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.     

Sentinel lymphatic mapping among women with early-stage cervical cancer: A systematic review

The presence of pelvic lymph node metastases is without doubt the most significant prognostic factor that determines recurrences and survival of women with early-stage cervical cancer. To avoid the underdiagnosis of lymph node metastasis, pelvic lymphadenectomy procedure is routinely performed with radical hysterectomy procedure. However, the pelvic lymphadenectomy procedure may not be necessary in most of these women due to the relatively low incidence of pelvic lymph node metastasis. The removal of large numbers of pelvic lymph nodes could also render non-metastatic irreversible damages for these women, including vessel, nerve, or ureteral injuries; formation of lymphocysts; and lymphedema. Over the past decades, the concept of sentinel lymph node biopsy has emerged as a popular and widespread surgical technique for the evaluation of the pelvic lymph node status in gynecologic malignancies. The histological status of sentinel lymph node should be representative for all other lymph nodes in the regional drainage area. If metastasis is non-existent in the sentinel lymph node, the likelihood of metastatic spread in the remaining regional lymph nodes is very low. Further lymphadenectomy is therefore not necessary for a patient with negative sentinel lymph nodes. Since the uterine cervix has several lymphatic drainage pathways, it is a challenging task to assess the distribution pattern of sentinel lymph nodes in women with early-stage cervical cancer. This review article will adapt the methodology proposed in these studies to systematically review sentinel lymphatic mapping among women with early-stage cervical cancer.     

Sentinel lymph node status in patients with locally advanced cervical cancers and impact of neoadjuvant chemotherapy

Objectives. Neoadjuvant chemotherapy (NAC) is used in locally advanced cervical cancers with the aim to decrease the size of the tumor and to allow for less radical surgery. Despite of the fact that the high response rate of the tumor has been well established, the impact of NAC on sentinel lymph node (SN) detection and status has not been explored to date.Methods. Our study included 82 patients with locally advanced cervical cancers (FIGO IB1 > 3 cm, IB2, IIA2 and selected IIB) out of which 51 patients were referred to SN biopsy prior to NAC and 31 patients to radical surgical procedure including SN biopsy after three courses of “dose density” NAC. In both groups, the prevalence of macrometastases, micrometastases and isolated tumor cells (ITC) in SN was compared.Results. The total of 179 SNs was evaluated. SN detection rate in the whole cohort reached 87.8% per patient and 60.9% bilaterally, without significant difference between both groups. In the group with upfront SN biopsy prior to NAC the prevalence of macrometastases, micrometastases and ITC amounted to 43.1% (22/51), 7.8% (4/51) and 7.8% (4/51) respectively. In the group with SN biopsy after previous NAC, macrometastases were detected in 22.6 (7/31) of patients in SN, whereas there was only one micrometastasis and no ITC detected in that group.Conclusions. Neoadjuvant chemotherapy did not influence the detection rate of SNs, yet it was associated with significantly reduced prevalence of metastatic involvement of SNs, especially almost completely eliminating low volume disease.     

Sentinel lymph node (SLN) concept in cervical cancer: Current limitations and unanswered questions

Sentinel lymph node (SLN) biopsy has been increasingly used in the management of early-stages cervical cancer instead of systematic pelvic lymph node dissection (PLND). The aim of this article is to give a critical overview of key aspects related to this concept, such as a necessity for reliable detection of micrometastases (MIC) in SLN and the requirements for SLN pathologic ultrastaging, low accuracy of intraoperative detection of SLN involvement, and still a limited evidence of oncological safety of the replacement of PLND by SLN biopsy only in ≥IB1 tumours due to unknown risk of MIC in non-SLN pelvic lymph nodes in patients with negative SLN, and absence of any prospective evidence.     

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.     

The role of sentinel lymph node biopsy in early-stage cervical cancer: A systematic review

Pelvic lymphadenectomy procedure is included as part of the standard protocol of radical hysterectomy for women with early-stage cervical cancer (Stage IA to IB1). However, an important sequel to lymphadenectomy procedure is the possible occurrence of lymphedema in the lower abdomen and lower extremities. Previous researches also find that women with lymphedema experience many emotional impacts, including depression, anxiety, and adjustment problems. Only approximately 10% of women with clinical stage IB cervical carcinoma were involved with metastatic disease. If we could better define the relevant lymphatic nodes that must be removed, it is then possible to limit routinely performed lymphadenectomy for regional nodal metastasis in the pelvis, and hence reduce the need for extended surgical staging (para-aortic lymphadenectomy). We systematically reviewed a body of literature and updated available information concerning the current progress on the application of sentinel lymph node biopsy in women with early-stage cervical cancer. All detection methods (preoperative injection of radiocolloid tracer, intraoperative injection of blue dye, or a combination of both techniques) demonstrated reasonable sensitivity (with a few exceptions), high specificity, low false-negative rate and high negative predictive value. The review of the literature in this paper should convince the readers that sentinel lymph node biopsy has the potential to improve the quality of life and the possibility to maintain relapse-free survival for women with cervical cancer. The proper identification of negative sentinel lymph node allows individualized therapy and may preclude the need of lymphadenectomy procedure in most of these women.     

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.     

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.     

Axillary lymph node dissection in the case of sentinel lymph node micrometastatic invasion: evaluation of three predictive models

Objective

To evaluate three predictive risk models of non-sentinel lymph node (NSLN) involvement in the case of micrometastatic sentinel node (SLN) involvement for breast cancer.

Study design

This retrospective study included 72 successive patients with micrometastatic SLN involvement who had surgery between March 1996 and October 2007. All patients had undergone immediate or delayed axillary lymph node dissection (ALND). The Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram, the Stanford nomogram and the Tenon score were applied to the population to calculate the probability of NSLN involvement.

Results

For the MSKCC nomogram with a threshold value of 10%, sensitivity was 50%, specificity was 70% and the negative predictive value (NPV) was 89%. The area under the receiver operating characteristic curve (AUC) was 0.6 (significant). Use of this nomogram would have avoided ALND in 49 out of 72 (68%) patients, but five out of 10 (50%) patients with NSLN involvement would not have been detected. With a threshold value of 7%, the AUC was 0.69, sensitivity was 90% and NPV was 97%. ALND would have been avoided in 31 out of 72 (43%) patients, with a 3% chance of leaving metastases when abstaining from ALND. For the Tenon score with a threshold value of 3.5, sensitivity was 50%, specificity was 72% and the AUC was 0.62. This was not clinically applicable because eight out of 10 (80%) patients with NSLN involvement would not have been detected. For the Stanford nomogram, the results could not be interpreted because the AUC was not significant.

Conclusion

None of the tested models are sufficiently reliable for use in daily practice. The MSKCC nomogram showed the most encouraging results, especially for a threshold value of 7%, but this has not been validated in the literature. Complete axillary dissection should be performed in the case of micrometastatic SLN involvement until more data become available.     

Identification of prognostic factors in patients with cervical cancer and supraclavicular lymph node recurrence

Objective

Patients with cervical cancer and supraclavicular lymph nodes (SLN) recurrence have a poor but heterogeneous prognosis. The aim of this study was to identify potential prognostic factors – including FDG-PET results – that may affect survival and treatment outcomes in patients with this group of patients.

Methods

Between January 2001 and December 2008, we identified a total of 31 consecutive patients with cervical cancer who had evidence of SLN recurrence. All participants underwent FDG-PET. Survival was measured from the date of documented SLN recurrence. The latency period was defined as the length of time from the date of first diagnosis to the date of SLN recurrence.

Results

The median follow-up time was 22.8 months (range: 4.7–105.1). The 3- and 5-year survival rates were 41% and 27.3%, respectively. Patients with intermediate SUV values (between 4.3 and 8) had a significantly better prognosis than subjects with both high (> 8) or low (< 4.3) SUV values (p = 0.004). Latency period < 2 years, SCC-Ag levels ≥ 4 ng/mL, recurrence extend beyond SLN, and SUV of < 4.3 > 8 were significant adverse prognostic factors by multivariate analysis. The 3-year overall survival (OS) rate of patients carrying 0–1 adverse prognostic factors was 90% (low-risk group), while 3-year OS rates for intermediate-risk group (2 factors) and high-risk group (3–4 factors) were 30% and 0%, respectively (p = 0.001).

Conclusion

Our results justify the use of PET (accurate extent of relapse and SUV) as a prognostic tool in patients with cervical cancer and SLN recurrence.     

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 detection in early stage uterine cervix carcinoma: a systematic review

OBJECTIVE: The aim of this study was to systematically review the diagnostic performance of Sentinel Node (SN) detection for assessing the nodal status in early stage cervical carcinoma, and to determine which technique (using blue dye, Technetium-99m colloid (99mTc), or the combined method) had the highest success rate in terms of detection rate and sensitivity. METHODS: A comprehensive computer literature search of English language studies in human subjects on Sentinel Node procedures was performed in MEDLINE and EMBASE databases up to July 2006. For each article two reviewers independently performed a methodological qualitative analysis and data extraction using a standard form. Pooled values of the SN detection rate and pooled sensitivity values of the SN procedure are presented with a 95% confidence interval (95% CI) for the three different SN detection techniques. RESULTS: We identified 98 articles, and 23 met the inclusion criteria, comprising a total of 842 patients. Ultimately, 12 studies used the combined technique with a sensitivity of 92% (95% CI: 84-98%). Five studies used 99mTc-colloid, with a pooled sensitivity of 92% (95% CI: 79-98%; p=0.71 vs. combined technique), and four used blue dye with a pooled sensitivity of 81% (67-92%, p=0.17 vs. combined technique). The SN detection rate was highest for the combined technique: 97% (95% CI: 95-98%), vs. 84% for blue dye (95% CI: 79-89%; p<0.0001), and 88% (95% CI: 82-92%, p=0.0018) for 99mTc colloid. CONCLUSION: SN biopsy has the highest SN detection rate when 99mTc is used in combination with blue dye (97%), and a sensitivity of 92%. Hence, according to the present evidence in literature the combination of 99mTc and a blue dye for SN biopsy in patients with early stage cervical cancer is a reliable method to detect lymph node metastases in early stage cervical cancer.     

Preoperative pelvic lymphoscintigraphy is of limited usefulness for sentinel lymph node detection in cervical cancer

Objectives

To analyze concordance between preoperative lymphoscintigraphy and intraoperative lymphatic mapping (ILM) for sentinel lymph node identification using technetium 99m-labeled-dextran 500 (99m-Tc) and patent blue dye in patients with early cervical cancer undergoing radical hysterectomy and pelvic lymphadenectomy, as well as to evaluate sentinel lymph node (SLN) detection.

Study design

Forty-seven patients underwent surgical treatment for cervical cancer. For SLN identification, 99m-Tc and blue patent were injected into the cervix on the eve and day of surgery, respectively. Preoperative pelvic lymphoscintigraphy was performed in all patients after 99m-Tc injection. Concordance between preoperative lymphoscintigraphy and ILM was evaluated.

Results

Of the 56 patients who underwent preoperative lymphoscintigraphy, 43 (81.13%) had at least one lymph node identified. Bilateral lymph nodes were identified in 21 (37.5%) patients. Sentinel lymph nodes detected on ILM had been previously found on preoperative lymphoscintigraphy in 66.7%, 67.2% and 0% in the right, left and central locations, respectively. In 14 patients (25%), only one lymph node was identified on preoperative lymphoscintigraphy, but more than one sentinel lymph node was detected on intraoperative mapping. In nine (16.1%) patients, lymphoscintigraphy showed only unilateral lymph nodes, but ILM identified bilateral sentinel lymph nodes.

Conclusion

The combination of patent blue and radionuclide techniques produced excellent results for SLN detection in cervical cancer. Preoperative lymphoscintigraphy does not offer any advantage over ILM for SLN identification.     

Sentinel lymph node mapping for endometrial cancer improves the detection of metastatic disease to regional lymph nodes

Objective

To compare the incidence of metastatic cancer cells in sentinel lymph nodes (SLN) vs. non-sentinel nodes in patients who had lymphatic mapping for endometrial cancer and to determine the contribution of metastases detected on ultrastaging to the overall nodal metastasis rate.

Methods

All patients who underwent lymphatic mapping for endometrial cancer were reviewed. Cervical injection of blue dye was used in all cases. Sentinel nodes were examined by routine hematoxylin and eosin (H&E), and if negative, by standardized institutional pathology protocol that included additional sections and immunohistochemistry (IHC).

Results

Between 09/2005 and 03/2010, 266 patients with endometrial cancer underwent lymphatic mapping. Sentinel node identification was successful in 223 (84%) cases. Positive nodes were diagnosed in 32/266 (12%) patients. Of those, 8/266 patients (3%) had the metastasis detected only by additional section or IHC as part of SLN ultrastaging. Excluding the 8 cases with positive SLN on ultrastaging only, 24/801 (2.99%) SLN and 30/2698 (1.11%) non-SLN were positive for metastatic disease (p = 0.0003).

Conclusion

Using a cervical injection for mapping, metastatic cells from endometrial cancer are three times as likely to be detected in SLN than in the non-sentinel nodes. This finding strongly supports the concept of lymphatic mapping in endometrial cancer to fine tune the nodal dissection topography. By adding SLN mapping to our current surgical staging procedures we may increase the likelihood of detecting metastatic cancer cells in regional lymph nodes. An additional benefit of incorporating pathologic ultrastaging of SLN is the detection of micrometastasis, which may be the only evidence of extrauterine spread.     

Evaluation of patients after extraperitoneal lymph node dissection for cervical cancer

OBJECTIVE: The presence of nodal metastases is an important prognostic factor in patients with cervical cancer. To adjust our therapy to the anatomic extent of the disease, we performed a surgical staging with extraperitoneal lymph node dissection (EPLND). The goal of our study was to evaluate the clinical outcome and side effects of the combined treatment approach of EPLND and either radical hysterectomy in case of early stage cervical cancer (FIGO Ia/b and IIa) and negative nodes, or pelvic radiotherapy/extended field radiotherapy with concomitant chemotherapy in case of positive nodes or advanced stage cervical cancer (FIGO IIb, III, and IVa). PATIENTS AND METHODS: Fifty-nine patients with primarily diagnosed invasive cervical cancer underwent EPLND. The value of this procedure as a diagnostic tool for evaluating the extent of disease was determined. Additionally, treatment-related complications and clinical outcomes were monitored. RESULTS: A total of 983 lymph nodes were removed during EPLND (mean 16.7). According to the results of EPLND, radical hysterectomy was abandoned due to histopathologically confirmed lymph node involvement by frozen section in 11 out of 36 patients with early stage cervical cancer (31%). The most common adverse effects directly related to surgery in general (EPLND or combined EPLND and radical hysterectomy) were lymph cysts in seven patients (12%). Only in the group of patients who received EPLND followed by radical hysterectomy, 2 out of 25 patients (8%) developed a severe ileus postoperatively (WHO Grade 3 toxicity). The treatment approach of combined EPLND followed by radio- and chemotherapy was without major complications (WHO Grade 3 or 4 toxicity). After a mean follow up of 28 months (range 6-60), 44 out of 58 patients (one patient lost to follow up) are without evidence of disease (76%), 2 patients have progressive disease (3%), and 12 patients died of their disease (21%). Using Kaplan-Meier analysis, the estimated 5-year overall survival rate for all patients is 64% (SD +/- 9%). Performing the Cox proportional regression analysis, in contrast to clinical FIGO staging (P = 0.24; ns), lymph node involvement was the only significant independent predictor for overall survival (P = 0.04). CONCLUSION: Our data support the approach of pretherapeutic surgical staging by performing EPLND as a diagnostic tool with a low complication rate. This allows an individualized treatment for cervical cancer patients.     

A feasibility study of sentinel lymph node mapping by cervical injection of a tracer in Japanese women with early stage endometrial cancer

Objective

The aim of this study was to investigate the feasibility of sentinel lymph node mapping characterized by a cervical tracer injection in endometrial cancer.

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.