Interpretation
We found that among patients with metastases, 95.65% had SLN metastases, suggesting that SLN is a rather sensitive assessment indicator of metastatic lymph nodes. Among methods of assessing the PLN status, SLNB is more suitable than imaging techniques16. Moreover, compared with PLND, SLNB reduces complications of PLND17, and no difference was observed in the recurrence-free survival rates of PLND and SLNB by a prospective trial18. Therefore, SLNB may be used as an alternative to PLND to prevent unnecessary and harmful interventions.
In this study, we explored the new application value of CNS as a promising SLN tracer for SLNB in early-stage cervical cancer. CNS is an advanced nanotechnology that consists of small molecules with lymphatic tropism. CNS with nanoparticles measuring 150 nm in diameter can pass readily through lymphatic vessels (diameter: 120–500 nm), but not through capillaries (diameter: 20–50 nm). Then, the CNS is identified, engulfed by macrophages, and brought to lymphatic vessels, such that it accumulates in the lymphatic system; therefore, CNS effortlessly stains lymph nodes. No patient exhibited anaphylactic reactions or serious adverse events in this study; this may be because CNS does not enter the bloodstream. Accordingly, SLNB with CNS should be considered safe. In recent years, CNS has proven to be beneficial as a lymph node tracer that allows lymph nodes to be explored during surgery for breast cancer, thyroid cancer, and gastric cancer19-21. For cervical cancer, the application of CNS was attempted with SLNB in a limited sample size of 40 patients in 2017, with DR of 95% (38/40), sensitivity of 100% (5/5), and NPV of 100%22. Therefore, our study was the first prospective study with a large sample size; it demonstrated a promising overall DR (91.29%), sensitivity (92.86%), and high NPV (99.29%), especially for patients with tumours smaller than 20 mm (97.75%, 100%, and 100%, respectively), thereby indicating its clinical value for SLNB in early-stage cervical cancer.
These indicators mentioned above in the first prospective multi-centre study that enrolled 590 patients, using technetium (99mTc) and patent blue were 88.6%, 77.4%, and 94.3%23. In a recent systematic review, indocyanine green (ICG) used in SLNB had a reported DR of 78% to 100% and sensitivity of 50% to 100%24. However, the tracers reportedly had some limitations. Their dependence on special expensive imaging technology could deter their use in developing countries25, additionally, its use is technically and logistically challenging. The 99mTc is expensive and produces radioactive contaminants; The blue dye is associated with allergic reactions, blue discoloration of body fluids, and rare cardiovascular reactions26-27. Therefore, compared with the traditional agents mentioned, CNS in SLNB for early-stage cervical cancer not only has good diagnostic accuracy but is also safer, more economical, easier to use, and not dependent on imaging technology.
According to our data, 85.71% of detected 1456 SLNs were in expected locations (i.e., iliac vessels and obturator). Less common locations were the aortic (6.94%), presacral (4.33%), and parametrial (3.02%) regions. This is consistent with the results of a review of 3012 SLNs (blue dye and 99mTc) 28. Therefore, SLNB helps surgeons not only during direct SLN resection with less disruption of the lymphatic architecture, thus making the procedure easier and faster18, but also in identifying occult SLNs outside the traditional dissection boundaries.
When trying to determine which subgroup of patients can obtain more benefits from SLNB, we found that the DR of patients with <20 mm tumours was significantly higher than that of patients with ≥20 mm tumours. Moreover, the sensitivity, specificity, and NPV of SLNB also improved in patients with <20 mm tumours. Similar outcomes were reported in a prospective multi-centre study22 and a review that assessed more than 600 cases (blue dye and radio-colloid)29. Therefore, SLNB with CNS is a promising procedure for well-selected early-stage cervical cancer patients, such as patients with tumour size <20 mm.
The FNR in our study is 7.14% (two false-negative cases with negative pathologic ultrastaging results), and it ranged from 0% to 50% in previous studies30. We implemented an ideal pathologic ultrastaging method to detect micro-metastasis, to further explore the causes of the two false-negative cases31; negative results were obtained, that have appeared in previous report32. Furthermore, the common characteristics of these two patients were summarised: tumour diameters larger than 20 mm with presence of DSI and LVSI (Table S3). These findings are consistent with those of previous studies that reported that FNR was higher for larger tumours (>20 mm), those with DSI (≥50%), and those with LVSI (blue dye, radio-colloid, and ICG)16,33-34. The prevalence can be attributed to the hypothesis that metastatic disease can alter the lymphatic drainage pattern35. Cancer cells spreading from the primary cancer mass may block the lymphatic path to the first lymph node or nodes. This may explain why there were few cases with failed SLN detection or false-negative results. Regarding the false-negative results, the lymphatic drainage and tracer may bypass the true SLN, which may be falsely recognised as an alternative node (a true non-SLN)36-37. This situation may result in false-negative cases.
Previous studies demonstrated that DSI, LVSI, large tumour size, and positive PLNs were prognostic factors for clinical outcomes38-39, and that tumours larger than 20 mm and positive LVSI and DSI were significant risk factors for pelvic nodal metastasis40-41. We also found that tumours size, stage, and LVSI are independent risk factors for lymph node metastasis. The results of our study (CNS) are consistent with those of previous studies (blue dye, radio-colloid and ICG), which showed that FNR was higher for larger tumours (>20 mm), those with DSI (≥50%) and those with LVSI16,33-354. Therefore, to avoid the risk of false-negative cases and improve clinical outcomes, SLNB is more suitable for well-selected early-stage cervical cancer patients, especially in patients with tumours smaller than 20 mm, without DSI and LVSI, which are more likely benefit from SLNB. More clinical studies are required to confirm it.