The FSE aims to determine intraoperatively the SLN status. Current guidelines suggest to submit SLNs to FSE to decide if a hysterectomy is to be pursued during the same surgical intervention. When positive SLN is found at FSE, two decisions have to be made: on one hand, abandoning or performing the radical hysterectomy and on the other hand, abandoning or performing pelvic +/− paraaortic lymphadenectomy. If a radical hysterectomy is performed in this setting, it has to be considered nonetheless that combined treatment should be avoided due to the increased morbidity of surgery associated with adjuvant radiotherapy.[9,81] The SLN status is particularly crucial in case of fertility-sparing procedure since trachelectomy should not be performed if SLN are involved. This selective nodal sampling is particularly appropriate for the patients with the lowest risk of node involvement who are potentially eligible to simple trachelectomy or conisation.
The accuracy of FSE constitutes one of the main limitations of the SLN biopsy because of its limited diagnostic value and low ability to detect low-volume metastases such as Isolated Tumor Cells (ITCs) and micrometastases.[83–88] If all type of metastases are considered, sensitivity ranged from 42.3% to 87.5% and negative predictive value ranged from 89.7% to 98% whereas sensitivity ranged from 56.4% to 88.9% and negative predictive value ranged from 91% to 98.8% if ITCs were excluded.[84,85,87–90] These wide ranges of value in the literature might be explained by the poor sensitivity of FSE to detect low-volume metastases (ITCs and micrometastases), a better sensitivity for macrometastases and different SLN involvement rate in each population study.[84,89] Applying FSE in a population with less macrometastases and more low-volume metastases may lead to a decreased sensitivity of FSE. By simply bisecting the SLN along its long axis and staining with hematoxylin-eosin (HE), a non-negligible proportion of macrometastases would also be missed by FSE in 14.9% to 16.7% of cases.[84,90] Slicing 2-mm intervals the SLN along the short axis may increase the accuracy of intraoperative SLN examination.[86,87]
Several other factors may affect the false-negativity rate of FSE. A meticulous and specific protocol of pathologic processing, a higher volume of cases and the pathology team expertise might improve this technique.[85,90] The FSE is more efficient in smaller tumor size (<20 mm or <20 cm3) since the risk of low-volume metastases is higher in larger tumor.[84,90] The presence of LVSI and preoperative brachytherapy were also associated with false negativity of FSE.[84,90]
Clinical relevance by focusing on macroscopic suspicious nodes has to be determined. For grossly suspicious SLN, a single section seems appropriate and surrounding adipose tissue lied to the node should be spared to assess extranodal extension. The presence of enlarged nodes nonetheless had no impact on the accuracy of intraoperative examination SLN. By contrast, performing frozen section of grossly normal nodes is subject to debate and caution should be paid for small nodes. Levelling the blocks too deep may expose to the risk of loss of tissue for final pathologic examination and may adversely affects the quality of ultrastaging and immunohistochemistry. The accuracy of FSE might be improved by using alternative technique such as the one-step nucleic acid amplification (OSNA) technique or HPV DNA testing. Recently, Bizzarri et al. have shown that OSNA technique was efficient to detect intraoperatively low-volume metastases in SLN.
The small number of sampled nodes during the SLN biopsy allows to use more sensitive processing techniques such as immunohistochemistry and polymerase chain reaction (PCR). Ultrastaging, combining serial sectioning and immunohistochemistry, enhances to detect low-volume such as ITCs (<0.2 mm) and micrometastases (0.2–2 mm) which are rarely found with one-cut section and conventional coloration. This strategy increases the prevalence of node-positive patients up to 15% and improves the nodal staging, especially when SLN are detected in both hemipelvis. Moreover, performing ultrastaging and immunohistochemistry on non-SLN does not change the false-negative rate. Compared to OSNA technique, Santoro et al. highlighted that ultrastaging protocol had higher sensitivity and more reliability in prediction pelvic non-SLN status. SLNs bring also other valuable prognostic information. In patients with negative SLN, HPV-mRNA is a molecular marker for disseminated tumor cells and its detection in negative SLN is an independent prognostic factor of recurrence. In early-stage cervical, the SLN is the site of a pre-metastatic lymphangiogenesis (pre-metastatic niche) which lead to specific humoral immune response. In a near future, these immunologic factors will provide a more precise prognostic assessment compared to current surgicopathologic factors.
The clinical significance of low volume metastases (micrometastases and ITCs) remains unclear. According to the revised FIGO classification, the presence of micrometastases is classified as IIIC stage whereas ITCs might be noted without modifying the stage.[8,97] Few data are available on ITCs prognostic value but ITCs seem to have no impact on oncologic outcomes and do not change oncologic management. In a retrospective cohort of 894 patients, Horn et al. reported that patients with micrometastasis had a significant decreased 5-year disease-free survival compared to N0 patients (68.9 vs. 91.4%, P<0.001) and micrometastasis were found to be an independent prognostic factor by multivariate analysis. In a multicentric retrospective cohort of 645 patients, Cibula et al. found that micrometastases in SLN was associated with a similar overall survival as macrometastases, whereas ITCs had no impact on overall survival. These results were concordant to those published by Colturato et al. who have shown that micrometastasis was a significant risk factor for tumor recurrence (P≤0.030).
However, these results are counterbalanced by most recent prospective studies.43 In SENTICOL I cohort, no significant difference in disease-free survival between patients with positive or negative lymph nodes was found (91.6% vs. 90.4%, respectively; P=0.49). In addition, among the 8 patients with SLNs positive for micrometastases, only one had a vaginal recurrence. These preliminary results have to be interpretated with caution because ultrastaging was performed on SLN a few months after primary surgery and did not impact on adjuvant treatment decision. Nonetheless, these results were confirmed in the pooled analysis of SENTICOL I and II cohorts and patients with low-volume metastasis had similar disease-free survival (DFS) (92.7%) to N0 patients (93.6%). In a subset of 19 patients with low-volume metastases (10 with micrometastases and 9 with ITCs), the authors concluded that adjuvant treatment did not seem to affect the recurrence rate (P=0.5) and disease-free survival was comparable to those reported in historical cohorts.
Due to the low prevalence of ITCs and micrometastases, prospective multicenter clinical trials seem hardly appropriate to confirm these data and a large collaborative network cooperation would be required to determine the risk associated with these low-volume metastases in cervical cancer and their subsequent management.
Chin Clin Oncol. 2021;10(2):18 © 2021 AME Publishing Company