ReviewDetection of melanoma micrometastases in sentinel nodes – The cons
Introduction
Metastatic behavior and survival of melanoma patients correlate with risk factors such as tumor thickness (Clark and Breslow) and the presence of ulceration of the primary, the presence and number of metastatic regional lymph nodes and non-visceral or visceral metastases [1], [2]. 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 benefit for ELND [3], [4], [5], [6]. The WHO-14 study demonstrated a potential benefit in patients with micrometastatic disease in the ELND specimen [6]. Also the long-term follow-up results of the USA Intergroup trial [5] showed some potential benefit in patients with melanomas of intermediate thickness as did a database matched paired analysis in patients with primary melanomas between 1.2 and 3.5 mm, by Morton and co-workers [7].
Morton introduced the Sentinel Node (SN) concept which is, based on the premise that a tumor will undergo an orderly progression of dissemination through afferent lymphatic channels to SNs before spreading into other regional, non-SNs as primary route of metastasis [8], [9]. The SN biopsy procedure is now used worldwide in primary melanoma patients with an identification rate of 95–100% using high quality dynamic lymphoscintigraphy and preoperative use of a handheld probe and the injection of patent blue [7], [10], [11], [12], [13], [14]. The introduction of routine preoperative lymphoscintigraphy for patients with melanoma has provided new insights into lymphatic anatomy and physiology and several studies have demonstrated that cutaneous lymphatic drainage pathways are variable among patients [15], [16], [17], [18]. The SN procedure has been demonstrated to be the most accurate staging procedure and compared with the ELND technique more lymph node metastases are found due to accurate histopathological work-up and sampling the correct lymph nodal basin [19].
Section snippets
Identification of positive sentinel nodes
Identification rates of positive SNs in patients with primary melanomas vary considerably in the literature. Usually rates of 15–20% are reported, depending on Breslow thickness of the primary tumors [2], [10], [14], [19]. Methods for the histopathological work-up of SNs varies considerably between institutes and new pathology protocols may have lead to an increase in SN positivity [20], [21]. The EORTC protocol introduced by Cook et al. [20] for histopathologic work-up and examination of SNs,
Prognostic information of sentinel nodes
The SN procedure has been recognized as the most important prognostic factor for disease-free and overall survival of melanoma patients [12], [14], [25], [26]. In the literature, 5-year disease-free survival (DFS) rates of 78–88% for SN negative and 39–53% for SN positive patients have been reported, respectively [10], [12], [14], [19], [22], [23], [25]. Also the 5-year overall survival (OS) rates are significantly different between SN negative and positive patients being 88–95% for SN negative
Additional lymph node positivity
Most patients with a positive SN undergo completion lymph node dissection (CLND) with approximately 10–33% of the non-SNs in the specimen containing further metastases [9], [14], [23], [25], [28]. This is indirect proof that the technique is reliable, since in the majority of patients the SN is the only lymph node, which contains metastatic melanoma cells. But, as a consequence, the majority of SN positive patients undergo unnecessary additional surgery with its associated morbidity [29].
Sentinel node tumor burden and survival
Again the concept of orderly progression of lymph node melanoma metastases was analyzed by several authors, demonstrating SN tumor burden as a prognostic factor not only for additional non-SN positivity, but also for overall survival [23], [33], [35], [40], [43], [44], [45], [46], [47], [48], [49]. Several cut-off points and histological criteria were reported to be important with significant differences in survival between positive SN patients (Table 1). Carlson et al. [23] found the SN tumor
Therapeutic value of sentinel node biopsy
Previous non-randomized studies have suggested a possible therapeutic benefit for SN staged patients with lymph node metastases who underwent a CLND compared to patients who initially underwent only a wide local excision (WLE) of the primary tumor, followed later by a therapeutic lymph node dissection (TLND) for clinically positive regional lymph nodes [7], [55], [56]. However, due to the non-randomized nature of these studies, a number of problems could have been anticipated. Because of
Ultrasound as staging technique
In spite of the absence of proof of a survival benefit, associated with SN staging, the procedure is useful for prognostic information and stratifying patients in randomized phase III systemic adjuvant therapy trials, to create more homogeneous patient populations to determine whether adjuvant systemic trials are of benefit [60]. Moreover, SN staging may well improve long-term locoregional control in the lymph node basin compared to the patients who underwent a delayed lymph node dissection. At
Conclusion
The SN technique in melanoma patients gives important prognostic information, but has no effect on survival. It is not mandatory or standard of care to perform a SN biopsy in melanoma patients. The technique should be reserved for patients who want to be informed on the prognostic information and for randomisation in future adjuvant trials. 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
Conflict of interest statement
The authors have no conflict of interest.
References (69)
- et al.
Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO melanoma programme
Lancet
(1998) - et al.
Location of sentinel lymph nodes in patients with cutaneous melanoma: new insights into lymphatic anatomy
J Am Coll Surg
(1999) - et al.
Pathologic staging of melanoma
Semin Oncol
(2002) - et al.
Sentinel lymphonodectomy does not increase the risk of loco-regional cutaneous metastases of malignant melanomas
Eur J Cancer
(2005) - et al.
High positive sentinel node identification rate by EORTC melanoma group protocol prognostic indicators of metastatic patterns after sentinel node biopsy in melanoma
Eur J Cancer
(2006) - et al.
Morbidity and prognosis after therapeutic lymph node dissections for malignant melanoma
Eur J Surg Oncol
(2007) - et al.
Predictors of nonsentinel lymph node positivity in patients with a positive sentinel node for melanoma
J Am Coll Surg
(2005) - et al.
Clinical relevance of melanoma micrometastases (<0.1 mm) in sentinel nodes: are these nodes to be considered negative?
Ann Oncol
(2006) - et al.
Predicting residual lymph node basin disease in melanoma patients with sentinel lymph node metastases
Am J Surg
(2003) - et al.
Prediction of non-sentinel node status and outcome in sentinel node-positive melanoma patients
Eur J Surg Oncol
(2008)
Size of sentinel node metastases predicts other nodal disease and survival in malignant melanoma
Am J Surg
Prognosis depends on micro-anatomic patterns of melanoma micrometastases within the sentinel node (SN). A multicenter study in 388 SN positive patients
Eur J Cancer – Supplements
Patients with lymphatic metastasis of cutaneous malignant melanoma benefit from sentinel lymphonodectomy and early excision of their nodal disease
Eur J Cancer
Lymph node status and survival in cutaneous malignant melanoma–sentinel lymph node biopsy impact
Eur J Surg Oncol
European approach to adjuvant treatment of intermediate- and high-risk malignant melanoma
Semin Oncol
Ultrasonography or palpation for detection of melanoma nodal invasion: a meta-analysis
Lancet Oncol
Reduction of need for operative sentinel node procedure in melanoma patients: fifty percent identification rate of sentinel node positivity by ultrasound (US)-guided fine needle aspiration cytology (FNAC) in 400 consecutive patients
Eur J Cancer Suppl
Ultrasound-guided fine needle aspiration cytology of axillary lymph nodes in breast cancer patients. A preoperative staging procedure
Eur J Cancer
Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma
J Clin 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 to 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
The orderly progression of melanoma nodal metastases
Ann Surg
Clinical outcome of stage I/II melanoma patients after selective sentinel lymph node dissection: long-term follow-up results
J Clin Oncol
Sentinel lymph node biopsy for melanoma: how many radioactive nodes should be removed?
Ann Surg Oncol
Review and evaluation of sentinel node procedures in 250 melanoma patients with a median follow-up of 6 years
Ann Surg Oncol
The sentinel lymph node status is an important factor for predicting clinical outcome in patients with stage I or II cutaneous melanoma
Cancer
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
Single-dose isotope injection for both preoperative lymphoscintigraphy and intraoperative sentinel lymph node identification in melanoma patients
Melanoma Res
Correlation between preoperative lymphoscintigraphy and metastatic nodal disease sites in 362 patients with cutaneous melanomas of the head and neck
Ann Surg
The reproducibility in routine clinical practice of sentinel lymph node identification by pre-operative lymphoscintigraphy in patients with cutaneous melanoma
Ann Surg Oncol
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2013, Gynecologic OncologyCitation Excerpt :This finding coincides with clinical significance of SLN ITC of other tumors, such as melanoma and breast cancer. SLN ITC in melanoma breast cancer are usually disregarded, patients are considered as node-negative as they do not have worse DFSE and OS, and management need not be altered [34–38]. However, some studies find that patients with ITC SLN disease appear to present a more biologically aggressive melanoma, associated with faster time to recurrence [39].
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2009, European Journal of CancerCitation Excerpt :Patients with minimal SN tumour burden have excellent survival rates, which are identical to SN negative patients.16,22,27,28 Moreover, these patients have similar primary tumour characteristics to SN negative patients and they rarely, if ever have additional lymph node metastases in their CLND specimen.16,22,27,28 Finally, the Multicenter Selective Lymphadenectomy Trial-1 (MSLT-1) did not demonstrate any survival benefit for patients undergoing a SN procedure followed by a CLND when positive, compared to patients who only received wide local excision (WLE) followed by a Delayed Lymph Node Dissection (DLND) when metastases became clinically apparent.4
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