Bilateral ultrastaging of sentinel lymph node in cervical cancer: Lowering the false-negative rate and improving the detection of micrometastasis

doi:10.1016/j.ygyno.2012.08.035

Gynecologic Oncology

Volume 127, Issue 3, December 2012, Pages 462-466

https://doi.org/10.1016/j.ygyno.2012.08.035 Get rights and content

Abstract

Objective

To evaluate the sensitivity of sentinel node (SN) ultrastaging and to define parameters that may reduce the overall false-negative rate in women with early-stage cervical cancer.

Methods

We analyzed data from a large retrospective multicenter cohort group with FIGO stages IA–IIB cervical cancer in whom at least one SN was identified and systematic pelvic lymphadenectomy was uniformly performed. All who were SN negative by initial evaluation were subjected to ultrastaging.

Results

In all, 645 patients were evaluable. SN were detected bilaterally in 72% of cases and unilaterally in 28%. Patients with optimal bilateral SN detection were significantly more likely to have any metastasis detected (33.3% vs. 19.2%; P < 0.001) as well as micrometastasis detected in their SN (39.6% vs. 11.4%). SN ultrastaging resulted in a low overall false-negative rate of 2.8% (whole group) and an even lower false-negative rate of 1.3% for patients with optimal bilateral mapping. Patients with false-negative SN after ultrastaging had a higher prevalence of LVSI and more frequent unilateral SN detection. Sensitivity of SN ultrastaging was 91% (95% CI: 86%–95%) for the whole group and 97% (95% CI: 91%–99%) in the subgroup with bilateral SN detection.

Conclusion

These data confirm previous observations that optimal bilateral SN detection substantially decreases the false negative rate of SN ultrastaging and increases detection of micrometastasis. In patients with bilateral SN detection, the sensitivity of SN ultrastaging is not reduced in more advanced stages of the disease. SN mapping and ultrastaging should become standard practice in the surgical management of early-stage cervical cancer.

Highlights

► Bilateral SN detection substantially decreases the false-negative rate of SN ultrastaging and increases detection of metastases, especially micrometastasis. ► SN ultrastaging improves metastatic lymph node detection, especially low-volume disease, including micrometastasis and isolated tumor cells. ► In patients with bilateral SN detection, sensitivity of SN ultrastaging is not reduced in more advanced stages of the disease.

Introduction

Metastatic involvement of pelvic lymph nodes is the most important prognostic factor in early-stage cervical cancer. The use of sentinel lymph node (SN) biopsy is being explored extensively in this population. SN evaluation has been reported to improve the accuracy of lymph node staging [1], [2], [3], assist in triaging patients toward surgery or radiotherapy [4], and facilitate the selection of candidates for fertility-sparing treatment [5]. Furthermore, detection of nodal metastasis is potentially improved by pathologic ultrastaging, which includes multiple serial sectioning and immunohistochemical assessment of the SN. SN ultrastaging allows for the detection of low-volume metastasis of less than 2 mm, including both micrometastasis (MM) and isolated tumor cells (ITC). We have recently shown that micrometastasis but not isolated tumor cells are associated with an equivalent risk for overall survival as the presence of macrometastasis [2].

The major concern about performing SN alone (that is, without simultaneous systematic pelvic lymphadenectomy) is that the SN biopsy will yield false-negative staging results. In other words, there may be a metastasis present in a regional non-sentinel lymph node that is not detected with SN ultrastaging. Low false-negative rates of SN staging in cervical cancer patients have been reported from single institutional experiences, especially in tumors smaller than 2 cm [6], [7], [8], [9]. In contrast, a German multicenter validation study observed an unsatisfactory sensitivity of SN biopsy (77.7%); however, ultrastaging of SN had not been performed in this group's study, so important data on micrometastasis were missing for the analysis [10]. More recently, a French group reported on a prospective study in which SN staging reached a sensitivity of 92% in the whole cohort of 135 patients with small tumors of stages IA to IB1 and no false-negative case was found in a subset of patients with a bilaterally detected SN [11].

The aims of this study were to evaluate the false-negative rate of SN ultrastaging in patients with operable stages IA–IIB cervical cancer, and to identify parameters that may have a negative impact on SN sensitivity. To our knowledge, this is the largest study on the SN concept in early-stage cervical cancer published so far.

Section snippets

Patients and methods

We analyzed data from a multicenter retrospective cohort study that included 645 patients in whom SN biopsy followed by systematic pelvic lymphadenectomy was performed, and from whom SN ultrastaging data were available.

The following inclusion criteria were applied for enrollment into the study: FIGO stages IA–IIB cervical cancer, primary surgical treatment, SN detection on at least one pelvic side followed by systematic pelvic lymphadenectomy in standard anatomical regions, ultrastaging

Results

Basic characteristics of the total study population are summarized in Table 1. Final lymph node status based on a combination of SN ultrastaging and nSN evaluation showed ITC in 4% of cases, micrometastasis in 7%, macrometastasis in 21%, and negative nodes in 68%.

SN were accurately detected on both sides (bilateral optimal mapping) in 72% of cases (n = 463), while unilateral detection was noted in 28% (n = 182) (Table 2). The majority of unilaterally detected SN were found on the right side

Discussion

In this large multicenter study we observed a high sensitivity (97%) and low false-negative rate (1.3%) of SN staging when SN were detected bilaterally. Bilateral SN detection and pathologic ultrastaging increased the detection of micrometastasis. Furthermore, pathologic ultrastaging of SN allowed for the identification of lymph node metastasis in 11% of patients with only low-volume disease in SN that would be missed by standard pathologic processing.

The main limitation of our study is its

Conflict of interest statement

The authors have no conflicts of interest to disclose.

Acknowledgments

The study has been supported by grant no. RVO‐VFN64165/2012 from the Ministry of Health of the Czech Republic, by Charles University in Prague (UNCE 204024) and PRVOUK-P27/LF1/1.

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Lymph node metastases (pN+) in presumed early-stage cervical cancer negatively impact prognosis. Using federated learning, we aimed to develop a tool to identify a group of women at low risk of pN+, to guide the shared decision-making process concerning the extent of lymph node dissection.
Women with cervical cancer between 2005 and 2020 were identified retrospectively from population-based registries: the Danish Gynaecological Cancer Database, Swedish Quality Registry for Gynaecologic Cancer and Netherlands Cancer Registry. Inclusion criteria were: squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma; The International Federation of Gynecology and Obstetrics 2009 IA2, IB1 and IIA1; treatment with radical hysterectomy and pelvic lymph node assessment. We applied privacy-preserving federated logistic regression to identify risk factors of pN+. Significant factors were used to stratify the risk of pN+.
We included 3606 women (pN+ 11%). The most important risk factors of pN+ were lymphovascular space invasion (LVSI) (odds ratio [OR] 5.16, 95% confidence interval [CI], 4.59–5.79), tumour size 21–40 mm (OR 2.14, 95% CI, 1.89–2.43) and depth of invasion>10 mm (OR 1.81, 95% CI, 1.59–2.08). A group of 1469 women (41%)—with tumours without LVSI, tumour size ≤20 mm, and depth of invasion ≤10 mm—had a very low risk of pN+ (2.4%, 95% CI, 1.7–3.3%).
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Finding the sentinel lymph node in early cervical cancer: When is unusual not uncommon?
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To report our institutional experience with sentinel lymph node (SLN) detection using indocyanine green for cervical cancer, in terms of detection rates, detection of SLN at unusual locations, and factors associated with unusual SLN locations. In addition, we performed a systematic review of the literature to identify factors associated with unusual SLN localizations.
This is a retrospective cohort study of women with early-stage cervical cancer undergoing sentinel lymph node mapping between 2015 and 2019. Outcome measures were SLN detection rates, detection rates of unusual locations for SLN and risk factors for aberrant lymphatic drainage pathways. In addition, studies evaluating factors associated with unusual SLN locations in cervical cancer were assessed in a systematic review.
A total of 100 patients were included. The unilateral SLN detection rate was 88%, whereas the bilateral detection rate was 75%. In 37% of all patients, SLN were found in unusual locations, and in 10% of patients SLN were solely found in unusual locations. Body mass index (BMI) was associated with finding SLN in unusual locations, with unusual nodes detected in 52% of patients with BMI <25 kg/m² and in 28% of patients with BMI ≥25 kg/m². The systematic review identified three studies, identifying lower BMI, nulliparity and tumor size of >20 mm as factors associated with finding SLN at unusual locations.
Aberrant drainage sites represent a significant proportion of SLN detected in cervical cancer. Factors associated with increased rates of unusual nodal locations are a lower BMI, with a possible association with nulliparity and tumor size of >20 mm.
Value of routine cytokeratin immunohistochemistry in detecting low volume disease in cervical cancer
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Citation Excerpt :
Lymph node involvement is the strongest prognostic factor for survival in cervical cancer and impacts therapeutic strategy for patients [1]. To assess nodal stage accurately and efficiently, the sentinel lymph node (SLN) procedure in cervical cancer has emerged [2,3]. This procedure maps lymphatic drainage from the primary tumor by injecting a tracer in the cervix.
In cervical cancer, sentinel lymph nodes (SLNs) are processed according to the pathological ultrastaging protocol. According to current guidelines, immunohistochemistry with pancytokeratin antibodies is performed in addition to step sectioning with hematoxylin and eosin (H&E), aiding the detection of low volume disease (micrometastasis and isolated tumor cells (ITC)). We studied the added clinical value, and costs, of routine immunohistochemistry (IHC).
We retrospectively included all FIGO stage IA-IIA1 cervical cancer patients who had undergone SLN procedures at UMC Utrecht from 2008 to 2020. Pathological data were derived from the Dutch Pathology Registry (PALGA) including SLN tumor status and number of slides stained with IHC.
In total 234 cervical cancer patients were included. In the 516 surgically resected SLN specimens, 630 SLNs were discovered by the pathologist. Hereof, 579 SLNs from 211 patients were routinely processed with IHC. IHC identified three patients with micrometastasis and five patients with ITC undetected with H&E staining. Thereby, IHC significantly increased the number of patients with low volume disease from 11 (5.3%) to 19 patients (9.1%) (p = 0.04). To achieve this, 3791 slides were stained with IHC at an estimated additional cost of €94,775. In 1.4% (95% CI 0.3%–4.3%) of patients routine use of IHC adjusted the adjuvant treatment.
Routine use of IHC increases detection of low volume disease in cervical cancer SLNs compared to step sectioning with H&E alone by nearly 4%, with an impact on therapeutic strategy-decisions in about 1% of patients. In view of the high associated costs, cost-effectiveness of routine IHC is questionable.
Sentinel node in gynecological cancers
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Sentinel node biopsy (SNB) is a minimally invasive technique for assessing the nodal involvement in some gynecological cancers. This technique is safe and feasible in early stages of cervical and vulvar cancers, while is still matter of controversy in early endometrial, vaginal and ovarian cancers. It is indicated for squamous cell carcinoma of vulva with T < 4 cm, > 1 mm depth of invasion and cN0. In cervical cancer, it is advised in stages IA1 with lymphovascular invasion to IB2. In endometrial cancer, it may be considered in patients with apparent uterine-confined disease and cN0 or no obvious extra-uterine disease at exploration or even in high-risk histologies. Preoperative lymphoscintigraphy and SPECT/CT images are crucial to mapping the lymphatic drainage of gynecologic cancers for planning a tailored surgery. Indocyanine green-^99mTc-nanocolloid has been recently used in vulvar and cervical cancers with good results, but remains to be confirmed in further studies. Intraoperatively, the handheld gamma probe may be supplemented with the use of a portable gamma camera or an intraoperative freehand SPECT. The ultra-staging should be performed in negative sentinel nodes at hematoxylin and eosin analysis for detecting micro-metastatic disease. Finally, SNB should be done in institutions with expertise in this procedure.
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To evaluate the oncologic and obstetric outcomes of patients with low-risk cervical cancer who underwent conization and lymphatic evaluation to preserve fertility.
Data were collected retrospectively from September 2013 to February 2021. Eligibility criteria included Women with cervical cancer (aged <45 years) who underwent fertility preservation treatment, [stage IA1 with positive lymphovascular space invasion (LVSI), stage IA2, or stage IB1 (≤2 cm) with less <10 mm cervical stromal invasion, according to the International Federaltion of Gynecology and Obstetrics (FIGO) 2018 staging system] aged ≤45 years who wished to preserve their fertility were included in this study. All patients were treated with cervical conization(s) and laparoscopic lymph node evaluation [pelvic lymphadenectomy and/or sentinel lymph node (SLN) mapping]. Oncologic and obstetric outcomes were evaluated.
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Cervical conization with lymph node assessment by SLN mapping/lymphadenectomy is an oncologic safe procedure in patients with low-risk cervical cancer.
Ultrastaging protocol in sentinel lymph node for apparent early stage ovarian cancer
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The objective of the present study is to determine the role of sentinel lymph node (SLN) ultrastaging in apparent early-stage ovarian cancer.
We previously demonstrated the feasibility of SLN in early-stage ovarian cancer in a pilot study and in a clinical trial (NCT03452982). The SLN of the 30 patients involved in both were processed following an ultrastaging protocol. The cost of ultrastaging processing was also reported.
A SLN was detected in up to 91.3% and 90% in the pelvic and para-aortic region, respectively. In all cases, a SLN was detected at least in one field, pelvic or para-aortic. The mean time from injection to SLN resection was 53.3 ± 20.3 min. Two of 30 (6.6%) patients had a contralateral SLN in the para-aortic field, but no patients had contralateral SLN within the pelvic field after injection. The mean number of harvested SLN was 2.1 ± 1.4 (range: 0–5) and 2.7 ± 1.5 (range: 0–7) in the pelvic and para-aortic region, respectively.
Two patients were upgraded to stage IIIA1 because of lymph node metastasis. In the first case, based on single sections and haematoxylin and eosin (H&E) examination, a pelvic SLN micrometastasis (1 mm) was found on the first H&E section. By using the ultrastaging protocol, the size of the metastasis was increased to 2.1 mm (macrometastasis). In the same patient, the ultrastaging study of the inframesenteric para-cava SLNs found isolated tumour cells in the subcapsular and interfollicular lymph nodes sinus in one of the two SLN harvested (in one of the sections at the fourth and fifth ultrastage levels). The other upstaged case was a para-aortic macrometastasis in a patient in whom the SLN was not identified in the para-aortic field because of the absence of migration from the infundibulo-pelvic stump injection.
The cost of ultrastaging in each patient depended on the total number of SLN retrieved, averaging 96.8 € (range: 0–230.5) and 124.5 € (range: 0–322.7€) for pelvic and para-aortic SLN, respectively.
A uniform protocol for ultrastaging is essential for lower-volume metastasis detection and to provide reproducible information between upcoming studies, as evidence about SLN in ovarian cancer is growing.

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^☆: The study has been supported by grant no. RVO‐VFN64165/2012 from the Ministry of Health of the Czech Republic. No funding has been received from the National Institutes of Health (NIH); Welcome Trust; Howard Hughes Medical Institute (HHMI); or other similar organizations.

¹: Formerly from the Department of Pathology and Gynecology, VU Academic Medical Center, Amsterdam, The Netherlands.

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Bilateral ultrastaging of sentinel lymph node in cervical cancer: Lowering the false-negative rate and improving the detection of micrometastasis☆

Abstract

Objective

Methods

Results

Conclusion

Highlights

Introduction

Section snippets

Patients and methods

Results

Discussion

Conflict of interest statement

Acknowledgments

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Ann Oncol

Gynecol Oncol

Gynecol Oncol

Gynecol Oncol

Surg Oncol

Lancet Oncol

Ultrastaging improves detection of metastases in sentinel lymph nodes of uterine cervix squamous cell carcinoma

Am J Surg Pathol