Robotically assisted fluorescence-guided lymph node mapping with ICG for gynecologic malignancies: a feasibility study

Objective

Traditional techniques of sentinel lymph node (SLN) mapping for endometrial and cervical cancer present challenges which may be overcome with newer technologies such as near infrared (NIR) imaging of the fluorescent dye Indocyanine green (ICG). We performed a feasibility and dose-finding study to define the dose of ICG required to identify pelvic and para-aortic sentinel lymph nodes with robotically assisted endoscopic NIR imaging after cervical injection.

Methods

20 subjects with cervical or endometrial carcinoma were prospectively enrolled for SLN mapping. ICG was injected into the cervical stroma at 3 o'clock and 9 o'clock Data was collected for the number of nodes identified, the location of SLN's, the duration of procedure and the pathology characteristics of the SLN's compared to the non-sentinel lymph nodes.

Results

20 subjects received cervical injection with at least one SLN observed in 17 subjects. 15 of the 17 subjects who received 1 mg injections of ICG mapped a SLN for an observed detection rate of 88% (95% CI is (64%,99%)). A median of 4.5 SLN's was identified per patient. Three patients had lymphatic metastases, one of whom had a positive SLN. No adverse events were identified.

Conclusions

A 1 mg cervical injection of ICG identified a SLN in 88% of patients (95% CI is (64%, 99%)). Robotically assisted fluorescence imaging is a feasible, safe, time efficient and reliable method for lymphatic mapping in early stage cervical and endometrial cancer.     

Accuracy of sentinel lymph node detection following intra-operative cervical injection for endometrial cancer: A prospective study

Objective

The objective of this study is to evaluate the detection rate and diagnostic accuracy of sentinel lymph node (SLN) mapping using intra-operative cervical injection of filtered 99mTc-sulfur colloid (99mTc-SC) and patent blue in patients with endometrial cancer.

Methods

Prospective evaluation of the first 100 endometrial cancer patients undergoing SLN mapping using cervical injection of patent blue combined with filtered 99mTc-SC in the operating room was done. Patients underwent robotic-assisted lymphatic mapping with frozen section, hysterectomy, BSO, and completion bilateral lymphadenectomy (including para-aortic nodes in grade 2 and 3 tumors).

Results

At least one SLN was detected in 92% of patients; in 66 of these (72%) bilateral SLN were detected, and in 15 cases the SLN was in the para-aortic area. Eleven percent of all patients had lymph node metastases, and 4 of which had pre-operative grade 1 tumor. The SLN was the only positive node in 44% of the cases with positive nodes. Sensitivity was 89% with 1 false negative result, yielding a negative predictive value of 99% (95% CI 93-100). Specificity was 100% (95% CI 94-100), and positive predictive value was 100% (95% CI 60-100). No complications or anaphylactic reactions were noted.

Conclusions

Intra-operative SLN biopsy, using cervical injection of patent blue and filtered 99mTc-SC in endometrial cancer patients is feasible and yields adequate detection rates.     

The importance of applying a sentinel lymph node mapping algorithm in endometrial cancer staging: beyond removal of blue nodes

Objective

To determine the false-negative rate of a surgical sentinel lymph node (SLN) mapping algorithm that incorporates more than just removing SLNs in detecting metastatic endometrial cancer.

Methods

A prospective database of all patients who underwent lymphatic mapping for endometrial cancer was reviewed. Cervical injection of blue dye was used in all cases. The surgical algorithm is as follows: 1) peritoneal and serosal evaluation and washings; 2) retroperitoneal evaluation including excision of all mapped SLNs and suspicious nodes regardless of mapping; and 3) if there is no mapping on a hemi-pelvis, a side-specific pelvic, common iliac, and interiliac lymph node dissection (LND) is performed. Paraaortic LND is performed at the attendings' discretion. The algorithm was retrospectively applied.

Results

From 9/2005 to 4/2011, 498 patients received a blue dye cervical injection for SLN mapping. At least one LN was removed in 95% of cases (474/498); at least one SLN was identified in 81% (401/498). SLN correctly diagnosed 40/47 patients with nodal metastases who had at least one SLN mapped, resulting in a 15% false-negative rate. After applying the algorithm, the false-negative rate dropped to 2%. Only one patient, whose LN spread would not have been caught by the algorithm, had an isolated positive right paraaortic LN with a negative ipsilateral SLN and pelvic LND.

Conclusions

Satisfactory SLN mapping in endometrial cancer requires adherence to a surgical SLN algorithm and goes beyond just the removal of blue SLNs. Removal of any suspicious node along with side-specific lymphadenectomy for failed mapping are an integral part of this algorithm. Further validation of the false-negative rate of this algorithm is necessary.     

Impact of sentinel lymph node biopsy on the therapeutic management of early-stage endometrial cancer: Results of a retrospective multicenter study

Objective

The aim of this study is to assess the impact of sentinel lymph node (SLN) mapping and ultrastaging on the therapeutic management of early-stage endometrial cancer.

Methods

This retrospective multicenter study covered the period from January 2000 through December 2012 and included 304 women with presumed low- or intermediate-risk endometrial cancer. Node staging, histology results, and the effects of both on therapeutic management were assessed in two groups: those who underwent the SLN mapping and ultrastaging procedure and those treated in accordance with French guidelines.

Results

The SLN procedure detected metastatic lymph nodes in three times more women than lymphadenectomy did (16.2% versus 5.1%, p = 0.03). Specifically, it found 7 macrometastases (5.1%) and 15 micrometastases (11%); 11 of the latter (8.1%) were detected by serial sectioning and immunohistochemistry (IHC), that is, pathologic ultrastaging. The SLN biopsy false-negative rate was 0% (95% CI: 0–1.6%). This ultrastaging enabled us to modify the adjuvant therapy for half the patients. Women with micrometastases detected by the SLN procedure were treated with external beam radiotherapy (EBRT), while those whose SLN biopsies were negative received vaginal brachytherapy (VBT) or clinical follow-up. SLN biopsies had no impact on recurrence-free survival.

Conclusion

SLN mapping and ultrastaging improved staging and made it possible to adapt adjuvant therapy to risk of recurrence.     

Accuracy of robotic sentinel lymph node detection (RSLND) for patients with endometrial cancer (EC)

Objectives

Lymphadenectomy as a part of the staging for EC patients is controversial. Sentinel lymph node detection has been introduced to determine which patients would benefit from adjuvant therapy and to limit morbidities associated with a full pelvic nodal dissection. The purpose of this study is to evaluate diagnostic accuracy and detection rate of robotic sentinel lymph node detection (RSLND) as a part of the surgical staging for EC.

Methods

A retrospective database of all patients who underwent intraoperative lymphatic mapping using cervical injection methylene blue followed by RSLND as a part of their procedure was reviewed. Sentinel lymph node (SLN) was initially examined by routine Hematoxylin and Eosin (H&E) and ultrastaging by immunohistochemistry (IHC).

Results

Between 4/2011 and 6/2013, 120 patients with endometrial cancer underwent RSLND. The median age was 62 years (25–87); median BMI was 32 (18–76). Out of 120 patients, only one patient underwent RSLND with fertility preservation; and 119 patients underwent robotic hysterectomy and surgical staging with RSLND. None of the cases was converted to an open procedure. At least 1 SLN was detected in 86% (103/120) of the patients. Bilateral SLNs were detected in 52% (62/120). Positive nodes were identified in 8% (10/120) of the patients. Of those with SLN (+), 50% (5/10) were by ultrastaging (IHC) alone. No patients had positive regional nodes without SLN (+).

Conclusions

RSLND using methylene blue cervical injection can identify SLN in most patients with EC. IHC ultrastaging improves the detection of node positive disease when compared to traditional pathological evaluation.     

Establishing a sentinel lymph node mapping algorithm for the treatment of early cervical cancer

Objective

To establish an algorithm that incorporates sentinel lymph node (SLN) mapping to the surgical treatment of early cervical cancer, ensuring that lymph node (LN) metastases are accurately detected but minimizing the need for complete lymphadenectomy (LND).

Methods

A prospectively maintained database of all patients who underwent SLN procedure followed by a complete bilateral pelvic LND for cervical cancer (FIGO stages IA1 with LVI to IIA) from 03/2003 to 09/2010 was analyzed. The surgical algorithm we evaluated included the following: 1. SLNs are removed and submitted to ultrastaging; 2. any suspicious LN is removed regardless of mapping; 3. if only unilateral mapping is noted, a contralateral side-specific pelvic LND is performed (including inter-iliac nodes); and 4. parametrectomy en bloc with primary tumor resection is done in all cases. We retrospectively applied the algorithm to determine how it would have performed.

Results

One hundred twenty-two patients were included. Median SLN count was 3 and median total LN count was 20. At least one SLN was identified in 93% of cases (114/122), while optimal (bilateral) mapping was achieved in 75% of cases (91/122). SLN correctly diagnosed 21 of 25 patients with nodal spread. When the algorithm was applied, all patients with LN metastasis were detected; with optimal mapping, bilateral pelvic LND could have been avoided in 75% of cases.

Conclusions

In the surgical treatment of early cervical cancer, the algorithm we propose allows for comprehensive detection of all patients with nodal disease and spares complete LND in the majority of cases.     

Sentinel lymph node biopsy in the management of early-stage cervical carcinoma

Objectives

We aimed to determine the sentinel lymph node detection rates, accuracy in predicting the status of lymph node metastasis, and if pathologic ultrastaging improves the detection of micrometastases and isolated tumor cells at the time of primary surgery for cervical cancer.

Methods

A prospective, non-randomized study of women with early-stage (FIGO stage IA1 with lymphovascular space involvement — IIA) cervical carcinoma was conducted from June 2003 to August 2009. All patients underwent an intraoperative intracervical blue dye injection. Patients who underwent a preoperative lymphoscintigraphy received a 99 m Tc sulfur colloid injection in addition. All patients underwent sentinel lymph node (SLN) identification followed by a complete pelvic node and parametrial dissection. SLN were evaluated using our institutional protocol that included pathologic ultrastaging.

Results

SLN mapping was successful in 77 (95%) of 81 patients. A total of 316 SLN were identified, with a median of 3 SLN per patient (range, 0-10 SLN). The majority (85%) of SLN were located at three main sites: the external iliac (35%); internal iliac (30%); and obturator (20%). Positive lymph nodes (LN) were identified in 26 (32%) patients, including 21 patients with positive SLN. Fifteen of 21 patients (71%) had SLN metastasis detected on routine processing. SLN ultrastaging detected metastasis in an additional 6/21 patients (29%). Two patients had grossly positive LN at exploration, and mapping was abandoned. Three of 26 (12%) patients had successful SLN mapping; however, the SLN failed to identify the metastatic LN. Of these 3 false negative cases, 2 patients had a metastatic parametrial node as the only positive LN with multiple negative pelvic nodes including negative SLN. One patient with stage IA1 disease and lymphovascular invasion had unilateral SLN mapping and a metastatic common iliac LN identified on completion lymphadenectomy of the contralateral side that did not map. The 4 (5%) patients with unsuccessful mapping included 1 who had grossly positive nodes identified at the time of laparotomy; the remaining 3 occurred during each surgeon's initial SLN mapping learning phase.

Conclusion

SLN mapping in early-stage cervical carcinoma yields high detection rates. Ultrastaging improves micrometastasis detection. Parametrectomy and side-specific lymphadenectomy (in cases of failed mapping) remain important components of the surgical management of selected cases.     

Detection of sentinel lymph nodes in patients with endometrial cancer undergoing robotic-assisted staging: a comparison of colorimetric and fluorescence imaging

Objective

To retrospectively compare results from lymphatic mapping of pelvic sentinel lymph nodes (SLN) using fluorescence near-infrared (NIR) imaging of indocyanine green (ICG) and colorimetric imaging of isosulfan blue (ISB) dyes in women with endometrial cancer (EC) undergoing robotic-assisted lymphadenectomy (RAL). A secondary aim was to investigate the ability of SLN biopsies to increase the detection of metastatic disease.

Methods

Thirty-five patients underwent RAL with hysterectomy. One mL ISB was injected submucosally in four quadrants of the cervix, followed by 0.5 mL ICG [1.25 mg/mL] immediately prior to placement of a uterine manipulator. Retroperitoneal spaces were dissected for colorimetric detection of lymphatic pathways. The da Vinci^® camera was switched to fluorescence imaging and results recorded. SLN were removed for permanent analysis with ultra-sectioning, H&E, and IHC staining. Hysterectomy with RAL was completed.

Results

Twenty-seven (77%) and 34 (97%) of patients had bilateral pelvic or aortic SLN detected by colorimetric and fluorescence, respectively (p = 0.03). Considering each hemi-pelvis separately, 15/70 (21.4%) had “weak” uptake of ISB in SLN confirmed positive with fluorescence imaging. Using both methods, bilateral detection was 100%. Ten (28.6%) patients had lymph node (LN) metastasis, and 9 of these had SLN metastasis (90% sensitivity, one false negative SLN biopsy). Seven of nine (78%) SLN metastases were ISB positive and 100% were ICG positive. Twenty-five had normal LN, all with negative SLN biopsies (100% specificity). Four (40%) with LN metastasis were detected only by IHC and ultra-sectioning of SLN.

Conclusions

Fluorescence imaging with ICG detected bilateral SLN and SLN metastasis more often than ISB, and the combination resulted in 100% bilateral detection of SLN. Ultra-sectioning/IHC of SLN increased the detection of lymph node metastasis.     

Change in clinical management of sentinel lymph node location in early stage cervical cancer: the role of SPECT/CT

Objective

The aim of this study was to investigate the feasibility of the sentinel lymph node (SLN) identification with SPECT/CT lymphoscintigraphy imaging in the early stage invasive cervical cancer in patients undergoing radical hysterectomy and pelvic lymphadenectomy.

Methods

Between March 2007 and June 2009, a prospective consecutive study was designed for SLN mapping. Twenty-two patients with cervical cancer FIGO stage IB1 (n = 20) or stage IIA1 (n = 2) underwent SLN identification with preoperative SPECT/CT and planar images (technetium-99 m colloid albumin injection around the tumor) and posterior intraoperative detection with both blue dye and a handheld or laparoscopic gamma probe. Complete pelvic lymphadenectomy was performed in all cases by open (n = 2) or laparoscopic (n = 20) surgery.

Results

In the present series, a total of 35 SLN were detected with planar images and 40 SLN were identified and well located by SPECT/CT lymphoscintigraphy (median 2.0 nodes per patient). In 5/22 patients (22.7%) SPECT/CT procedure improves the number of localized SLN. Intraoperatively, 57 SLNs were identified, with a median of 3 SLNs per patient by gamma probe (a total of 53 hot nodes) and a median of 2 nodes per patient after blue dye injection (a total of 42 blue nodes). Microscopic nodal metastases (eight nodes, corresponding to four patients) were confirmed in 18.18% of cases; all these lymph nodes were previously detected as SLN. The remaining 450 nodes, including SLNs, following complete pelvic lymphadenectomy, were histologically negative.

Conclusions

Sentinel lymph node detection is improved by SPECT/CT imaging because of the increased number of SLN detected and the better tridimensional anatomic location, allowing easier intra-operative detection with gamma probe and showing, in this series, a 100% negative predictive value.     

Sentinel lymph node mapping with pathologic ultrastaging: A valuable tool for assessing nodal metastasis in low-grade endometrial cancer with superficial myoinvasion

Objective

To report the incidence of nodal metastases in patients presenting with presumed low-grade endometrioid adenocarcinomas using a sentinel lymph node (SLN) mapping protocol including pathologic ultrastaging.

Methods

All patients from 9/2005 to 12/2011 who underwent endometrial cancer staging surgery with attempted SLN mapping for preoperative grade 1 (G1) or grade 2 (G2) tumors with < 50% invasion on final pathology, were included. All lymph nodes were examined with hematoxylin and eosin (H&E). Negative SLNs were further examined using an ultrastaging protocol to detect micrometastases and isolated tumor cells.

Results

Of 425 patients, lymph node metastasis was found in 25 patients (5.9%) on final pathology—13 cases on routine H&E, 12 cases after ultrastaging. Patients whose tumors had a DMI < 50% were more likely to have positive SLNs on routine H&E (p < 0.005) or after ultrastaging (p = 0.01) compared to those without myoinvasion.

Conclusions

Applying a standardized SLN mapping algorithm with ultrastaging allows for the detection of nodal disease in a presumably low-risk group of patients who in some practices may not undergo any nodal evaluation. Ultrastaging of SLNs can likely be eliminated in endometrioid adenocarcinoma with no myoinvasion. The long-term clinical significance of ultrastage-detected nodal disease requires further investigation as recurrences were noted in some of these cases.     

Prognostic significance of low volume sentinel lymph node disease in early-stage cervical cancer

Objective

Evaluate prognostic significance of low volume disease detected in sentinel nodes (SN) of patients with early stages cervical cancer. Although pathologic ultrastaging of SN allows for identification of low volume disease, including micro-metastasis and isolated tumor cells (ITC), in up to 15% of cases, prognostic significance of these findings is unknown.

Methods

A total of 645 records from 8 centers were retrospectively reviewed. Enrolled in our study were patients with early-stage cervical cancer who had undergone surgical treatment including SN biopsy followed by pelvic lymphadenectomy and pathologic ultrastaging of SN.

Results

Macrometastasis, micrometastasis, and ITC were detected by SN ultrastaging in 14.7%, 10.1%, and 4.5% patients respectively. False negativity of SN ultrastaging reached 2.8%. The presence of ITC was not associated with significant risk, both for recurrence free survival and overall survival. Overall survival was significantly reduced in patients with macrometastasis and micrometastasis; hazard ratio for overall survival reached 6.85 (95% CI, 2.59-18.05) and 6.86 (95% CI, 2.09-22.61) respectively. Presence of micrometastasis was an independent prognostic factor for overall survival in a multivariable model.

Conclusion

Presence of micrometastasis in SN in patients with early stage cervical cancer was associated with significant reduction of overall survival, which was equivalent to patients with macrometastasis. No prognostic significance was found for ITC. These data highlight the importance of SN biopsy and pathologic ultrastaging for the management of cervical cancer.     

Diagnostic accuracy of sentinel node in endometrial cancer by using hysteroscopic injection of radiolabeled tracer

Objective

Retrospective and perspective series have shown the feasibility of sentinel lymph-node (SLN) identification of pelvic nodes in endometrial cancer using a cervical injection of tracers. We designed a perspective study to assess the detection rate and diagnostic accuracy of the SLN procedure by means of hysteroscopic injection of a radiolabeled tracer in endometrial cancer patients.

Methods

Patients with endometrial cancer underwent hysteroscopic technetium injection. SLN assessment was performed intraoperatively. A systematic pelvic and paraaortic dissection was carried out thereafter. SLNs were examined by standard and immunochemistry methods. The primary endpoint was estimation of sensitivity and negative predictive value (NPV) of sentinel-node biopsy.

Results

From 2005 to 2010, 80 consecutive patients entered the study. No severe complications occurred during or after the injection or during surgical SLN biopsy. At least one SLN was detected in 76 of the 80 eligible patients. Fifty nine patients were evaluable according to the study protocol. Ten of these patients (17%) had node metastases. Thirty-three patients (56%) had SLN in the para-aortic area. NPV was 98% (95% CI 89.4-100) and sensitivity 90% (55.5-99.8).

Conclusions

SLN detection for endometrial cancer patients has a high sensitivity and NPV when injection is carried out by hysteroscopy. The occurrence of a 56% of sentinel node in paraaortic area may suggest a better sensitivity in this area using hysteroscopic injection compared to cervical injection.     

A comparison of colorimetric versus fluorometric sentinel lymph node mapping during robotic surgery for endometrial cancer

Objective

The study objective was to compare the ability to detect sentinel lymph nodes (SLNs) in women with endometrial cancer (EC) or complex atypical hyperplasia (CAH) using fluorometric imaging with indocyanine green (ICG) versus colorimetric imaging with isosulfan blue (ISB).

Methods

Women underwent SLN mapping, with either ISB or ICG, during robotic-assisted total laparoscopic hysterectomy (RA-TLH) from September 2012 to March 2014. SLNs were submitted for permanent pathologic analysis. Completion lymphadenectomy and ultrastaging were performed according to institutional protocols.

Results

RA-TLH and SLN mapping was performed in 71 women; 64 had EC (64) and 7 had CAH. Age, body mass index (BMI), stage and tumor characteristics were similar in the ICG versus the ISB cohorts. Overall, SLNs were identified bilaterally (62.0%), unilaterally (21.1%), or neither (16.9%), and in 103 of 142 hemi-pelvises (72.5%). The mean number of SLNs retrieved per hemipelvis was 2.23(SD 1.7). SLNs were identified in the hypogastric (76.8%), external iliac (14.2%), common iliac (4.5%) and paraaortic (4.5%) regions. ICG mapped bilaterally in 78.9% of women compared with 42.4% of those injected with ISB (p = 0.02). Five women (7%) had positive lymph nodes, all identified by the SLN protocol (false negative rate: 0%). On multivariate analysis, BMI was negatively correlated with bilateral mapping success (p = 0.02). When stratified by dye type, the association with BMI was only significant for ISB (p = 0.03).

Conclusions

Fluorescence imaging with ICG may be superior to colorimetric imaging with ISB in women undergoing SLN mapping for endometrial cancer. SLN mapping success is negatively associated with increasing patient BMI only when ISB is used.     

Intraoperative near-infrared fluorescence imaging for sentinel lymph node detection in vulvar cancer: first clinical results

Objective

Disadvantages of the combined sentinel lymph node (SLN) procedure with radiocolloid and blue dye in vulvar cancer are the preoperative injections of radioactive tracer in the vulva, posing a painful burden on the patient. Intraoperative transcutaneous imaging of a peritumorally injected fluorescent tracer may lead to a one-step procedure, while maintaining high sensitivity. Aim of this pilot study was to investigate the applicability of intraoperative fluorescence imaging for SLN detection and transcutaneous lymphatic mapping in vulvar cancer.

Methods

Ten patients with early stage squamous cell carcinoma of the vulva underwent the standard SLN procedure. Additionally, a mixture of 1 mL patent blue and 1 mL indocyanin green (ICG; 0.5 mg/mL) was injected immediately prior to surgery, with the patient under anesthesia. Color and fluorescence images and videos of lymph flow were acquired using a custom-made intraoperative fluorescence camera system. The distance between skin and femoral artery was determined on preoperative CT-scan as a measure for subcutaneous adipose tissue.

Results

In 10 patients, SLNs were detected in 16 groins (4 unilateral; 6 midline tumors). Transcutaneous lymphatic mapping was possible in five patients (5 of 16 groins), and was limited to lean patients, with a maximal distance between femoral artery and skin of 24 mm, as determined on CT. In total, 29 SLNs were detected by radiocolloid, of which 26 were also detected by fluorescence and 21 were blue.

Conclusions

These first clinical results indicate that intraoperative transcutaneous lymphatic mapping using fluorescence is technically feasible in a subgroup of lean vulvar cancer patients.     

Value of sentinel node mapping in cancer of the cervix

Objectives

To compare the relative value of two methods of detection for the sentinel lymphatic nodes (SLNs): colorimetric with Isosulfan blue (ISB) and radio-isotopic with Technetium-99 (Tc99), and to evaluate the concept of the SLN mapping applied to cervical cancer.

Methods

From October 2000 to December 2006, radical surgery was planned in 211 patients who presented early-stage cancer of the cervix. Both ISB and Tc99 were used to detect the SLNs. In all cases, we proceeded with laparoscopy for the identification and removal of the SLNs, followed by a complete pelvic lymphadenectomy with or without para-aortic node sampling. The SLNs were sent for frozen section (1 level) and were ultra-staged (6 levels) for final pathology. Detection rate, sensitivity and negative predictive value (NPV) were calculated.

Results

Among the 211 patients, ISB (n = 152) identified at least 1 SLN in 92.8% of the cases. With Tc99 (n = 166), the detection rate of SLN increased to 96.9%. When both techniques were used together (n = 107), Tc99 was significantly better than ISB by 7.8% (p = 0.0094) and at least 1 SLN (hot and/or blue) was found in 99.1% of the cases. In 16.7% of patients, a SLN was located in aberrant sites, including 3.8% in the para-aortic area. Thirty-three out of the 211 patients (15.6%) had lymph node metastases. When considering only the 181 patients with bilateral SLNs identified, the NPV of SLN is 100% after ultra staging on final pathology and 94.2% on frozen section (FS).

Conclusion

Sentinel node mapping is feasible using laparoscopy. The radio-isotopic technique adds significantly to the rate of detection. The main benefits of SLN mapping in cervical cancer are the detection of micro-metastases on ultra staging which might be missed on routine pathological evaluation, and identification of aberrant drainage sites. However, the current frozen section techniques lack sensitivity to identify very small metastases and need refinement. SLN mapping should become the standard of care in the modern management of cervical cancer and complete pelvic lymphadenectomy could be avoided when bilateral SLNs are detected in patients with lesions less than 2 cm.     

Sentinel lymph node biopsy in endometrial cancer: meta-analysis of 26 studies

Objective

The validity of the sentinel lymph node (SLN) procedure for the assessment of nodal status in patients with endometrial cancer is unclear. We aimed to assess the diagnostic performance of this procedure.

Methods

We searched the PubMed and Embase databases for studies published before June 1, 2011. Eligible studies had a sample size of at least 10 patients, and reported the detection rate and/or sensitivity of the SLN biopsy.

Results

We identified 26 eligible studies, which included 1101 SLN procedures. The overall weighted-mean number of harvested SLNs was 2.6. The detection rate and the sensitivity were 78% (95% confidence interval [CI] = 73%-84%) and 93% (95% CI = 87%-100%), respectively. Significant between-study heterogeneity was observed in the analysis of the detection rate (I-squared statistic, 80%). The use of pericervical injection was correlated with the increase of the detection rate (P = 0.031). The hysteroscopic injection technique was associated with the decrease of the detection rate (P = 0.045) and the subserosal injection technique was associated with the decrease of the sensitivity (P = 0.049), if they were not combined with other injection techniques. For the detection rate, significant small-study effects were noted (P < 0.001).

Conclusions

Although SLN biopsy has shown good diagnostic performance in endometrial cancer, such performance should be interpreted with caution because of significant small study effects. Current evidence is not yet sufficient to establish the true performance of SLN biopsy in endometrial cancer.     

Updates in Sentinel Lymph Node Mapping in Gynecologic Cancer

Purpose of Review

The aim of this study is to review the indications, techniques, and outcomes of sentinel lymph node (SLN) mapping in endometrial, cervical, and vulvar cancers.

Recent Findings

In endometrial cancer, the prospective FIRES trial showed that the negative predictive value of SLN mapping was 99.6%. Furthermore, multi-institutional retrospective studies comparing SLN mapping to traditional lymphadenectomy have found comparable survival between the two techniques, in both type 1 and type 2 endometrial cancer. In cervical cancer, randomized data from the SENTICOL-2 study has demonstrated significant reduction in postoperative complications without compromising survival with SLN mapping as compared to SLN mapping and pelvic lymphadenectomy. In vulvar cancer, the GROINS-V-II study protocol was amended to mandate inguinofemoral lymphadenectomy in all patients with SLN macrometastasis greater than 2 mm after unacceptably high rates of groin recurrences were observed on interim analysis. SLN mapping is now included in the treatment guidelines of the National Comprehensive Cancer Network guidelines for endometrial, cervical, and vulvar cancer as an acceptable lymphatic assessment technique in select patients.

Summary

SLN biopsy is a safe and effective alternative to systematic lymphadenectomy for women with early-stage endometrial, cervical, and vulvar cancer. Recent data has validated the excellent sensitivity and negative predictive value of this technique in carefully selected patients, without compromising survival. The use of an algorithm that mandates pathologic ultrastaging on all SLNs, and ipsilateral lymphadenectomy in cases of failed bilateral mapping improves sensitivity and negative predictive value. All suspicious lymph nodes should be resected regardless of the location of the SLN. In patients with vulvar cancer, SLN biopsy is an acceptable standard of care for patients with unifocal tumors, less than 4 cm in largest diameter, and clinically and radiographically negative groin nodes.

     

The incidence of isolated para-aortic nodal metastasis in completely staged endometrial cancer patients

Objective

To describe and review the incidence of para-aortic (PA) nodal metastasis in completely staged endometrial cancer patients who are negative for pelvic nodal metastasis.

Methods

Using an institutionally maintained database, we identified all patients with endometrial cancer from 2002 to 2006 who had both pelvic and aortic nodal dissections and determined the rate of isolated para-aortic nodal metastasis in non-malignant (i.e. negative) pelvic nodes.

Results

201 endometrial cancer patients were surgically treated at our institution from 2002 to 2006. 171 patients had both pelvic and PA nodes removed during surgery, and specimens examined by a pathologist. Only 2 (1.2%) had PA nodes that tested positive for malignance (i.e. positive PA nodes) with pelvic nodes that tested negative for malignance (i.e. negative pelvic nodes). The final International Federation of Gynecology and Obstetrics (FIGO) grade for the endometrial tumor cells in the two patients was “G1” with endometrioid adenocarcinoma and “G3” with endometrioid adenocarcinoma and mucinous differentiation, respectively.

Conclusion

Based on the very low incidence of patients inflicted with endometrial cancer that have positive para-aortic lymph nodes (PALNs) with negative pelvic nodes found both in our literature review (1.5%) and in our own study (1.2%), the addition of PA lymphadenectomy in all patients was found to have minimal diagnostic and therapeutic value. At the present, the role of complete PA lymphadenectomy in all patients with endometrial cancer should be re-examined. Individualized algorithms should be developed based on risk factors and status of pelvic nodes.     

Lymph node metastasis in endometrioid adenocarcinomas of the uterine corpus with occult cervical involvement

Objective

Surgical-pathologic studies have defined the risk of lymphatic metastasis in clinical stage I endometrial cancers. However, data on the risk of lymph node metastasis in endometrial cancers involving the uterine cervix are less robust. The aim of this study was to determine the risk of lymphatic metastasis in patients with endometrial cancers with occult tumor extension to the uterine cervix.

Methods

Our institutional tumor registry identified all patients with endometrioid endometrial cancers who underwent comprehensive surgical staging. Patients with gross involvement of the cervix and patients with extra-uterine disease were excluded. The risk of lymphatic metastasis associated with cervical involvement was analyzed in the context of known uterine risk factors for lymphatic metastasis such as age, depth of invasion, grade, and lymphovascular space invasion (LVSI).

Results

We identified 169 patients who met inclusion and exclusion criteria. Univariate analyses revealed that LVSI (p < 0.01), tumor grade (p < 0.01), depth of myometrial invasion (p < 0.01), tumor free distance (p < 0.01), tumor size (p = 0.02), and cervical involvement (p < 0.01) were associated with lymphatic metastasis while age at diagnosis (p = 0.85) was not. Multivariate analyses revealed that only LVSI (p < 0.01), tumor grade (p = 0.02), and depth of myometrial invasion (p = 0.03) were independently associated with lymphatic metastasis.

Conclusion

Cervical involvement is not an independent predictor of lymphatic metastasis in endometrial cancer. In an unstaged patient, decisions regarding adjuvant treatment or additional diagnostic procedures such as lymphadenectomy should be based on uterine factors.     

Identification of inguinofemoral lymph node metastases by methylation markers in vulvar cancer

Objective

Lymph node status in early-stage vulvar cancer can be accurately assessed by the sentinel-node (SN) procedure. Molecular techniques, such as DNA-methylation assay, might improve SN assessment. In this study, we selected methylation markers for vulvar cancer and determined if these methylation markers were suitable for lymph node assessment.

Methods

We performed methylation specific PCR on DNA isolated from primary tumors, metastatic lymph nodes, and negative lymph nodes from twenty vulvar cancer patients using the following genes: P16INK4a, MGMT, TWIST1, CADM1, TERT, and TFPI2. For P16INK4a and MGMT immunohistochemistry was performed on primary tumors and metastatic lymph nodes in order to explore intratumor heterogeneity in gene expression patterns.

Results

TERT was methylated in all vulvar cancers, P16INK4a in 13/20, TFPI2 in 12/20, CADM1 in 11/20, MGMT in 9/20, and TWIST1 in 7/20. A panel of three methylation markers (P16INK4a, TERT and TFPI2) reached a sensitivity of 67% and specificity of 100% for detection of metastatic lymph nodes. Immunohistochemistry showed intratumor heterogeneity for expression of P16INK4a and MGMT in respectively 55% and 45% of primary tumors.

Conclusions

Our study shows methylation for one or more methylation markers in all vulvar cancers. Despite a specificity of 100% our panel of three methylation markers had only moderate sensitivity for metastatic lymph node detection, thereby limiting its applicability for lymph node assessment. Intratumor heterogeneity for expression of P16INK4a and MGMT may reflect intratumor heterogeneity for methylation patterns and thereby in general explain the moderate sensitivity of our marker panel for detection of metastases.