Annals of Oncology Advance Access originally published online on September 12, 2006
Annals of Oncology 2006 17(10):1578-1585; doi:10.1093/annonc/mdl176
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© 2006 European Society for Medical Oncology
sarcomas and melanoma |
Clinical relevance of melanoma micrometastases (<0.1 mm) in sentinel nodes: are these nodes to be considered negative?
1 Department of Surgical Oncology, Erasmus University Medical Center–Daniel den Hoed Cancer Center
2 Department of Statistics, Erasmus University Medical Center–Daniel den Hoed Cancer Center
3 Department of Pathology, Erasmus University Medical Center–Daniel den Hoed Cancer Center, The Netherlands
* Correspondence to: Prof A. M. M. Eggermont, Department of Surgical Oncology, Erasmus University Medical Center–Daniel den Hoed Cancer Center, 301 Groene Hilledijk, 3075 EA, Rotterdam, the Netherlands. Tel: +31-10-4391851; Fax: +31-10-4391011; E-mail: a.m.m.eggermont{at}erasmusmc.nl
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Abstract |
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As only about 20% of sentinel node (SN) positive melanoma patients have additional non-SN lymph node involvement in the Completion Lymph Node Dissection (CLND) specimen, we tried to identify a SN positive patient group, which can be spared CLND. Micro anatomic analyses of metastatic SNs were performed to identify patient/tumor and/or SN factors predicting additional non-SN positivity as well as disease-free and overall survival. SN positivity was found in 77 of 262 stage I/II patients, included into a prospective database (10/97–5/04). Of 74 patients pathology material was available for re-evaluation. Micro anatomic analyses categorized topography of SN-metastases, Starz classification and amount of SN tumor burden. Additional non-SN positivity, DFS, OS and was calculated for all analyses. Mean Breslow thickness was 3.5 mm (0.8–12.0); mean FU was 35 (6–81) months. There was no additional non-SN positivity for SN-micrometastases <0.1 mm. Topography of SN involvement had no impact on OS. Estimated 5-year OS rates for the different groups of <0.1 mm, 0.1–1.0 mm and >1.0 mm SN tumor burden were 100%, 63% and 35% respectively. Distant metastases were exceedingly rare (1/16 = 6.3%) in <0.1 mm SN-positive patients. On multivariate analysis the SN tumor burden was the most important prognostic factor for DFS (P = 0.005) and OS (P = 0.03). Distant metastasis-free survival was identical (91%) to the 5-yr OS of SN negative patients, the estimated 5-yr OS was 100% for these patients and additional non-SN positivity was not observed. Therefore, our data suggest that patients with sub-micrometastases (<0.1 mm) in the SN may be judged as SN negative, as non-stage III, and are highly unlikely to benefit from CLND, which we no longer recommend.
Key words: sentinel node, melanoma, pathology, micro anatomic, prognosis
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introduction |
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The Sentinel Node (SN) procedure is a staging procedure for primary melanoma patients without clinically detectable nodal metastases [1, 2]. Depending on known prognostic factors of the primary tumor, such as the Breslow thickness and ulceration, 15–30% of the clinical stage I or II patients have histopathologically identifiable metastases in their SNs [2–4]. Most patients with a positive SN undergo completion lymph node dissection (CLND) with approximately 10% to 33% of the non-SNs in the specimen containing further metastases [2, 4–7]. The SN status has been demonstrated to be the most powerful prognostic value for disease-free (DFS) and overall survival (OS) of patients with primary melanoma. SN negative patients can achieve excellent long-term survival, whereas approximately 35–50% of SN positive patients die of their disease within 5 years [2–4, 8–10]. A number of studies have tried to identify patient, tumor and SN characteristics that predict additional non-SN positivity [6, 7, 11–18]. Breslow thickness and ulceration of the primary tumor have been identified as prognostic factors for additional non-SN positivity [13–15]. More often SN tumor burden has been described as prognostic factor for additional non-SN positivity and overall survival [7, 13–17]. The location of the metastasis in the SN has also been described by Dewar et al. as prognostic factor for additional non-SN positivity [18]. Other classifications have been developed to divide SN positive patients in different risk groups for additional non-SN positivity and survival [11, 12, 15]. On the other hand, McMasters et al. found no significant characteristics in their group of melanoma patients studied for additional non-SN positivity or for survival [6].
Methods for the histopathological work-up of SNs varies considerably between institutes and new pathology protocols [19, 20] may have lead to an increase in SN positivity. This increase in SN positivity may reflect an increase in diagnosis of minimal and perhaps biologically less aggressive disease [2]. Because only a small proportion of SN positive patients has additional nodal involvement at the time of SN, it has become increasingly important to identify factors that may predict non-SN positivity, which might spare SN positive patients the unnecessary morbidity of a completion lymph node dissection.
This study was performed to analyze if any patient and/or tumor characteristics, SN tumor burden or the location of the metastasis in the SN, might be prognostic for additional non-SN positivity, DFS and OS. As a result, an attempt was made to identify patients who could be spared the morbidity of a CLND, without compromising their survival chances.
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methods |
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Patients with tumor positive SNs were identified from the SN database at the Erasmus University Medical Center–Daniel den Hoed Cancer Center (Rotterdam, The Netherlands). This database consists of 262 patients, who were operated on between October 1997 and May 2004, of whom 77 were SN positive (29%). The median and mean Breslow thickness of all 262 patients was 2.0 mm and 2.8 mm respectively. Briefly, inclusion criteria for patients to undergo a SN biopsy consisted of a tumor with at least 1.00 mm Breslow thickness or Clark IV/V or ulceration of the primary tumor. Exclusion criteria were palpable lymph node metastases or signs of distant metastases.
SNs were identified by the standard triple technique of preoperative lymphoscintigraphy with the use of a radioactive nanocolloid, intraoperative use of patent blue dye and the intraoperative use of a hand-held gamma probe. The SNs were pathologically analyzed according to the EORTC Melanoma Group protocol [19], which required transhilar bivalving and stepsectioning from both faces of the lymph node. Staining was performed with H&E, S100 and HMB-45.
SN slides of three (out of 77) patients could not be retrieved from the archives and therefore 74 patient's slides were re-evaluated for this study. During re-evaluation location of the metastasis in the SN was determined according to Dewar et al. [18] in the various categories; only subcapsular involvement, only parenchymal involvement, combined subcapsular and parenchymal involvement, multiple discrete deposits (multifocal involvement), or extensive involvement of a large proportion of the SN.
Patients were divided by SN characteristics into different categories according the S classification (old and new versions) by Starz et al. [11, 12]. The old S classification consisted of three categories; S1, S2 and S3 and these categories were based on the number of positive sections (n) and the maximum distance from the interior margin to the capsule of the SN (d). The criteria for these respective categories was n 
1 and d 1 mm for S1, n > 2 and d 1 mm for S2 and n > 2 and d > 1 mm for S3. [11] The new S classification had different criteria for the three different categories SI, SII and SIII, these were d 0.3 mm for SI, d > 0.3 mm and 1 mm for SII and d > 1 mm for SIII [12]. The size of the SN tumor burden was also recorded, three different tumor burden size groups were defined, sub-micrometastases (clusters of more than 10 cells, but < 0.1 mm), tumor burden 0.1 mm–1 mm and tumor burden > 1 mm. If multiple lesions were present within a SN, the largest lesion was recorded.
Statistical analyses were all performed with Stata version 8.2 (Stata Corporation, College Station, Texas, USA). Disease-free and overall survival were calculated from time of SN until recurrence of the disease or death respectively. Patients without such an event at their last follow-up were censored at that time. Univariate analyses of end-points was performed using the Kaplan-Meier method and the log-rank test. Multivariate analyses to determine the prognostic value of covariates regarding disease-free and overall survival were performed using the Cox's proportional hazard model. P values of less than 0.05 were considered as significant.
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results |
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Baseline characteristics of all reviewed patients (n = 74) are depicted in Table 1. The average age was 47 years (range 16–76 years). The mean and median Breslow thickness were 3.5 mm and 3.0 mm, respectively (range 0.8–12.00 mm). The distribution of SN characteristics, the S classification (old and new versions) according to Starz et al. [11, 12] and the location according to Dewar et al. [18] are shown in Table 2. The mean and median follow-up time were 35 and 30 (6–81) months respectively. In patients with sub-micrometastases (<0.1 mm) SN tumor burden, the mean and median Breslow thickness were 2.4 mm and 1.7 mm, respectively and 37% of these patients had ulcerated primary tumors. This was compared to the SN-negative population in the whole Rotterdam series and found to be very similar as in the SN-negative population the mean and median Breslow thickness were 2.5 mm and 1.9 mm, respectively and 23% of these patients had ulcerated primary tumors [2].
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CLND characteristics were missing for seven patients, because either they refused CLND (n = 2) or preferred follow-up with ultrasound (n = 5). Therefore, only 67 patients were analyzed for additional non-SN positivity. Table 3 shows an analysis of additional non-SN positivity by patient, tumor and SN characteristics. The number of positive SNs was a significant predictor of additional non-SN positivity (P = 0.02) as well as the absence of ulceration (P = 0.05). Borderline not significant (P = 0.07) was SN tumor burden (<0.1 mm versus
0.1 mm). The estimated 3-year DFS for all SN positive patients was 57%, 3-year and 5-year OS were 80% and 63% respectively.
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The estimated OS for the three different categories of the old S classification was not statistically significant (Figure 1A) (P = 0.16), however, the new S classification did approach significance with an estimated 3-year OS of the respective categories of 96%, 80% and 57% (Figure 1B) (P = 0.055). The OS according to the distribution of the different location categories by Dewar was significantly different per category and is shown in Figure 2A (P = 0.05). Figure 2B shows the OS of a simplified classification of extensive versus non-extensive metastatic involvement of the SNs according to the Dewar classification, which is also significantly different for the two groups (P = 0.004).
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The estimated 5-year OS rates were significantly different between the different SN tumor burden groups and were 100%, 63% and 35% respectively (Figure 3A) (P = 0.03). Two patients with sub-micrometastasis (<0.1 mm) involvement developed a recurrence of the disease during follow-up. One patient had a local recurrence at the site of the primary and subsequently developed an in-transit metastasis. During follow-up the patient also developed multiple lung metastases, but is still alive with disease after 30 months. The other patient developed an in-transit metastasis, which was removed surgically and is alive and without evidence of disease after 41 months follow-up. Figure 3B shows the distant metastasis free survival (DMFS) according to the three different groups of SN tumor burden (P = 0.06). The estimated 3-year DMFS for the respective groups was 91%, 56% and 44%.
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The estimated 5-year OS rates for ulcerated and not ulcerated primary tumors were 45% and 75% respectively (Figure 4) (P = 0.01). Gender, age, the number of positive sections per SN, the number of positive SNs, Breslow thickness and Clark level all had no significant effect on estimated survival rates in the univariate analysis.
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Table 4 shows the univariate analysis for disease free survival (DFS). SN tumor burden (P = 0.005) and ulceration (P = 0.05) were significant independent prognostic factors for DFS on multivariate analysis (Table 5). Table 4 also shows the univariate analysis for overall survival. Only SN tumor burden (P = 0.03) was a significant independent prognostic factor for overall survival on multivariate analysis (Table 5).
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discussion |
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TopAbstractintroductionmethodsresultsdiscussionReferences |
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The SN procedure is the most accurate staging procedure for regional lymph node metastases in melanoma patients, without the substantial morbidity associated with an elective lymph node dissection. The SN status has been recognized as the most important prognostic factor for disease-free and overall survival of melanoma patients [1–4]. Patients with negative SN status generally have an excellent long-term survival with 90–95% 5-years OS, whereas a positive SN status is associated with a 5-years OS rate of 50–65% [2–4, 8–10].
Approximately 67% to 90% of SN positive patients do not have further non-SNs that contain tumor deposits in the completion lymph node dissection specimen [2, 4, 5, 7]. As a consequence, the majority of SN positive patients undergo unnecessary surgery with its associated morbidity. It has been proposed by other authors to identify patient, tumor and SN characteristics, which could be predictive of non-SN positivity, in order to spare SN positive patients needless surgery [12–18], similar to the widely accepted situation in breast cancer. Breast cancer patients with sub-micrometastases (<0.2 mm) in the SN do not undergo a completion axillary lymph node dissection, because these patients will not recur regionally, and therefore additional surgery can be safely omitted [21, 22].
In melanoma, the tumor and SN characteristics; Breslow thickness and ulceration of the primary tumor, the number of positive SNs, SN metastatic tumor burden and tumor penetrative depth within the SN have all been identified as indicative factors for additional non-SN positivity [13–16]. These factors are all merely indicative and to this date no factor has been identified, which can absolutely predict non-SN positivity. Reeves et al. [15] proposed a size/ulceration classification of SN positive patients by the size of the metastasis in the SN and the ulceration status of the primary. This SU score was a significant prognostic indicator for additional non-SN positivity, but Gietema et al. [23] did not demonstrate the predictive value of this classification in their study. In the present study the absence of ulceration was predictive of additional non-SN positivity (P = 0.05), this contradicting outcome cannot be explained and might be due to the relatively small number of patients in this study. On the other hand, the presence of ulceration was an independent prognostic factor for DFS on multivariate analysis (P = 0.05) as was previously demonstrated by us and other authors [2, 24, 25]. The number of positive SNs was a significant predictive factor for further additional non-SN positivity (P = 0.02), both in the present study and in a previous study of Salti et al. [26].
The micro anatomic classification by Dewar et al. [18] seemed to be a promising prognostic tool for SN positive patients. However, the size (or the depth) of the SN tumor burden is considerably different for the different locations of metastases. In the present study the size of SN tumor burden seems to be the essential factor and not so much the location of the metastases. This is supported by the study of Dewar et al., because the locations with very small SN tumor burden have an excellent prognosis in contrast to the locations with larger sizes of SN tumor burden. In the study by Scolyer et al. [17] neither subcapsular nor parenchymal deposits of the metastases were a significant predictive factor for additional non-SN positivity. They did demonstrate, however, that the group of patients with extensive involvement had a higher rate of additional non-SN metastases compared with the patients with non-extensive involvement. SN tumor burden was an independent prognostic factor for additional non-SN positivity in the study of Vuylsteke et al. [14], no additional non-SN involvement was seen in patients with SN metastases of <0.3 mm. However, Carlson et al. [7] did not find SN tumor burden to be a significant predictor of non-SN involvement in their patient population. In the present study no additional non-SN positivity in the group of patients with minimal SN tumor burden (<0.1 mm) was demonstrated, but this was borderline statistically not significant (P = 0.07).
Breslow thickness was identified by studies by Lee et al. [13] and Sabel et al. [16] as an indicative for additional non-SN positivity, but this was not a predictive factor for additional non-SN positivity in the present study. Nor were gender, age, Clark level, number of positive sections and Starz classifications (old and new) predictive factors for additional non-SN positivity in the present study.
In the present study, SN tumor burden was a significant prognostic factor for overall survival (P = 0.03). More importantly there was an estimated 5-year overall survival rate of 100% in the group of patients with single cells metastatic involvement of the SN. Despite two local failures, distant metastases are exceedingly rare (1/16 = 6.3%) and the estimated 5-year distant metastasis-free survival of 91% was identical to the SN negative patient group, previously reported [2[. Mean and median Breslow thickness and ulceration of the primary tumors of SN negative patients was also comparable with minimal SN tumor burden (<0.1 mm). The median Breslow thickness was 1.9 mm versus 1.7 mm, mean Breslow thickness was 2.5 mm versus 2.4 mm, ulceration was 23% versus 37% for SN negative versus minimal SN tumor burden (<0.1 mm), respectively [2]. Furthermore, no additional non-SN positivity was seen and, although this was not significant, it seems likely that it would be significant in a larger patient population. Considering all this, the amount of SN tumor burden seems to be an excellent prognostic factor for overall survival.
In the study of Vuylsteke et al. [14] survival was only reported to be significantly important for SN tumor burden in combination with the Breslow thickness and the presence/absence of additional non-SN metastases. This classification does not seem be a very useful classification for clinical use. Carlson et al. [7] found the SN tumor burden to be a significant indicative for survival, however three groups (isolated melanoma cells, clusters of cells and 2 mm) had very similar 3-year overall survival rates in contrary to the group of patients with SN tumor burden larger than 2 mm, which had a significantly worse estimated overall survival. In a review study on the different applications of the TNM classification for all tumor types, Hermanek et al. [27] studied the significance of isolated tumor cells (sub-micrometastases, defined as deposits 0.2 mm) and concluded that isolated clusters of tumor cells should be distinguished from micrometastases. Also, because the prognostic significance of isolated clusters of tumor cells is unknown, it should not be considered in the TNM classification for any tumor type, but should be documented none-the-less [27].
The location classification according to Dewar et al. [18] was not a significant prognostic factor for disease-free or overall survival on uni- and multivariate analyses (results not shown). However, when simplified to extensive versus non-extensive ‘the location’ was a significant prognostic factor for DFS and OS on univariate analysis, but did not remain as an independent prognostic factor on multivariate analysis. The location of the metastasis seems to be a less significant prognostic factor for DFS and OS than the size of the SN tumor burden. Ulceration of the primary tumor and the new Starz classification were both significant factors on univariate analysis for overall survival (both P = 0.02). But, neither remained as an independent prognostic value for OS after multivariate analysis.
The present study shows an important observation, that sub-micrometastasis (<0.1 mm) involvement of the SN, or what others call isolated clusters of melanoma cells (more than 10 cells) is a biologically very different from ‘larger’ micrometastatic disease. As a consequence of this different, less aggressive disease, which has an identical estimated 5-year distant metastasis free survival (91%) comparable to the OS rate for SN negative patients, and a 0% non-SN positivity rate these patients could possibly be spared the morbidity of a CLND, without compromising their survival chances.
The interim results of the MSLT-I trial [9] shows in the ITT analysis a 13% survival benefit for the SN positive patients over patients which underwent a delayed or therapeutic lymph node dissection (TLND). However, patients with sub-micrometastases were considered SN positive and stratified as such into this trial [28, 29]. Our data, in 22% (16/74) of the SN positive patients the tumor burden was <0.1 mm and projected 5-yr survival was 100%. This indicates that these patients (possibly up to 22% of the population) might be considered as ‘biologically’ false positive and will probably incorrectly improve the outcome of patients who underwent a SN procedure versus the patients that underwent a TLND in the observation arm of the MSLT-1 trial.
Sub-micrometastases (clusters of more than 10 cells, but <0.1 mm) may not be considered as metastatic melanoma and as a consequence these patients are highly unlikely to benefit from CLND. Therefore we explain this situation to the patient and do not recommend CLND for melanoma sub-micrometastases. Importantly these patients have such excellent prognosis that they should not be stratified as stage III patients, when entered into adjuvant therapy trials. As a consequence randomizing patients with RT-PCR positive sentinel nodes for additional lymph node dissection seems highly unlikely to be of any benefit to patients and thus it's added value in clinical trials is very doubtful.
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Received for publication March 5, 2006. Revision received June 25, 2006. Accepted for publication June 26, 2006.
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