Lymph-Vascular Space Invasion in Patients with Stages IA2-IIA2 Cervical Cancer Treated with Laparoscopic versus Open Radical Hysterectomy.

OBJECTIVE: To explore the relationship between laparoscopic radical hysterectomy (LRH) and cervical cancer lymph-vascular space invasion (LVSI) by comparing the prevalence of LVSI in cervical cancer patients who underwent LRH versus open radical hysterectomy (ORH).
METHODS: The study participants were 1087 cervical cancer patients (FIGO 2009 stages IA2-IIA2) with pathologically confirmed with or without LVSI who underwent radical hysterectomy at Shengjing Hospital of China Medical University from 2013 through 2018. The patients were divided according to the type of surgical procedure into an LRH group (n=148) and an ORH group (n=939).
RESULTS: In the LRH group, 31.76% of patients (47/148) had LVSI-positive tumors compared to 33.23% of patients (312/939) in the ORH group; the difference was not significant (p=0.724). No between-group differences in LVSI prevalence according to lymph node metastasis, interstitial infiltration depth, differentiation degree, and parametrial infiltration were found. However, the number of LVSI-positive patients whose cervical cancer lesions >4 cm (stage I B2 and II A2) was significantly higher in the LRH group than in the ORH group (Odds Ratio [OR] 0.333, 95% confidence interval [CI] 0.157-0.706, p=0.005). The 3-Year disease-free survival (DFS) in the LRH group is lower than that in the ORH group (94.75% vs 97.27%), but there was no significance (P=0.187). Furthermore, the percentage of LVSI-positive tumors in patients with lymph node metastases was significantly higher than those without lymph node metastases (OR 2.897, 95% CI 2.129-3.942, p=0.000). The 3-Year DFS were 98.22% in the LVSI negative patients and 93.78% in the LVSI positive patients, the difference was significant (P=0.002).
CONCLUSION: A higher risk of lymph node metastasis and a lower 3-Year DFS was found in the LVSI-positive patients. In case of LVSI, it would be dangerous to treat patient in laparoscopy, especially in case of cervical cancer lesions >4cm.

Introduction

Since Nezhat1 reported the first case of total laparoscopic radical hysterectomy (LRH) in 1992, many more studies2–7 have suggested that LRH is a feasible and safe surgical treatment option for cervical cancer, and it has advantages such as less bleeding, a lower risk of infection, more rapid postoperative recovery, and shorter hospital stay, with similar relapse, 5-year survival, and tumor-free survival rates, compared with open radical hysterectomy (ORH). Therefore, LRH for cervical cancer has been gradually accepted and popularized by both doctors and patients. The 2018 National Comprehensive Cancer Network (NCCN) Guidelines recommend treating stages IA2-IIA cervical cancer with ORH, LRH, or robot-assisted LRH.

However, a prospective, multi-center, randomized controlled study, reported in 2018 by Ramirez et al,8 showed that the LVSI-positive patients with stage IA1, IA2, and IB1 cervical cancer had poorer prognoses after LRH than after ORH. Meanwhile, Melamed et al9 drew a similar conclusion from a retrospective epidemiologic study. Compared with other positive studies,10–15 these reports of negative effects of LRH took the international gynecological research and practice community by surprise. LVSI is one of the factors used to select the subsequent treatment plan in cervical cancer patients and influences their prognosis. The aim of this study was to explore the effects of LRH on LVSI by comparing the prevalence of LVSI in cervical cancer patients who underwent LRH or ORH.

Methods

Patients

The study participants were 1087 cervical cancer patients treated at Shengjing Hospital of China Medical University from 2013 through 2018. The inclusion criteria were as follows: 1) a clinical diagnosis of FIGO 2009 stage IA2-IIA2 cervical cancer, 2) initial treatment by LRH or ORH, 3) a pathologic diagnosis of squamous cell carcinoma with or without LVSI, but no LVSI-positive patients on pre-operative cervical biopsies. 4) absence of malignant or borderline tumors at other sites. 5) no neo adjuvant chemotherapy prior to surgery. 6) All patients underwent systematic pelvic lymph node dissection, with or without aortic lymph node dissection. 7) Sentinel lymph nodes were not performed. Postoperative adjuvant therapy was performed according to Sedlis standard for those patients with moderate risk factors, or to those with three high-risk factors (lymph node metastasis, parametrial infiltration and positive surgical margin). Based on the initial operation mode, the patients were divided into an LRH group and an ORH group. In the patients who underwent LRH, CO2-insufflated pneumoperitoneum was established, and a cup-type uterine manipulator was used during the operation. The LRH group patients had a mean age 47.02±8.70 years (range, 25–68 years) and the ORH group patients had a mean age of 49.53±9.32 years (range, 22 to 77 years). There was no significant difference in the age and clinical stage distribution between the two groups (p=0.211 and 0.917, respectively) (Table 1).

Table 1

The Characteristics of the Patients Who Underwent Laparoscopic versus Open Radical Hysterectomy

	LRH		ORH		P value
	n	%	n	%
Age (years)	47.02±8.70		49.53±9.32		0.211
IA2	4	2.70	10	1.06
IB1	72	48.65	396	42.17
IB2	9	6.08	136	14.48
IIA1	41	27.70	216	23.00
IIA2	22	14.86	181	19.28
Total	148		939

Abbreviations: LRH, laparoscopic radical hysterectomy; ORH, open radical hysterectomy.

Follow-Up

Patients who underwent surgery between January 1, 2013 and December 31, 2016 were followed up by professional gynecologists through telephone. And the last follow-up time was December 31, 2019. The postoperative adjuvant chemoradiotherapy conditions, survival status, survival time, reasons of death, recurrence time and location were recorded. Disease-free survival (DFS) and overall survival (OS) were calculated. DFS was defined as the time (months) from surgery to recurrence. OS was defined as the time (months) from surgery to death. Data of patients with no evidence of death or recurrence was censored.

Methods

Normally distributed quantitative data are presented as mean ± standard deviation (SD). Independent Samples were analyzed using Mann–Whitney U-Test. The qualitative data were analyzed with the χ2 test or Fisher’s Exact Test. Survival analysis was carried out through Kaplan-Meier method and compared with Log rank test. Univariate and multivariate Cox proportional hazards regression analysis were used to calculate the factors associated with the DFS and OS of the cervical cancer patients. The data analysis was conducted through Statistical Package for Social Sciences (IBM SPSS, Version 25, Armonk, NY) and R version 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria). A p-value <0.05 indicated a statistically significant difference.

Results

Clinical Staging and LVSI

Of the 1087 patients, 148 (13.62%) composed the LRH group and 939 (86.38%) composed the ORH group. Forty-seven patients (31.76%) in the LRH group and 312 patients (33.23%) in the ORH group had positive LVSI; the difference was not significant (p=0.724). A total of 468 patients (LRH, 72, 48.65% and ORH, 396, 42.17%) were classified as clinical stage IB1, accounting for 43.05% of the study participants; 20 (27.78%) and 144 (36.36%) patients with LVSI-positive tumors in the LRH and ORH groups, respectively, were classified as stage IB1. The overall between-group difference was not significant (p=0.18). No significant between-group difference in LVSI prevalence was observed in patients diagnosed with stage IA2 combining IB1 and stage IIA cervical cancers (p=0.240 and 0.468, respectively). The clinical stage distribution and LVSI status of the patients in the two groups are shown in Table 2.

Table 2

Lymph-Vascular Space Invasion (LVSI) According to Clinical Stage in Patients Who Underwent Laparoscopic or Open Radical Hysterectomy

LRH/ORH	FIGO Stage	LVSI (-)		LVSI (+)		Total		P value
			%		%		%
	IA2	2/6	1.35/0.64	2/4	1.35/0.43	4/10	2.70/1.06	0.18
	IB1	52/252	35.14/26.84	20/144	13.51/15.34	72/396	48.65/42.17
	IB2	6/93	4.05/9.90	3/43	2.03/4.58	9/136	6.08/14.48
	IIA1	34/152	22.97/16.19	7/64	4.73/6.82	41/216	27.70/23.00
	IIA2	7/124	4.73/13.21	15/57	10.14/6.07	22/181	14.86/19.28
	Total	101/627	68.24/66.77	47/312	31.76/33.23	148/939	100/100

Abbreviations: LRH, laparoscopic radical hysterectomy; ORH, open radical hysterectomy.

Lesion Size and LVSI

There were significantly more patients with LVSI-positive cervical cancer lesions >4 cm (stage I B2 and II A2) in the LRH group than in the ORH group (Odds Ratio [OR] 0.333, 95% confidence interval [CI] 0.157-0.706, p=0.005), but there was no significant between-group difference in the number of patients with LVSI-positive cervical cancer lesions ≤4 cm (stage IA2, IB1, and IIA1) (p=0.053). No significant between-group differences were found in the number of patients with LVSI-positive cervical cancer lesions ≤2 cm and >2 cm (p=0.271 and 0.605, respectively) or ≤2 cm and 2-4 cm (stage IB1) (p=0.690 and 0.207, respectively). (Table 3)

Table 3

Lymph-Vascular Space Invasion According to Size of Cervical Cancer Lesion in Patients Who Underwent Laparoscopic versus Open Radical Hysterectomy

		LVSI (−)		LVSI (+)		Total	P value
			%		%
LRH/ORH	Cervical cancer lesions≤4cm	88/410	75.21/65.92	29/212	24.79/34.08	117/622	0.053
	Cervical cancer lesions >4 cm	13/217	41.94/68.45	18/100	58.06/31.55	31/317	0.005
LRH/ORH	Cervical cancer lesions≤2cm	51/212	71.83/64.24	20/118	28.17/35.76	71/330	0.271
	Cervical cancer lesions>2 cm	50/415	64.94/68.14	27/194	35.06/31.86	77/609	0.605
LRH/ORH (stage IB1)	Cervical cancer lesions≤2cm	24/101	70.59/65.16	10/54	29.41/34.84	34/155	0.690
	Cervical cancer lesions 2~4cm	28/151	73.68/62.66	10/90	26.32/37.34	38/241	0.207

Abbreviations: LRH, laparoscopic radical hysterectomy; ORH, open radical hysterectomy.

Lymph Node Metastasis and LVSI

Twenty-three patients (15.54%) in the LRH group and 188 patients (20.02%) in the ORH group had lymph node metastasis; the difference was not significant (p=0.220). No between-group difference was found in the number of LVSI-positive patients regardless of lymph node metastasis (p=0.826 and 0.831, respectively). Forty-three patients (29.05%) in the LRH group and 318 patients (33.87%) in the ORH group underwent aortic lymph node dissection, and all aortic lymph node metastases were associated with pelvic lymph node metastases. Furthermore, the number of LVSI-positive patients with lymph node metastasis was markedly higher than the number of LVSI-positive patients without lymph node metastasis in both groups (OR 3.479, 95% CI 1.395–8.676, p=0.008 and OR 2.810, 95% CI 2.025–3.898, p=0.000, respectively). Finally, the percentage of LVSI-positive patients among the patients with lymph node metastasis and aortic lymph node metastases was also significantly higher than among the patients without lymph node metastasis and aortic lymph node metastases (OR 2.881, 95% CI 2.118–3.919, p=0.000 and OR 5.625, 95% CI 1.905–16.611, p=0.001) (Table 4).

Table 4

Lymph-Vascular Space Invasion in Cervical Carcinoma Patients with Lymph Node Metastases Who Underwent Laparoscopic versus Open Radical Hysterectomy

		LVSI (−)		LVSI (+)		Total	P value
			%		%
LRH/ORH	Lymph node metastatic carcinoma	10/89	43.48/47.34	13/99	56.52/52.66	23/188	0.826
	No	91/538	72.80/71.64	34/213	27.20/28.36	125/751	0.831
LRH/ORH	Aortic lymph node metastasis	0/5	0/33.33	1/10	100/66.67	1/15	1.000
	No	28/220	66.67/72.61	14/83	33.33/27.39	42/303	0.465

Abbreviations: LRH, laparoscopic radical hysterectomy; ORH, open radical hysterectomy.

Interstitial Infiltration Depth, Differentiation Degree, or Periuterine Invasion and Prevalence of LVSI

Among the patients with tumors showing interstitial infiltration depth >1/2 cm and ≤1/2 cm, there were 29 and 18 cases of positive LVSI in the LRH group, and 224 and 88 cases of positive LVSI in the ORH group, respectively; no significant between-group differences were observed (p=0.812 and 1.000). Among the patients with tumors showing high, moderate, and low differentiation, there were no statistical between-group differences in LVSI (p=0.208, 0.459, and 1.000). None of patient’s tumors were positive for parametrial infiltration (Table 5).

Table 5

Lymph-Vascular Space Invasion According to Interstitial Infiltration Depth and Differentiation in Patients Who Underwent Laparoscopic versus Open Radical Hysterectomy

		LVSI (−)		LVSI (+)		Total	P value
			%		%
LRH/ORH	Interstitial infiltration depth ≤1/2 cm	42/203	70.00/69.76	18/88	30.00/30.24	60/291	0.812
	Interstitial infiltration depth >1/2 cm	59/424	67.05/65.43	29/224	32.95/34.57	88/648	1.000
LRH/ORH	High differentiation	5/40	55.56/78.43	4/11	44.44/21.57	9/51	0.208
	Moderate differentiation	81/533	70.43/66.79	34/265	29.57/33.21	115/798	0.459
	Low differentiation	15/54	62.50/60.00	9/36	37.5/40.00	24/90	1.000

Abbreviations: LRH, laparoscopic radical hysterectomy; ORH, open radical hysterectomy.

Survival Analysis

Median follow-up was 47 months (range, 36–74months) in the ORH group versus 63 months (range, 36–75months) in the LRH group. Among all the 715 patients who were followed up, 5 patients had recurrence in the LRH group and 17 patients had recurrence in the ORH group, 1 patients died in the LRH and 5 patients died in the ORH group (Table 6). The 3-Year OS were 98.91% in the LRH group and 99.20% in the ORH group (Log-Rank P=0.564, Figure 1C). Accordingly, the 3-Year mortality were 1.09% and 0.8% (Log-Rank P=0.564). The 3-Year DFS were 94.75% and 97.27% for the LRH and ORH groups, respectively. The 3-Year DFS in the LRH group is lower, but there was no significance (Log-Rank P=0.187, Figure 1D). Besides, there were 3 deaths in the LVSI negative patients and 3 deaths in the LVSI positive patients. The 3-Year OS were 99.41% and 98.56%, respectively (Log-Rank P=0.259, Figure 1A). The 3-Year DFS were 98.22% in the LVSI negative patients and 93.78% in the LVSI positive patients, the difference was significant (Log-Rank P=0.002, Figure 1B).

Table 6

The Follow-Up Cases of the Two Groups from 2013 to 2016

LRH/ORH	FIGO Stage	LVSI (−)		LVSI (+)		Total	LVSI (−)		LVSI (+)
			%		%		Recurrence	Death	Recurrence	Death
	IA2	2/4	2.17/0.64	1/3	1.09/0.48	3/7	0/0	0/0	0/0	0/0
	IB1	32/167	34.78/26.81	13/81	14.13/13.00	45/248	0/2	0/0	1/2	0/1
	IB2	3/69	3.26/11.08	2/15	2.17/2.41	5/84	0/1	0/0	1/3	0/0
	IIA1	18/113	19.57/18.14	4/44	4.35/7.06	22/157	1/1	1/1	1/4	0/2
	IIA2	4/94	4.35/15.09	13/33	14.13/5.30	17/127	1/3	0/1	0/1	0/0
	Total	59/447	64.13/71.75	33/176	35.87/28.25	92/623	2/7	1/2	3/10	0/3

Abbreviations: LRH, laparoscopic radical hysterectomy; ORH, open radical hysterectomy.

Figure 1

Survival outcomes of the followed up patients. (A) Overall survival (OS) curves of the lymph-vascular space invasion (LVSI) negative versus positive patients. (B) Disease-free survival (DFS) curves of the LVSI negative versus positive patients. (C) OS curves of the patients in the laparoscopic radical hysterectomy (LRH) group versus open radical hysterectomy (ORH) group. (D) DFS curves of the patients in the LRH group versus ORH group.

Furthermore, univariate and multivariate Cox analysis were conducted to identify the factors associated with the DFS of the cervical cancer patients. Through univariate Cox analysis, tumor size, LVSI, interstitial infiltration depth, and lymph node metastases were identified to be associated with the DFS of the patients. Then, tumor size (HR=2.369, 95CI%: 1.215–3.211, P=0.008), LVSI (HR=3.417, 95CI%: 1.457–8.011, P=0.005) and interstitial infiltration depth (HR=2.123, 95CI%: 1.123–4.065, P=0.021) were proved to be independent prognostic factors of DFS for the cervical cancer patients through multivariate Cox analysis.

Discussion

Since the first report in 2018,8,9 more studies16–18 have focused on the possible adverse effects of LRH on the prognosis of patients with early cervical cancer, and some have recommended ORH for cervical cancer patients.19 LVSI, tumor size, lymph node metastasis, interstitial infiltration depth, and parametrial infiltration all adversely influence the prognosis of early cervical cancer patients,20,21 and similar results were found in this study. In particular, we compared the prevalence of LVSI in cervical cancer patients who underwent LRH or ORH, and found that the number of patients with LVSI-positive cervical cancer lesions >4 cm was significantly higher in the LRH group than in the ORH group (p=0.005). This finding suggests that in case of LVSI it would be dangerous to treat patient in laparoscopy, especially in case of bulky tumor.

Hu et al16 also found that at a tumor diameter >4 cm, the overall survival (OS) and progression-free survival (PFS) in a cohort of patients who underwent LRH were significantly shorter than in those who underwent abdominal radical hysterectomy (ARH), and they recommended ARH as the first-line surgical treatment option when the patient’s tumor diameter is >4 cm. Pedone Anchora L et al observed in their study22 that at a tumor size >20 mm, LRH, compared with ORH, was significantly associated with an increased relapse rate, and they identified tumor size as the primary factor influencing surgical approach selection. In our study, however, no significant between-group differences in LVSI were found according to cervical cancer lesion size ≤2cm and >2 cm, clinical stage, lymph node metastasis, and interstitial infiltration depth. The 3-year DFS of the patients in the LRH group is lower, but there was no significant between-group difference. Further, in our study, it would be more likely that LVSI is associated with a higher risk of lymph node metastases, regardless of LRH or ORH. There are studies23–27 indicating that LVSI, together with other pathological characteristics such as tumor size, result in an increased risk of lymph node metastasis, that is one of the most important prognostic factors in cervical cancer.

Unlike ORH, LRH requires the establishment of a pneumoperitoneum through CO2-insufflation and the application of a uterine manipulator and electric instruments. The continuously perfusing and flowing CO2 in pneumoperitoneum insufflation has a mechanical effect of diffusing the detached tumor cells and tissue particles,28–30 while the friction and compression effects of the uterine manipulator on the upper vagina and tumor tissues, and peritoneal contamination during intracorporal colpotomy may increase the risk of intraperitoneal tumor exposure, tumor cell detachment, local implantation and distant dissemination and metastasis31–33. A larger cervical cancer tumor size corresponds to a higher risk of tumor exposure, compression, and detachment and a greater risk of tumor dissemination to the abdominopelvic cavity during laparoscopic surgery.34–38 In our study, there were significantly more LVSI-positive patients with cervical cancer lesions >4 cm in the LRH group than in the ORH group and LVSI is associated with a higher risk of lymph node metastases, which shows that cervical cancer lesion size >4 cm greatly increases the risks of tumor exposure, dissemination and intralymphatic metastasis. We also found there was a lower 3-Year DFS in the patients with positive LVSI than those without positive LVSI. Considering the possible adverse effects of CO2-insufflated pneumoperitoneum and the application of uterine manipulators and electric instruments, LRH may be a less-preferred option for surgical treatment of patients with cervical cancer lesions >4 cm or lymph node metastasis.

In conclusion, a higher risk of lymph node metastasis and a lower 3-Year DFS was found in the LVSI-positive patients. In case of LVSI, it would be dangerous to treat patient in laparoscopy, especially in case of cervical cancer lesions >4cm. Thus, LRH may lead to possible adverse effects on the prognosis of these patients. ORH should be the first-line surgical treatment option for these patients. Review this article, we provide a new perspective to explore the adverse effects of LRH on cervical cancer, and we do have some new findings, but due to the limitation of small sample size and short follow-up time, further study is needed to identify the possible mechanisms of adverse effects of LRH on the prognosis of patients with cervical cancer.