Update on sentinel lymph node evaluation in gynecologic malignancies

Abstract

Purpose of review

Sentinel lymph node (SLN) dissections have been shown to be sensitive for the evaluation of nodal basins for metastatic disease and are associated with decreased short-term and long-term morbidity when compared with complete lymph node dissection. There has been increasing interest in the use of SLN technology in gynecologic cancers. This review assesses the current evidence-based literature for the use of SLN dissections in gynecologic malignancies.

Recent findings

Recent literature continues to support the safety and feasibility of SLN biopsy for early-stage vulvar cancer with negative predictive value approaching 100% and low false-negative rates. Alternatively, for endometrial cancer most studies have reported low false-negative rates, with variable sensitivities and have reported low detection rates of the sentinel node. Studies examining the utility of SLN biopsy in early-stage cervical cancer remain promising with detection rates, sensitivities, and false-negative rates greater than 90% for stage 1B₁ tumors.

Summary

SLN dissections have been shown to be effective and safe in certain, select vulvar cancer patients and can be considered an alternative surgical approach for these patients. For endometrial and cervical cancer, SLN dissection continues to have encouraging results and however needs further investigation.

Introduction

Over the last two decades, there has been a growing interest in the use of sentinel lymph node (SLN) biopsy in gynecologic malignancies. The SLN is defined as the first lymph node in a chain of lymph nodes within a lymphatic basin that receives drainage from the primary tumor. Therefore, if the sentinel node is negative, the remainder of the lymph nodes in the nodal basin should be free of disease as well. SLN biopsy was first employed in penile cancer as reported by Cabanas in 1977 [1]. Since that time, it has become the standard of care in breast cancer and melanomas. Over the last decade, there has been increasing interest in the use of SLN biopsy in gynecologic cancers. The negative predictive value (NPV) of SLN dissection is near 100% and is predictive of the status of nonsentinel nodes within the lymphatic basin for breast and vulvar malignancies. SLN dissections have been demonstrated to decrease both short-term and long-term morbidity associated with complete nodal dissections and lymphadenectomies [2,3].

In this review, we will examine the recently expanding body of literature on the application of SLN biopsy in vulvar, endometrial and cervical malignancies.

Vulvar cancer

Vulvar cancer remains a rare gynecologic malignancy with only 3580 new cases and 900 deaths from this disease in 2009 [4]. Historically, the surgical management of vulvar cancer consisted of a radical vulvectomy with en bloc inguinofemoral lymphadenectomy. However, the morbidity associated with these procedures was unacceptably high with nearly 70% of patients reporting chronic lymphedema and 85% having wound breakdown [5]. In an effort to decrease morbidity associated with the surgical treatment of vulvar cancers, different surgical modalities have been employed. The current standard surgical management is a radical wide local excision or radical vulvectomy with either deep or superficial inguinal node dissection. Although this method has decreased the morbidity associated with surgery significantly, up to 20–40% of patients will still have wound breakdown and 30–70% will suffer from lymphedema [6–9].

The presence of inguinal lymph node involvement is directly correlated with survival in vulvar cancer patients, making the evaluation of inguinal lymph nodes crucial. The 5-year survival rate in patients with negative inguinal lymph nodes is 96% compared to 80% in patients with two or less positive nodes and 12% in patients with greater than two positive nodes. However, only 27% of patients who undergo inguinal lymphadenectomy will have positive lymph nodes. Therefore, more than 70% of women will have an inguinal node dissection without any clinical benefit [10].

In light of these findings, a search for a minimally invasive technique to evaluate the inguinal lymph nodes was begun. In 1979, DiSaia et al. [11] put forth the concept that the superficial inguinal lymph nodes lying between the superficial (Camper’s) fascia and the deeper cribriform fascia represent the SLNs for the vulva. Levenback et al. [12] performed the first sentinel node biopsy feasibility study in patients with vulvar cancer. They used isosulfan blue dye as a tracer intra-operatively, based on the technique described by Morton et al. for cutaneous melanoma [13,14]. A number of studies followed, which have shown SLN dissection to be safe and feasible with low false-negative rates [14–19]. These studies have reported a nearly 100% NPV with a combined technique that included pre-operative injection of a radioactive tracer (technetium-99 sulfur colloid) and intra-operative blue dye (isosulfan blue or methylene blue) [2]. A large multicenter trial evaluating the feasibility and accuracy of SLN biopsy in vulvar cancer patients was published by Hampl et al. [20] in 2008. This multicenter study included 127 patients with stage T1–T3 squamous cell cancer lesions. SLNs were detected in 125 of the 127 patients (detection rate 98%), the false-negative rate was 7.7%, and the sensitivity was 92.3%. There were three cases with a false-negative lymph node, all in patients with midline vulvar lesions. The high false-negative rate is possibly explained by the inclusion of patients with large tumors, two of the patients had tumors greater than 4 cm. Additionally, the study did not require experience with the sentinel node procedure in order to participate, which may have led to a higher false-negative rate [2]. The GOG has recently completed accrual of a large multicenter accuracy study on sentinel node biopsy followed by inguinofemoral lymphadenectomy in vulvar cancer patients (GOG 173), results on the NPV are currently still pending.

Prior to the past few years, most SLN biopsies were followed by complete inguinal lymphadenectomy, regardless of nodal status. However, recently multiple studies have been published evaluating the safety of SLN biopsy in vulvar cancer alone. Rodier et al. [21] first reported their results of eight patients that underwent SLN biopsy alone and found no groin recurrences with a median follow-up of 4.5 months. Multiple additional studies followed reporting similarly low groin recurrences after SLN biopsy alone with follow-up ranging from 4 months to 4.6 years [2,22–24]. Moore et al. [24] reported on 35 patients with SLN dissection of which 31 patients had negative SLN dissection and were subsequently followed with conservative management. In these 31 patients there were 41 groins evaluated and after a median follow-up of 29 months there were two groin node recurrences resulting in recurrence rate of 4.3%. Recently, the results of a multicenter observational study, the GROningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V-I) were published [25]. In this study a sentinel node biopsy was performed, using radioactive tracer and blue dye, in patients with unifocal vulvar squamous cell carcinoma less than 4 cm in diameter. Patients were followed if they had a negative sentinel node after ultrastaging and underwent inguinal lymphadenectomy if they had a positive sentinel node. Four hundred and three patients were enrolled and 276 had negative SLNs. They reported eight groin recurrences (2.9%) with a median follow-up of 35 months. In addition, this study reported decreased morbidity in patients after sentinel node biopsy alone compared to those patients in the study that underwent complete inguinal lymphadenectomy. Lymphedema was only reported in 1.9% of patients undergoing SLN biopsy compared to 25.2% of patients with a complete inguinal lymphadenectomy [25].

With a growing body of evidence supporting the feasibility and safety of SLN biopsy in vulvar cancer, additional questions continue to arise. Currently, the dilemma of the proper management of patients with a positive SLN is still unclear. At the sixth biennial meeting of the International Sentinel Lymph Node Society an expert panel issued a statement regarding the use of SLN biopsy in patients with gynecologic cancers [26]. In this statement, the panel was unable to reach a consensus on the care of patients with positive SLN biopsy. They offered two options: completions of lymphadenectomy and no further dissection but groin irradiation [26]. In addition, the clinical significance of micrometastases in patients with vulvar cancer remains unclear. The GROINSS-V-II study is currently underway, which is a multicenter observational study of patients with a positive SLN who are treated with radiotherapy plus or minus chemotherapy. Further research in this area is warranted.

In summary, SLN biopsy in early-stage vulvar cancer patients appears to be a reasonable alternative to complete inguinal lymphadenectomy. The expert panel statement issued in 2008 from the International Sentinel Node Society stated patients with clinical stage I–II vulvar cancer should be offered SLN biopsy as an alternative to lymphadenectomy when ‘the SLN biopsy is performed by a skilled multidisciplinary team in well-selected patients’. In review of the literature, patients are good candidates for SLN biopsy if they have tumors 4 cm or less, clinically negative groins, and tumor invasion greater than 1mm [2,25]. In addition, all patients with midline tumors should have bilateral SLN biopsies performed. However, given the high mortality rate (75%) associated with false-negative results, it is important for gynecologic oncologists to demonstrate competence in their ability to identify SLN using a standardized technique followed by complete inguinal lymphadenectomy [25,26]. An expert panel recommended an arbitrary number of 10 consecutive cases with successful SLN identification and no false-negative results be performed prior to performing SLN biopsy without lymphadenectomy [26]. However, this number may be difficult for many gynecologic oncologists to obtain due to the small number of vulvar cancer cases in North America. The actual measure of competence remains to be determined.

Endometrial cancer

Endometrial cancer is the most common gynecologic malignancy, with approximately 43 000 new diagnoses in the United States each year [27]. Many of these patients will undergo comprehensive surgical staging, including pelvic and periaortic lymphadenectomy, as part of the management of their disease. However, lymphadenectomies are associated with increased morbidity and mortality in a patient population that most often has nonmetastatic disease to the nodal basins draining the uterus [28]. Given this, there has been increased interest in the role of SLN biopsy for patients with endometrial cancer.

To date, there is no consensus on the most accurate method of performing SLN biopsy in patients with uterine corpus malignancies. Multiple approaches to injecting tracer have been examined, many with relatively low detection rates. Robova et al. [29] compared injection of radioactive tracer and blue dye subserosally with injection of radioactive tracer hysteroscopically in 101 women with clinical stage I or II endometrial cancer. They noted a SLN detection rate of 73.1% in the subserosal group versus 50% in the hysteroscopic group [29]. A study of cervical injection of blue dye and radioactive tracer in 42 patients with grade 1 disease noted a SLN detection rate of 86% with false-negative rate of 0% [30]. Khoury-Collado et al. [31] confirmed these findings in their study of 115 patients when they noted an overall SLN detection rate of 85% utilizing cervical injection of blue dye with or without radioactive tracer. Interestingly, when the cases from the first 27 months of the study were analyzed separately from the remaining 15 months, they noted a significantly lower SLN detection rate in the beginning of the study compared with later in the study (78 versus 94%). Additionally, when individual providers were evaluated, SLN detection rate increased significantly after their first 30 cases (77 versus 94%). False-negative rates improved over time as well, with two false-negative cases in the first 64 patients and no false-negative cases in the remaining patients [32]. These studies suggest acceptable SLN detection rates may be achieved after cervical injection of tracer given an adequate learning curve. Also, the very low false-negative rates reported are consistent with the findings of other authors [32,33]. However, it remains unclear if the cervical injection leads to the identification of the SLN that is representative of the location of the endometrial tumor.

There is currently no recommendation as to the best surgical approach for identifying SLN intra-operatively. One study of 34 women has attempted to answer this question. They found significantly higher SLN detection rates in patients undergoing laparoscopic assisted vaginal hysterectomy (82%) than those undergoing total abdominal hysterectomy (41%) [34]. It should be noted that patients in this study had pericervical injection of blue dye only. Further investigation with different injection methods and the addition of radioactive tracer is warranted.

Given that SLN detection rates remain low, the value of pre-operative imaging has been evaluated in women undergoing SLN biopsy for endometrial cancer. Ballester et al. [35] found a low correlation between day-before lymphoscintigraphy (LSG) and intra-operative findings. However, a recent study found that utilizing LSG in combination with pericervical injection of blue dye and intra-operative gamma probes gave SLN detection rates of 90%. Additionally, when LSG was replaced with SPEC-CT, SLN detection rates increased to 100% [36]. Although this study is limited by its small sample size, it holds promise for future research.

Overall, though there are low false-negative rates, SLN detection rates remain low for SLN biopsy in endometrial cancer, especially when compared with other gynecologic malignancies. Additionally, many questions remain as to the best method of tracer injection as well as operative approach. Large studies comparing these techniques would be helpful in determining what protocol is best.

Cervical cancer

Although not included as part of the clinical FIGO staging for cervical malignancies, lymph node metastasis is one of the most important prognosticators for patients with early-stage cervical cancer. Currently, the standard of care for women with cervical cancer undergoing surgical resection includes a bilateral pelvic lymphadenectomy. These procedures have both short-term and long-term morbidity including nerve and vascular injury, lymphocysts, and lymphedema [37]. The potential of SLN biopsy to reduce the morbidity and mortality associated with pelvic lymphadenectomy has led researchers to seek methods of nodal evaluation with decreased morbidity, such as SLN evaluation in patients with cervical cancer.

Studies evaluating the accuracy and feasibility of SLN biopsy in cervical cancer have been promising, with high SLN detection rates with relatively low false-positive rates. Darlin et al. [38] recently noted an overall SLN detection rate of 90%. However, when analysis was limited to patients with tumors smaller than 2 cm, they reported a SLN detection rate of 94% with both sensitivity and NPV at 100%. This confirms the previous findings of Altgassen et al. [39], who performed one of the largest studies of SLN biopsy in cervical cancer to date. This study examined 590 patients, included all stages of cervical cancer and found an overall detection rate of 88.6% and a sensitivity of 77.4%. However, in the 249 patients with tumors measuring 2 cm or less, there was a sensitivity of 90.5%and a negative predictive value of 99.1% [39]. However, Altgassen et al. [39] reported a false-negative rate of 22.6%, much higher than in other trials. As well, one other study of 58 patients reported a similar false-negative rate of 16.7% [40]. With these studies in mind, the majority of reports on SLN biopsy in cervical cancer have much lower false-negative rates including those that approach 0% [38,41,42]. SLN biopsy has also been reported to lead to improved detection of lymph node metastasis. Gotzak-Uzan et al. [43] describe a higher detection rate of lymph node metastasis in patients undergoing SLN biopsy (17%) compared with those undergoing pelvic lymphadenectomy (7%). Purported theories for this finding include ultrastaging techniques utilized by pathologists for SLN examination, SLN found in locations not typically dissected during lymphadenectomy, or lymph nodes simply being missed by surgeons during lymphadenectomy.

Thus far, SLN biopsy for locally advanced cervical cancer has been considered unreliable secondary to reported high false-negative rates and low SLN detection rates. In a study examining 44 patients with stage IB1-IIB cervical cancer with tumors greater than 3 cm, a SLN detection rate of 77% was reported [44]. In another trial, however, the authors reported a sensitivity of 92% and a negative predictive value of 95% for 33 patients with tumors greater than 2 cm [38].

The findings of studies evaluating SLN biopsy for patients with cervical cancer continue to herald promising results. This is especially true for patients with tumors less than 2 cm. It will be several years before the findings of GOG 206, an ongoing, multicenter trial examining the utility of SLN biopsy in early cervical cancer patients, are available. These results will likely direct future research on this topic.

Conclusion

SLN biopsy has become the standard of care for lymph node evaluation for patients with melanoma and breast cancer. In early-stage vulvar cancer patients SLN biopsy is a safe and reasonable alternative to complete inguinal lymphadenectomy when performed by a skilled multidisciplinary team.

For cervical cancer patients, SLN biopsy is feasible in patients with small tumors (<2 cm) however more questions need to be answered before SLN evaluation can be considered a standard of care for this disease. Finally, in endometrial cancer, the SLN detection rates remain low and there is no agreement regarding the best technique. Further studies evaluating the feasibility of this procedure are still needed.

Key points.

• Sentinel lymph node dissection in vulvar malignancies is safe and is an alternative standard of care for evaluation of inguinal lymph nodes for metastatic disease.

• Sentinel lymph node dissection has a NPV that approaches 100%.

• Sentinel lymph node dissection for vulvar cancer has decreased short and long term morbidity compared with traditional inguinal node dissections.

• Sentinel lymph node dissection for cervical and endometrial cancers needs further evaluation and should be done on research protocols.