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How Safe Is Sentinel Lymph Node Biopsy in Patients With Vulvar Cancer?

The University of Texas M.D. Anderson Cancer Center, Houston, TX

In the current issue, Van der Zee et al¹ provide important data suggesting that the sentinel lymph node (SLN) concept can be safely applied in patients with vulvar cancer. In this study, a group of 276 patients with a negative SLN biopsy (SLNB) were observed for a median of 35 months, and 202 patients had a minimum follow-up time of 2 years. Eight groin relapses (2.9%) were observed. Exclusion of patients with multifocal disease reduced the failure rate to 2.3%. The authors concluded that SLNB, when performed by a skilled multidisciplinary team, was safe for patients with early vulvar cancer. To readers who have followed the development of SLNB for patients with breast cancer or melanoma, this observation may seem obvious and slow in its development. To some gynecologic oncologists treating vulvar cancer, declaring SLNB safe will seem premature. How can these two seemingly disparate positions be true at the same time?

It has been 30 years since Ramon Cabanas² used lymphography in patients with penile carcinoma to describe the SLN as the first site of lymphatic drainage from a primary tumor. The SLN was not identified by location, as Gould et al³ suggested in patients with parotid tumors, but rather by an imaging procedure. The following year, DiSaia et al⁴ recognized the potential benefit of the SLN concept for patients with vulvar cancer and described "utilizing the superficial inguinal lymph nodes as the sentinel nodes for treatment planning." Many gynecologic oncologists began performing superficial inguinal lymphadenectomy, which reduced the incidence of wound breakdown lymphedema compared with standard inguinal femoral lymphadenectomy. In April 1992, the Gynecologic Oncology Group (GOG) reported the results of protocol 74,⁵ which had a similar design to the study by Van der Zee et al. A total of 121 patients with negative superficial inguinal lymph nodes were observed, and nine (7.3%) had a groin relapse. This relapse rate was compared with the long-term follow-up of 81 control patients treated with complete inguinal femoral lymphadenectomy on GOG protocol 36. Among the historical controls, there were no groin relapses. The GOG properly rejected superficial inguinal lymphadenectomy, and most gynecologic oncologists resumed performing inguinal femoral lymphadenectomy.

Coincidentally, in April 1992, Morton et al⁶ described the modern lymphatic mapping procedure in patients with cutaneous melanoma. In 2001, 13 cancer centers from around the world pooled their results for a total of 17,600 melanoma patients, including more than 3,000 patients who underwent SLNB. One of the important findings was the prognostic significance of detection of clinically apparent, compared with clinically occult, lymph node metastases. As a result, the nodal category for the American Joint Committee on Cancer staging for melanoma was amended to distinguish micrometastases from macrometastases, effectively establishing SLNB as a standard procedure for cutaneous melanoma patients.⁷ Around the same time, SLNB was rapidly embraced by breast cancer surgeons and patients. Just as surgical oncologists were moving toward SLNB for these two common tumors, gynecologic oncologists were moving in the other direction, toward more extensive lymphadenectomy for patients with vulvar cancer.

Despite the disappointing results of GOG protocol 74, many gynecologic oncologists began performing SLNB in vulvar cancer patients. By 2000, there were enough single-institution experiences supporting SLNB for patients with vulvar cancer to mount two large multicenter trials. The GOG began a validation trial in December 1999, which is still accruing patients, to determine the sensitivity and false-negative rate of SLNB in a large community-based setting. The Dutch investigators began an observational trial in March 2000, which is reported in this issue of the Journal of Clinical Oncology.

How can a new procedure be described as safe? In declaring the safety of SLNB in vulvar cancer, Van der Zee et al¹ assumed a 2% relapse rate in patients receiving the current standard treatment. The authors’ own work suggests that the acceptable relapse rate for patients is as close to zero as possible,⁸ and patients consider lymphedema as an acceptable toxicity to achieve this degree of safety. The 2% relapse rate is high compared with the GOG historical controls. However, the historical GOG patients underwent an extensive inguinal femoral lymphadenectomy that most gynecologic oncologists no longer perform because of the associated morbidity.

How does the 3% false-negative rate compare with experiences at other disease sites? Large single-institution studies report false-negative rates of 4% to 5% in validation trials of SLNB in patients with breast cancer and melanoma. In the multi-institutional community setting, the National Surgical Adjuvant Breast and Bowel Project B-32 investigators found a false-negative rate of 9.8% in patients with early breast cancer.⁹ Despite these high numbers, isolated axillary failures are considered rare in patients with early breast cancer because the majority of SLN-negative patients receive adjuvant treatment that effectively treats microscopic metastases.

This situation is different from vulvar cancer. Adjuvant therapy for vulvar cancer (regional radiotherapy) is exclusively based on lymph node status. Mortality from local relapse in the groin is high in all studies, including the study reported here. The current treatment paradigm for vulvar cancer does not leave room for error in the determination of lymph node status.

There is no doubt that early detection of locoregional metastatic disease benefits patients. Morton et al¹⁰ demonstrated that early detection of metastatic disease with SLNB among intermediate-risk melanoma patients resulted in a survival advantage compared with patients undergoing lymphadenectomy at the time of recurrence. Why is this? Analysis of lymph node–positive melanoma patients indicates that the tumor burden of metastatic disease (ie, the size and number of metastases) is a critical factor in determining survival. Many studies in breast and melanoma patients have demonstrated that ultrastaging of SLNs increases the detection of metastatic disease by at least 20% compared with routine analysis. Gynecologic oncologists who are resistant to the SLN concept do not offer patients the opportunity for vital prognostic information from ultrastaging of SLNs with increased detection of micrometastases.

The experience of the Dutch group is a reminder that the safety of the SLN concept does not depend solely on the skill of the surgeon. Inaccurate interpretation of preoperative lymphoscintigraphy by the nuclear medicine specialist or of ultrastaging findings by the pathologist accounted for three of the patients who experienced a relapse. The SLN concept requires a multidisciplinary team to make the procedure safe for the patient. The current study by Van der Zee et al¹ was a multicenter study with 15 participating sites that enrolled a median of 21 patients (range, three to 113 patients). This suggests that more than half of the patients came from just a few sites where the multidisciplinary team was experienced. Vulvar cancer is so rare that most gynecologic oncologists outside of major referral centers infrequently see eligible patients, making it difficult for some gynecologic oncologists to gain experience with SLNB. The data from GOG protocol 173 may provide more information about how SLNB is performed in a community-based setting.

Gynecologic oncologists wishing to offer SLNB to patients should consider taking the following precautions to reduce the risk for false-negative results. Perform approximately 10 SLNBs followed by lymphadenectomy to provide an opportunity to learn the procedure. Select patients carefully, excluding patients with multifocal or large tumors. Use preoperative imaging (computed tomography, magnetic resonance imaging, and ultrasonography) to exclude patients with gross nodal involvement in whom the mapping procedure might be inaccurate if physical examination is indeterminate, including obese patients for whom physical examination is especially unreliable. Use preoperative lymphoscintigraphy to help determine the laterality of lesions with ambiguous locations close to, but not involving, the midline. During the case, if any doubts arise regarding the adequacy of the mapping procedure, abandon SLNB and perform a lymphadenectomy. Communicate personally and directly with the pathologist regarding the management of the SLN. The pathologist should understand the consequences of a false-negative SLNB. Finally, consider closer follow-up of SLN-negative patients with imaging to detect rare nodal failures as soon as possible.

This report also raises many new questions regarding the care of women with vulvar cancer. What is the best management of women with a positive SLN? In half of node-positive patients, the SLN is the only positive node. These patients may be curable with lymphadenectomy. The morbidity of inguinal radiotherapy in an undissected groin is low, which makes inguinal radiotherapy an attractive alternative. What is the role of chemotherapy? Perhaps there is a group of SLN-negative patients with other high-risk factors (ie, deep invasion, lymphovascular space invasion, or large tumor) who are presumably at an increased risk of a false-negative result and should, therefore, receive adjuvant therapy despite the negative SLN. Should the nodal category of staging for vulvar cancer be amended as it was for melanoma? Discriminating micrometastasis from macrometastasis in patients with melanoma and breast cancer has been a major benefit to patients, and I believe that our governing bodies should consider similar action. There is every reason to believe that the success of the SLN concept in improving outcomes in patients with breast cancer and melanoma can be replicated in patients with vulvar, cervical, and endometrial cancer.

Congratulations to Van der Zee et al for their enormous contribution to the care of women with vulvar cancer. These data will accelerate the acceptance of SLNB as an option for patients with vulvar cancer. In the final analysis, safety is determined during preoperative counseling by individual patient-physician pairs based on their experience and risk tolerance. It is the responsibility of gynecologic oncologists and their colleagues to implement this technique into practice with care to avoid preventable false-negative results.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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

REFERENCES

1. Van der Zee AGE, 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[Abstract/Free Full Text]

2. Cabanas RM: An approach for the treatment of penile carcinoma. Cancer 39:456-466, 1977[CrossRef][Medline]

3. Gould E, Winship T, Philbin PH, et al: Observations on a "sentinel node" in cancer of the parotid. Cancer 13:77-78, 1960[CrossRef][Medline]

4. DiSaia PJ, Creasman WT, Rich WM: An alternate approach to early cancer of the vulva. Am J Obstet Gynecol 133:825-832, 1979[Medline]

5. Stehman FB, Bundy BN, Dvoretsky PM, et al: Early stage I carcinoma of the vulva treated with ipsilateral superficial inguinal lymphadenectomy and modified radical hemivulvectomy: A prospective study of the Gynecologic Oncology Group. Obstet Gynecol 79:490-497, 1992[Abstract/Free Full Text]

6. Morton DL, Wen DR, Wong JH, et al: Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127:392-399, 1992[Medline]

7. Balch CM, Buzaid AC, Soong SJ, et al: Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635-3648, 2001[Abstract/Free Full Text]

8. de Hullu JA, Ansink AC, Tymstra T, et al: What doctors and patients think about false-negative sentinel lymph nodes in vulvar cancer. J Psychosom Obstet Gynaecol 22:199-203, 2001[Medline]

9. Julian TB, KD, Brown A, et al: Preliminary technical results of NSABP B-32, a randomized phase III clinical trial to compare sentinel node resection to conventional axillary dissection in clinically node-negative breast cancer patients. Presented at the 27th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2004

10. Morton DL, Thompson JF, Cochran AJ, et al: Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 355:1307-1317, 2006[Abstract/Free Full Text]

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