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Clinical Nuclear Medicine:
doi: 10.1097/RLU.0000000000000366
Review Article

Sentinel Lymph Node Mapping in Melanoma: The Issue of False-Negative Findings

Manca, Gianpiero MD*; Rubello, Domenico MD; Romanini, Antonella MD; Boni, Giuseppe MD*; Chiacchio, Serena MD*; Tredici, Manuel MD*; Mazzarri, Sara MD*; Duce, Valerio MD*; Colletti, Patrick M MD§; Volterrani, Duccio MD*; Mariani, Giuliano MD*

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From the *Regional Center of Nuclear Medicine, University of Pisa Medical School, Pisa; †Department of Nuclear Medicine, Santa Maria della Misericordia Hospital, Rovigo; ‡Department of Oncology, University of Pisa Medical School, Pisa, Italy; and §Department of Radiology, University of Southern California, Los Angeles, CA.

Received for publication November 18, 2013; revision accepted December 16, 2013.

Conflicts of interest and sources of funding: none declared.

Reprints: Domenico Rubello, MD, Department of Nuclear Medicine, PET Unit, Santa Maria della Misericordia Hospital, Via Tre Martiri 140, 45100 Rovigo, Italy. E-mail: domenico.rubello@libero.it.

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Abstract

Management of cutaneous melanoma has changed after introduction in the clinical routine of sentinel lymph node biopsy (SLNB) for nodal staging. By defining the nodal basin status, SLNB provides a powerful prognostic information. Nevertheless, some debate still surrounds the accuracy of this procedure in terms of false-negative rate. Several large-scale studies have reported a relatively high false-negative rate (5.6%–21%), correctly defined as the proportion of false-negative results with respect to the total number of “actual” positive lymph nodes. In this review, we identified all the technical aspects that the nuclear medicine physician, the surgeon, and the pathologist should take into account to improve accuracy of the procedure and minimize the false-negative rate. In particular, SPECT/CT imaging detects more SLNs than those found by planar lymphoscintigraphy. Furthermore, the nuclear medicine community should reach a consensus on the radioactive counting rate threshold to better guide the surgeon in identifying the lymph nodes with the highest likelihood of housing metastases (“true biologic SLNs”). Analysis of the harvested SLNs by conventional techniques is also a further potential source for error. More accurate SLN analysis (eg, molecular analysis by reverse transcriptase–polymerase chain reaction) and more extensive SLN sampling identify more positive nodes, thus reducing the false-negative rate.The clinical factors identifying patients at higher-risk local recurrence after a negative SLNB include older age at diagnosis, deeper lesions, histological ulceration, and head-neck anatomic location of the primary lesion.The clinical impact of a false-negative SLNB on the prognosis of melanoma patients remains controversial, because the majority of studies have failed to demonstrate overall statistically significant disadvantage in melanoma-specific survival for false-negative SLNB patients compared with true-positive SLNB patients.When new more effective drugs will be available in the adjuvant setting for stage III melanoma patients, the implication of an accurate staging procedure for the sentinel lymph nodes will be crucial for both patients and clinicians. Standardization and accuracy of SLN identification, removal, and analysis are required.

The concept of lymphatic mapping for oncologic surgery lies in the paradigm that lymph fluid from a primary tumor drains to a particular regional lymph node, known as “sentinel lymph node” (SLN), passing then to other nodes (second-tier or second-echelon lymph nodes). When tumor cells detach from the primary tumor to enter the lymphatic circulation, the first lymph node they encounter in their path is the SLN, which is thus at the greatest risk of hosting metastases. In fact, the afferent vessel collects lymph from the tumor and conveys it to the SLN, which acts as the first-line filter for tumor cells. Other lymph nodes may then be involved, in a sequential stepwise manner (Fig. 1).

FIGURE 1
FIGURE 1
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Therefore, the procedure of sentinel lymph node biopsy (SLNB) is based on the paradigm that lymphatic drainage from the site of the primary tumor is not erratic, but takes place in anatomic “orderly” fashion, that is, involving the SLN first, then the remaining nodes of a specific lymphatic basin. This concept, which has proven to hold valid as to the mode of progression of metastases through the lympathic vessels of a solid tumor (such as the melanoma), allows the oncologic surgeon to perform accurate lymph node staging of the disease by removing only the lymph nodes that are most likely to be metastatic. In this way, in a considerable proportion of patients, it is possible to avoid more invasive procedures such as regional complete lymph node dissection (CLND). Thus, the mini-invasive procedure of SLNB minimizes the incidence of morbidity associated with CLND systematically performed de novo in melanoma patients, by exposing to the risk of lymphedema and/or other CLND-associated complications only the patients who could mostly benefit from lymphadenectomy. This technique also enhances the identification of metastasis smaller than 0.2 mm in lymph nodes, by guiding the pathologist to analyze in depth the lymph node (or few nodes) most likely to have metastatic disease.

Sentinel lymph node biopsy identifies 20% to 25% of patients presenting with clinically occult lymphatic regional metastasis at diagnosis, and it is now well established that the tumor status of the SLN is the single most important prognostic factor for patients with early-stage cutaneous melanoma; this parameter has therefore been included in the current staging system.1,2 Furthermore, there is initial indication that melanoma patients whose CLND has been carried out following detection of clinically occult lymph node disease have a better chance of survival compared with patients undergoing CLND based on clinical evidence of disease.3

All these features have favored the diffusion of routine SLNB at an unprecedented pace in oncologic surgery worldwide. Nevertheless, large-scale adoption of this surgical procedure has raised various problems. There is in fact great variability in the false-negative rates reported by the literature, that is, histopathologic classification of an SLN as negative in the presence of metastasis in other non-SLN nodes. The impact of false-negative SLNB on the prognosis of melanoma patients is still unclear, because the long-term outcomes of ongoing controlled clinical follow-up studies are not yet available.4 However, overall diagnostic accuracy of SLNB would become relevant if a drug were made available, which could modify the survival of stage III melanoma patients.

Morton et al,5 who introduced SLNB for melanoma patients, initially performed routine CLND for validation of the technique and found an encouraging low incidence of false-negative results, about 1%. De novo CLND was then rapidly abandoned, and the false-negative cases were subsequently estimated based on detection of tumor recurrence in a previously mapped nodal basin in which the SLN had been classified as metastasis-free. Initial studies based on this approach revealed a higher than expected incidence of false-negative results with respect to earlier reports by Morton.6–8 Subsequently, various large-scale studies from prominent institutions and collaborative groups worldwide confirmed relatively high false-negative rates, ranging between 5.6% and 21% (Table 1).3,9–14 The false-negative rates observed in the interim analysis of the Multicenter Selective Lymphadenectomy Trial I (MSLT-1) and in the Sunbelt Melanoma Trial were also in this range (17.6% and 10.8%, respectively).3,13

TABLE 1
TABLE 1
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Some concern has been raised about such false-negative rates raise, which are variable and certainly higher than those reported in the initial lymphadenectomy-based studies—during validation of the SLNB concept in patients with melanoma. According to Thompson et al,15 the responsibility for this unfavorable occurrence is to be shared by the nuclear medicine physician, the surgeon, and the pathologist. Nevertheless, there are other possible sources of failure of the SLNB approach in melanoma. In particular, the paradigm of orderly, sequential metastatic dissemination through the lymphatic system may not always apply in the case of this particular tumor, which is characterized by a certain degree of intrinsic biologic variability. For instance, lymph flow can be blocked in a massively metastatic SLN,16 thus causing the radiocolloid and/or the blue dye to be conveyed to a “new” SLN that might not yet contain metastatic tumor cells. Alternatively, it may be hypothesized that tumor cells pass through an SLN and lodge in the next-echelon lymph node without producing metastasis in the SLN (Fig. 2). In this regard, the kinetics of melanoma cells in lymphatic vessels is still unclear; therefore, a false-negative finding could be explained by the fact that tumor cells are still “in transit” at the time of SLNB.

FIGURE 2
FIGURE 2
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Because the intrinsic variability in lymphatic drainage and in the biology of melanoma cannot be modified as factors affecting the accuracy of SLNB (especially in terms of false-negative findings), the main purposes of this review are as follows:

  • to identify the technical issues that the nuclear physician, the surgeon, and the pathologist should carefully consider to improve the accuracy of SLNB by minimizing its false-negative rate;
  • to describe the clinicopathologic features of melanoma that are more often associated with a false-negative SLNB; and
  • to elucidate the clinical impact of a false-negative SLNB on the prognosis of melanoma patients.
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DEFINITION OF TERMS

A crucial issue in this scenario is the definition and calculation of the false-negative rate. Some scholars have considered the number of false-negative SLN biopsies (usually identified by local lymph node recurrence after a negative SLNB) relative to all the SLNB procedures performed (Table 2A). This is a biased representation of the false-negative rate, and the resulting value is generally not relevant for patients and surgeons. Instead, a more stringent criterion to consider is the ratio of true-negative SLNBs referred to all negative procedures (false negatives plus true negatives); this concept basically translates into the negative predictive value (NPV) of SLNB (Table 2B), which has been reported to range between 94% and 98.5% in several studies conducted in melanoma patients (Table 1). This parameter is very important for any patient when SLNB is being considered; in fact, the patient should be informed that the procedure is not reliable in 2 to 6 instances out of 100 when the biopsy is negative for metastasis. Nevertheless, the NPV is still not the false-negative rate, which should instead be defined as the ratio of false-negative results (negative SLNB patients with recurrent disease) with respect to the overall number of “actual” positive lymph nodes (false negatives plus true positives; Table 1C). In a large series of patients with melanoma submitted to SLNB, this rate has been reported to range between 5.6% and 21% (Table 2). According to this definition, the false-negative rate is complementary to sensitivity, which is defined as the proportion of “actual” SLN-positive patients (actual = false negatives plus true positives) identified by SLNB (Table 1D).

TABLE 2
TABLE 2
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It should be noted that any parameter representing the likelihood that an actual positive lymph node will be missed by SLNB (false-negative result) relies on the pretest likelihood that any lymph nodes are actually metastatic. In other words, if all the lymph nodes in a patient are free from metastasis, it makes no difference which nodes are removed during SLNB, because the outcome is always a “true negative.” Therefore, melanoma patients with high risk of metastasis to the regional nodes are those bound to have a false-negative SLNB. Thus, different series of patients submitted to SLNB using the same accurate techniques present different false-negative rates and NPVs, according to the predicted risk of developing lymph nodal metastases. Moreover, because nodal relapse may clinically appear up to many years after primary surgery, the overall actual positive cases, and consequently the false-negative rate, may increase with longer duration of follow-up.

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TECHNICAL ISSUES AFFECTING FALSE-NEGATIVE SLNB

Despite striking advances in the technology and expertise of SLN mapping, it is surprising that false-negative rates as high as 15% have been reported by major research centers (Table 1). Nevertheless, it is conceivable that this relatively high false-negative rate does not depend on the SLN paradigm not being valid, but rather on some shortcomings in nuclear medicine technology, surgical technique, and histopathologic analysis. “Success rates” for SLN identification are generally reported to range between 97% and 100%.15 However, these values can be deceptive, because they merely indicate the proportion of patients in whom at least 1 SLN was identified and removed, while they do not define the proportion of patients in whom all SLNs identified by accurate preoperative lymphoscintigraphy with dynamic imaging were intraoperatively detected and harvested for analysis. In this regard, the definition of SLN is sometimes incorrect17; furthermore, one cannot claim that SLN identification has been successful only because a lymph node containing some radioactivity and/or some blue has been harvested, because this could actually be a second-tier node. For example, an investigation in patients with head-neck melanomas showed a 99.3% success rate for the identification of at least 1 node considered to be an SLN, but in only 70% of patients were all SLNs (identified as such by preoperative lymphoscintigraphy) found intraoperatively and removed.18 Such discordance could explain, at least in part, the occurrence of a certain fraction of false-negative SLNBs.

A possible source of technical error in the identification of the “true” SLN is represented by incorrect radiocolloid administration. In particular, the radiocolloid must be injected as close as possible to the biopsy site or scar, so that drainage from that site actually reflects dermal lymphatic drainage from that specific area of the skin. Furthermore, it is well known that a radiocolloid injection deeper than subdermal may reduce the accuracy of true SLN identification in a similar manner as injection at some distance from the biopsy site. In an interesting study by Uren et al,19 patients with melanoma scheduled for SLNB underwent lymphoscintigraphy on 2 separate occasions 1 day apart; the same nodes were not always identified in the 2 scans, thus suggesting that minor technical variations could result in some SLNs being missed.

An additional possible source of technical error in lymphoscintigraphic mapping can be exact localization of the SLN(s) relying only on planar imaging, especially in the head and neck region and in the trunk. In this regard, higher false-negative rates have been reported when the primary melanoma is located in the head and neck.14,20 Thanks to enhanced resolution and improved anatomic localization of SLNs,21 SPECT/CT imaging during lymphoscintigraphy allows more accurate nodal mapping and reduces morbidity from SLNB procedures for primary melanomas of the trunk and head and neck.22 In this regard, SLNB in the head and neck region is technically quite demanding, because the lymph nodes are often small and close to the injection site, where most of the injected radiocolloid is retained. In particular, distinguishing whether the SLN is deep or superficial or located inside or just outside the parotid gland is crucial. The added value of SPECT/CT in patients with melanomas located in the trunk or head and neck is obvious when the SLN is not visualized on planar lymphoscintigraphy or when it is located adjacent to the injection site, whereas the benefits of SPECT/CT imaging are less clear for patients with melanoma of the limbs. In the surgeon’s experience, SLNs are better localized by SPECT/CT imaging, which can detect additional “nonvisualized locations” in more than one-third of the procedures.23 In addition, by producing 3-dimensional volume-rendering images SPECT/CT defines the location of SLNs in relation to critical anatomic structures, such as muscles, nerves, and blood vessels. By observing the images in the operating room, the surgeon is provided with an excellent overview of SLN mapping, being thus greatly facilitated in his/her search for the SLNs and for the optimal surgical approach for removal (Fig. 3).

FIGURE 3
FIGURE 3
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With a study in 85 patients with melanoma, van der Ploeg et al22 demonstrated the added value of SPECT/CT imaging, which resulted in a different incision (other than that planned on the basis of planar lymphoscintigraphy) in 17 patients, an incision at another site in 8, and an additional incision in 5 patients. Moreover, SPECT/CT detected 12 SLNs that had not been seen on planar imaging; of the 10 of 12 additional SLNs that were harvested, 2 contained metastasis. These studies provide strong evidence that more accurate lymphoscintigraphy imaging techniques may decrease the false-negative rate, especially in location with complex anatomy such as the head and neck regions and the trunk.

From the surgical point of view, the operational definition of an SLN is itself somewhat arbitrary, particularly regarding the amount of radioactivity that a lymph node should contain for being considered “hot” enough for harvesting and analysis. In this regard, multiple radioactive lymph nodes are often detected in the same lymphatic basin, either by lymphoscintigraphy and/or by intraoperative γ-probe counting. Especially if drainage of the radiocolloid has not been adequately monitored during lymphoscintigraphy, it is not always clear whether all these radioactive lymph nodes represent true SLNs or whether they simply are upper-tier nodes sequentially visualized by the radiocolloid after passing through the first, true SLN. Some authors base SLN identification on the absolute number of counts in the nodes, whereas others consider the ratio of the in vivo or ex vivo radioactive counts in the node relative to background or to neighboring non-SLNs.24,25 All such modalities are somewhat arbitrary, and debate is still open regarding the optimal strategy for removing radioactive lymph nodes for analysis. An empiric threshold corresponding to 10% or more of the counting rate in the hottest SLN is widely reported in the literature,26 but it may lead to the superfluous removal of multiple non-SLNs.24 Furthermore, this empirical criterion was not correctly validated with long-term follow-up to assess the false-negative rate, that is, lymph node metastasis appearing in basins that had been classified as negative by SLNB.

The fact that international guidelines lack a unique definition for the intrasurgical detection of SLNs possibly contributes to the relatively high false-negative rate of SLNB.27 It is, therefore, mandatory for the nuclear medicine community to reach a consensus on the radioactive counting rate threshold to best guide the surgeon in the identification of those lymph nodes with the highest probability of harboring metastases (true biologic SLNs), thus avoiding the unnecessary removal of radioactive non-SLNs and reducing the morbidity associated with the procedure.

As detailed above, false-negative rates of SLNB ranging from 6% to 21% in patients with melanoma have been reported (Table 1). Part of these false-negative cases is due to inadequate histopathologic analysis, such as hematoxylin-eosin (H&E) staining alone.28 Immunohistochemistry (IHC) and especially molecular biology techniques (eg, reverse transcriptase–polymerase chain reaction [RT-PCR]) improve dramatically the capability of detecting microscopic metastatic disease in SLNs of patients with melanoma. Nevertheless, although IHC with antibodies to S-10029 or HMB-45 antigens30 has 10% to 30% greater sensitivity for identifying micrometastases than does H&E staining,28 it still has a sizeable false-negative rate (6%–11.5%).7,31 More recently, application of molecular analysis with RT-PCR has enabled the “upstaging” of an additional 13% to 30% of patients whose SLNs were negative when analyzed by conventional H&E and IHC staining.32–36

Manca et al37 have proposed a protocol optimized to reduce the false-negative rate in the identification of metastatic disease in melanoma SLNs. To this purpose, a 20% threshold relative to the hottest lymph node was adopted for intraoperative counting, whereas SLN analysis was based on RT-PCR combined with conventional H&E and IHC. After a median follow-up of 55 months, excellent results were reported in a group of 124 patients with clinical stage I–II cutaneous melanoma, that is, a 99% NPV and a 3.6% false-negative rate.37 On the other hand, the extremely high sensitivity of molecular analysis based on RT-PCR entails the possible risk of increasing the number of false-positive cases.38

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FACTORS AND OUTCOMES ASSOCIATED WITH FALSE-NEGATIVE SLNB IN MELANOMA PATIENTS

In a study by Scoggins et al,13 3 tumor-related factors were found to be associated with a greater risk of false-negative SLNB: older age of the patient, reduced Breslow thickness of the lesion, less frequent presence of lymphovascular invasion. The correlation between advanced age and SLN status is especially interesting, considering that in older patients a decreased rate of tumor-positive SLNs is observed, despite an overall worse outcome.39,40 In this regard, an age-related lymphatic dysfunction might explain these results and constitute the pathophysiologic basis for an increased risk of a false-negative SLN result in elderly patients.14,41 Conway et al41 have shown that the lymphatic function evaluated by radiocolloid transit to and uptake within the SLN declines with age. This putative age-associated lymphatic dysfunction might depend on reduced transit of lymph from the primary site to the SLN; alternatively, the dysfunction might depend on the reduced filtering function of the aging lymph node, with a greater degree of pass-through of tumor cells contained in the lymph to second-echelon nodes. Either of these causes could enhance the false-negative SLNB rates in elderly patients.

Scoggins et al13 found that false-negative results were linked to decreased Breslow thickness and less lymphovascular invasion on multivariate analysis. As a matter of fact, patients with false-negative SLNB seem to present less aggressive primary tumors than patients with true-positive results. It follows that false-negative cases are more likely to be associated with less advanced primary melanomas, probably because of a lower microscopic tumor burden in the SLN, more difficult to identify by conventional H&E and IHC staining.

On the other hand, other studies14,20 have shown that worse clinicopathologic factors were associated with higher false-negative rates. In particular, the meta-analysis by Valsecchi et al42 (which includes >25,000 patients) has shown that the false-negative rate increases with the proportion of ulcerated lesions and with increasing Breslow thickness, both features being associated with more aggressive tumor behavior.

Jones et al14 have demonstrated that male sex (75.9%; P < 0.001) and patients with thicker lesions (mean Breslow thickness, 2.7 vs 1.8 mm; P < 0.01) were more likely to have a local recurrence after a negative SLNB. Moreover, ulcerated lesions were found significantly more often in negative SLNB patients who presented recurrent lesions than in negative SLNB patients who did not have recurring lesions (32.5% vs 13.5%; P < 0.001).

Other authors9,13,43,44 have shown the false-negative SLNB being significantly associated with local/in-transit recurrence. This observation contrasts with the fact that the false-negative rate is positively correlated with thinner tumors and absent lymphovascular invasion (since greater tumor thickness and lymphovascular invasion are generally associated with local/in-transit recurrence).13 These data suggest that patients with false-negative SLNB are more likely to house endolymphatic metastatic disease acting as a repository for future SLN metastases.

In other studies, regression and/or increased mitotic activity have emerged as further indices of more aggressive primary tumors associated with false-negative SLNB. However, no definitive data on this issue are available so far.45,46

An additional factor identified in the meta-analysis by Valsecchi et al42 as possibly influencing the SLNB performance is the so-called “successfully mapped proportion” of patients (PSM), that is, the ratio between number of patients with at least 1 excised SLN and total number of patients undergoing SLNB. Valsecchi et al42 observed PSM improvement over time in the majority of published series, possibly reflecting a learning curve and increasing ability in the surgical technique. In their meta-analysis, Valsecchi et al42 concluded that false-negative rate of SLNB decreases as PSM improves, thus suggesting that greater surgical volumes are associated with better SLNB performance and improved regional control of the disease.

Surgical error is another important factor that may result in a false-negative SLNB.47 Should the surgeon misidentify or be unable to identify the SLN, a node containing metastatic cells might be left behind, and a certain proportion of these cells would progress onto clinically detectable disease. Regarding the surgeon’s inexperience, a minimum of 30 cases to familiarize with the SLN technique has been claimed to be necessary.5 In this regard, Morton et al48 observed that the false-negative rate is reduced by 50% once the surgeons learn technique.

Finally, a significant positive correlation was found between false-negative rate and duration of follow-up,14,42 as well as between false-negative rate and fewer SLNs harvested (mean number, 1.81 vs 2.09; P < 0.05).14

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CLINICAL IMPACT OF A FALSE-NEGATIVE SLNB ON THE PROGNOSIS OF MELANOMA PATIENTS

Ongoing debate still surrounds the therapeutic impact of SLNB in patients with melanoma. The MLST-13 failed to demonstrate better melanoma-specific survival for patients submitted to SLNB versus those who were only observed. Therefore, some scholars have argued against the clinical value of SLNB in patients with melanoma, considering that the overall outcome of adjuvant therapy is still controversial for this disease.49–51

Therefore, the critical issue is that it is still not clear whether early detection of metastatic lymph node disease followed by therapeutic CLND and adjuvant therapy can improve the overall survival of patients with melanoma. In this section, we review the data that can help to clarify whether the overall survival of patients with false-negative SLNB is worse than that of patients with true-positive sentinel nodes.

In an important recent work, Jones et al14 evaluated the predictors and patterns of recurrence of disease in melanoma patients with a negative SLNB, based on quite a prolonged follow-up (median, 61 months; range, 1–154 months). Only 21 of 520 patients with negative SLNB (or 4%) developed lymph node recurrence of melanoma in the lymphatic basin that had originally been classified as negative. Despite this small number of the whole population of melanoma patients, this subset allows to look into the problem as to whether the early diagnosis and early removal of local nodal metastatic disease can improve the survival of cutaneous melanoma patients. This issue was not the principal goal of the study by Jones et al,14 but their results suggest that an early diagnosis and treatment of regional metastatic disease are actually able to ameliorate survival. Only 17 of 104 patients (or 16.3%) with positive SLNB (and therefore submitted to therapeutic CLND) had metastasis in additional lymph nodes of the same basin besides the SLN. Instead, 71.4% (10 out of 14) of patients with originally negative SLNB that resulted to be false-negative underwent CLND and proved to have multiple positive nodes. This difference was statistically highly significant. Because the total number of metastatic nodes is an important predictor of outcome in melanoma patients,2 the observation that more positive nodes in the patients who had local node recurrence suggests that early treatment may avoid the spread of disease beyond the SLN and improve survival.

The above results are consistent with those of the MLST-1 trial,3 which demonstrated that, among patients with lymph node metastasis, the average number of metastatic nodes was significantly lower for the SLNB group (wide excision + SNLB, with immediate CLND in case of metastatic SLN, i-CLND) than for the observation group (wide excision + clinical follow-up, with delayed CLND in case of clinical evidence of metastasis, d-CLND), that is, 1.4 vs 3.3 with P = 0.001, and confirms an increase in the number of involved lymph nodes in the nodal basin during follow-up in the observation group.3 This underscores the importance of an early diagnosis and treatment of regional metastatic disease, being the number of metastatic lymph nodes an independent prognostic factor for survival.2 In this regard, the MSLT-1 trial showed that, although SNLB did not improve overall survival, it did increase disease-free survival. In particular, there was a lower rate of local nodal relapse in the SNLB group (3.4%) with respect to the observation group (15.6%); moreover, there were fewer overall recurrences in the SNLB group (20.7% vs 26.8%).3 Subsequent follow-up data of the same MSLT-1 trial have confirmed a trend for lower proportion of distant metastases in the SNLB group than in the observation group (18.1% vs 21.2%).52 Finally, the MSLT-I trial has reported a statistically significant improvement in 5-year survival (72.3% ± 4.6% vs 52.4% ± 5.9%), when regional lymph node metastases were treated by SNLB and i-CLND versus observation and d-CLND (hazard ratio for death, 0.51; P = 0.004).3

The evidence so far acquired demonstrates that early identification and treatment of regional metastatic disease may prevent the progression of disease beyond the SLN and possibly improve overall survival. These data also suggest that patients with a false-negative SLNB, defined as clinically recurrent melanoma in a lymphatic basin that had originally been classified as negative at SLNB, could have a worse prognosis than true-positive SLN patients (generally diagnosed with micrometastatic disease), due to the more advanced stage of the disease at the time of presentation.

Unfortunately, this issue remains controversial because the majority of studies on this subject have failed to demonstrate a statistically significant worse melanoma-specific overall survival for false-negative SLNB patients compared with true-positive SLNB patients.11,20 In fact, only 1 study has reported worse overall survival for patients with a false-negative SLNB53; however, in this study, the false-negative SLNB rate was greater than 18%, a value that raises some concern about overall accuracy of the procedure and/or the data reported.53

In the Sunbelt Melanoma Trial, Scoggins et al13 found that the survival of patients with false-negative SLNB was not different from those with true-positive SLNB, a result in contrast with the MSLT-1 trial,3 that is, that the survival in the d-CLND group was worse than that in the i-CLND group (see above). The Sunbelt Melanoma Trial is certainly one of the most important studies aimed at assessing clinical outcomes associated with false-negative results; a possible type II statistical error concerning overall survival of patients with a false-negative sentinel node was hypothesized by the same authors. This question is currently being addressed by the second MSLT,4 designed to evaluate the impact of CLND on disease-free and overall survival in patients with early SLN metastasis.

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CONCLUSIONS

As new more effective drugs are under development for treating patients with metastatic melanoma, it is even more important for clinicians to better assign melanoma disease to a correct stage category so that melanoma patients could be treated in an adjuvant setting with the new molecules and hopefully experience an improvement in their survival. Stage III melanoma patients have a survival rate ranging between 70% and 39%.1 Currently, interferon is the only available drug inducing an improvement in progression-free survival (17%) and, to a lesser extent (9%), in overall survival.54–56 On the other hand, we are awaiting for the long-term results of a randomized trial, whose accrual has been completed, testing the efficacy of ipilimumab in the adjuvant setting in stage III melanoma patients.57 In case new more effective drugs would become available in the adjuvant setting, the implication of an accurate staging procedure for the lymph node status will be crucial for both patients and clinicians. To this purpose, standardization and accuracy of SLN identification, removal, and analysis are required. It is high time that further attention is devoted to such an important area of clinical investigation.

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REFERENCES

1. 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. 2001; 19: 3635–3648.

2. Balch CM, Soong SJ, Gershenwald JE, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001; 19: 3622–3634.

3. Morton DL, Thompson JF, Cochran AJ, et al. Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med. 2006; 355: 1307–1317.

4. Morton DL. Overview and update of the phase III Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLT-II) in melanoma. Clin Exp Metastasis. 2012; 29: 699–706.

5. Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992; 127: 392–399.

6. Gershenwald JE, Tseng CH, Thompson W, et al. Improved sentinel lymph node localization in patients with primary melanoma with the use of radiolabeled colloid. Surgery. 1998; 124: 203–210.

7. Gershenwald JE, Colome MI, Lee JE, et al. Patterns of recurrence following a negative sentinel lymph node biopsy in 243 patients with stage I or II melanoma. J Clin Oncol. 1998; 16: 2253–2260.

8. Jacobs IA, Chevinsky AH, Swayne LC, et al. Gamma probe-directed lymphatic mapping and sentinel lymphadenectomy in primary melanoma: reliability of the procedure and analysis of failures after long-term follow-up. J Surg Oncol. 2001; 77: 157–164.

9. Chao C, Wong SL, Ross MI, et al. Patterns of early recurrence after sentinel lymph node biopsy for melanoma. Am J Surg. 2002; 184: 520–524;

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10. Testori A, De Salvo GL, Montesco MC, et al. Clinical considerations on sentinel node biopsy in melanoma from an Italian multicentric study on 1,313 patients (SOLISM-IMI). Ann Surg Oncol. 2009; 16: 2018–2027.

11. Nowecki ZI, Rutkowski P, Nasierowska-Guttmejer A, et al. Survival analysis and clinicopathological factors associated with false-negative sentinel lymph node biopsy findings in patients with cutaneous melanoma. Ann Surg Oncol. 2006; 13: 1655–1663.

12. Cascinelli N, Bombardieri E, Bufalino R, et al. Sentinel and nonsentinel node status in stage IB and II melanoma patients: two-step prognostic indicators of survival. J Clin Oncol. 2006; 24: 4464–4471.

13. Scoggins CR, Martin RC, Ross MI, et al. Factors associated with false-negative sentinel lymph node biopsy in melanoma patients. Ann Surg Oncol. 2010; 17: 709–717.

14. Jones EL, Jones TS, Pearlman NW, et al. Long-term follow-up and survival of patients following a recurrence of melanoma after a negative sentinel lymph node biopsy result. JAMA Surg. 2013; 148: 456–461.

15. Thompson JF, Stretch JR, Uren RF, et al. Sentinel node biopsy for melanoma: where have we been and where are we going? Ann Surg Oncol. 2004; 11: 147S–151S.

16. Leijte JA, van der Ploeg IM, Valdes Olmos RA, et al. Visualization of tumor blockage and rerouting of lymphatic drainage in penile cancer patients by use of SPECT/CT. J Nucl Med. 2009; 50: 364–367.

17. Thompson JF, Uren RF. What is a `sentinel’ lymph node? Eur J Surg Oncol. 2000; 26: 103–104.

18. de Wilt JH, Thompson JF, Uren RF, et al. Correlation between preoperative lymphoscintigraphy and metastatic nodal disease sites in 362 patients with cutaneous melanomas of the head and neck. Ann Surg. 2004; 239: 544–552.

19. Uren RF, Howman-Giles R, Chung DK, et al. The reproducibility in routine clinical practice of sentinel lymph node identification by pre-operative lymphoscintigraphy in patients with cutaneous melanoma. Ann Surg Oncol. 2007; 14: 899–905.

20. Carlson GW, Page AJ, Cohen C, et al. Regional recurrence after negative sentinel lymph node biopsy for melanoma. Ann Surg. 2008; 248: 378–386.

21. Vermeeren L, van der Ploeg IM, Olmos RA, et al. SPECT/CT for preoperative sentinel node localization. J Surg Oncol. 2010; 101: 184–190.

22. van der Ploeg IM, Valdes Olmos RA, Kroon BB, et al. The yield of SPECT/CT for anatomical lymphatic mapping in patients with melanoma. Ann Surg Oncol. 2009; 16: 1537–1542.

23. Vidal-Sicart S, Valdes Olmos RA. Preoperative and intraoperative lymphatic mapping for radioguided sentinel node biopsy in cutaneous melanoma. In: Mariani G, Manca G, Orsini F. , eds. Atlas of Lymphoscintigraphy and Sentinel Node Mapping. Milan, Italy: Springer-Verlag; 2013; 169–180.

24. Coit DG. The “true” sentinel lymph node: in search of an operational definition of a biological phenomenon. Ann Surg Oncol. 2001; 8: 187–189.

25. Morton DL, Bostick PJ. Will the true sentinel node please stand? Ann Surg Oncol. 1999; 6: 12–14.

26. McMasters KM, Reintgen DS, Ross MI, et al. Sentinel lymph node biopsy for melanoma: how many radioactive nodes should be removed? Ann Surg Oncol. 2001; 8: 192–197.

27. Rossi CR, De Salvo GL, Trifiro G, et al. The impact of lymphoscintigraphy technique on the outcome of sentinel node biopsy in 1,313 patients with cutaneous melanoma: an Italian Multicentric Study (SOLISM-IMI). J Nucl Med. 2006; 47: 234–241.

28. Gibbs JF, Huang PP, Zhang PJ, et al. Accuracy of pathologic techniques for the diagnosis of metastatic melanoma in sentinel lymph nodes. Ann Surg Oncol. 1999; 6: 699–704.

29. Cho KH, Hashimoto K, Taniguchi Y, et al. Immunohistochemical study of melanocytic nevus and malignant melanoma with monoclonal antibodies against S-100 subunits. Cancer. 1990; 66: 765–771.

30. Walts AE, Said JW, Shintaku IP. Cytodiagnosis of malignant melanoma. Immunoperoxidase staining with HMB-45 antibody as an aid to diagnosis. Am J Clin Pathol. 1988; 90: 77–80.

31. Gadd MA, Cosimi AB, Yu J, et al. Outcome of patients with melanoma and histologically negative sentinel lymph nodes. Arch Surg. 1999; 134: 381–387.

32. Shivers SC, Wang X, Li W, et al. Molecular staging of malignant melanoma: correlation with clinical outcome. JAMA. 1998; 280: 1410–1415.

33. Bostick PJ, Morton DL, Turner RR, et al. Prognostic significance of occult metastases detected by sentinel lymphadenectomy and reverse transcriptase–polymerase chain reaction in early-stage melanoma patients. J Clin Oncol. 1999; 17: 3238–3244.

34. Blaheta HJ, Ellwanger U, Schittek B, et al. Examination of regional lymph nodes by sentinel node biopsy and molecular analysis provides new staging facilities in primary cutaneous melanoma. J Invest Dermatol. 2000; 114: 637–642.

35. Romanini A, Manca G, Pellegrino D, et al. Molecular staging of the sentinel lymph node in melanoma patients: correlation with clinical outcome. Ann Oncol. 2005; 16: 1832–1840.

36. Mocellin S, Hoon DS, Pilati P, et al. Sentinel lymph node molecular ultrastaging in patients with melanoma: a systematic review and meta-analysis of prognosis. J Clin Oncol. 2007; 25: 1588–1595.

37. Manca G, Romanini A, Pellegrino D, et al. Optimal detection of sentinel lymph node metastases by intraoperative radioactive threshold and molecular analysis in patients with melanoma. J Nucl Med. 2008; 49: 1769–1775.

38. Scoggins CR, Ross MI, Reintgen DS, et al. Prospective multi-institutional study of reverse transcriptase polymerase chain reaction for molecular staging of melanoma. J Clin Oncol. 2006; 24: 2849–2857.

39. Chao C, Martin RC 2nd, Ross MI, et al. Correlation between prognostic factors and increasing age in melanoma. Ann Surg Oncol. 2004; 11: 259–264.

40. Statius Muller MG, van Leeuwen PA, de Lange-De Klerk ES, et al. The sentinel lymph node status is an important factor for predicting clinical outcome in patients with Stage I or II cutaneous melanoma. Cancer. 2001; 91: 2401–2408.

41. Conway WC, Faries MB, Nicholl MB, et al. Age-related lymphatic dysfunction in melanoma patients. Ann Surg Oncol. 2009; 16: 1548–1552.

42. Valsecchi ME, Silbermins D, de Rosa N, et al. Lymphatic mapping and sentinel lymph node biopsy in patients with melanoma: a meta-analysis. J Clin Oncol. 2011; 29: 1479–1487.

43. Clary BM, Brady MS, Lewis JJ, et al. Sentinel lymph node biopsy in the management of patients with primary cutaneous melanoma: review of a large single-institutional experience with an emphasis on recurrence. Ann Surg. 2001; 233: 250–258.

44. Kretschmer L, Beckmann I, Thoms KM, et al. Factors predicting the risk of in-transit recurrence after sentinel lymphonodectomy in patients with cutaneous malignant melanoma. Ann Surg Oncol. 2006; 13: 1105–1112.

45. Roach BA, Burton AL, Mays MP, et al. Does mitotic rate predict sentinel lymph node metastasis or survival in patients with intermediate and thick melanoma? Am J Surg. 2010; 200: 759–763;

discussion 754–763


46. Balch CM, Gershenwald JE, Soong SJ, et al. Update on the melanoma staging system: the importance of sentinel node staging and primary tumor mitotic rate. J Surg Oncol. 2011; 104: 379–385.

47. Karim RZ, Scolyer RA, Li W, et al. False negative sentinel lymph node biopsies in melanoma may result from deficiencies in nuclear medicine, surgery, or pathology. Ann Surg. 2008; 247: 1003–1010.

48. Morton DL, Cochran AJ, Thompson JF, et al. Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg. 2005; 242: 302–311;

discussion 303–311


49. Thomas JM. Sentinel-node biopsy in melanoma. N Engl J Med. 2007; 356: 418

author reply 419–421


50. A’Hern RP. Sentinel-node biopsy in melanoma. N Engl J Med. 2007; 356: 418

author reply 419–421


51. Grichnik JM. Sentinel-node biopsy in melanoma. N Engl J Med. 2007; 356: 418–419;

author reply 419–421


52. Morton DL, Cochran AJ, Thompson JF. The rationale for sentinel-node biopsy in primary melanoma. Nat Clin Pract Oncol. 2008; 5: 510–511.

53. Caraco C, Marone U, Celentano E, et al. Impact of false-negative sentinel lymph node biopsy on survival in patients with cutaneous melanoma. Ann Surg Oncol. 2007; 14: 2662–2667.

54. Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996; 14: 7–17.

55. Mocellin S, Pasquali S, Rossi CR, et al. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst. 2010; 102: 493–501.

56. Mocellin S, Lens MB, Pasquali S, et al. Interferon alpha for the adjuvant treatment of cutaneous melanoma. Cochrane Database Syst Rev. 2013; 6: CD008955

57. Eggermont AM, Testori A, Maio M, et al. Anti–CTLA-4 antibody adjuvant therapy in melanoma. Semin Oncol. 2010; 37: 455–459.

Keywords:

sentinel lymph node; lymphatic mapping; melanoma; false-negative rate; SPECT/CT imaging; RT-PCR; intraoperative radioactive threshold

Copyright © 2014 by Lippincott Williams & Wilkins

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