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Multicenter Validation Study of the Sentinel Lymph Node Concept in Cervical Cancer: AGO Study Group

Christopher Altgassen, Hermann Hertel, Antje Brandstädt, Christhardt Köhler, Matthias Dürst, Achim Schneider

From the Department of Obstetrics and Gynecology, University of Schleswig-Holstein, Luebeck; Department of Obstetrics and Gynecology, Medical School Hannover, Hannover; Information Sciences and Documentation, Institute of Medical Statistics, and Department of Obstetrics and Gynecology, Friedrich-Schiller-University, Jena; and Department of Gynecology and Gynecologic Oncology, Universitätsmedizin Berlin, Charité, Berlin, Germany

Corresponding author: Achim Schneider, MD, MPH, Universitätsmedizin Berlin, Charité, Department of Gynecology and Gynecologic Oncology, Hindenburgdamm 30, D-12203 Berlin, Germany; e-mail: achim.schneider{at}charite.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Purpose Single-institution case series have demonstrated the feasibility of the sentinel concept in cervical cancer. However, the diagnostic accuracy remains to be validated. We evaluated detection rate and diagnostic accuracy to predict the histopathologic pelvic nodal status in patients with cervical cancer of all stages.

Patients and Methods In a hypothesis-based, prospective, multicenter cohort study, patients underwent lymph node detection after labeling with technetium, patent blue, or both. After systematic pelvic and, if indicated, para-aortic node dissection, all lymph nodes were histopathologically examined. Detection rate, sensitivity, and negative predictive value (NPV) were calculated.

Results According to the protocol, 590 patients were eligible. Detection rate of pelvic sentinel nodes was 88.6% (95% CI, 85.8% to 91.1%) and was significantly higher for the combination of technetium and patent blue (93.5%; 95% CI, 90.3% to 96.0%). Of 106 patients with pelvic lymph node metastases, 82 had pelvic sentinel node metastases. The overall sensitivity was 77.4% (95% CI, 68.2% to 85.0%), which was lower than 90%, the predefined noninferiority margin (P < .001). Sensitivity in women with tumors 20 mm (90.9%), with bilateral detection (87.2%), or with both substances applied (80.3%) was higher compared with the total population. The overall NPV was 94.3% (95% CI, 91.6% to 96.4%) and was higher in patients with tumors 20 mm (99.1%; 95% CI, 96.6% to 100%) compared with patients with tumors more than 20 mm (88.5%; 95% CI, 82.9% to 92.8%; P < .001).

Conclusion In our cohort (all stages), sensitivity of the sentinel concept was low. However, patients with tumor diameter 20 mm may profit from this concept.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Individualization of treatment to reduce therapy-associated morbidity is a current trend in surgery. The latest progress in the surgical treatment of breast cancer was the recommendation of the sentinel concept after trials revealed a sensitivity of 88.6% to 91.2% and a negative predictive value (NPV) of 91.1% to 95.7%.^1,2 The advantage of the sentinel technique is the reduction of lymphadenectomy if sentinel lymph nodes (SLNs) predict accurately their regional status.

In cervical cancer, lymph node status is the most important prognostic factor.³ Therefore, lymphadenectomy remains the gold standard. If lymph node metastases are present at the time of primary surgery, 5-year survival rate decreases from 85% to 50%.^3,4 Extended lymphadenectomy can cause unfavorable adverse effects. Because more than 90% of the nodes are free of metastases,⁵ the majority of patients could be protected from morbidity if the concept is applicable. Studies show that the findings in the pelvic SLNs accurately predict the state of the regional lymph nodes.^6,7 Yet, the accuracy of this method requires validation. On the basis of early data,^8,9 we hypothesized that the sensitivity of sentinel node biopsy is more than 90%.

	PATIENTS AND METHODS

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This prospective study was approved by the institutional review committee (0175-02/00). All centers signed an agreement to strictly follow the protocol.

Between December 1998 and October 2006, each patient with cervical cancer was considered for enrollment. Published data available at the beginning of the study were used to establish eligibility for enrollment.^7,10 Inclusion criteria were as follows: invasive cancer (all stages), intention of surgical staging, complete pelvic lymphadenectomy in case of negative SLNs or one positive SLN, and absence of pregnancy and appropriate tracer application. Exclusion criteria included preoperatively detected metastatic disease, previous lymphadenectomy, tumor involvement of the adnexae, lymphoscintigraphy within 14 days before surgery, and allergy. Initially, neoadjuvant therapy was not considered as an exclusion criterion. Later, we decided to exclude patients who received neoadjuvant therapy because an influence on sentinel diagnosis could not be excluded. Patients who signed informed consent were enrolled.

Tracer
The day before surgery, 1 mL of 60 MBq technetium-99m (^99mTc) Albu-Res or Nanocoll (Amersham, Braunschweig, Germany) was injected in four divided aliquots beneath intact-appearing cervical epithelium. Dye (4 mL) was injected after induction of anesthesia and before draping. The participating gynecologists decided at the beginning of their participation which labeling substance they would use for the duration of the study.

Surgery and Lymph Node Processing
Patients underwent a complete pelvic lymphadenectomy either by laparoscopy or by an open approach.¹¹ The pelvic basin was defined as the area along the external, internal, and common iliac vessels including the parametrial lymph nodes. Pelvic lymph node dissection was determined to be adequate if 15 lymph nodes including SLNs could be identified or at least one SLN harbored metastatic disease. The amount of 15 lymph nodes was chosen as an average in daily routine where 15 to 20 pelvic nodes are harvested. This was recently confirmed.¹² Additionally, we showed that the number of nodes harvested depends on the pathologist's count.¹³ Therefore, lymph node count cannot be a clear indicator for radicality. Indication for para-aortic lymphadenectomy was at the discretion of the surgeon and included the upper part of the common iliac artery, the aorta and cava up to the renal veins, and the presacral area. All areas were inspected for stained/hot SLNs. SLNs were extracted separately, and this was followed by systematic lymphadenectomy. All nodes were processed identically by the pathologists. If metastatic disease was visible, simple sections were submitted. Normal-appearing nodes were cut perpendicular to the long axis into 3- to 4-mm sections and submitted for routine staining (hematoxylin and eosin) and evaluation. Immunohistochemical stains were not recommended within the protocol.

Statistics
The primary objective was to estimate the detection rate and the diagnostic accuracy of the SLN concept in terms of sensitivity and NPV in the total population and, secondarily, according to the labeling substances used. Histopathologic findings of pelvic SLNs (index test) were part of the total pelvic nodal status (reference). Thus, false-positive results were impossible by definition. The test was considered to be true positive if at least one SLN harbored metastatic disease. It was regarded as false negative if all SLNs were free of metastatic disease but non-SLNs showed metastases. It was considered true negative if all lymph nodes were free of metastases.

The hypothesis on the magnitude of sensitivity was phrased to show noninferiority compared with 96.5%. A clinically relevant noninferiority margin (like a clinically relevant difference in superiority trials) had to be chosen in advance. Because sensitivity lower than 90% was assumed to be unacceptable for the SLN concept, we chose 90% as the noninferiority margin. A sample size of 100 patients with pelvic lymph node metastases was necessary to show noninferiority of sensitivity by a one-sided binomial test with a power of 80% at an level of .05.

Detection rate was calculated as the number of patients with at least one detected SLN over the total number of patients who underwent labeling and SLN mapping. The proportion of true positives (patients with both positive pelvic SLN and pelvic nodal status) within patients with pelvic lymph node metastases was estimated as sensitivity. NPV resulted from dividing the number of true negatives (patients with both negative pelvic SLN and pelvic nodal status) by the number of all patients without pelvic lymph node metastases. Exact 95% CIs for the proportions were calculated.

Subgroup analysis was performed by a two-sided ² test or Fisher's exact test as appropriate ( = .05). Except for the comparison of labeling techniques, which was prespecified in the protocol, all further subgroup analyses were explorative. Data were managed within an Access database (Microsoft, Redmond, WA) and analyzed with SAS (version 9.1; SAS Institute, Cary, NC).

	RESULTS

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Between December 1998 and October 2006, 603 patients were enrolled in 18 centers. In 12 patients, the surgeon did not search for SLNs, and in one patient, no labeling substance was administered. To validate diagnostic accuracy, 83 patients had to be excluded consecutively; 12 patients had received neoadjuvant therapy (including three without pelvic SLN detection), no pelvic SLN was detected in 64 patients, and pelvic lymph node status was inconclusive or unknown in seven patients (Fig 1).

View larger version (25K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Distribution of patients eligible for analysis of detection rate and diagnostic accuracy (flowchart). SLN, sentinel lymph node.

A median of 24 nonsentinel pelvic lymph nodes (range, two to 70 nodes) were removed in 507 patients. In 190 patients who underwent para-aortic lymph node dissection, a median of 12.5 lymph nodes (range, one to 47 nodes) were removed.

Accuracy of the Diagnostic Test
In three of 507 patients, the histopathologic status of the SLNs was inconclusive (blue dye, n = 2; ^99mTc, n = 1). These patients were excluded from estimation of sensitivity and NPV.

Pelvic lymph node metastases were described in 106 patients. In 82 patients, SLNs correctly predicted metastatic disease, and in 24 patients, no metastases were found within the SLNs. Sensitivity was 77.4% (95% CI, 68.2% to 85.0%) and was significantly lower than 90% (P < .001; Table 3). NPV was 94.3% (95% CI, 91.6% to 96.4%) and did not differ statistically according to the labeling agent (P = .8; Table 4).

Ancillary Analyses
Which subpopulation might benefit from the sentinel concept in particular? Tumor size 20 mm or more than 20 mm in the histologic specimen was used as a cutoff because it is used for the decision regarding surgery versus chemoradiation.³ Furthermore, we assessed the influence of unilateral or bilateral detection of SLNs and the impact of diagnostic conization for accuracy.

Of the eligible population, the tumor was 20 mm in diameter in 249 patients and more than 20 mm in diameter in 305 patients. Detection rate of pelvic SLN was 94.0% (95% CI, 90.2% to 96.6%) in patients with smaller tumors and was significantly higher compared with patients with larger tumors (83.6%; 95% CI, 78.9% to 87.6%; P < .001; Table 2).

According to tumor size, a significantly improved NPV and a nonsignificantly higher sensitivity in patients with smaller tumors versus patients with larger tumors were demonstrated (sensitivity: 90.9% v 72.7%, respectively; Table 3; NPV: 99.1% v 88.5%, respectively; P < .001; Table 4). The prevalence of negative lymph nodes was 90.5% for smaller tumors compared with 67.8% for larger tumors.

If SLNs were detected in only one pelvic side compared with both sides regardless of tumor size, sensitivity increased from 69.6% (95% CI, 54.2% to 82.3%) to 87.2% (95% CI, 74.2% to 95.2%; P = .046). NPV increased from 91.0% (95% CI, 85.4% to 95.1%) to 96.5% (95% CI, 92.5% to 98.8%; P = .062).

In patients with smaller tumors, no differences in sensitivity and NPV were seen according to preceding conization and unilateral or bilateral SLN detection.

	DISCUSSION

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This study was designed in 1998, and the protocol was amended in 1999 and 2000. We used conditions that are easily applicable to clinical routine. Tumor size was not limited because it is difficult to measure clinically and by imaging techniques. Also, analysis of the SLNs by the pathologists did not include microsectioning or immunochemistry because this is not part of clinical routine. Ultrastaging of SLNs has the potential to detect additional metastases and, therefore, will increase sensitivity and NPV. Whether ultrastaging really improves diagnostic accuracy has still to be determined.¹⁶

We evaluated a hypothesis for diagnostic accuracy of SLNs to predict the histopathologic pelvic nodal status in cervical cancer of all stages. According to our results, of 100 patients with cervical cancer, SLNs would not be detected in 11 patients and 14 patients would have positive SLNs, both resulting in a complete pelvic lymphadenectomy. Seventy patients would benefit from less aggressive dissection as a result of true-negative SLN findings, and in four patients with false-negative SLNs, pelvic lymph node metastases would not be detected (Fig 2).

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Probability of diagnostic outcome in all patients eligible for analysis of detection rate and diagnostic accuracy (flowchart). SLN, sentinel lymph node.

Our data suggest that it has to be questioned whether the sentinel concept is applicable in cervical cancer irrespectively of tumor size. In our population, from our point of view, the sensitivity was too low to rely on the sentinel status as a rationale to omit complete pelvic lymphadenectomy. The impact of overlooked lymph node metastases in patients with cervical cancer is severe and cannot be compared with patients with breast cancer. Missed metastatic axillary lymph nodes can be detected clinically. Five-year survival rate after isolated axillary recurrence is 49%¹⁹ compared with a 2-year survival rate of 19% in patients with recurrent cervical cancer.²⁰ Studies emphasize that the presence of lymph node metastases reduces 5-year disease-free survival from 89% to 50%²¹ because metastases might lead to pelvic sidewall recurrence, which is difficult to detect in an early phase and hard to cure.

Preliminary work using dye showed that it has to be administered subepithelially in four quadrants of the intact cervix and that 4 mL is superior to smaller volumes.^17,22 Detection rate varies between 63% and 93% if only dye is used. In our study, the detection rate was 82%. Studies applying ^99mTc alone are rare, and detection rate varies between 70% and 96%.^23,24 The advantage of ^99mTc is the chance to detect an aberrant localization of SLNs.^{25 99m}Tc in addition to blue dye increases detection rate significantly²⁶; detection rates vary between 80% and 100%.^18,27 In our study, combined labeling led to a significantly improved detection rate of 94% (P < .001).

The rate of bilateral sentinel detection varies between 19% and 90%.^{6,17,18,24,26,28-30} Proponents of bilateral detection argue that the cervix is a midline organ, and therefore, lymphatic drainage involves both pelvic sides. They do not regard unilateral SLN detection as reliable, although unilateral lymph node metastases were reported in 73% of patients.³¹ Data show that lymph nodes might be clogged with debris. Therefore, a history of inflammatory disease or surgery might have altered bilateral drainage towards unilateral.^32,33 This is supported by studies on recurrent cancer in which the regional lymph node status was predicted correctly by the SLN,³⁴ although the drainage system was severely altered through primary surgery. Therefore, we regarded the pelvic basin as a unit; if one SLN was detected, bilateral lymph node dissection could be omitted. If the sentinel concept is evaluated per pelvic side, all estimations should consider that a simple side-wise approach could be biased by correlated data. Our approach probably overestimates the false-negative rate if transferred to a side-wise SLN concept. However, fewer patients will profit from the SLN concept because bilateral detection occurs in only 70% of patients.²⁶

In our study, sensitivity improved significantly from 70% to 87% and the NPV improved by 5.5% (not significant) in patients with bilateral SLNs versus unilateral SLNs. In patients with tumors 20 mm, sensitivity and NPV did not differ significantly with regard to unilateral or bilateral detection. The discrepancy between improved sensitivity in the overall cohort and no significant differences in the cohort of patients with smaller tumors might be a result of the distribution of disease severity and the prevalence of metastatic disease (Tables 3 and 4).

Application failure, a learning curve, or sentinel localization close to the site of application can hamper SLN detection.^26,35,36 Intense staining and strong irradiation next to the application site obscure detection of parametrial SLNs. In our study, four of 24 patients with false-negative SLNs had parametrial lymph node metastasis in the paracervical tissue removed with the cervix. Parametrial SLNs are present in 2% to 17% of patients.^{7,17,23,26,27,35,37,38} The prognostic impact on recurrence and survival in patients with parametrial lymph node metastases in absence of pelvic lymph node metastases is unclear.³⁹ This might be a result of the fact that these nodes are removed along with the hysterectomy specimen or irradiated after initial surgical treatment. Therefore, the prognostic impact of false-negative parametrial SLNs in absence of pelvic or para-aortic lymph node metastases can be limited.

Gross metastatic disease leads to partial filling of that particular lymph node.¹⁷ This observation is supported by a lymphangiography.⁴⁰ Dynamic scintigraphy revealed that only a limited amount of tracer remained for a short period in metastatic lymph nodes before spilling over and accumulating in echelon nodes. Thus, metastatic disease can alter lymphatic drainage. This might be valid for cervical cancer as well³⁶ and may explain our rate of false-negative findings, especially in advanced disease where we found SLNs free of metastatic disease next to large lymph node metastases.

Can patients with smaller tumors benefit from the sentinel procedure? In one case series, detection rate decreased significantly from 73% to 20% in cancers larger than 40 mm.⁷ Other studies have shown an inverse correlation between detection rate and tumor size.^17,35,41

In our study, the detection rate was 94% in cancers 20 mm compared with 84% in cancers greater than 20 mm (P < .001). NPV was 99% for smaller cancers compared with 89% for larger cancers (P < .001), and sensitivity was 91% v 73%, respectively (P = .091). Applying these results to 100 patients with cervical cancer 20 mm, 85 patients would benefit from less aggressive lymph node dissection as a result of true-negative SLN findings, and in one patient with false-negative SLNs, pelvic lymph node metastases would not be detected (Fig 3).

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Probability of diagnostic outcome in patients with cervical cancer 20 mm eligible for analysis of detection rate and diagnostic accuracy (flowchart). SLN, sentinel lymph node.

We excluded 10 patients with unknown or inconclusive results on pelvic lymph nodes from estimation of diagnostic accuracy (Fig 1). In a sensitivity analysis, we assessed the extent of selection bias. Sensitivity varied within a range of 75% to 78% and NPV varied within a range of 92% to 94% in the worst and best cases, respectively.

Because of lack of acceptance, it was impossible to establish a reference center for histopathologic review. This might have introduced a center-specific bias based on differing evaluation algorithms. Evaluation of all lymph nodes did not differ within each unit. Because of the fact that histopathologic findings of SLNs could influence the interpretation of the remaining lymph nodes, a diagnostic review bias was unavoidable. In addition, because pathologists were not blinded against the type of node (SLN or non-SLN), a test review bias might be possible, resulting in an overestimation of the test validity.

Apart from labeling techniques, comparison of subgroups regarding tumor size, unilateral or bilateral detection, and preceding diagnostic conization was not prespecified in the protocol. Thus, the corresponding results have to be interpreted cautiously and must be confirmed in independent data sets.

SLN analysis may have a future role if ultrastaging has a correlation with prognosis. Human papilloma virus–associated markers have the highest potential for identification of viable tumor cells, whereas cytokeratin is not a useful marker in patients with this type of cancer.^42,43 The prognostic value of human papilloma virus mRNA detection is currently being evaluated in this cohort.

According to our data based on an unselected cohort of patients with all stages of cervical cancer, systematic lymphadenectomy cannot be omitted at the moment. Whether patients with small tumors, bilateral pelvic sentinel nodes, and special examination of SLNs can be spared from systematic lymphadenectomy has to be investigated in further studies.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Christopher Altgassen, Hermann Hertel, Antje Brandstädt, Matthias Dürst, Achim Schneider

Administrative support: Matthias Dürst, Achim Schneider

Provision of study materials or patients: Christopher Altgassen, Hermann Hertel, Christhardt Köhler, Achim Schneider

Collection and assembly of data: Christopher Altgassen, Hermann Hertel, Antje Brandstädt, Achim Schneider

Data analysis and interpretation: Christopher Altgassen, Antje Brandstädt, Matthias Dürst, Achim Schneider

Manuscript writing: Christopher Altgassen, Matthias Dürst, Achim Schneider

Final approval of manuscript: Christopher Altgassen, Hermann Hertel, Antje Brandstädt, Christhardt Köhler, Matthias Dürst, Achim Schneider

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The study group included the following participants: N. Haefner, C. Greinke, B. Müller, B. Härtwig, M. Dürst, Friedrich-Schiller-University, Jena; C. Koehler, J. Schwarz, B. Grimm, K. Hasenbein, M. Lanowska, U. Braig, A. Schneider, Charité, Campus Benjamin Franklin and Campus Mitte, Berlin; A. Paseka, H. Urbanczyk, T. Dimpfl, Community Hospital, Kassel; U. Mahnert, U. Hoyme, Helios Clinic, Erfurt; S. Ackermann, M. Beckmann, Friedrich-Alexander-University, Erlangen-Nuremberg; Ludwig-Maximillian-University, Munich; C. Liebrich, U. Petry, Community Hospital, Wolfsburg; H. Hertel, P. Hillemanns, Medical School Hannover; R. Woidat, J. Volz, Central Community Hospital, Bielefeld; J. Lux, M. Fleisch, P. Fasching, D. Rein, H.-G. Bender, Heinrich-Heine-University, Duesseldorf; T. Kuehn, Community Hospital Gifhorn, Gifhorn; C. Altgassen, K. Diedrich, University of Schleswig-Holstein, Campus Luebeck; N. Tryfillis, B. Lampe, Community Hospital Leverkusen, Leverkusen; M. Abou-Dakn, A. Woeckel, J. Strecker, A. Ebert, E. Ulrich, W. Mendling, Vivantes Humboldt Hospital, Berlin-Reickendorf; I. Groell de Rivera, C. Hoess; Community Hospital, Ebersberg; L. Leithner, R. v. Hugo, Community Hospital, Bamberg; M. Rauchholz, H.-G. Meerpohl, St. Vincentius Hospital, Karlsruhe; P. Brandner, K. Neis, Caritas Hospital St Theresia, Saarbruecken; R. Stoecklein, H. Vogt, A. Wischnik, Community Hospital, Augsburg, Germany.

	ACKNOWLEDGMENTS

 
We thank J. Ziegler, C. Dietrich, and K. Polte for their excellent data management and Ing. H. Hoyer, MSc, for support in data analysis.

	NOTES

 
Supported in part by the Deutsche Krebshilfe (German Cancer Aid), Bonn, Germany.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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Submitted August 8, 2007; accepted January 28, 2008.

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