High positive sentinel node identification rate by EORTC melanoma group protocol: Prognostic indicators of metastatic patterns after sentinel node biopsy in melanoma

doi:10.1016/j.ejca.2005.10.023

European Journal of Cancer

Volume 42, Issue 3, February 2006, Pages 372-380

https://doi.org/10.1016/j.ejca.2005.10.023 Get rights and content

Abstract

Methods to work-up sentinel nodes (SN) vary considerably between institutes. This single institution study evaluated the positive SN-identification rate of the EORTC Melanoma Group (MG) protocol and investigated the prognostic value of the SN status regarding disease-free survival (DFS) and overall survival (OS) and evaluated the locoregional control after the SN procedure. Multivariate and univariate analyses using Cox’s proportional hazard regression model was employed to assess the prognostic value of covariates regarding DFS and OS.

The positive SN-identification rate was 29% at a median Breslow thickness of 2.00 mm and the false-negative rate was 9.4%. Breslow thickness and ulceration of the primary correlated with SN status. SN status, ulceration and site of the primary tumour correlated with DFS. SN status and ulceration of the primary correlated with OS. The in-transit metastasis rate correlated with SN-positivity, Breslow thickness and ulceration. Projected 3-year OS was 95% in SN-negative and 74% in SN-positive patients. Transhilar bivalving of the SN with step sections from the central planes is simple and had a high SN-positive detection rate of about 30%. The SN status is the most important predictive value for DFS and OS. In-transit metastasis rates correlated with SN-positivity, Breslow thickness and ulceration of the primary.

Introduction

Of all the different types of cancer, melanoma has a share of 1% of all cases. Metastatic behavior and survival correlate with risk factors such as tumour thickness and the presence of ulceration of the primary, the presence and number of metastatic regional lymph nodes and non-visceral or visceral metastases [1]. A number of underpowered randomized trials have evaluated the impact of the adjuvant surgical procedure the elective lymph node dissection (ELND) in melanoma and have failed to demonstrate a survival advantage by ELND 2, 3, 4, 5. The most recent randomized trial, the WHO 14 demonstrated a potential benefit in patients with micrometastatic disease in the ELND specimen [5] and suggested that the Sentinel Node procedure might therefore be of benefit to patients in the management of primaries >1.5 mm. Also the long-term follow-up results of the USA Intergroup trial showed some potential benefit in patients with melanomas of intermediate thickness [4], as did a database matched paired analysis in patients with primary melanomas between 1.2 mm and 3.5 mm, by Morton and co-workers [6].

At the basis of these developments is the work of Morton in the late 1980’s and early 1990’s, who formulated the sentinel node (SN) procedure, which is based on the concept that a tumour will undergo an orderly progression of dissemination with the local lymphatic system as primary route of metastasis [7]. Whether this SN procedure, followed by complete lymph node dissection in case of a positive SN, results in survival benefit has been investigated in the Multicenter Selective Lymphadenectomy Trial (MSLT-I), which has not yet reached full maturity for final analysis.

Identification rates of positive SN in patients with primary melanomas thicker than 1.0 mm vary considerably in the literature. Usually rates of 15–20% are reported. Vulysteke [8] found 19% SN-positive patients in a total of 209 patients with a median Breslow thickness of 1.41 mm. Doubrovsky [9] and Gerschenwald [10] found 18% and 15% SN-positive patients in a total of 672 and 580 patients with a median Breslow thickness of 2.30 mm and 1.80 mm respectively. Balch [1] and Morton [11] found 13.9% and 19% SN-positive patients in a total of 3126 and 1159 patients respectively.

Methods to work-up SN vary considerably between institutes. This single institution study evaluates the positive SN-identification rate of the EORTC Melanoma Group (MG) protocol. This study also investigates the prognostic value of the SN status regarding disease-free survival and overall survival and it evaluates the locoregional control, specifically on recurrence patterns in the SN investigated lymph node basin(s) and on rates of in-transit metastasis after the SN procedure.

Section snippets

Patients

From October 1997 to May 2004, 262 patients with malignant melanomas, with a Breslow thickness of at least 1.00 mm and/or at least a Clark level IV or if ulceration was present, underwent a sentinel lymph node bioposy (SLNB) at our institute (Erasmus Medical Center, Daniel den Hoed Cancer Center, Rotterdam, the Netherlands). Patient characteristics, operation notes and follow-up were all entered in a prospective database. The average age was 48 years (range 16–83 years). The mean Breslow

SN identification and status

In 262 patients, 256 underwent preoperative lymphoscintigraphy (LS), 6 did not have the preoperative lymphoscintigraphy due to logistical problems. In these 256 patients, a total of 334 lymph node basins were recognized through LS, with a total of 601 lymph nodes recognized. This resulted in an average of 1.80 lymph node per lymph node basin.

During all the operations a total of 510 lymph nodes were harvested (they were either stained blue and/or radioactive, see Patients and Methods), with an

Discussion

In this single institution study we confirm the high detection rate of the EORTC MG protocol.

In the present study at least one SN was found in 100% of the patients during the surgical biopsy, this is comparable with other studies, which reported success rates between 98.5% and 100% 8, 10, 17, 18. The false negative rate found in the present study was 9.4%, this is also comparable with other studies, in which rates between 7% and 18% are reported 17, 18, 19, 20.

The Cook protocol [16] for the

Conflict of interest statement

None declared.

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Patients with cutaneous melanoma and a positive sentinel node (SN) are currently eligible for adjuvant treatment with targeted therapy and immune checkpoint inhibitors. Near-infrared (NIR) fluorescence imaging could be an alternative and less invasive tool for SN biopsy to select patients for adjuvant treatment. One potential target for NIR is the mesenchymal-epithelial transition factor (MET). This study aimed to assess MET immunoreactivity in positive SNs and to evaluate its potential diagnostic, prognostic and therapeutic value.
In this retrospective study, positive SN samples from patients with primary cutaneous melanoma were collected to assess MET immunoreactivity. To this end, paraffin-embedded SNs were stained for MET (monoclonal antibody D1C2). A 4-point Histoscore was used to determine cytoplasmic and membranous immunoreactivity (0 negative/1 weak/2 moderate/3 strong). Samples were considered positive when ≥10% of the cancer cells showed MET expression (staining intensity ≥1). Patient and clinicopathological characteristics were used for descriptive statistics, binary logistic regression, and survival analyses.
Positive MET immunohistochemistry was observed in 24 out of 37 samples (65%). No statistically significant associations were found between MET positivity and the following prognostic factors: Breslow thickness (P = 0.961), ulceration (P = 1.000), and SN tumor burden (P = 0.792). According to MET positivity, Kaplan-Meier curves showed no significant differences in survival.
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Citation Excerpt :
In our opinion, a such high number of NN was attributable to the accuracy of the updated EORTC protocol but there could be additional factors. We enrolled only pT1b or higher-stage melanoma and adopted the 8th edition of the AJCC; by contrast, all previous studies did not rule out pT1a cases and had been performed before the 8th edition (several studies showed as the modifications in the 8th edition of the AJCC staging manual led to a variation in the number of pT1b melanomas eligible for SLNB) [1–24]. A risk for such a high detection of NN is the over-diagnosis of MM, especially in this clinical scenario (SLNB of melanoma).
The diagnosis of nodal nevi (NN) is challenging as they mimic melanoma metastases (MM), with a detection rate mostly ranging between 1% and 11% in sentinel lymph node biopsy (SLNB). Herein, we assessed the incidence of NN and the association with the clinical-pathological features of primary melanoma, adopting the updated European Organisation for Research and Treatment of Cancer (EORTC) protocol for SLNB.
All cases of paired melanoma and SLNB were retrospectively evaluated (April 2019-May 2020). Appropriate statistical tests were adopted, with significant variables included in the logistic regression model.
81 patients and a total of 186 lymph nodes (LNs) were included. Eleven patients had only NN and 4 had both NN and MM (18.5%); 29 LNs (15.6%) showed at least one NN and 12 (6.5%) showed more than one NN (a total amount of 43 NN was detected). All NN and none MM stained for p16. NN were associated with age < 60 years (p: 0.042), no ulceration (p: 0.025) and nevus-associated melanoma (NAM) (p: 0.018), with this latter being the only predictor at the logistic regression model (p: 0.022).
The updated EORTC protocol shows a high number of NN and highlights a strong association with NAM.
Hematoxylin and eosin or double stain for CD34/SOX10: Which is better for the detection of lymphovascular invasion in cutaneous melanoma?
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Lymphovascular invasion (LVI) is considered an unfavorable prognostic factor in cutaneous melanoma (CM). However, its detection by hematoxylin and eosin (H&E) is challenging, with discordant data about its association with clinical-pathological features and no previous studies investigating the inter- (IrOA) and intra-observer (IaOA) agreement. Herein, we tested H&E and double staining (DS) for CD34/SOX10 to detect the LVI in a cohort of 92 CMs, evaluating the IrOA, the IaOA, and the association with the other clinical-pathological features.
Five authors independently evaluated 92 consecutive and retrospectively enrolled cases of CMs. We assessed the IrOA (Fleiss’s Kappa/FK and intraclass correlation coefficient/ICC) and the IaOA (Cohen’s Kappa/CK) with both H&E and CD34/SOX10. Furthermore, we compared the LVI assessment with the two stains and analyzed the association with other clinical-pathological features [χ² tests for dichotomous and categorical data; Student t-test (normal distribution) and Mann-Whitney U-test (non-normal distribution) for continuous data].
The IrOA was almost identical with H&E (FK=0.446; ICC=0.805) and CD34/SOX10 (FK=0.454; ICC=0.810); by contrast, the IaOA was higher with H&E for one pathologist (CK: 0.809) and with CD34/SOX10 for the other one (CK: 0.563). Applying previously defined criteria, LVI was detected in 10 (9.2%) and 11 (10.1%) cases with H&E and CD34/SOX10, respectively (p = 1.000). Both H&E and CD34/SOX10 were significantly associated with vertical growth phase (H&E, p: 0.014; CD34/SOX10, p: 0.010), mitosis ≥ 1/mm2 (H&E, p: 0.000; CD34/SOX10, p: 0.004), pT (H&E, p: 0.000; CD34/SOX10, p: 0.001), Breslow thickness (H&E, p: 0.000; CD34/SOX10, p: 0.001), and lymph node and/or distant metastasis (H&E, p: 0.005; CD34/SOX10, p: 0.000); only H&E was associated with ulceration (p: 0.002) and distant metastasis (p: 0.000), conversely, only CD34/SOX10 was associated with lymph node metastasis (p: 0.003).
CD34/SOX10 does not improve the IrOA and the IaOA of the LVI assessment in CM; furthermore, H&E and CD34/SOX10 show a similar profile of association with the other unfavorable clinical-pathological features of CM. As result, CD34/SOX10 could be a redundant diagnostic tool if applied for the prognostic characterization of not-selected CM in a routine diagnostic scenario.
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Disseminated tumor cells (DTCs) spread systemically yet distinct patterns of metastasis indicate a range of tissue susceptibility to metastatic colonization. Distinctions between permissive and suppressive tissues are still being elucidated at cellular and molecular levels. Although there is a growing appreciation for the role of the microenvironment in regulating metastatic success, we have a limited understanding of how diverse tissues regulate DTC dormancy, the state of reversible quiescence and subsequent awakening thought to contribute to delayed relapse. Several themes of microenvironmental regulation of dormancy are beginning to emerge, including vascular association, co-option of pre-existing niches, metabolic adaptation, and immune evasion, with tissue-specific nuances. Conversely, DTC awakening is often associated with injury or inflammation-induced activation of the stroma, promoting a proliferative environment with DTCs following suit. We review what is known about tissue-specific regulation of tumor dormancy on a tissue-by-tissue basis, profiling major metastatic organs including the bone, lung, brain, liver, and lymph node. An aerial view of the barriers to metastatic growth may reveal common targets and dependencies to inform the therapeutic prevention of relapse.
Timing of sentinel node biopsy independently predicts disease-free and overall survival in clinical stage I-II melanoma patients: A multicentre study of the Italian Melanoma Intergroup (IMI)
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Sentinel lymph node biopsy (SNB) still remains a key procedure to appropriately stage melanoma patients and to select those who are candidate to novel treatments with immunotherapy and targeted therapy in the adjuvant setting. The impact of timing of SNB on disease-free survival (DFS) and overall survival (OS) is still unclear.
The study was conducted at 6 Italian Melanoma Intergroup (IMI) centres and included 8953 consecutive clinical stage I-II melanoma patients who were diagnosed, treated, and followed up between November 1997 and March 2018. All patients were prospectively included in dedicated IMI database. Multivariable Cox regression analyses were performed to investigate how baseline characteristics and time interval until SNB are related to DFS and OS.
Considering the whole population, at multivariable analysis, after adjusting for age, gender, Breslow thickness, site, ulceration, and the SNB status, a delay in the timing of SNB was associated with a better DFS (adjusted hazard ratio [aHR, delayed versus early SNB] 0.98, 95% confidence interval [CI] 0.97–0.99, p < 0.001) and OS (aHR 0.98, 95% CI 0.97–0.99, p = 0.001). Specifically, in patients with a negative SNB status, a beneficial impact of delayed SNB (i.e. at least 32 days after primary excision) was confirmed for DFS (aHR 0.70, 95%CI 0.63–0.79, p < 0.001) and OS (aHR 0.69, 95%CI 0.61–0.78, p < 0.001), whereas in those with a positive SNB status, DFS (aHR 0.96, 95%CI 0.84–1.09, p = 0.534) and OS (aHR 0.94 95%CI 0.81–1.08, p = 0.374) were not significantly different in patients with early or delayed SNB.
Our study does not support a strict time interval for SNB. These results may be useful for national guidelines, for counselling patients and reducing the number of high urgency referrals.
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The optimal management of melanoma with positive sentinel lymph node (SLN) remains unclear. Completion lymph node dissection (CLND) only yields additional positive non-SLN in 20% of cases and its benefits on survival remains debatable.
An online database search of Medline was performed; key bibliographies were reviewed. Studies comparing outcomes after CLND versus observation were included. Odds ratios (ORs) with the corresponding 95% confidence intervals (CIs) by random fixed effects models of pooled data were calculated. The primary endpoints were disease-free survival (DFS), melanoma-specific survival (MSS), and overall survival (OS).
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High positive sentinel node identification rate by EORTC melanoma group protocol: Prognostic indicators of metastatic patterns after sentinel node biopsy in melanoma

Abstract

Introduction

Section snippets

Patients

SN identification and status

Discussion

Conflict of interest statement

Lancet

Surg Oncol

Eur J Surg Oncol

Eur J Cancer

Eur J Surg Oncol

Eur J Surg Oncol

Ann Surg Oncol

Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system

J Clin Oncol

Inefficacy of immediate node dissection in stage 1 melanoma of the limbs

N Engl J Med

A prospective randomized study of the efficacy of routine elective lymphadenectomy in management of malignant melanoma. Preliminary results

Cancer

Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0–4.0 mm). Intergroup Melanoma Surgical Trial

Ann Surg Oncol

Lymphatic mapping and sentinel lymphadenectomy for early-stage melanoma: therapeutic utility and implications of nodal microanatomy and molecular staging for improving the accuracy of detection of nodal micrometastases

Ann Surg

Technical details of intraoperative lymphatic mapping for early stage melanoma

Arch Surg

Clinical outcome of stage I/II melanoma patients after selective sentinel lymph node dissection: long-term follow-up results

J Clin Oncol

Sentinel node biopsy provides more accurate staging than elective lymph node dissection in patients with cutaneous melanoma

Ann Surg Oncol

Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients

J Clin Oncol

Multicenter Selective Lymphadenectomy Trial Group. Interim results of the Multicenter Selective Lymphadenectomy Trial (MSLT-I) in clinical stage I melanoma

J Clin Oncol Supplement ASCO meeting abstracts