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From the Departments of Surgery (SHE, OEN, BBRK) and Nuclear Medicine (RAVO, CAH), The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
Correspondence: Address correspondence and reprint requests to: Susanne H. Estourgie, MD, Department of Surgery, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; Fax: 31-20-512-2554; E-mail: s.estourgie{at}nki.nl
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Methods: A total of 250 patients with cutaneous melanoma were studied prospectively. Preoperative lymphoscintigraphy was performed after injection of 99mTc-nanocolloid intradermally around the primary tumor or biopsy site (.32 mL, 65.5 MBq [1.8 mCi]). The sentinel node was surgically identified with the aid of patent blue dye and a gamma ray detection probe. The median follow-up was 72 months.
Results: Lymphoscintigraphic visualization was 100%, and surgical identification was 99.6%. In 60 patients (24%), 1 or more sentinel nodes were tumor positive at initial pathology evaluation. Late complications after sentinel node biopsy of the remaining 190 patients were seen in 35 patients (18%). The false-negative rate was 9%. In-transit metastases were seen in 7% of sentinel node–negative and 23% of sentinel node–positive patients. The estimated 5-year overall survival rates were 89% and 64%, respectively (P < .001).
Conclusions: This study confirms that the status of the sentinel node is a strong independent prognostic factor. The false-negative rate and the incidence of in-transit metastases in sentinel node–positive patients are high and have to be weighed against the possible survival benefit of early removal of nodal metastases.
Key Words: Analysis • Melanoma • Morbidity • Recurrence • Sentinel node • Survival
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INTRODUCTION |
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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The next day, patent blue dye (Laboratoire Guerbet, Aulnay-Sous-Bois, France) in a mean volume of 1.0 mL was administered intradermally, completely surrounding the tumor or biopsy site. Intraoperative detection of radioactivity was performed with a gamma ray detection probe (Neoprobe; Johnson & Johnson Medical, Hamburg, Germany). Both tracers were used to identify the sentinel node. All procedures were performed by one of two experienced surgeons or under their supervision by a resident or fellow. A hot spot on the lymphoscintigraphic image was considered to be a sentinel node if an afferent lymphatic channel was visualized, if the hot spot was the first one seen in a sequential pattern, or if the hot spot was the only one depicted. An afferent blue lymphatic vessel coming directly from the tumor site also defined a node as the sentinel node. This definition has been discussed in more detail previously.8 After sentinel node biopsy, a wide local excision was performed of the primary melanoma site with 1- or 2-cm margins, depending on the Breslow thickness. Frozen-section investigation was not routinely performed. All sentinel nodes were formalin-fixated, bisected, paraffin-embedded, and cut at a minimum of six levels at 50- to 150-µm intervals. Pathologic evaluation included hematoxylin and eosin and immunohistochemical staining (S-100 and HMB-45). Even the presence of a small cluster of tumor cells within the sentinel node was considered as "tumor positive." All patients were followed up at our own institute.
Lymphoscintigraphic and surgical results, postoperative complications, late complications, follow-up, recurrence pattern, overall survival, and disease-free survival were evaluated. The median follow-up duration was 72 months (range, 12.3–104.4 months).
At The Netherlands Cancer Institute, results of a sentinel node procedure are considered falsely negative if the initial pathologic evaluation reveals no tumor cells in the sentinel node but one or more nonsentinel nodes are tumor positive. These cases were detected either during surgery, by means of incidental removal of other nodes, or during follow-up evaluation as a clinical recurrence if no other signs of regional recurrence were observed at that time. The false-negative rate was calculated over the entire group of patients with tumor-positive lymph nodes. No confirmatory lymphadenectomies were performed on any of these patients; hence, only a preliminary false-negative rate can be given. The 5-year negative predictive value was calculated with the Kaplan-Meier method.
Disease-free and overall survival curves were constructed with the Kaplan-Meier method and were analyzed with the log-rank procedure. Multiple regression analysis was performed with the Cox proportional hazard model. The model selected for regression was created by the backward elimination method, using a P value of .05 as the exclusion limit. Follow-up was measured from the date of sentinel node surgery in our institute. For survival, the event was death, and for disease-free survival, the event was disease recurrence or death. In the absence of an event, censoring took place at the last follow-up.
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RESULTS |
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2 basins in 71 patients (28%). An interval sentinel node was found outside a recognized node field in 41 (12%) of 337 cases.
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Pathology
In 60 patients (24%), 1 or more sentinel nodes were tumor positive at the initial pathology evaluation (Table 2). Three patients had metastatic disease in two different lymph node basins. A therapeutic lymph node dissection was performed in all 60 patients. In seven patients (12%), at least one additional tumor-positive lymph node was identified. The thinnest primary melanoma associated with an involved sentinel node had a Breslow thickness of 1.1 mm.
The sentinel node was tumor free in 190 patients. In one of these patients, additional serial sectioning at a later stage showed metastatic disease in the sentinel node after all.
Complications
One patient had a generalized allergic skin reaction to the patent blue dye. Postoperative complications were seen in 23 (9.2%) of the 250 patients: wound infection (n = 5), seroma (n = 4), wound infection with seroma (n = 5), wound infection with wound dehiscence (n = 1), lymph fistula (n = 3), transient sensibility impairment (n = 1), transient neuropraxia (n = 2), and hematoma (n = 2). All resolved without long-term sequelae.
In 60 patients, lymph node clearance was performed after removal of a tumor-positive sentinel node. Postoperative or late complications occurred in 29 (48%) of these 60 patients: seroma (n = 12), edema of the leg (n = 10), infection of the lymphadenectomy wound (n = 10), infection of the limb (n = 3), wound necrosis (n = 2), wound dehiscence (n = 2), hematoma (n = 1), and transient neuropraxia (n = 1).
Late complications after sentinel node biopsy were seen in 35 (18%) of the remaining 190 patients: minor edema of the leg (n = 23), infection of the leg (n = 6), seroma (n = 2), transient sensibility impairment (n = 5), and transient neuropraxia (n = 2). All but 1 of the 23 patients with edema had melanoma on the leg; the remaining patient had a trunk melanoma.
False-Negative Results
Thus far, 12 patients presented with a recurrence in a previously mapped basin after excision of a tumor-free sentinel node. All the sentinel nodes of these patients were re-reviewed, and additional slides were obtained by the pathologist. Five of these 12 patients developed their lymph node metastases after in-transit metastases and were not considered to have had a false-negative result. The patient in whom one of the three lymphoscintigraphically visualized sentinel nodes could not be identified during surgery developed lymph node metastases in that very area.
One patient presented with both a lymph node recurrence and in-transit metastases simultaneously 9 months after the sentinel node procedure. Additional serial sectioning of the sentinel node at that time revealed tumor cells after all. One patient with a melanoma in the head and neck region developed a lymph node recurrence after 11 months. Retrospective analysis of this procedure showed that the possible cause of the false-negative result was that the injected radioactive dose was only 14.0 MBq (.38 mCi). The remaining four patients developed their nodal recurrence after 4, 14, 41, and 41 months. The sentinel node biopsy results of these last six patients were considered to be falsely negative. Three of these patients died of disease, one patient died from a ruptured abdominal aneurysm, and the other two are alive without evidence of disease. The false negative rate is 9.1% (6 of 66) so far, with a median follow-up of 72 months. Patients with a tumor-free sentinel node have a 96.5% chance of remaining true negative (negative predictive value) in the first 5 years (Fig. 1). If we also consider the procedure in patients with lymph node metastases after in-transit metastases to be falsely negative, then the false-negative rate would be 15.5% (11 of 71).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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Another explanation for the false-negative results could be that the technique is insufficient. However, after years of experience, a consensus has now been obtained. The best chance to find all sentinel nodes and to avoid the risk of removing too many nonsentinel nodes is offered by a combined approach of lymphoscintigraphy, a gamma ray detection probe, and blue dye.1,5,17 Blue lymphatics enable the surgeon to discriminate between first- and second-echelon nodes. This is especially helpful when multiple hot spots are visualized on the lymphoscintigraphic images. Not only have surgical skills evolved the last few years, but the pathologic evaluation has also improved. The current consensus is that it is best to also perform serial sectioning and immunohistochemical staining to minimize the risk of missing metastasis in a sentinel node.1 Even this secure approach may sometimes falter, as was seen in one of our patients. There should be a balance, though, between sensitivity and workload for the pathologist.
Some authors suggest that false-negative results may be due to obstruction of lymphatics.18 This obstruction might be caused by tumor emboli in the lymphatics between the site of melanoma and the regional node basin or by a sentinel node grossly invaded by tumor. Others suggest reseeding of the regional node basin by tumor cells still in transit at time of the sentinel node procedure as a cause of a false-negative result.14 If this would be true, one could propose performing the sentinel node procedure a few months after the excision of the melanoma. Other potential causes for false-negative results are the limited reproducibility of lymphoscintigraphy and lymphatic vessels bypassing the first node.19,20
Other unresolved issues are the clinical consequences of the sentinel node procedure. What should be done if a tumor-positive sentinel node is collected? Should one perform a regional lymph node dissection? Additional tumor-positive lymph nodes were identified in only 12% of our patients who underwent a therapeutic lymph node dissection. We found no additional nodes involved if the primary tumor had a Breslow thickness of 
1.1 mm. An interesting recent finding is that two simple morphometric parameters of the sentinel node metastasis seem to indicate whether or not more nodes are involved.21 If completion regional node dissection is performed, how extensive should such a dissection be: e.g., should parailiac and obturator nodes be removed in the groin? A second issue that has to be addressed is whether early lymph node dissection in patients with occult metastases improves locoregional control and survival. The Intergroup study showed that elective lymph node dissection improved survival in patients with nonulcerated melanomas with a tumor thickness of 1.0 to 2.0 mm or with a limb melanoma.22 In a prospective, randomized trial, Cascinelli et al.23 showed in this regard that survival is better if regional node dissection is performed for nonpalpable lymph node metastases as compared with palpable metastases. They concluded that sentinel node biopsy might become a tool to identify this subgroup of patients. The Multicenter Selective Lymphadenectomy Trial deals with this issue and evaluates survival and regional control of patients randomized to wide local excision and observation versus wide local excision and sentinel node biopsy with therapeutic lymph node dissection in case of a positive sentinel node.4 The results are not expected before 2005. A third clinical issue that has to be addressed is whether adjuvant systemic therapy with interferon improves survival in patients with occult lymph node metastases. Results of current research in the United States and Europe, such as the Sunbelt Melanoma Trial and the European Organization for Research and Treatment of Cancer trials, are awaited.7,24–26 In this respect, a quantitative meta-analysis of trials on the value of adjuvant interferon has been recommended.27
The fact that the clinical benefits of early identification of patients with lymph node metastases are not well known brings us to possible disadvantages of the sentinel node procedure in melanoma patients. In our study, only 24% of the patients had a tumor-positive sentinel node. This implies that 76% of patients underwent an unnecessary procedure if the standard technique would otherwise have been a wait-and-see policy. Moreover, the procedure is not without morbidity. Complications of the sentinel node procedure include allergic reactions to the blue dye. This occurred in only one patient (.4%) in our study but can be seen in up to 2.5%, according to the literature.28 Mild postoperative complications were seen in 9% and late complications after sentinel node biopsy in 18% of our patients. When the morbidity is compared with that of elective lymph node dissection, however, the sentinel node procedure is preferable.29
A possibly more serious complication is the potential entrapment of tumor cells, leading to in-transit metastases.15,30 An in-transit metastasis incidence of 23% in sentinel node–positive patients versus 7% in sentinel node–negative patients was seen in our study. A high 18% incidence of in-transit metastases was also mentioned in the presentation of a series of 186 sentinel node–positive patients treated at the M. D. Anderson Cancer Center.13 A report in the pre–sentinel node era from the same institution with a minimum follow-up of 10 years showed a 10% incidence of in-transit metastases in a group of 1001 lymph node–positive patients, most of whom had palpable metastases.31 Intuitively, one would expect the incidence of in-transit metastases to be higher in patients with more advanced disease, such as palpable lymph node metastases. However, in that same publication, the incidence of in-transit metastases was 27% in node-positive patients in whom elective lymph node dissection was performed and 4% when immediate node dissection was performed when nodal metastases became palpable (P < .001). An incidence of 27% of locoregional cutaneous recurrences in sentinel node–positive patients was seen in another study as well.30 These numbers make one wonder whether sentinel node biopsy should perhaps be deferred to a later stage. However, the situation is unclear, because other investigators have found more favorable results. Doting et al.12 showed isolated in-transit metastases in 8% and 4% of sentinel node–positive and sentinel node–negative patients, respectively. Essner et al.32 compared the incidence of in-transit metastases in node-negative patients who underwent sentinel node biopsy and those who underwent elective lymphadenectomy. No statistical difference was found (2.6% vs. 3.8%). The incidence of in-transit metastases in sentinel node–positive patients was 13% in a study by Clary et al.33
So why should we perform a sentinel node procedure? The main reasons are that the sentinel node status is the strongest independent predictor of outcome in patients with melanoma and that the sentinel node biopsy provides more accurate staging.2,3,32,34–36 Other studies show identical survival plots to seen in our study, albeit with a shorter follow-up. Furthermore, the procedure can be used to identify patients at high risk of systemic disease and interested in participation in clinical trials on adjuvant therapy.29,37 However, no standard regional or adjuvant systemic therapy with a confirmed effect on overall survival has been identified. The substantial false-negative rates in some studies, the morbidity, and the seemingly high incidence of in-transit metastases have to be weighed against the possible survival benefit of early removal of lymph node metastases and the prognostic information.
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ACKNOWLEDGMENTS |
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The acknowledgments are available online at www.annalssurgicaloncology.org.
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FOOTNOTES |
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Received for publication January 29, 2003. Accepted for publication April 8, 2003.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONREFERENCES |
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