ABSTRACT: The sentinel node evaluation has revolutionized the modern surgical management of cutaneous melanoma and breast cancer. In gynecologic oncology, sentinel node mapping has been mainly studied in vulvar and cervical cancer. In vulvar cancer, data from 12 studies including 353 cases indicate that the sentinel node detection rate is 92% and the negative-predictive value is 99%. Three groin recurrences have been documented so far (< 1%). The technique has more recently been studied in cervical cancer. Data from 12 studies including 323 cases indicate a lower sentinel node detection rate of 80% to 86% and a negative- predictive value of 99%. Three false-negative cases have been reported so far (< 1%). Review of the literature suggests that the combined approach with blue dye and lymphoscintigraphy is superior to the blue dye alone for sentinel node detection. It also suggests that the sentinel node mapping technique is feasible in vulvar and cervical cancer and that it may become a valuable alternative to the traditional groin and pelvic lymphadenectomy. However, results have not been duplicated in large multi-institutional trials, and the technique should still be performed in the context of clinical trials. Complications of the sentinel node mapping technique are rare and usually benign but physicians should be aware of the serious risk of anaphylactic reaction to the blue dye (1% to 2%). Before this technique becomes a standard approach in the management of gynecologic malignancies, more data will be needed to clarify some of the related controversies.
The concept of sentinel node mapping was proposed by Cabanas in 1977 for the management of patients with penile cancer, using lymphangiography of the dorsal lymphatics of the penis. Fifteen year later, Morton applied the same concept to the management of cutaneous melanoma using an intraoperative blue dye injection for localization of the sentinel node. Lymphoscintigraphy using a radioactive tracer (technetium [Tc]-99) was added to the blue dye technique by Krag et al, to help localize sentinel nodes located in unusual or aberrant lymphatic basins such as in melanoma of the trunk. Experience in melanoma and breast cancer has shown that this combined technique is superior to the use of blue dye alone for the detection of the sentinel node,[4-6] and it has become the standard approach in the clinical management of those malignancies in several cancer centers.
The general objectives of nodal staging are threefold: (1) establish the prognosis, (2) obtain regional control, and (3) improve survival. The traditional, complete lymphadenectomy is associated with potentially significant morbidity. Thus, the goal of sentinel node mapping is to accurately determine the status of the regional lymph nodes while reducing the morbidity of the procedure. In this article, we will review the technique and literature on sentinel node mapping in vulvar and cervical cancer and emphasize some of the controversies.
Vulvar cancer represents only about 5% of gynecologic cancers. The International Federation of Gynecology and Obstetrics (FIGO) surgical staging is determined after the removal of the primary vulvar lesion and regional lymph node dissection. Unfortunately, the majority of patients with clinical stage I/II vulvar cancer do not clearly benefit from the inguinofemoral dissection, because only about 10% to 15% have lymph node metastasis.
In addition, nodal staging is associated with several potential complications such as the formation of lymphocysts and seromas, wound infection and breakdown, pain and paresthesia, vascular and neural injuries, and adhesion formation. The longterm and often debilitating lymphedema is particularly troublesome. This condition occurs more frequently in patients who receive adjuvant radiation therapy, and these patients are at higher risk of secondary lymphangitis and cellulitis.
Currently, two different methods are available to locate the sentinel node: the blue dye technique and lymphoscintigraphy. Data suggest that the two methods are complementary and the best results are obtained by combining them.
• Lymphoscintigraphy—Lymphoscintigraphy-The principle of lymphoscintigraphy is to inject a weakly radioactive tracer at the interface between the tumor and the normal tissue, where the lymphatic network is rich and abundant. It is important to avoid intratumoral injection. Usually 1.0 to 1.5 mL of filtered Tc-99 radiocolloid, with an activity of 0.4 to 0.8 mCi, is injected very superficially under the dermis with a 27-gauge needle. The tracer is picked up by the microlymphatics surrounding the tumor and is transported via the lymphatic channels to the regional lymph nodes, where it accumulates. In vulvar cancer, it is worthwhile applying an anesthetic cream locally, 30 to 60 minutes before the injection, because the Tc-99 injection burns and is very painful.
Only one anterior lymphoscintigram with a posterior transmission flood can be performed as early as 15 minutes after the injection to locate the sentinel node, which appears as a black dot. The nuclear medicine specialist can mark the skin to locate the sentinel node to be removed by the surgeon, as it is usually located superficially in the node-bearing area of the groin. However, this part is not absolutely essential.
• Blue Dye Technique—Conversely, the blue dye is injected immediately before surgery. After induction of general anesthesia, 2 mL of isosulfan blue dye (Lymphazurin 1%) is injected at the periphery of the vulvar lesion, also using a 27-gauge needle. Surgery begins with the sentinel node mapping. A small incision is made over the inguinal crease, and the surgeon carefully looks for blue channels that normally lead to a blue lymph node. Care is taken to avoid disruption of the lymphatic channels and bleeding.
The handheld gamma probe (eg, Navigator, Autosuture) is then passed along the area in a search for areas of high radioactivity. A count is performed on the hottest area, which usually corresponds to the blue node. The blue/hot node is removed separately, and a radioactive count is done again ex vivo for correlation. The sentinel node is sent to the pathologist for frozen section. The gamma probe is passed along the area again, looking for other hot areas. Additional nodes may be considered secondary sentinel nodes if their radioactivity count is 10 times the background count. A complete superficial and deep node dissection should then be completed, at least until data from large cooperative group studies confirm the accuracy and reproducibility of the sentinel node mapping technique. Without such confirmation, the technique cannot be considered a standard of care. Depending on the location of the lesion, sentinel node mapping can be done unilaterally or bilaterally, and the vulvar surgery itself is completed afterwards.
• Assessment—Removed sentinel nodes are sent for immediate frozen section. If they look grossly involved by tumor, only one section is performed to confirm the diagnosis. If they look normal, a random section is examined to look for the presence of cancer cells. For the final pathologic analysis, "ultrastaging" of the sentinel node is performed, which involves three sections per node, perpendicular to the long axis of the node (every 40 to 50 μm). Each level is stained for hematoxylin and eosin (H&E) and one is also stained for immunohistochemical analysis with cytokeratins (CAM 5.2 and AE1:AE3) to look for the presence of micrometastasis.
• Procedure Overvie—Figure 1 shows an example of sentinel node mapping in vulvar cancer. First, Tc-99 is injected superficially at the periphery of the lesion. A lymphoscintigram is peformed 20 minutes later, showing in this case a unilateral uptake on the right side of the groin (Figure 1A). Just prior to surgery, blue dye is injected again superficially at the periphery of the tumor. Note the onset of blue lymphatic tracking under the skin (Figure 1B). The right groin is then explored with the handheld gamma probe. Like others, we have noticed that the sentinel node is often located quite medially in the groin (Figure 1C).
Once a hot spot has been detected, the groin is further explored searching for a blue node, with particular attention to meticulous surgical technique to avoid bleeding in the field and disruption of the blue lymphatics. Note the blue lymphatics entering the bluish node (Figure 1D). Sometimes, more than one blue node is removed (Figure 1E). Extracorporeal count is always performed on the sentinel node removed to make sure that the hot node detected in the groin is really the one that has been removed. The extracorporeal count also helps determine, when more than one sentinel node is removed, which one is the primary sentinel node (it should be the one with the highest count, Figure 1F). The issue of secondary sentinel node is not clarified at this point.
Review of the Literature
Clinical examination or imaging techniques cannot reliably detect the presence of lymph node metastasis in vulvar cancer. Even the use of newer noninvasive imaging techniques such as the positron-emission tomography (PET) scan are relatively insensitive in predicting lymph node metastasis in vulvar cancer. Up until now, the standard of care has been a complete superficial and deep groin node dissection, either unilateral or bilateral, which is unfortuantely associated with significant morbidity.
Recently, the concept of sentinel node biopsy has been performed in other malignancies such as breast cancer. Although the long-term morbidity of sentinel node mapping has not been formally reported yet in vulvar cancer, a comparative study in breast cancer confirms a reduced hospital stay and postoperative morbidity in patients who underwent sentinel node biospy as opposed to complete axillary node dissection. The potential of sentinel node mapping in reducing the morbidity of a traditional complete inguinofemoral lymph node dissection in vulvar cancer is thus enormous.
In vulvar cancer, accumulating data indicate that the sentinel node mapping technique is feasible and highly accurate in predicting the status of the inguinofemoral lymph nodes; most studies have also confirmed that the combined technique is superior to the blue dye alone in identifying the sentinel node.[11-22] Puig-Tintoré et al recently summarized 12 series published since 1997, totaling 353 cases (Table 1). The negative predictive value was 100%, except in one series (96%). The review also indicates that the sensitivity of the blue dye technique alone in detecting the sentinel node is only 56% to 88% and that the addition of lymphoscintigraphy significantly improves the sentinel node detection rate to nearly always 100%. Their conclusion is that the available data are strong enough to recommend the routine use of sentinel node mapping in the management of vulvar cancer.
Conversely, one published multiinstitutional study using the blue dye alone reported a sentinel node identification rate of only 56% with two false-negative cases. Of note, three of the five participating centers contributed six cases or fewer, suggesting that efficacy and reproducibility of the technique may be lower when applied at centers with less experience. Also, the sensitivity of the technique may not be as good in the presence of clinically suspicious groin nodes, such that the mapping technique should probably be limited to the detection of subclinical metastasis.