Feasibility of Sentinel Lymph Node Mapping With Carbon Nanoparticles in Cervical Cancer: A Retrospective Study

Abstract

Introduction

This retrospective study aims to investigate the feasibility of using carbon nanoparticles to detect sentinel lymph nodes (SLNs) in cervical cancer.

Methods

This study involved 174 patients with cervical cancer. Cervix tissues adjacent to the cancer were injected with 1 mL of carbon nanoparticles (CNPs) at the 3 and 9 o’clock positions according to the instructions. The pelvic lymph nodes were then dissected, and the black-stained sentinel lymph nodes were sectioned for pathological examination.

Results

Of 174 cases, 88.5% of patients (154/174) had at least 1 sentinel lymph node, and 131 patients (75.29%) had bilateral pelvic sentinel lymph nodes. The left pelvic lymph node was the most common sentinel lymph node (34.16%). At least 1 sentinel lymph node was observed in 285 out of 348 hemipelvises, with a detection rate of a side-specific sentinel lymph node of 81.89%. In total, 47 hemipelvises had metastasis of the lymph node, and 33 involved the sentinel lymph node, with a sensitivity of 70.21% and a false-negative rate of 29.79%. There were 238 hemipelvises with no metastasis of the lymph node, as well as negative sentinel lymph nodes, with a specificity of 100% and a negative predictive value of 94.44%. The univariate analysis demonstrated that risk factors included tumor size (OR .598, 95% CI: .369-.970) and deep stromal invasion (OR .381, 95% CI: .187-.779). The deep stromal invasion was the only variable for the false-negative detection of a sentinel lymph node.

Conclusion

Sentinel lymph node mapping with carbon nanoparticles might be applied to predict the metastasis of pelvic lymph nodes in cervical cancer. However, tumor size and deep stromal invasion might negative influence the detection rate of SLN.

Keywords

cervical cancer carbon nanoparticles sentinel lymph node mapping

Introduction

Cervical cancer is the fourth most commonly diagnosed cancer among women after breast, colorectal, and lung cancer. There were approximately 570,000 new cases and 311,000 cervical cancer deaths in 2018 worldwide.¹ In China, there were approximately 110,000 new cases and 55,000 cervical cancer deaths in 2018.² Persistent high-risk human papillomavirus (hrHPV) is the main cause of cervical cancer worldwide. The morbidity and mortality of cervical cancer have declined in developed countries due to HPV vaccine promotion and the regular screening strategies using hrHPV, Pap smears, and colposcopy alone or in combination.^3,4 In less-developed countries, however, cervical cancer is still one of the main causes of death for women.

Lymphadenectomy is the most common treatment for early cervical cancer. It is estimated that 14.8% of early cervical cancer patients have a metastasis of the lymph node.⁵ According to the staging system of the 2018 International Federation of Gynecology and Obstetrics (FIGO 2018), cases of lymph node metastasis are specifically designated as stage IIIC^*, demonstrating that lymph node metastasis is the main prognostic factor in cervical cancer. Lymph node metastasis is associated with various complications, including nerve injury, bleeding, and urinary tract complications after systematic pelvic lymph node resection.^6,7 Therefore, sentinel lymph node (SLN) mapping has received increasing attention.

SLN detection in penile, breast, and skin cancer is standard diagnostic management. SLN biopsy rather than systematic pelvic lymph node dissection has increasingly been applied in the standard procedures of early-stage cervical cancer cases. In 1995, SLN biopsy using the blue dye lymphazurin was first reported for cases of cervical cancer,⁸ with isosulfan blue reported for cases of endometrial cancer the following year.⁹ Carbon nanoparticle suspension (CNS) is a novel tracer applied in SLN biopsy for early-stage cervical cancer patients to increase lymph node retrieval.^10,11 In China, radical hysterectomy is widely used in the initial treatment of early-stage cervical cancer, while SLN biopsy is not. Therefore, we performed a retrospective study of SLN biopsy using CNS to evaluate the feasibility of SLN biopsy in early-stage cervical cancer.

Materials and Methods

Study Design and Patient Enrollment

A retrospective study was conducted of 174 cervical cancer patients who underwent SLN mapping from January 1, 2018 to August 31, 2021 at the First Affiliated Hospital with Nanjing Medical University. The ethics was approved by Ethic Committee of the first affiliated hospital with Nanjing medical university (approved number: 2022-SR-531). Informed consent of patients was obtained. The reporting of this study conforms to STROBE guidelines.¹² All patient details were de-identified before analysis. All patients had early-stage cervical cancer (<IIb) evaluated by imaging and histopathology via biopsy or loop excision. They underwent SLN biopsy followed by standard treatment (radical hysterectomy/modified radical hysterectomy and systemic pelvic lymphadenectomy, with or without sampling the para-aortic lymph node). The inclusion criteria were as follows: no evidence of bulky mass or dubious pelvic lymph nodes metastasis or distant metastasis according to imaging examinations before surgery; surgery was the initial treatment, and informed consent was provided. The exclusion criteria included those patients under 18 years of age or older than 80 years, pregnant women, the incidence of other tumors within 5 years, contraindication for surgically treated, and suspicions of more advanced stages (>IIa2) according to imaging and gynecological examinations. Five proficient gynecologic oncologists which had 3 years’ experience performed the SLN mapping.

CNS Injection and Surgical Procedure

Before CNS injection, the retroperitoneum was exposed, and lymph node basins were revealed. SLN mapping was conducted by injecting 1 mL containing 25 mg of CNS (Lummy Pharmaceutical Co., Chongqing, China; approval number H20073246) into the ectocervix at the 3 and 9 o’clock positions both superficially and deep into the stroma according to the previously reported methods.^10,11 Before injection, the contents were aspirated to confirm that CNS was not injected into vessels, and the syringe was kept in place for a few seconds after injection to reduce leakage. The lymphatic duct, which was stained black resulted in black-stained lymph nodes (Figure 1). SLN was defined as the first black-stained lymph node (s) or group of lymph nodes. Radical hysterectomy and systemic bilateral pelvic lymphadenectomy were conducted in all cases. Some cases underwent para-aortic lymph node sampling to the level of inferior mesenteric artery if there was a metastasis of pelvic SLNs according to the results of frozen sections of SLN.

Figure 1.

Black-stained lymph nodes by carbon nanoparticles (white arrows).

Histopathological Evaluation

Pathologist expert in gynecologic oncology examined all specimens, including SLNs and non-SLNs. SLN biopsies were staged similar to breast cancer, containing recognized prognostic data such as disease extent, tumor size, grade, type, status of lymph node, vascular invasion, marginal status, and receptor status.¹³ Hematoxylin-eosin staining (H&E staining) was performed to evaluate whether tumors affected the lymph node, and the specimen was divided in half in case it was not an SLN. Then we analyzed the detection rate of SLN, sensitivity, false-negative rate (FNR), specificity, and negative predictive value (NPV) to evaluate the feasibility of CNP in detecting SLN.

Statistical Analysis

The clinical data were retrieved from the medical documents. Descriptive statistics were applied to analyze demographic, clinical information, and SLN mapping characteristics. All statistical analyses were conducted using Stata software (version 15.1, Armonk, NY, USA). Categorical variables were analyzed by the chi-square test (continuity correction chi-square test or Fisher’s exact test). The t test or the χ² test was applicated in the univariate analysis to select variables for further multivariate analysis. Multivariate binary logistic regression analyses were used to identify the association between these independent factors and SLN detection. A P-value <.05 was considered statistically significant.

Results

From January 1, 2018 to August 31, 2021, 174 cases of early-stage cervical cancer which was predicted by gynecological examination and imaging before surgery underwent an SLN biopsy with CNS injection. No patient experienced anaphylactic reactions or other serious adverse events associated with CNS. Patient demographics, clinical information, and tumor characteristics are summarized in Table 1. The average age of the patients was 48 years (22–77 years). Final histological examinations revealed squamous carcinoma (74.71%). Stage IB1 was the most common stage (28.74%), followed by IB2 (24.71%), with 37 patients finally diagnosed as stage IIIC after surgery according to FIGO2018 due to pathological validation of the pelvic lymph node metastasis. Four stage IIB patients were also enrolled and had a lymphadenectomy; 24 patients (13.79%) underwent a previous loop excision. The most common surgery performed was laparotomic (68.97%), and 14 patients received neoadjuvant chemotherapy due to a tumor larger than 4 cm. Seventy-nine tumors were smaller than 4 cm and larger than 2 cm (45.4%), 62 patients (36.47%) had LVSI, 70 had superficial 1/3 stroma invasion (41.18%), and 85 were histological grade 3.

Table 1.

Clinic-Pathological Characteristics of Patients Enrolled in This Study.

Characteristics	Values	Percentage
Age (years)
<=45 years	71	40.8
>45 years	103	59.2
FIGO stage
IB1	50	28.74
IB2	43	24.71
IB3	13	7.47
IIA1	20	11.49
IIA2	7	4.02
IIB	4	2.3
IIIC	37	21.26
Neoadjuvant chemotherapy
No	160	91.95
Yes	14	8.05
Surgical approach
Laparotomic	120	68.97
Laparoscopic	54	31.03
Previous LEEP history(n)
No	150	86.21
Yes	24	13.79
Lymph node metastasis
No	137	78.74
Yes	37	21.26
LVSI
No	108	62.07
Yes	66	37.93
Tumor size
<2 cm	61	35.06
2-4 cm	79	45.4
>4 cm	34	19.54
Stroma invasion (170)
Superficial 1/3	74	42.53
Middle 1/3	29	16.67
Deep 1/3	35	20.11
Full invasion	36	20.69
Histological grade
G1	20	11.49
G2	69	39.66
G3	85	48.85
Histological type
Squamous cell carcinoma	130	74.71
Adenocarcinoma	36	20.69
Adenosquamous carcinoma	8	4.6

Tables 2 and 3 show the characteristics of patients who underwent SLN mapping. Among 174 patients, 154 had at least one SLN with a detection rate of 88.5%, and 131 (75.29%) had bilateral pelvic SLNs. No SLN was detected in 20 patients. The two most common SLN was the left pelvic lymph node (34.16%) and right pelvic lymph node (33.64%), and 26 patients (9.7%) had the SLN as the only positive node. Eleven patients were confirmed with lymph node metastasis on one side but no SLN.

Table 2.

Clinic-Pathological Factors for the Performance of SLN.

Variable	Unsuccessful detection	Successful detection	Univariate		Multivariate
Variable	Unsuccessful detection	Successful detection	OR (95%CI)	P	OR (95%)	P
Number of patients	43	131
Neoadjuvant chemotherapy	43	131	.561 (.177-1.775)	.338	.595 (.166-2.132)	.425
Yes	5	9
No	38	122
Histological grade			1.000 (.502-1.993)	.998	1.411 (.648-3.072)	.386
Gl-2	22	67
G3	21	64
Deep stromal invasion	42	132	.381 (.187-.779)	.007	.390 (.172-.888)	.025
Yes	17	50
No	25	82
Lymphovascular invasion	42	132	1.044 (.505-2.159)	.907	1.422 (.629-3.216)	.398
Yes	15	51
No	27	81
Tumor diameter	43	131	.598 (.369-.970)	.035	.628 (.348-1.134)	.123
<2 cm	11	50
2-4 cm	19	60
>4 cm	13	21
Histological type	42	131	.810 (.444-1.479)	.498	.816 (.429-1.553)	.536
Squamous cell carcinoma	29	100
Adenocarcinoma	11	25
Adenosquamous carcinoma	2	6

Table 3.

Location of Sentinel Lymph Nodes (SLNs) (n = 595) in Women With Early-Stage Cervical Cancer.

Variable	Value	%
Location of SLNs (n = 1724)
Parametrial	8	.46
Left pelvic	589	34.16
Right pelvic	580	33.64
Left common iliac	225	13.05
Right common iliac	251	14.56
Presacral	10	.58
Aortal	61	3.54
Detection rate
Failed detection	20	11.49
Unilateral detection	23	13.22
Bilateral detection	131	75.29

Table 4 displays that at least one SLN was detected in 285 of 348 hemipelvises with a side-specific SLN detection rate of 81.89%. In total, 47 hemipelvises had lymph node metastasis, 33 of which involved the SLN, with a sensitivity of 70.21% (defined as the ratio of patients with metastatic SLNs and patients with metastatic lymph nodes) (95% CI: 54.92%-82.21%) and a FNR of 29.79%. There were 238 hemipelvises with negative lymph node metastasis, which had all negative SLNs, with a specificity of 100% (95% CI: 98.02%-100%) and a negative NPV of 94.44% (95% CI: 90.65%-96.81%).

Table 4.

Performance of SLN Mapping Defined as Side-Specific.

	All n = 174, hemipelvis n = 285
Side-specific detection rate (%)	81.89
Sensitivity (%, 95% CI)	70.21 (54.92-82.21)
Specificity (%, 95% CI)	100 (98.02-100)
FNR (%)	29.79 (17.79-45.08)
FPR (%)	0
NPV (%, 95% CI)	94.44 (90.65-96.81)

Univariable logistic regression of the risk factors was performed to evaluate the detection of SLN (Table 2), showing that the risk factors included tumor size (OR .598, 95% CI: .369-.970; P = .035), and deep stromal invasion (OR .381, 95% CI: .187-.779; P = .007). For multivariate analysis, the variable selection was made by backward elimination, revealing that deep stromal invasion was the final variable for the detection of SLN.

Discussion

Lymph node metastasis is an important prognostic factor for patients with various cancers. Indeed, several studies have proved that SLN mapping is feasible and accurately predicts lymph node status in patients with endometrial cancer, with an overall detection rate of 86.9% (95% CI: 82.9%-90.8%). Using indocyanine green by cervical injection is preferred.¹⁴ For breast cancer, SLN biopsy is regarded as the gold standard for upfront axillary staging in early breast cancer. Furthermore, the clinical value, feasibility and safety of SLN biopsy have been confirmed in several randomized controlled trials.¹⁵ The present study showed that an SLN biopsy in an early-stage cervical cancer surgery was feasible. The side-specific detection rate of SLN by CNS was 81.89% for the 174 cervical cancer cases who underwent SLN biopsy. Cibula et al¹⁶ reported that the most widely studied tracers for SLN mapping are blue dye (methylene or isosulfan blue), technetium-99m radiocolloid (99mTc), and a combination of methods, with a sensitivity of 81%, 91%, and 97%, respectively.^17-19 Recently, an increasing number of studies have focused on fluorescent indocyanine green (ICG) applied for SLN mapping of cervical cancer as it could improve SLN detection.^20,21 Hou et al²² reported that the bilateral detection rate was significantly higher for combined ICG and CNP than CNP alone (75.3% vs 54.3%). However, ICG requires special fluorescence laparoscopy, whereas compared to traditional mapping techniques, CNS has more advantages, including no radiation exposure, no pain, no need for special instruments during operation, and a much lower cost. More evidences of using CNS for SLN mapping are required, especially comparisons to other tracers.

The feasibility of CNS in cervical cancer has been investigated. Wang et al²³ reported that the overall and bilateral detection rate were 93.3% (42/45) and 60.0% (27/45), respectively. Liu et al²⁴ summarized 21 patients with cervical cancer and found that the detection rate of SLN was 95.24% (20/21). Lu et al¹⁰ reported a detection rate of SLN in cervical cancer of 95% (38/40), as well as the NPV of 100%. Ya et al¹¹ reported that the detection rate of SLN of CNS was 91.29%, sensitivity of 96.65%, false-negative rate (FNR) of 4.35%, and negative predictive value (NPV) of 99.29%. In this study of 174 patients, 154 had at least one SLN, with a detection rate of 88.5% (154/174). In total, 47 hemipelvises had metastasis of the lymph node, 33 of which involved the SLN, with a sensitivity of 70.21% (95% CI: 54.92%-82.21%) and an FNR of 29.79%. The NPV of our study was 94.44%. This result is much lower than recent studies,^17-19 and the possible reason was that our study had lower sample size and the differences of proportions of all stages of cervical and perhaps because 123 patients had tumors over 2 cm accounting for 64.94% of the total, and only 70 patients had superficial 1/3 stroma invasion (41.18%). However, it did not influence the application of carbon nanoparticles in mapping SLN in cervical cancer overall.

Furthermore, logistic analysis was performed to reveal the factors associated with the false-negative detection of SLN, demonstrating that tumor size and invasion depth were significant variables in the univariate analysis. Larger tumors are more exposed so that some carbon nanoparticles may be injected into the tumor, and tumor central necrosis will cause CNP leakage into the vagina, reducing the detection rate of SLNs. Studies suggest that tumor size is an important factor that affects SLN mapping. Wydra et al²⁵ and Zarganis et al²⁶ reported that the SLN detection rate was 95.6% and 94.1%, respectively, when the diameter of the tumor was <2 cm, with an SLN detection rate of only 58% and 78.2%, respectively, when the tumor diameter was >2 cm. Ya et al¹¹ also confirmed a higher detection rate for cervical cancer patients with a tumor less than 20 mm (97.75% vs 71.91%). In our univariate analysis, although tumor size affected the SLN detection rate, in the multivariate analysis, only invasion depth was a significant variable for detection of SLN. Invasion depth also influenced the detection rate of SLN, as reported by Kim et al,²⁰ which was consistence with our study. However, no observed differences in detection rate were found based on the depth of the stromal invasion by Ya et al.¹¹ Wydra et al²⁵ also found that lymphatic vascular space invasion (LVSI) could increase the false-negative detection of SLN, but no differences were observed in our study. Furthermore, Wang et al²³ also reported that elevated body mass index was associated with decreased bilateral detection rate. In summary, tumor size and invasion depth negatively affect the detection of SLN, which was confirmed by previous studies. However, more studies are required to confirm the predictive value of invasion depth in SLN detection.

Limitations

Our study is a unicentral retrospective study with limitations. The main limitation of the dataset is that it fails to compare CNS with other tracer dyes or standard-of-care. Furthermore, the sample size of the present study was insufficient and not calculation and justification. To minimize selection bias, we enrolled all cases who underwent SLN biopsy with CNS. Although feasibility of SLN mapping in cervical cancer, based on the results of this study, it is impossible to conclude that this method can take the place of comprehensive pelvic lymph node dissection, which was also preferred for surgical treatment of cervical cancer. Future prospective work in multiple centers is required to confirm the importance of SLN biopsy in early-stage cervical cancer.

Conclusion

In conclusion, SLN mapping with CNS is feasibility and has a high detection rate in cervical cancer. It is feasible to apply CNS for SLN biopsy in early-stage cervical cancer patients. Tumor size and deep stromal invasion might negative influence the detection rate of SLN. We should be cautious about employing CNS for SLN biopsy for large or invasive tumors and instead choose systematic mediastinal lymphadenectomy. To assess whether SLN biopsies by CNS alone may be applied in early cervical cancer, large-scale prospective trials should be conducted. Urgently required are detailed protocols for SLN biopsies in cases of cervical cancer.

Supplemental Material

Supplemental Material - Feasibility of Sentinel Lymph Node Mapping With Carbon Nanoparticles in Cervical Cancer: A Retrospective Study

Supplemental Material for Feasibility of Sentinel Lymph Node Mapping With Carbon Nanoparticles in Cervical Cancer: A Retrospective Study by Wei Sun, Xing Chen, Shilong Fu, and Xiaohao Huang in Cancer Control.

Footnotes

Acknowledgments

We thank Freescience () for its linguistic assistance during the preparation of this manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Young Scholars Fostering Fund of the First Affiliated Hospital of Nanjing Medical University (PY2021003).

Ethical Approval

The ethics was approved by Ethic Committee of the first affiliated hospital with Nanjing medical university (approved number: 2022-SR-531).

ORCID iD

Xing Chen

Supplemental Material

Supplemental material for this article is available online.

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