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Journal of Clinical Oncology, Vol 26, No 18 (June 20), 2008: pp. 2930-2931 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.3964
Quality Control in Sentinel Lymph Node Biopsy in Cervical CancerDivision of Gynecologic Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
In the current issue, Altgassen et al1 report on a prospective multicenter study comprising the largest number of cervical cancer patients in a single study undergoing sentinel lymph node (SLN) mapping. The authors analyzed 507 patients between December 1998 and October 2006 and included patients with cervical cancers of all stages. Although the majority of participating centers used both blue dye and technetium-99 for the SLN procedure, the protocol allowed either alone. The SLN and the nodes from the systematic lymphadenectomy were submitted for routine staining (hematoxylin and eosin); no ultrastaging was performed. It is important to note that the detection rate was calculated based on the number of patients with at least one detected SLN. The detection rate of pelvic SLN overall was 88.6% (95% CI, 85.8% to 91.1%) and was higher if a combination of technetium and patent blue was used (93.5%; 95% CI, 90.3% to 96%). Overall sensitivity of pelvic SLN detection was 77.4% (95% CI, 68.2% to 85.0%), which was lower than the predefined noninferiority margin of 90%. The subgroup analyses showed that the sensitivity of SLN detection was higher for patients with tumors Since the introduction of sentinel node mapping in early-stage melanomas by Morton et al,2 the SLN procedure has replaced systematic lymphadenectomies in both melanoma and breast cancer populations.3,4 More recently, among gynecologic malignancies, SLN mapping with blue dye and lymphoscintigraphy has been studied in both vulvar5-7 and cervical cancers.8,9 There have been many single-institution series in the literature reviewing their experiences with SLN mapping in cervical cancer, demonstrating high detection rates from 86% to 100%.8-10 In a recent systematic review, the sentinel node detection rate with the combined technique was 97%, with a sensitivity of 92%.11 However, the most recent multicenter study in this issue by Altgassen et al1 did not achieve similar detection and sensitivity rates as those previously published. The authors should be congratulated for accomplishing and advancing the SLN procedure in clinical practice by conducting a large multicenter study. However, this study raises further questions. Why did this promising procedure have less than the expected results? Will a systematic lymphadenectomy ever be omitted in cervical cancer? Will change in practice only be affected by a randomized trial? The results of this study highlight how the success of SLN detection depends on technique, individual surgeon experience, and the patient population chosen for this procedure. This multicenter study is a good example of how excellent results may be diluted if stringent criteria are not widely applied to a general population. The technical aspect of the SLN procedure plays a key role in maximizing results. Quality assurance, including physician training and experience, methods of detection, and central pathology review for both the primary tumor and lymph nodes are essential components to maximize success. For example, the multicenter study of SLN in vulvar cancer by van der Zee et al12 required each center to have successful experience with sentinel nodes in at least 10 vulvar cancer patients, use both blue dye and technetium, and submit the SLN for pathologic assessment by a protocol that included ultrastaging. Without stringent quality control measures, the overall sensitivity of the procedure can be significantly reduced. Although this study's strength in patient numbers could only be achieved by including multiple centers, if not all centers had proven experience with the SLN procedure, the decreased detection rate could be a result of the obligatory learning phase, the definition of detection used, and lack of the other quality controls listed earlier. Altgassen et al1 accrued approximately 600 patients over 7 years from 18 centers. On average, that is less than five patients per year per center and potentially even less per surgeon. Although the ideal number of procedures required in cervix cancer has not been identified, Morton et al13 suggested a learning phase of at least 30 consecutive patients per center for cutaneous melanoma, whereas De Hullu et al5 suggested at least 20 consecutive patients for vulvar cancer. Time to perfect the technique, not only with the operative procedure itself, but also in conjunction with nuclear medicine and pathology, is important to consider before dismissing the sentinel node procedure. It would be interesting to know whether the accuracy was higher in the second half of the patients compared with the first half. The main theoretical benefit of the SLN procedure is to reduce the requirement for a complete lymphadenectomy with its associated morbidity in a patient population at low risk for lymph node metastases. In early-stage cervical cancer, the incidence of pelvic lymph node metastasis is approximately 10%14; therefore, if the SLN is negative, 90% of patients can avoid a full pelvic lymphadenectomy and the associated morbidity of blood loss, neural injury, lymphocyst, and lymphedema. It is unclear whether more advanced cancers can obtain the same benefit and whether the SLN concept is valid in such patients. Altgassen et al1 included all stages of cervical cancer (20% of patients had stage IIA or greater). The incidence of pelvic lymph node involvement is approximately 25% to 30% for stage II cervical cancers15 and higher for subsequent stages. These tumors are also likely to present with adverse primary tumor features such as clinical tumor size more than 3 cm, depth of invasion more than 10 mm, and presence of capillary-lymphatic space involvement.16 Therefore, the likelihood of recommending adjuvant therapy postoperatively is high, and the usefulness of an SLN procedure in morbidity reduction in this clinical scenario is questionable. Although it is likely that these patients were included in this study because of the higher incidence of lymph node metastases, locally advanced tumors are more likely to have grossly involved nodes or parametrial invasion. It has been previously demonstrated that nodes with metastatic disease and parametrial involvement can alter the lymphatic drainage pattern; therefore, the SLN procedure should be abandoned if the lymph nodes are obviously involved.17,18 This could explain why Altgassen et al1 noted that the sensitivity of the SLN procedure was improved in patients with a tumor size less than 20 mm. Restricting the SLN procedure to those with earlier stage cervix cancer will not only improve the sensitivity of the procedure, but also reduce the morbidity in a group that can benefit from it most. The definition of detection influences the results when evaluating SLNs. When the SLN detection rate is quantified, many authors believe it should be based per hemipelvis rather than per patient.9,19,20 When SLNs are detected unilaterally, this should not be considered a false-negative finding; however, the contralateral hemipelvis requires a complete lymphadenectomy. This method of evaluating the SLN lowers the false-negative rate and improves the sensitivity of the SLN procedure. Proving this point, in a subgroup analysis by Altgassen et al,1 the sensitivity rate was higher in those with bilateral detection of SLN. Besides the benefit of decreasing morbidity by using the SLN procedure, there are additional benefits that should not be overlooked. The SLN can be found in unusual locations, such as the common iliac nodes, presacral nodes, or occasionally para-aortic nodes, without involvement of the external iliac, internal iliac, or obturator nodes.9 Detecting these aberrant pathways subsequently alters treatment decisions, which could ultimately translate into improved outcome. Finally, ultrastaging of SLNs may detect micrometastases that are not identified on standard hematoxylin and eosin staining. Although the relevance of this finding is unclear, these patients may be at a higher risk of locoregional recurrence compared with true node-negative patients.9 The authors are to be commended for carrying out such a large prospective study of SLN mapping in patients with cervical cancer. This study provides further information regarding SLN mapping in this disease and demonstrates how detection and sensitivity rates of this procedure are dependent on a number of factors. It also demonstrates the difficulty of duplicating the results of single centers of excellence when applied to a larger population of patients, clinicians, and institutions. Caution should be exercised by any center that develops an SLN program for cervical cancer patients; it requires a dedicated effort by a multidisciplinary team including nuclear medicine and pathology and time to allow for the accumulation of experience. Finally, methods to decrease the false-negative rate, such as abandoning the technique in the presence of grossly abnormal nodes, evaluating each hemipelvis independently, and ultrastaging the SLN, will help maximize the procedure's detection and sensitivity rates and allow us to move forward with using the SLN procedure in standard practice. Should a randomized study be performed? Ideally, a clinical trial would be designed as an equivalency trial. Unfortunately, the sample size required to evaluate a relapse rate of 10% compared with 15% in early-stage cervical cancer patients is greater than 1,800 patients. Such a study would be the largest ever in cervical cancer and not likely feasible. Therefore, it seems likely that we will have to rely on phase II data. However, strict quality controls will have to be built into these protocols. By adhering to the strict criteria described, we can improve detection and sensitivity rates of the SLN procedure. Perhaps then, we can be more assured that we can omit systematic lymphadenectomies in patients with early-stage cervical cancer. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Lilian T. Gien, Allan Covens Provision of study materials or patients: Lilian T. Gien, Allan Covens Collection and assembly of data: Lilian T. Gien, Allan Covens Data analysis and interpretation: Lilian T. Gien, Allan Covens Manuscript writing: Lilian T. Gien, Allan Covens Final approval of manuscript: Lilian T. Gien, Allan Covens REFERENCES
1. Altgassen C, Hertel H, Brandstädt A, et al: Multicenter validation study of the sentinel lymph node concept in cervical cancer: AGO Study Group. J Clin Oncol 26:2943-2951, 2008 2. Morton DL, Wen DR, Wong JH, et al: Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127:392-399, 1992 3. Morton DL, Cochran AJ, Thompson JF, et al: Sentinel node biopsy for early-stage melanoma: Accuracy and morbidity in MSLT-1, an international multicenter trial. Ann Surg 242:302-311, 2005[Medline] 4. Krag DN, Anderson SJ, Julian TB, et al: Technical outcomes of sentinel lymph node resection and conventional axillary lymph node dissection in patients with clinically node-negative breast cancer: Results from the NSABP B-32 randomized phase III trial. Lancet Oncol 8:881-888, 2007[CrossRef][Medline] 5. De Hullu JA, Hollema H, Piers DA, et al: Sentinel lymph node procedure is highly accurate in squamous cell carcinoma of the vulva. J Clin Oncol 18:2811-2816, 2000 6. Levenback C, Coleman RL, Burke TW, et al: Intraoperative lymphatic mapping and sentinel node identification with blue dye in patients with vulvar cancer. Gynecol Oncol 83:276-281, 2001[CrossRef][Medline] 7. Hauspy J, Beiner M, Harley I, et al: Sentinel lymph node in vulvar cancer. Cancer 110:1015-1023, 2007[CrossRef][Medline] 8. Levenback C, Coleman RL, Burke TW, et al: Lymphatic mapping and sentinel node identification in patients with cervical cancer undergoing radical hysterectomy and pelvic lymphadenectomy. J Clin Oncol 20:688-693, 2002 9. Hauspy J, Beiner M, Harley I, et al: Sentinel lymph nodes in early stage cervical cancer. Gynecol Oncol 105:285-290, 2007[CrossRef][Medline] 10. Dargent D, Martin X, Mathevet P: Laparoscopic assessment of the sentinel lymph node in early stage cervical cancer. Gynecol Oncol 79:411-415, 2000[CrossRef][Medline] 11. Van de Lande J, Torrenga B, Raijmakers PGHM, et al: Sentinel lymph node detection in early stage uterine cervix carcinoma: A systematic review. Gynecol Oncol 106:604-613, 2007[CrossRef][Medline] 12. van der Zee A, Oonk MH, De Hullu JA, et al: Sentinel node dissection is safe in the treatment of early stage vulvar cancer. J Clin Oncol 26:884-889, 2008 13. Morton DL, Thompson JF, Essner R, et al: Validation of the accuracy of intraoperative lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: A multicenter trial—Multicenter Selective Lymphadenectomy Trial Group. Ann Surg 230:453-463, 1999[CrossRef][Medline] 14. Steed H, Rosen B, Murphy J, et al: A comparison of laparoscopic-assisted radical vaginal hysterectomy and radical abdominal hysterectomy in the treatment of cervical cancer. Gynecol Oncol 93:588-593, 2004[CrossRef][Medline] 15. Sakuragi N, Satoh C, Takeda N, et al: Incidence and distribution pattern of pelvic and paraaortic lymph node metastasis in patients with stages IB, IIA, and IIB cervical carcinoma treated with radical hysterectomy Cancer 85:1547-1554, 1999[CrossRef][Medline] 16. Delgado G, Bundy B, Zaino R, et al: Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study. Gynecol Oncol 38:352-357, 1990[CrossRef][Medline] 17. O’Boyle JD, Coleman RL, Bernstein SG, et al: Intraoperative lymphatic mapping in cervix cancer patients undergoing radical hysterectomy: A pilot study. Gynecol Oncol 79:238-243, 2000[CrossRef][Medline] 18. Weaver DL: Sentinel lymph node biopsy in breast cancer: Creating controversy and defining new standards. Adv Anat Pathol 8:65-73, 2001[CrossRef][Medline] 19. Barranger E, Coutant C, Cortez A, et al: Sentinel node biopsy is reliable in early-stage cervical cancer but not in locally advanced disease. Ann Oncol 16:1237-1242, 2005 20. Plante M, Renaud MC, Tetu B, et al: Laparoscopic sentinel node mapping in early-stage cervical cancer. Gynecol Oncol 91:494-503, 2003[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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20 mm (90.9%) and with bilateral detection (87.2%). The authors have concluded that systematic lymphadenectomy in patients with cervical cancer should not be omitted at this time. 
