History and background

Although pelvic lymphadenecto my has been used traditionally for more than a century in the surgical treatment of early cervical cancer, uniform conclusions have not been reached regarding the optimal number of lymph nodes that should be removed within the standard scope of lymphadenectomy. Standardizing lymphadenectomy is essential for further improvement of surgical quality and for improved survival of patients with cervical cancer. We reviewed existing studies on the prognostic value of the number of lymph nodes retrieved.

Tracing the development history of cervical cancer surgical treatment, Ernst Wertheim standardized radical abdominal hysterectomy in 1912, which made this cancer curable and formed the basis of current treatment for early-stage cervical cancer. Dr. Fred J. Taussig subsequently realized the importance of careful removal of the pelvic nodes during this operative procedure. Dr.Taussig believed that even if metastatic disease had been eradicated from the lymph nodes, recurrence might take place in the pelvic nodes. Therefore, he dissected these lymph nodes and their lymphatic channels en bloc during surgery [1]. After that, Joe Vincent Meigs combined radical abdominal hysterectomy with Taussig’s en bloc pelvic lymph node dissection procedure, establishing a milestone in the treatment of cervical cancer. From his vast experience, Dr. Meigs felt that positive lymph nodes could not be detected by inspection, palpation,or visualization and that the only way to determine whether lymph nodes were positive was via pathological examination in the laboratory after their removal [1].Thereafter, lymph node dissection was performed together with radical hysterectomy, achieving an 89.7%5-year survival rate for stage I disease, and a 63.0% 5-year survival rate for stage II disease, far surpassing Wertheim’s 18.4% overall 5-year survival rate [1]. Meigs demonstrated that lymphatic invasion was much more common than previously believed and that en bloc resection of lymphatic tissue afforded greater survival benefit. As a result of these efforts, pelvic lymphadenectomy has been performed for years.

网络沟通由于在沟通同步性上的区别，又被划分为同步沟通和异步沟通。同步沟通(Synchronous Communication) 是指互动信息的发送和接受是在同一时间段进行的，互动双方同时在线，一方所做的动作可以被另一方实时观察及感知。异步沟通(Asynchronous Communication) 则是信息的发送与接收在时间点上错开，互动双方所进行的操作在时间上有一定的滞后性。两者的差别在于互动是否同时，也就是时间维度的差别。[1]

Today, cervical cancer remains the fourth most prevalent female malignancy and the fourth leading cause of cancer deaths in women worldwide [2]. With gradual popularization of cervical cancer screening, the early diagnosis rate of cervical cancer has improved, and the proportion of detection of early cervical cancer has increased. For early cervical cancer, the present standard method of surgical treatment is radical hysterectomy plus pelvic lymph node dissection, with or without para-aortic lymph node sampling; systematic pelvic lymph node dissection is an integral part of the surgical procedure recommended to treat early-stage cervical cancer.However, no consensus has been reached as to what extent pelvic lymphadenectomy should be conducted,and there are no unified conclusions about the scope of pelvic lymphadenectomy in cervical cancer.

Benedetti-Panici et al found that in patients with cervical cancer, the lymph node metastasis rate was 7%in the deep common iliac, 28% in the superficial common iliac, 7% in the deep obturator, 86% in the superficial obturator, 29% in the external iliac, 8% in the internal iliac, 7% in the presacral, and 29% in the parametrial lymph nodes [3]. Therefore, for the purpose of treatment,those researchers suggested that systematic dissection of all the lymphatic tissue located around the cervix and the pelvic vessels should be performed in these patients, to completely remove potential sites of metastasis, including the eight groups of lymph nodes listed above [3]. In reports by Lim et al and by Pieterse et al, pelvic lymphadenectomy included the bilateral common iliac, external iliac, internal iliac, and obturator, a total of four groups of lymph nodes[4–5]. However, Ditto et al included the presacral lymph nodes in addition to these four groups [6]. Subsequently,Batista et al pointed out that systemic lymphadenectomy also included the parametrial lymph nodes in addition to the above four groups of lymph nodes [7]. Hu et al felt that systematic pelvic lymphadenectomy should also include the inguinal lymph nodes in addition to the above four groups [8]. The scope of lymphadenectomy can directly influence the number of pelvic lymph nodes dissected (NPLD). Moreover, the NPLD can vary greatly depending on the anatomy of the patient, the status of lymphoid tissue peripheral inflammation and adhesion,the standards of the surgeon, the extent of surgery, and examination by a pathologist. In previous studies, the mean or median number of pelvic nodes removed ranged from 13–65 [9–10]. In a report by Verleye et al, removal of more than 11 pelvic nodes was suggested as one of the quality indicators for pelvic lymphadenectomy [11]. Up to now, how many lymph nodes should be removed to obtain the best treatment effect remains unknown. Some studies have focused on the relationship between the prognosis of patients with pelvic lymphadenectomy and the number of lymph nodes removed, with the aim of helping to standardize pelvic lymphadenectomy in early cervical cancer.

Related research

Whereas some studies proved a positive correlation between the number of lymph nodes removed and the prognosis of patients with cervical cancer, no obvious correlation was found in other studies. Suprasert et al retrospectively analyzed 826 patients with radical hysterectomy and pelvic lymphadenectomy, stratifying them into four groups according to NPLD: 11–20, 21–30,31–40, and ≥ 41 lymph nodes. The researchers found no statistically significant difference among the four groups with respect to 5-year disease-free survival (DFS), and NPLD was independent of the 5-year DFS in a further multivariate analysis; the authors finally concluded that NPLD was not an independent prognostic factor in patients with early cervical cancer [12]. However, in that study, only 5-year DFS was chosen as a prognostic indicator, and overall survival (OS) and cancer-specific survival were not included. In addition, the study did not include patients who had fewer than 11 lymph nodes removed; therefore, it cannot be concluded that NPLD and prognosis are absolutely unrelated. In 2013, Ditto et al investigated 526 cervical cancer patients treated with radical surgery and found that the total number of lymph nodes removed did not affect the survival of these patients, in multivariable analysis [6]. However, those authors did not divide patients into groups according to the total number of lymph nodes, which might have an impact on the result; hence, the relationship between these factors requires further study.

Conflict of interest

In addition, several studies have indicated that some factors (histopathological type, tumor size, neoadjuvant chemotherapy, and lymph node status) can influence the relationship between patient prognosis and the total number of lymph nodes removed.

台达在2018 SPS展会中推出全新木工机械、包装机械专用高阶运动控制解决方案，应用于水处理的自动化解决方案以及高阶自动化设备等，以精准控制、灵活高速运动等特色协助客户设备智能升级：

When looking at surgery as the principal treatment for early cervical cancer, there are two approaches:surgery after neoadjuvant chemotherapy and direct surgical treatment. Kim et al divided patients into two groups using a cutoff of 20 lymph nodes removed. They found that removing a greater number of lymph nodes could improve DFS in patients without neoadjuvant chemotherapy. However, for patients who underwent radical surgery after neoadjuvant chemotherapy, there was no obvious relationship between the total number of lymph nodes removed and prognosis [15].

Lim et al reviewed 180 patients with FIGO stage IB–IIA cervical cancer after radical surgery, separating them into a bulky (tumor size ＞ 4 cm) group and non-bulky(tumor size ≤ 4 cm) group. The authors found that the total number of lymph nodes removed was an independent prognostic factor with tumors ＞ 4 cm in diameter, which meant that more extensive lymphadenectomy increased the survival of patients with bulky cervical cancer.However, with tumors ＜ 4 cm in diameter, there was no significant correlation between the total number of lymph nodes dissected and OS or DFS [4].

From the current studies reviewed, we can conclude that there may be a positive correlation between the prognosis of patients with cervical cancer and the number of lymph nodes removed, in general. In the presence of lymph node metastasis, lymph nodes should be removed as extensively as possible for better prognosis, while aiming to reduce intraoperative and postoperative complications.When there is no lymph node metastasis, the prognosis of cervical cancer patients and the number of lymph nodes removed may be not related. However, whether lymph nodes are metastatic can only be completely and precisely determined by radical pelvic lymphadenectomy, to ensure their complete removal. Pelvic lymphadenectomy is the best available surgical treatment at present. As such,the procedure requires additional research, to standardize treatment. To date, there is limited research on whether neoadjuvant chemotherapy, tumor size, histologicalpathological type, or lymph node status can influence the relationship between extent of lymphadenectomy and prognosis. Further multicenter, prospective studies with large samples are warranted.

Conclusions

The study by Shah et al indicated that when the lymph nodes were positive, more extensive lymphadenectomy had no effect on survival; However, for women with negative lymph nodes, more extensive lymphadenectomy was associated with improved survival [13]. By contrast,Zhou et al found that the total number of lymph nodes removed in patients with lymph node metastasis was an independent prognostic factor for cause-specific survival and OS. In other words, the greater the number of lymph nodes excised, the better the survival outcome. However,there was no correlation between the total number of lymph nodes removed and prognosis of patients without lymph node metastasis [14]. These two studies were SEER studies; however, the study by Zhou et al. had a larger sample size (11,830 versus 5222 patients), and a larger proportion of patients were diagnosed after 2000(76.4% versus 48%); therefore, the conclusions of Zhou et al may be more reliable. In the same way, Mao et al.studied 359 cases of patients with FIGO stage IA–IIB cervical cancer without lymph node metastasis, dividing them into five groups, according to the number of lymph nodes removed: ＜ 10, 11–15,16–20, 21–25, and ＞ 25.The authors found that when there was no lymph node metastasis, the total number of lymph nodes resected was unrelated to prognosis [16]. Similarly, Wu et al classified patients with early cervical cancer and without lymph node metastasis into two groups by the number of lymph nodes removed10. In univariate analysis, those authors found that the total number of lymph nodes excised was a prognostic variable in OS whereas it was irrelevant for cause-specific survival. However, multivariate analysis indicated that the total number of lymph nodes resected was unrelated to the prognosis of patients without lymph nodes metastasis [17]. It can thus be concluded that the number of lymph nodes removed is positively related to prognosis when there is lymph node metastasis, but it is not associated with prognosis when there is no lymph node metastasis. However, this conclusion requires additional and more sophisticated studies for confirmation.

Acknowledgement

We thank Zehua Wang for guidance, Jing Cai and Jianfeng Guo for making corrections, and Guanghua Xu for helpful comments.

In their study, Shah et al. investigated data of 5522 women with stage IA2–IIA cervical cancer who underwent radical hysterectomy with lymphadenectomy;study participants were included in the Surveillance,Epidemiology, and End Results (SEER) database. In that study, the total number of lymph nodes dissected was divided into four groups: ＜ 10, 10–20, 21–30, and ＞ 30.The researchers found that, compared with patients who had fewer than 10 nodes removed, patients with 21–30 nodes removed were 24% less likely to die from their tumors, and those with ＞ 30 nodes removed were 37% less likely to die. The authors concluded that more extensive lymphadenectomy was related to improved survival [13].Similarly, Lim et al studied patients with FIGO stage IB–IIA cervical cancer, splitting patients into two groups according to a cutoff of 40 lymph nodes removed. The authors found that patients who had ＞ 40 lymph nodes removed had a better prognosis, showing that the total number of lymph nodes removed had a significant effect on DFS and OS [4]. Likewise, Zhou et al studied 11,830 women included in the SEER database with stage IA2–IIA cervical cancer who underwent radical hysterectomy with lymphadenectomy, allocating them into four groups:1–10, 10–20, 21–30, ＞ 30 lymph nodes removed. The authors found that the number of lymph nodes removed was an independent prognostic factor, which meant that the more lymph nodes were removed, the better the survival outcome [14]. From the above studies, we can conclude that the total number of lymph nodes dissected may be positively related to the prognosis of patients.

Zhou et al reviewed 7920 patients with cervical squamous carcinoma and 3910 patients with cervical adenocarcinoma; all cancers were FIGO stage IA2–IIB.Those authors found that the number of lymph nodes removed was an independent positive prognostic factor in squamous carcinoma but was not related to the prognosis of patients with adenocarcinoma [14].

✉

References

1. Meigs Jv. Radical hysterectomy with bilateral pelvic lymph node dissections; a report of 100 patients operated on five or more years ago. Am J Obstet Gynecol, 1951, 62: 854–870.

2. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer, 2015, 136: E359–386.

3. Benedetti-Panici P, Maneschi F, Scambia G, et al. Lymphatic spread of cervical cancer: an anatomical and pathological study based on 225 radical hysterectomies with systematic pelvic and aortic lymphadenectomy. Gynecol Oncol, 1996, 62: 19–24.

4. Lim S, Cho K, Lee S, et al. Effect of number of retrieved lymph nodes on prognosis in FIGO stage IB-IIA cervical cancer patients treated with primary radical surgery. J Obstet Gynaecol Res, 2017, 43: 211–219.

5. Pieterse QD, Kenter GG, Gaarenstroom KN, et al. The number of pelvic lymph nodes in the quality control and prognosis of radical hysterectomy for the treatment of cervical cancer. Eur J Surg Oncol,2007, 33: 216–221.

6. Ditto A, Martinelli F, Lo VS, et al. The role of lymphadenectomy in cervical cancer patients: the significance of the number and the status of lymph nodes removed in 526 cases treated in a single institution.Ann Surg Oncol, 2013, 20: 3948–3954.

7. Batista TP, Bezerra AL, Martins MR, et al. How important is the number of pelvic lymph node retrieved to locorregional staging of cervix cancer. Einstein (Sao Paulo), 2013, 11: 451–455.

8. Hu T, Li X, Zhang Q, et al. Could the extent of lymphadenectomy be modified by neoadjuvant chemotherapy in cervical cancer? A largescale retrospective study. PLoS One, 2015, 10: e0123539.

9. Sakuragi N. Up-to-date management of lymph node metastasis and the role of tailored lymphadenectomy in cervical cancer. Int J Clin Oncol, 2007, 12: 165–175.

10. Hosaka M, Watari H, Mitamura T, et al. Survival and prognosticators of node-positive cervical cancer patients treated with radical hysterectomy and systematic lymphadenectomy. Int J Clin Oncol,2011, 16: 33–38.

11. Verleye L, Vergote I, Reed N, et al. Quality assurance for radical hysterectomy for cervical cancer: the view of the European Organization for Research and Treatment of Cancer--Gynecological Cancer Group (EORTC-GCG). Ann Oncol, 2009, 20: 1631–1638.

12. Suprasert P, Charoenkwan K, Khunamornpong S. Pelvic node removal and disease-free survival in cervical cancer patients treated with radical hysterectomy and pelvic lymphadenectomy. Int J Gynaecol Obstet, 2012, 116: 43–46.

13. Shah M, Lewin SN, Deutsch I, et al. Therapeutic role of lymphadenectomy for cervical cancer. Cancer, 2011, 117: 310–317.

14. Zhou J, Zhang WW, Wu SG, et al. The impact of examined lymph node count on survival in squamous cell carcinoma and adenocarcinoma of the uterine cervix. Cancer Manag Res, 2017, 9: 315–322.

15. Kim HS, Kim JH, Chung HH, et al. Significance of numbers of metastatic and removed lymph nodes in FIGO stage IB1 to IIA cervical cancer: Primary surgical treatment versus neoadjuvant chemotherapy before surgery. Gynecol Oncol, 2011, 121: 551–557.

16. Mao S, Dong J, Li S, et al. Prognostic significance of number of nodes removed in patients with node-negative early cervical cancer.J Obstet Gynaecol Res, 2016, 42: 1317–1325.

17. Wu SG, Sun JY, He ZY, et al. Early-stage node negative cervical adenocarcinoma and squamous cell carcinoma show similar survival outcomes after hysterectomy: a population-based study. J Gynecol Oncol, 2017, 28: e81.