed a two-step approach to the systematic management of the
condition (3434. Favero G, Köhler C, Carvalho JP. Endometrial cancer in the
developing world: isn't it reasonable to perform surgical treatment
systematically in 2 steps? Int J Gynecol Cancer. 2014;24(5):822-3,
10.1097/IGC.0000000000000132
http://dx.doi.org/10.1097/IGC.0000000000...
). In this approach, women with
type I endometrial cancer undergo total extrafascial hysterectomy with bilateral
salpingo-oophorectomy but without nodal dissection upon diagnosis. Following this
primary intervention, all women are referred to cancer centers, where specialists
evaluate the clinical and pathological risk factors based on the analysis of
surgical specimens. Decisions about the need for an eventual reoperation to perform
retroperitoneal lymphadenectomy are based on the risk of nodal metastasis. We
consider that an early simple hysterectomy performed by a general gynecologist in a
general hospital would be more advantageous for these women than delayed, albeit
supposedly ideal, surgery. If necessary, lymphadenectomy is performed in a tertiary
hospital. A large, collaborative, prospective study should be performed to evaluate
the impacts of this innovative strategy on morbidity, mortality, and treatment cost
in patients with endometrial cancer, particularly in developing countries.
In conclusion, the prediction of LN involvement based on histology, grade, tumor size ≤2 cm and ≤50% myometrial invasion appears unlikely to have a large impact on surgical treatment of endometrial cancer in the Brazilian population. Our patients presented with larger and more advanced tumors, generally associated with delayed treatment. To address this situation in Brazil, we consider recommending performing a hysterectomy at a general hospital as soon as possible after diagnosis and later evaluating the need for LN dissection at a reference center. However, prospective studies to evaluate the morbidity, feasibility and cost of this systematic two-step surgical treatment need to be conducted before a national recommendation is made.
REFERENCES
-
1Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013;63(1):11-30,10.3322/caac.v63.1
» http://dx.doi.org/10.3322/caac.v63.1 -
2INCA. Instituto Nacional do Câncer. Incidência de câncer no Brasil. Available at: http://www.inca.gov.br/estimativa/2014/sintese-de-resultados-comentarios.asp Accessed August 2014.
» http://www.inca.gov.br/estimativa/2014/sintese-de-resultados-comentarios.asp -
3Maggino T, Romagnolo C, Zola P, Sartori E, Landoni F, Gadducci A. An analysis of approaches to the treatment of endometrial cancer in Western Europe: a CTF study. Eur J Cancer. 1995;31A(12):1993-7,10.1016/0959-8049(95)00316-9
» http://dx.doi.org/10.1016/0959-8049(95)00316-9 -
4Maggino T, Romagnolo C, Landoni F, Sartori E, Zola P, Gadducci A. An analysis of approaches to the management of endometrial cancer in North America: a CTF study. Gynecol Oncol. 1998;68(3):274-9,10.1006/gyno.1998.4951
» http://dx.doi.org/10.1006/gyno.1998.4951 -
5Goss PE, Lee BL, Badovinac-Crnjevic T, Strasser-Weippl K, Chavarri-Guerra Y, St Louis J, et al. Planning cancer control in Latin America and the Caribbean. Lancet Oncol. 2013;14(5):391-436, 10.1016/S1470-2045(13)70048-2
» http://dx.doi.org/10.1016/S1470-2045(13)70048-2 -
6Falcone F, Balbi G, Di Martino L, Grauso F, Salzillo ME, Messalli EM. Surgical Management of Early Endometrial Cancer: An Update and Proposal of a Therapeutic Algorithm. Med Sci Monit. 2014;20:1298-313,10.12659/MSM.890478
» http://dx.doi.org/10.12659/MSM.890478 -
7Koskas M, Genin AS, Graesslin O, Barranger E, Haddad B, Darai E, et al. Evaluation of a method of predicting lymph node metastasis in endometrial cancer based on five pre-operative characteristics. Eur J Obstet Gynecol Reprod Biol. 2014;172:115-9,10.1016/j.ejogrb.2013.10.028
» http://dx.doi.org/10.1016/j.ejogrb.2013.10.028 -
8Vidal F, Rafii A. Lymph node assessment in endometrial cancer: towards personalized medicine. Obstet Gynecol Int. 2013;2013:892465,10.1155/2013/892465
» http://dx.doi.org/10.1155/2013/892465 -
9Mariani 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(6):1506-19,10.1067/mob.2000.107335
» http://dx.doi.org/10.1067/mob.2000.107335 -
10Dowdy SC, Borah BJ, Bakkum-Gamez JN, Weaver AL, McGree ME, Haas LR, Keeney GL, et al. Prospective assessment of survival, morbidity, and cost associated with lymphadenectomy in low-risk endometrial cancer. Gynecol Oncol. 2012;127(1):5-10, 10.1016/j.ygyno.2012.06.035
» http://dx.doi.org/10.1016/j.ygyno.2012.06.035 -
11Mariani A, Dowdy SC, Podratz KC. New surgical staging of endometrial cancer: 20 years later. Int J Gynaecol Obstet. 2009;105(2):110-1,10.1016/j.ijgo.2009.02.008
» http://dx.doi.org/10.1016/j.ijgo.2009.02.008 -
12Mariani 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;109(1):11-8,10.1016/j.ygyno.2008.01.023
» http://dx.doi.org/10.1016/j.ygyno.2008.01.023 -
13Kumar S, Mariani A, Bakkum-Gamez JN, Weaver AL, McGree ME, Keeney GL, et al. Risk factors that mitigate the role of paraaortic lymphadenectomy in uterine endometrioid cancer. Gynecol Oncol. 2013;130(3):441-5,10.1016/j.ygyno.2013.05.035
» http://dx.doi.org/10.1016/j.ygyno.2013.05.035 -
14Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet. 2009;105(2):103-4,10.1016/j.ijgo.2009.02.012
» http://dx.doi.org/10.1016/j.ijgo.2009.02.012 -
15Coronado PJ, Fasero M, Baquedano L, Martinez-Maestre MA, Casado A, Vidart JA, et al. Impact of the lymphadenectomy in high-risk histologic types of endometrial cancer: a matched-pair study. Int J Gynecol Cancer. 2014;24(4):703-12, 10.1097/IGC.0000000000000120
» http://dx.doi.org/10.1097/IGC.0000000000000120 -
16May K, Bryant A, Dickinson HO, Kehoe S, Morrison J. Lymphadenectomy for the management of endometrial cancer. Cochrane Database Syst Rev 2010:CD007585.
-
17Dogan NU, Gungor T, Karsli F, Ozgu E, Besli M. To what extent should para-aortic lymphadenectomy be carried out for surgically staged endometrial cancer? Int J Gynecol Cancer. 2012;22(4):607-10,10.1097/IGC.0b013e3182434adb
» http://dx.doi.org/10.1097/IGC.0b013e3182434adb -
18Courtney-Brooks M, Scalici JM, Tellawi AR, Cantrell LA, Duska LR. Para-aortic lymph node dissection for women with endometrial adenocarcinoma and intermediate- to high-risk tumors: does it improve survival? Int J Gynecol Cancer. 2014;24(1):91-6,10.1097/IGC.0000000000000008
» http://dx.doi.org/10.1097/IGC.0000000000000008 -
19Kim HS, Suh DH, Kim MK, Chung HH, Park NH, Song YS. Systematic lymphadenectomy for survival in patients with endometrial cancer: a meta-analysis. Jpn J Clin Oncol. 2012;42(5):405-12,10.1093/jjco/hys019
» http://dx.doi.org/10.1093/jjco/hys019 -
20McMeekin DS. What should lymphadenectomy offer in early-stage endometrial cancer: lots of variables, little control. Am J Obstet Gynecol. 2011;205(6):509-10,10.1016/j.ajog.2011.09.003
» http://dx.doi.org/10.1016/j.ajog.2011.09.003 -
21Kitchener H, Swart AM, Qian Q, Amos C, Parmar MK, group As. Efficacy of systematic pelvic lymphadenectomy in endometrial cancer (MRC ASTEC trial): a randomised study. Lancet. 2009;373 (9658):125-36.
-
22Kodama J, Seki N, Ojima Y, Nakamura K, Hongo A, Hiramatsu Y. Risk factors for early and late postoperative complications of patients with endometrial cancer. Eur J Obstet Gynecol Reprod Biol. 2006;124(2):222-6,10.1016/j.ejogrb.2005.06.027
» http://dx.doi.org/10.1016/j.ejogrb.2005.06.027 -
23Franchi M, Ghezzi F, Riva C, Miglierina M, Buttarelli M, Bolis P. Postoperative complications after pelvic lymphadenectomy for the surgical staging of endometrial cancer. J Surg Oncol. 2001;78(4):232-7;discussion 37-40.
-
24Han SS, Lee SH, Kim DH, et al. Evaluation of preoperative criteria used to predict lymph node metastasis in endometrial cancer. Acta Obstet Gynecol Scand. 2010;89(2):168-74, 10.3109/00016340903370114
» http://dx.doi.org/10.3109/00016340903370114 -
25Saarelainen SK, Peltonen N, Lehtimäki T, Perheentupa A, Vuento MH, Mäenpää JU. Predictive value of serum human epididymis protein 4 and cancer antigen 125 concentrations in endometrial carcinoma. Am J Obstet Gynecol. 2013;209(2):142.e1-6,10.1016/j.ajog.2013.04.014
» http://dx.doi.org/10.1016/j.ajog.2013.04.014 -
26Luomaranta A, Lohi J, Bützow R, Leminen A, Loukovaara M. Prediction of para-aortic spread by gross pelvic lymph node findings in patients with endometrial carcinoma. Int J Gynecol Cancer. 2014 ;24(4):697-702,10.1097/IGC.0000000000000113
» http://dx.doi.org/10.1097/IGC.0000000000000113 -
27Weinberg LE, Kunos CA, Zanotti KM. Lymphovascular space invasion (LVSI) is an isolated poor prognostic factor for recurrence and survival among women with intermediate- to high-risk early-stage endometrioid endometrial cancer. Int J Gynecol Cancer. 2013 ;23(8):1438-45,10.1097/IGC.0b013e3182a16c93
» http://dx.doi.org/10.1097/IGC.0b013e3182a16c93 -
28Narayan K, Khaw P, Bernshaw D, Mileshkin L, Kondalsamy-Chennakesavan S. Prognostic significance of lymphovascular space invasion and nodal involvement in intermediate- and high-risk endometrial cancer patients treated with curative intent using surgery and adjuvant radiotherapy. Int J Gynecol Cancer. 2012;22(2):260-6,10.1097/IGC.0b013e318230c264
» http://dx.doi.org/10.1097/IGC.0b013e318230c264 -
29Watari H, Todo Y, Takeda M, Ebina Y, Yamamoto R, Sakuragi N. Lymph-vascular space invasion and number of positive para-aortic node groups predict survival in node-positive patients with endometrial cancer. Gynecol Oncol. 2005;96(3):651-7,10.1016/j.ygyno.2004.11.026
» http://dx.doi.org/10.1016/j.ygyno.2004.11.026 -
30Loizzi V, Cormio G, Lorusso M, Latorre D, Falagario M, Demitri P, et al. The impact of lymph vascular space invasion on recurrence and survival in patients with early stage endometrial cancer. Eur J Cancer Care (Engl). 2014;23(3):380-4.
-
31Gerber B, Krause A, Müller H, Reimer T, Külz T, Kundt G, et al. Ultrasonographic detection of asymptomatic endometrial cancer in postmenopausal patients offers no prognostic advantage over symptomatic disease discovered by uterine bleeding. Eur J Cancer. 2001;37(1):64-71,10.1016/S0959-8049(00)00356-7
» http://dx.doi.org/10.1016/S0959-8049(00)00356-7 -
32Todo 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;375(9721):1165-72,10.1016/S0140-6736(09)62002-X
» http://dx.doi.org/10.1016/S0140-6736(09)62002-X -
33Todo Y, Watari H, Kang S, Sakuragi N. Tailoring lymphadenectomy according to the risk of lymph node metastasis in endometrial cancer. J Obstet Gynaecol Res. 2014;40(2):317-21,10.1111/jog.12309
» http://dx.doi.org/10.1111/jog.12309 -
34Favero G, Köhler C, Carvalho JP. Endometrial cancer in the developing world: isn't it reasonable to perform surgical treatment systematically in 2 steps? Int J Gynecol Cancer. 2014;24(5):822-3, 10.1097/IGC.0000000000000132
» http://dx.doi.org/10.1097/IGC.0000000000000132
Publication Dates
-
Publication in this collection
July 2015
History
-
Received
9 Feb 2015 -
Reviewed
23 Mar 2015 -
Accepted
8 Apr 2015