DOI: https://doi.org/10.21203/rs.3.rs-707801/v1
Background: Radical hysterectomy and bilateral pelvic lymphadenectomy are standard treatments for early-stage cervical cancer. Pelvic lymph node metastasis (PLNM) is one of the critical factors affecting the postoperative prognosis of patients. Therefore, the identification of preoperative risk factors for PLNM will minimize its occurrence and improve prognosis. The purpose of this study was to investigate the risk factors for PLNM and its recurrence in patients undergoing radical hysterectomy for cervical cancer.
Methods: Medical records of 245 patients who underwent radical hysterectomy and bilateral pelvic lymphadenectomy as primary treatment for the International Federation of Gynaecology and Obstetrics (FIGO) stage IA-IIA cervical cancer between January 2010 and December 2015 at our hospital were reviewed. Age, FIGO stage, preoperative hemoglobin level, depth of stromal invasion, lymphovascular space invasion (LVSI), human papillomavirus(HPV) infection, parametrial infiltration, tumor diameter, number of lymphadenectomies, and pathological type were retrospectively analyzed. All patients were followed up for 5–10 years.
Results: Among the 245 patients, 185 (75.51%) had no PLNM, whereas 60 (24.49%) had PLNM. Preoperative hemoglobin level, FIGO stage, LVSI, parametrial infiltration, and tumor diameter differed significantly between the two groups (P<0.05). Multivariate analysis revealed preoperative hemoglobin <110 g/L, FIGO stage II, LVSI, parametrial infiltration, and tumor diameter ≥4 cm as significant risk factors for PLNM and recurrence of cervical cancer after surgery (P<0.05). PLNM was identified as the independent risk factor for recurrence in patients with cervical cancer after surgery (P<0.05).
Conclusions: PLNM is an important prognostic indicator for the clinical treatment of cervical cancer. Patients at a high risk of recurrence, especially PLNM patients, should be followed up closely after surgery to ensure the timely detection of recurrence and treatment.
Cervical cancer is one of the most common malignant tumors leading to death in women worldwide,and approximately 250,000 patients die from this disease each year [1, 2]. Radical hysterectomy and bilateral pelvic lymphadenectomy are standard treatments for early-stage cervical cancers. Surgery can not only eliminate the disease, but also provide accurate pathological staging information that clinicians can use to target adjuvant therapy.Pelvic lymph node metastasis (PLNM) is the primary route of metastasis in cervical cancer, directly affecting cervical cancer treatment and prognosis [3–5].
However, only 15% ~20% of patients with early cervical cancer have lymph node metastasis [6]. It means that more than 80% of patients with early-stage cervical cancer may have received unnecessary lymphadenectomy, which can lead to many postoperative complications. Therefore, it is essential to study risk factors affecting PLNM for the clinical treatment of cervical cancer. By preoperatively identifying the risk factors for PLNM, postoperative treatment planning and prognosis evaluation may be optimized.
The purpose of this retrospective study was to identify the risk factors for PLNM and recurrence, then provide insights into the treatment and prognosis of cervical cancer.
The clinical data of 245 patients with cervical cancer who underwent radical hysterectomy and bilateral pelvic lymphadenectomy at Tianjin Central Hospital of Gynecology and Obstetrics between January 2010 and December 2015 were retrospectively analyzed using the hospital medical records. The inclusion criteria in our study were as follows:1) confirmed diagnosis of cervical cancer by histopathological examination; 2) International Federation of Gynaecology and Obstetrics (FIGO) stage: IA-IIA; and 3) radical hysterectomy and bilateral pelvic lymphadenectomy. The exclusion criteria were as follows:1) incomplete clinical data; 2) preoperative metastatic cervical cancer; 3) cervical lymphoma, cervical melanoma, and other cervical nonepithelial tumors; and 4) case complicated by malignant tumors in other organ systems.
According to the presence or absence of PLNM, the patients were divided into two groups:1) PLNM(-) group: patients without PLNM (185, 75.51%); and 2) PLNM(+) group: patients with PLNM (60, 24.49%). All patients were followed up for 5–10 years, and based on follow-up data, they were divided into two groups: 1) Recurrence group: patients with recurrence (39, 15.92%) and 2) no recurrence group: patients without recurrence (206, 84.08%).
Age, preoperative hemoglobin level, FIGO stage, depth of stromal invasion, lymphovascular space invasion (LVSI), human papillomavirus (HPV) infection, parametrial infiltration, tumor diameter, number of lymphadenectomies, and pathological type were retrospectively analyzed (Fig. 1).
Patient anonymity was preserved as the data were collected from the hospital's electronic medical records. The research ethics committee of Tianjin Central Hospital of Gynecology and Obstetrics waived the requirement for ethics approval and informed consent because the study used previously stored data.
SPSS version 21.0 (SPSS Inc, Chicago, IL, USA) was used for statistical analysis. The two-by-two or fourfold contingency table (chi-square) test employing exact probabilities was used. Multivariate analysis was performed using a logistic regression model. All tests were two-sided, and the level of significance was set at P < 0.05.
The 245 patients included in the study were 27–70 (45.31 ± 6.42) years old, of whom 185 (75.51%) had no PLNM, whereas 60 (24.49%) had PLNM. All patients were followed up for 5–10 years, and 39 (16.25%) patients relapsed.
Patients in both groups were subdivided into two levels, depending on age, HPV infection, preoperative hemoglobin level, FIGO stage, depth of stromal invasion, LVSI, parametrial infiltration, tumor diameter, number of lymphadenectomies, and pathological type. Age, HPV infection, number of lymphadenectomies, and pathological type did not differ significantly between the the PLNM(+) and PLNM(-) groups; however, preoperative hemoglobin level, FIGO stage, depth of stromal invasion, LVSI, parametrial infiltration, and tumor diameter differed significantly. The number of patients with preoperative hemoglobin < 110 g/L, FIGO stage II, deep stromal invasion, LVSI, parametrial infiltration, and tumor diameter ≥ 4 cm in the PLNM(+) group was significantly higher than that in the PLNM(-) group (P < 0.05) (Table 1).
| Characteristic | Patients (n) | PLNM(+) (n = 60, 24.49%) | PLNM(-) (n = 185, 75.51%) | Chi-square | P-value |
|---|---|---|---|---|---|
| Age (years) | |||||
| < 45 | 119 | 25 (41.67) | 94 (50.81) | 0.775 | 0.424 |
| ≥ 45 | 126 | 35 (58.33) | 91 (49.19) | ||
| HPV infection | |||||
| Yes | 165 | 39 (65.00) | 126 (68.11) | 0.019 | 0.899 |
| No | 80 | 21 (35.00) | 59 (31.89) | ||
| Preoperative hemoglobin level (g/L) | |||||
| < 110 | 75 | 34 (56.67) | 41 (22.16) | 5.998 | 0.015 |
| ≥ 110 | 170 | 26 (43.33) | 144 (77.84) | ||
| FIGO stage | |||||
| I | 122 | 13 (21.67) | 109 (58.92) | 8.113 | 0.005 |
| II | 123 | 47 (78.33) | 76 (41.08) | ||
| Deep stromal invasion | |||||
| Yes | 133 | 50 (82.76) | 83 (44.86) | 15.394 | 0.000 |
| No | 112 | 10 (18.33) | 102 (55.14) | ||
| Number of lymphadenectomies | |||||
| < 15 | 138 | 32 (53.33) | 106 (57.30) | 0.244 | 0.621 |
| ≥ 15 | 107 | 28 (46.67) | 79 (42.70) | ||
| LVSI | |||||
| Yes | 63 | 49 (81.67) | 14 (7.57) | 19.304 | 0.000 |
| No | 182 | 11 (18.33) | 171 (92.43) | ||
| Parametrial infiltration | |||||
| Yes | 53 | 45 (75.00) | 8 (4.32) | 22.676 | 0.000 |
| No | 192 | 15 (25.00) | 177 (95.68) | ||
| Pathological type | |||||
| SCC | 52 (86.67) | 162 (87.57) | 0.000 | 0.989 | |
| Non-SCC | 8 (13.33) | 23 (12.43) | |||
| Tumor diameter (cm) | |||||
| < 4 | 157 | 27 (45.00) | 130 (70.27) | 4.647 | 0.034 |
| ≥ 4 | 88 | 33 (55.00) | 55 (29.73) | ||
| PLNM, pelvic lymph node metastasis; FIGO, International Federation of Gynaecology and Obstetrics; LVSI, lymphovascular space invasion; HPV, human papillomavirus; SCC, squamous cell carcinoma | |||||
Logistic regression analysis was used to identify independent predictors for PLMN, and preoperative hemoglobin < 110 g/L, FIGO stage II, LVSI, deep stromal invasion, parametrial infiltration, and tumor diameter ≥ 4 cm were found to be independent risk factors for postoperative PLNM of cervical cancer ( P < 0.05) (Table 2).
| Characteristic | B | SE | Wald | P-value | OR (95% CI) |
|---|---|---|---|---|---|
| Preoperative hemoglobin level | 0.741 | 0.313 | 5.390 | 0.015 | 2.115(1.143–3.914) |
| FIGO stage | 0.986 | 0.355 | 7.647 | 0.006 | 2.687(1.334–5.414) |
| Deep stromal invasion | 1.198 | 0.254 | 15. 129 | < 0.001 | 3. 612 ( 2.388–5.997) |
| LVSI | 1.610 | 0.421 | 15.132 | 0.000 | 4.952(2.212–11.089) |
| Parametrial infiltration | 1.161 | 0.427 | 3.879 | 0. 001 | 2.614 (2.241–4.249) |
| Tumor diameter | 0.656 | 0.311 | 4.474 | 0.034 | 1.926(1.049–3.535) |
| PLNM, pelvic lymph node metastasis; FIGO, International Federation of Gynaecology and Obstetrics; LVSI, lymphovascular space invasion | |||||
All patients were followed up for 5–10 years, and 39 (16.25%) patients
relapsed. The number of patients with preoperative hemoglobin < 110 g/L, FIGO stage
II, LVSI, deep stromal invasion, parametrial infiltration, tumor diameter ≥ 4 cm, and PLNM in the recurrence group was significantly higher than that in the non-recurrence
group (P < 0.05). Age, HPV infection, number of lymphadenectomies, and pathological type did not differ significantly between the two groups (Table 3).
| Characteristic | Patients (n = 245) | No recurrence (n = 206, 84.08%) | Recurrence (n = 39, 15.91%) | Chi-square | P-value |
|---|---|---|---|---|---|
| Age (years) | |||||
| < 45 | 119 | 104 (50.49) | 15 (38.46) | 1.974 | 0.160 |
| ≥ 45 | 126 | 102 (49.51) | 24 (61.54) | ||
| HPV infection | |||||
| Yes | 165 | 144 (69.90) | 21 (53.84) | 2.861 | 0.092 |
| No | 80 | 62 (30.10) | 18 (46.15) | ||
| Preoperative hemoglobin level (g/L) | |||||
| < 110 | 75 | 50 (24.27) | 25 (64.10) | 5.449 | 0.021 |
| ≥ 110 | 170 | 156 (75.73) | 14 (35.90) | ||
| FIGO stage | |||||
| I | 122 | 111 (53.88) | 11 (28.21) | 5.217 | 0.029 |
| II | 123 | 95 (46.12) | 28 (71.79) | ||
| Deep stromal invasion | |||||
| Yes | 133 | 101 (49.03) | 32 (82.05) | 8.185 | 0.004 |
| No | 112 | 105 (50.97) | 7 (17.95) | ||
| Number of lymphadenectomies | |||||
| < 15 | 138 | 113 (54.85) | 25 (64.10) | 1.168 | 0.280 |
| ≥ 15 | 107 | 93 (45.15) | 14 (35.90) | ||
| LVSI | |||||
| Yes | 63 | 33 (16.02) | 30 (76.92) | 17.29 | 0.000 |
| No | 182 | 173 (83.98) | 9 (23.08) | ||
| Parametrial infiltration | |||||
| Yes | 53 | 25 (12.14) | 28 (71.29) | 13.974 | 0.002 |
| No | 192 | 181 (87.86) | 11 (28.21) | ||
| Pathological type | |||||
| SCC | 214 | 195 (37.31) | 19 (30.77) | 0.605 | 0.437 |
| Non-SCC | 31 | 11 (62.69) | 20 (69.23) | ||
| Tumor diameter (cm) | |||||
| < 4 | 157 | 146 (70.87) | 11 (28.21) | 6.217 | 0.034 |
| ≥ 4 | 88 | 60 (29.13) | 28 (71.79) | ||
| PLNM | |||||
| Yes | 60 | 29 (14.08) | 31 (79.49) | 18.219 | 0.000 |
| No | 185 | 177 (85.93) | 8 (20.51) | ||
| PLNM, pelvic lymph node metastasis; FIGO, International Federation of Gynaecology and Obstetrics; LVSI, lymphovascular space invasion; HPV, human papillomavirus; SCC, squamous cell carcinoma | |||||
Logistic regression analysis used to identify independent predictors for PLMN revealed preoperative
hemoglobin < 110 g/L, FIGO stage II, LVSI, deep stromal invasion, parametrial infiltration, tumor diameter ≥ 4 cm, and PLMN as independent risk factors for recurrence of cervical cancer (OR ≥ 1 and P < 0.05) (Table 4).
| Characteristic | B | SE | Wald | P-value | O R (95% CI) |
|---|---|---|---|---|---|
| Preoperative hemoglobin level | 0.822 | 0.358 | 5.272 | 0.022 | 2.275(1.128–4.590) |
| LVSI | 1.600 | 0.411 | 15.131 | 0.000 | 4.952(2.212–11.089) |
| Deep stromal invasion | 0. 912 | 0.138 | 8.268 | 0.001 | 1.825 (1. 675–3.111) |
| Parametrial infiltration | 1. 032 | 0.423 | 5.714 | 0.011 | 1.620 (1.366–2.124) |
| Tumor diameter | 0. 685 | 0.612 | 5.308 | 0.008 | 1.744 (1.187–3.146) |
| FIGO stage | 1.195 | 0.439 | 7.412 | 0.006 | 3.303(1.397–7.807) |
| PLNM | 1.104 | 0.367 | 9.030 | 0.003 | 3.016(1.468–6.195) |
| PLNM, pelvic lymph node metastasis; FIGO, International Federation of Gynaecology and Obstetrics; LVSI, lymphovascular space invasion | |||||
Radical hysterectomy and bilateral pelvic lymphadenectomy are still the primary clinical treatment methods for patients with early-stage cervical cancer. The 5-year survival rate after surgery is reported to be relatively high in patients with FIGO stage IA-IIA [7].. While for some patients, a radical cure is possible, there is a possibility of relapse within 18–24 months after the initial treatment [7]. PLNM is the main metastatic route of cancer cell proliferation and an essential determinant of prognosis [7, 8]. The incidence of PLNM in cervical cancer patients after surgery is reported to be about 30% [9]. In this study, the incidence of PLNM was similar at 24%.
The hemoglobin level reduces commonly in the perioperative period [10]. Moreover, anemia occurs in more than one-third of cancer patients, and severe anemia is a risk factor for death in such patients [11–13]. The level of hemoglobin, the primary oxygen carrier, directly affects the oxygen supply and oxygen content of the tumor. Preoperative blood transfusion and other strategies do not improve prognosis in cervical cancer patients, and in patients complicated with anemia, the tumor is highly aggressive, further deteriorating the prognosis [14, 15]. In this study, the number of patients with preoperative hemoglobin < 110 g/L was significantly higher in the PLNM(+) group than in PLNM(-) group(P < 0.02).And the number of patients with preoperative hemoglobin < 110 g/L was significantly higher in the recurrence groups than in the no-recurrence groups(P < 0.03). Moreover, preoperative hemoglobin < 110 g/L was identified as an independent risk factor for postoperative PLNM and recurrence of cervical cancer after surgery. This finding was consistent with the results of previous studies.
Tumor staging is a defining index of tumor growth and the extent of its spread. As the tumor stage increases, the depth and extent of tumor invasion to the surrounding tissue, the aggressiveness and malignancy of the tumor, and the recurrence rate increase significantly [3, 16]. LNM rates of Ia, Ib, IIa, and IIb stages are reported to be 10.5%,13.1%, 27.1%, and 50.0%, respectively [17], confirming that LNM increases with advanced FIGO stages. In this study, the number of FIGO stage II cervical cancer patients with PLNM was higher than the number of FIGO stage I cervical cancer patients with PLNM (P = 0.005). This finding is consistent with previously reported results.
LVSI, deep stromal invasion, parametrial infiltration, and tumor diameter are closely related to PLNM and the recurrence of early cervical cancer [18, 19]. LVSI is pathologically confirmed by the presence of malignant tumor cells between two layers of vascular endothelial tissue and is an important prognostic index of cervical cancer. Vascular infiltration is an independent risk factor for PLNM [20, 21]. When cancer cells invade the lymphatic space, they can promote the formation of tumor thrombosis and invade local lymph nodes through the lymphatic vessels, thus inducing parametrial infiltration and PLMN [22, 23]. Consistent with previous studies, in our study, the proportions of patients with LVSI (81.67%) and parametrial infiltration (75%) in the PLNM(+) group were significantly higher than those of patients in the PLNM(-) group (P < 0.005).
The tumor diameter can reflect the tumor growth time as tumor growth is a continuous invasion and proliferation process. The longer the growth time, the more likely is the lymph node metastasis [6, 7]. With an increase in tumor diameter and a prolonged growth period, the depth of stromal invasion tends to increase. The contact area between tumor tissue and lymphatic vessels and the risk of LNM also tend to significantly increase [18, 24, 25]. A study on the prognosis of 93 patients with early cervical cancer after surgery found that a tumor diameter ≥ 4 cm is a risk factor for PLNM and recurrence of cervical cancer [26]. In this study, the number of patients with tumor diameter ≥ 4 cm and deep stromal invasion differed significantly between the two groups (P < 0.005 and P < 0.05), consistent with previous studies.
Besides preoperative hemoglobin < 110 g/L, LVSI, deep stromal invasion, parametrial infiltration, and tumor diameter ≥ 4 cm, it was shown that PLNM is an independent risk factor for the recurrence of cervical cancer. LNM occurs in late-stage cancer. Postoperative invasion, metastasis, and recurrence are prone to occur in patients with PLNM. Thus, the postoperative survival rate tends to decrease [27, 28]. Pelvic lymph node dissection can effectively remove metastatic lymph nodes, reduce the tumor load, prevent LNM, and reduce the risk of distant recurrence [29, 30]. For patients with positive pelvic lymph nodes, the interval between recurrence is significantly shorter than for those with negative lymph nodes, and the risk of recurrence is relatively higher [6]. In this study, the proportion of patients with PLNM in the recurrence group was (79.47%) significantly higher than that in the non-recurrence group (P = 0.000). PLNM was therefore identified as an independent risk factor for recurrence in patients with cervical cancer after radical hysterectomy and bilateral pelvic lymphadenectomy.
The main strength of this study was the inclusion of patients with PLNM. The prognosis of this group of patients is poor, and adequate preoperative evaluation and postoperative follow-up are needed to improve the prognosis. Moreover, patients with recurrence after surgery were from the same group of patients with PLNM, thereby reducing bias and achieving more accurate results.
This study also has unavoidable limitations due to its retrospective design. First, we could not assess all variables potentially associated with residual lesions in this single-center study. Furthermore, because the study population was from one hospital, the external validity of our results may be low. Further prospective studies with a larger sample size and a broader context are needed.
In this study, we found that hemoglobin < 110 g/L, FIGO stage II, LVSI, deep stromal invasion, parametrial infiltration, and tumor diameter ≥ 4 cm are independent risk factors for postoperative PLNM and cervical cancer recurrence. Furthermore, PLNM is an independent risk factor for the postoperative recurrence of cervical cancer. LNM is an important prognostic indicator for the clinical treatment of cervical cancer. A comprehensive preoperative evaluation is strongly recommended to improve the curative effect and prognosis of cervical cancer and avoid PLNM. For patients with risk factors for PLNM, careful and systematic pelvic lymphadenectomy should be performed. Patients at a high risk of recurrence, especially those with PLNM, must be strictly followed up, and targeted treatment should be provided after surgery. Further research is needed to determine whether pelvic lymphadenectomy should be attempted only in high-risk individuals.
pelvic lymph node metastasis
lymphovascular space invasion
International Federation of Gynaecology and Obstetrics
human papillomavirus
squamous cell carcinoma
Ethics approval and consent to participate
This retrospective analysis was exempt from ethics committee approval at Tianjin Medical University, Tianjin Central Hospital of Gynecology and Obstetrics because the committee did not consider approval was necessary for a retrospective chart review. The data were collected through the institution’s electronic medical records while pserving patient anonymity. The research ethics committee waived the requirement for informed consent because the study used pviously stored data. Administrative permissions were not required to access and use the medical records described in our study.
Consent for publication
Not applicable.
Availability of data and materials
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Funding
The project name: Establishment and clinical application of early diagnosis system for cervical pcancerous lesions caused by HPV E6 and E7
Contract no.: 19YFZCSY00600
Authors’ contributions
XmW: project development, data collection, manuscript writing.
HyZh: data collection and data analysis.
JY: data collection and data analysis.
PpQ: project development.
All authors have read and approved the final manuscript.
Acknowledgment
We thank all participants in the study for their invaluable contribution.