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Sentinel lymph node biopsy in patients with thin melanoma: occurrence of nodal metastases and its prognostic value

European Journal of Dermatology. Volume 20, Numéro 1, 30-4, January-February 2010, Investigative report

DOI : 10.1684/ejd.2010.0837

Summary

Auteur(s) : Lenka Vermeeren, Fred Van der Ent, Prapto Sastrowijoto, Karel Hulsewé , Department of Surgery, Orbis Medical Centre Dr. H. van der Hoffplein 1, 6162 BG Sittard-Geleen, The Netherlands, Department of Pathology, Orbis Medical Centre, Dr. H. van der Hoffplein 1, 6162 BG Sittard-Geleen, The Netherlands.

ARTICLE

Auteur(s) : Lenka Vermeeren¹, Fred Van der Ent¹, Prapto Sastrowijoto², Karel Hulsewé¹

¹Department of Surgery, Orbis Medical Centre Dr. H. van der Hoffplein 1, 6162 BG Sittard-Geleen, The Netherlands
²Department of Pathology, Orbis Medical Centre, Dr. H. van der Hoffplein 1, 6162 BG Sittard-Geleen, The Netherlands

accepté le 28 Juillet 2009

Sentinel lymph node biopsy (SNB) is an accepted procedure to accurately stage a patient with a cutaneous melanoma, because it can determine the presence of (micro) metastases in the sentinel node. This has shown to be the most important predictor for survival in patients with a primary melanoma without clinical evidence for metastatic disease [1, 2]. Although subgroup analyses have suggested a survival benefit of finding a positive node on SNB compared to the discovery of positive nodes on clinical examination [2, 3], improvement of survival by SNB has not been convincingly demonstrated [4]. Completion lymph node dissection is generally accepted in the case of metastatic disease within the sentinel node. The value of completion lymph node dissection is disputable though, because evidence for improvement of outcome is lacking.

Several studies have shown a correlation between Breslow thickness and the risk of finding a positive sentinel node [1, 5]. Some authors have suggested that melanomas with a Breslow thickness of 1mm or less should not be treated by SNB, because of the very low risk of finding positive nodes [6, 7]. Furthermore, it seems unlikely that the outcome of patients with a thin melanoma will be improved by SNB, because even in thicker lesions no survival benefit of SNB has been demonstrated. However, no consensus exists regarding the exact appropriate limit for performing SNB. In fact, some studies have found sentinel node metastases in a significant number of patients with thin lesions (Breslow thickness ≤ 1 mm) [8-13]. As an alternative, to identify patients likely to benefit from SNB, the American Joint Committee on Cancer staging system (AJCC stage, 6^th edition) [14, 15] has been proposed. It has been suggested that in patients with AJCC stage 1a, as opposed to stage 1b (presence of ulceration or Clark invasion level IV or V), an SNB can be safely omitted [15].

The strong prognostic value of SNB has been clearly demonstrated in patients with intermediate thickness melanoma (Breslow thickness 1-4 mm) [1, 2], but not in patients with thinner lesions. Furthermore, patients with a thin melanoma (Breslow thickness ≤ 1 mm) have a good prognosis, with 5 year survival rates above 90% [5]. To determine whether patients with thin melanoma benefit from SNB, both the incidence of nodal metastases and the prognostic value of SNB are of importance.

The purpose of the current study was to identify the proportion of positive SNBs in patients treated for thin melanomas and to define an appropriate cut-off point for performing an SNB in this group. AJCC stage is compared to Breslow thickness as a predictor of SNB involvement. Furthermore, the prognostic value of SNB in patients with thin melanoma is compared to patients with thicker lesions.

Material and methods

Patients

From a prospective database, 248 medical records of patients treated with SNB for melanoma in the Maaslandhospital (as of 01.09.2009: Orbis Medical Centre, Sittard-Geleen), The Netherlands, were extracted. In 78 cases this involved a thin melanoma (Breslow-thickness ≤ 1 mm). All patients who underwent an SNB between January 1994 and August 2007 were included. Patients with a melanoma in situ or an non-cutaneous melanoma were not included.

Until 2004, all melanoma patients received a SNB, independent of their Breslow thickness. Our database and data from the literature indicated that nodal metastases rarely occurred in patients with a melanoma of Breslow thickness ≤ 0.75 mm. Therefore it was decided that, from 2004 onwards, SNB was only to be performed in patients with a melanoma of more than 0.75 mm.

A tumour deposit ≥ 2 mm in the sentinel node has been used to select patients for completion lymph node dissection, exept for one patient early in our study who received a completion lymph node dissection after finding a smaller metastasis. Data recorded in the database included gender, age at primary diagnosis, site of primary lesion, Breslow thickness, ulceration, Clark invasion level and histologic subtype. Furthermore, data of the sentinel node procedure and pathological evaluation of the node(s) were available. If patients were discharged from check-up, general practicioners were consulted to complete follow-up information. During the first five years of follow-up, no patients were lost to follow-up.

Sentinel node identification

Thirty-seven MBq of 99mTc-nanocolloid (Nanocoll, Nycomed Amerham Sorin, Saluggia, Italy) in 4 mL saline was injected intracutaneously around the scar of the excised primary melanoma. After tracer injection, both dynamic and static lymphoscintigraphy was performed in order to identify the sentinel nodes. Patients were operated on the same day. Just prior to incision, 0.8-1.0 mL of Patent Blue V (Laboratoire Guerbet, Aulnay-sous-Bois, France) was injected intracutaneously around the scar of the primary excision biopsy. Sentinel nodes were identified intra-operatively with the assistance of a hand-held gamma probe (Navigator, USCC, USA) and the blue dye technique. A sentinel lymph node was defined as a blue lymph node and/or a radioactive lymph node, with an ex vivo/background activity ratio of 10 or more, and consequently these nodes were excised. SNB was combined with, and done prior to, wide local excision of the biopsy site of the primary tumour.

Histopathological evaluation

All excised nodes were histologically evaluated at the department of Pathology of the Maaslandhospital. Histopathological analysis was performed by serial section and hematotoxin and eosin staining. From 1999 onwards, hematotoxin/eosin negative nodes were also routinely analysed by immunohistochemical staining (with S-100, MelanA and/or HMB-45).

Analysis

The patients were divided into 4 groups for analysis: ≤ 0.75 mm and 0.76-1.0 mm Breslow thickness and AJCC stage 1a and 1b. Subgroup results were analysed using Chi-square test.

Results

An SNB was performed because of a primary melanoma in 248 patients. Of these patients, 23.8% had a metastasis to the sentinel lymph node. In two patients (< 1%) the sentinel node procedure was unsuccessful (no sentinel nodes could be harvested). Seventy-eight patients received an SNB because of a thin melanoma. One of these patients had a positive deep excision margin after the primary excision, but the Breslow thickness could be reliably measured in the re-excision specimen (Breslow 0.28 mm). All other thin melanoma patients had negative deep excision margins. Median Breslow thickness in the thin melanoma group was 0.76 mm and 6.4% of these patients had a positive sentinel node. One patient had metastases in two sentinel nodes. Median follow-up in this group was 77 months. Patient characteristics for the whole melanoma group and the thin melanoma group are summarized in table 1. In table 2 details are given of the proportion of positive SNBs for the different classes of Breslow thickness in the whole population. A clear relationship between Breslow thickness and the chance of metastatic disease in the sentinel node is visible.

Five (12.8%) of the 39 patients with a melanoma of 0.76-1 mm Breslow thickness had a metastasis in the sentinel node, whilst, in the 39 patients with a melanoma of ≤ 0.75 mm Breslow thickness, no nodal metastases were found. This difference was statistically significant (Chi-square: p = 0.02).

If the thin melanoma population was divided into two groups according to AJCC stage, the results were as follows: 46 patients were AJCC stage 1a (no ulceration and Clark II, III), of whom 2 (4.3%) had a positive SNB. Thirty-two patients had an AJCC stage 1b thin melanoma (ulceration or Clark IV, V or both). In 3 of these patients (9.4%) the SNB was positive. This difference in positive sentinel nodes was not significant (Chi square: p = 0.38).

Tumour characteristics and follow-up of the node-positive patients are outlined in table 3. The first node positive patient had isolated tumour cells in the sentinel node and underwent a limited lymph node dissection only. Afterwards, patients with positive nodes underwent completion lymph node dissection if the tumour deposits were more than 2 mm. Therefore, two node-positive thin melanoma patients did not have a completion lymph node dissection. None of the node-positive patients developed tumour recurrence. In the node-negative group, 4 patients died during follow-up and another patient relapsed. One patient died of distant metastases after 66 months. One died of a meningeoma, and two others developed another primary melanoma and died of distant metastases. One node negative patient developed relapsing cutaneous metastases in 57 months, but is still alive after 10 years. None of these patients had in-transit metastases.

From 2004 onwards, SNB was performed only in patients with a melanoma of 0.76 mm Breslow thickness or more. This resulted in exlusion of, in all, 8 patients with a thin melanoma with a Breslow thickness less than 0.76 mm.
Table 1 Patient characteristics

	Cases	Age (years)	Gender	Location	Ulceration	Clark level
TOTAL	248	Median 51 Mean 52 (22-86)	F 50% M 50%	Trunk: 42% Extremity: 45.5% Head/neck: 12.5%	23.4%	II: 6% III: 32% IV: 51% V: 9% Unknown: 2%
THIN MELANOMA (Breslow thickness ≤ 1.0 mm)	78	Median 45 Mean 47 (25-86)	F 59% M 41%	Trunk: 32% Extremity: 56% Head/neck: 12%	6.4%	II: 15% III: 47% IV: 37%

Table 2 Proportion of positive sentinel nodes

Breslow	≤ 0.75 mm	0.76-1 mm	1.01-2 mm	2.01-3 mm	3.01-4 mm	> 4 mm
Number of patients	39	39	90	31	18	31
Sentinel lymph node positive	0%	12.8%	20%	22.6%	50.0%	64.5%

Table 3 Node positive thin melanoma patients

Patient	Age (years)	Breslow thickness (mm)	Clark Level	Ulceration	Size of nodal metastasis	Completion lymph node dissection (CLND)	Length of follow-up (months)	Follow-up
1	38	1.0	III	No	Isolated tumour cells (< 0.1 mm)	Negative (0/4)	55	No relapse
2	46	0.78	IV	No	0.8 mm	Not performed	34	No relapse
3	43	0.84	III	No	2 mm	Negative (0/23)	66	No relapse
4	52	0.99	V	No	> 2 mm, 2 positive sentinel nodes	Negative (0/13)	73	No relapse
5	25	0.84	IV	Yes	0.3 mm	Not performed	104	No relapse

Discussion

Patients with a thin melanoma represent a clinically important group. In our population, more than 30% of all melanoma patients had a thin melanoma. This is comparable to other studies, in which 30%-42% of the whole melanoma group consists of patients with a thin melanoma [9, 12, 15, 16]. Survival is good and recurrence rates are relatively low in thin melanoma patients [17], but late recurrence rates of 15% have been recorded [18]. Zapas et al. even found a recurrence rate of 35% in 20 patients with a melanoma of 0.8 mm-0.99 mm [19]. There is need for predictors of outcome, because of this clinically significant risk of recurrence.

Table 2 shows the strong association between Breslow thickness and sentinel node positivity, but even in patients with a melanoma of 0.76 mm-1 mm, sentinel lymph node metastases occurred in more than 12%. A summary of previous study results of studies with large patient cohorts (> 70 patients) is given in table 4. These studies also show sentinel lymph node metastases in a significant number of thin melanoma patients. In patients with a melanoma ≤ 0.75 mm we found no node-positive patients, and in previous studies as well, the rate of sentinel node-positive patients in this group is very low. These results imply that the limit for performing an SNB should be 0.76 mm and an SNB can be omitted in patients with a melanoma ≤ 0.75 mm.

As mentioned in the result section, from 2004 onwards, in our study, patients with a melanoma of 0.75 mm or less no longer received an SNB. This selection concerned 8 patients treated for a very thin melanoma in our hospital between January 2004 and August 2007. It is unlikely that this selection has influenced our results since none of these very thin melanoma patients had a recurrence during follow-up. Not only Breslow thickness, but also Clark invasion level and the presence of ulceration influence a patient’s prognosis and are also reported as risk factors for finding nodal metastases in melanoma [21, 24]. AJCC stage [14] takes both Clark invasion level and presence of ulceration into account and might form an accurate selection criterion to select patients with a thin melanoma who should receive an SNB [15, 21]. Some authors did not identify ulceration and Clark invasion as risk factors for nodal or distant metastasis, though, [28-30] and in our study selection of patients with a stage 1b melanoma was less accurate, when compared to Breslow thickness alone, as shown in table 4. Age and mitotic count are sometimes mentioned in relationship to sentinel node positivity, especially in patients with a thin melanoma [24, 27, 29]. Mitotic rate was not measured in our patient population, but Kesmodel et al. reported that a mitotic rate above zero appeared to be a significant predictor of SNB positivity in patients with thin melanoma [24]. Although our five node-positive patients were relatively young (mean 41 years, versus mean 47 years in all thin melanoma patients and mean 52 years in all melanoma patients), this group was too small to draw conclusions about age as a risk factor for nodal metastasis in our thin melanoma group.

Disease-free survival in our small node-positive thin melanoma group is 100% (with a mean follow-up of 66 months), which was better than disease-free survival in the node-negative thin melanoma patients. Other authors also found a disease-free survival of 100% in sentinel node positive thin melanoma patients [22, 31, 32], and Wong et al. found no correlation between SNB result and disease specific survival in their group of thin melanoma patients [13]. This suggests that the SNB might not be as prognostically important for patients with thin melanoma as it is in patients with intermediate thickness melanoma. Ranieri et al. on the other hand, found that disease free survival and overall survival in their group of thin melanoma patients were significantly associated with SNB results [11] and a recent large cohort-study of thin melanoma patients conducted by Wright et al. showed a 10-year melanoma-specific survival rate of 98% for node-negative thin melanoma patients versus 83% for node positive thin melanoma patients [27]. Unfortunately all the results regarding the prognostic value of SNB in thin melanoma patients are limited because of the small sample sizes and short follow-up information. It seems questionable, though to assume that the prognostic value of SNB is equal in this subgroup of melanomas compared to intermediate sized melanomas.

The indication for SNB and the prognostic value of SNB are not the only controversial issues in the treatment of thin melanoma. A recent study by Starz et al. reported a possible therapeutic effect of the SNB in thin melanoma patients (Breslow 0.76-1.0 mm) [26]. Disease free survival was 100% in the 87 thin melanoma patients who received SNB, which was significantly lower in a (historic) cohort of 61 thin melanoma patients who did not receive SNB. Furthermore, there seems to be no consensus regarding the therapeutic consequences that should follow after a positive SNB. Because small tumour deposits seem to correlate with high percentages of negative non-sentinel nodes, different criteria are proposed regarding the indication for a completion lymph node dissection after a positive SNB [33-36]. In our study, patients with a nodal tumour deposit of 2 mm or more in diameter routinely received completion lymph node dissection. This metastatic size has arbitrarily been chosen to prevent unnecessary co-morbidity of the completion lymph node dissection in patients with smaller tumour deposits, while evidence of survival benefit from the procedure is still lacking. This is local practice though and many melanoma surgeons use different selection criteria [37, 38].

Because no additional non-sentinel node metastases were found in 3 patients with completion lymph node dissection and disease free survival was 100% in node positive thin melanoma patients, we were not able to define the appropriate consequences of a positive SNB in this thin-melanoma study.
Table 4 Sentinel node biopsy in thin melanoma; previous study results

	Cases	Melanoma thickness	Positive node	Positive node in subdivision
Bedrosian et al. [16] 2000	71 (all with VGP)*	≤ 1.0 mm	5.6%	Breslow ≤ 0.75: 2.5% Breslow 0.76-1.0 mm: 9.7%
Statius Muller et al. [7] 2001	75	< 0.9 mm	0%
Oliveira et al. [20] 2003	77	≤ 1.0 mm	7.8%
Rousseau et al. [21] 2003	388	≤ 1.0 mm	4%	AJCC stage 1a: 3% AJCC stage 1b: 6%^†
Bleicher et al. [22] 2003	512	≤ 1.5 mm	4.9%	Breslow ≤ 0.75 mm: 1.7% Breslow 0.76-1.0 mm: 3.9% Breslow 1.01-1.5 mm: 7.1%
Agnese et al. [6] 2003	138	< 1.2 mm	1.4%
Stitzenberg et al. [12] 2004	146	≤ 1.0 mm	4%	3 of 6 patients with positive SNB^‡ had Breslow < 0.75 mm
Puleo et al. [23] 2005	409	≤ 1.0 mm	4.9%	Clark II, III: 4.4% Clark IV: 5.7%
Kesmodel et al. [24] 2005	181	≤ 1.0 mm	5%	Breslow ≤ 0.75 mm: 1.1% Breslow 0.76-1.0 mm: 8.9% Clark II/III: 2.9% Clark IV: 7.8% MR 0: 0% MR > 0: 8.7%^§
Vaquerano et al. [15] 2006	91	≤ 1.0 mm	6.6%	AJCC 1a: 4.9% AJCC 1b: 8.0%^†
Ranieri et al. [11] 2006	184	≤ 1.0 mm	6.5%	Breslow < 0.75 mm: 2.3% Breslow 0.75-1.0 mm: 10.2%
Wong et al. [13] 2006	223	≤ 1.0 mm	3.6%	Breslow < 0.75 mm: 0% Breslow 0.75-1.0 mm: 5.3%
Thompson et al. [25] 2006	187	≤ 1.0 mm	5%	All node positive patients had Breslow > 0.9 mm
Starz et al. [26] 2007	87	0.76-1.0 mm	11.5%
Wright et al. [27] 2008	631	≤ 1.0 mm	5%	Breslow ≤ 0.75 mm: 4% Breslow 0.76-1.0 mm: 6%
Current study	78	≤ 1.0 mm	6.4%	Breslow ≤ 0,75mm: 0% Breslow 0.76-1.0mm: 12.8% AJCC 1a: 4.3% AJCC 1b: 9.4%

Conclusion

Sentinel lymph node metastases occur in a significant percentage of patients with a thin melanoma (Breslow thickness 0.76-1 mm), but not in patients with a thinner melanoma (Breslow thickness ≤ 0.75 mm). In our population of thin melanoma patients, Breslow-thickness has been shown a useful predictor for SN metastases in patients with a thin melanoma. SNB can be omitted in patients with a melanoma with a Breslow thickness of 0.75 mm or less. The prognostic value of SNB in thin melanoma, as well as the therapeutic yield of completion lymph node dissection in case of a positive SNB, have not been clearly delineated. Complementary studies are necessary to define if, for thin melanoma patients, SNB has the same prognostic value as for patients with thicker lesions.

Acknowlegdements

Conflict of interest: none. Financial support: none.

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