Elsevier

Surgical Oncology

Volume 17, Issue 3, September 2008, Pages 175-181
Surgical Oncology

Review
Detection of melanoma micrometastases in sentinel nodes – The cons

https://doi.org/10.1016/j.suronc.2008.06.004Get rights and content

Abstract

The sentinel node (SN) procedure in melanoma patients is important for prognostic information, but has no impact on survival. Micrometastases are identified in approximately 20% of the SNs. When a Completion Lymph Node Dissection (CLND) is performed for positive SN, additional non-SN lymph node involvement is also approximately 20%. Several classification criteria have been proposed to identify patients with SNs without a risk for additional nodes or a good prognosis. Micro anatomic analyses of metastatic SNs suggest that patients with sub-micrometastases (<0.1 mm) in the SN may be judged as SN negative. Patients with this limited tumor burden in their SN have an excellent prognosis and are highly unlikely to benefit from CLND. New techniques such as ultrasound of the lymph nodal basin can be promising as an alternative for SN biopsy.

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)

  • N.W. Pearlman et al.

    Size of sentinel node metastases predicts other nodal disease and survival in malignant melanoma

    Am J Surg

    (2006)
  • A.C. van Akkooi et al.

    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

    (2007)
  • L. Kretschmer et al.

    Patients with lymphatic metastasis of cutaneous malignant melanoma benefit from sentinel lymphonodectomy and early excision of their nodal disease

    Eur J Cancer

    (2004)
  • P. Rutkowski et al.

    Lymph node status and survival in cutaneous malignant melanoma–sentinel lymph node biopsy impact

    Eur J Surg Oncol

    (2003)
  • A.M. Eggermont et al.

    European approach to adjuvant treatment of intermediate- and high-risk malignant melanoma

    Semin Oncol

    (2002)
  • M.L. Bafounta et al.

    Ultrasonography or palpation for detection of melanoma nodal invasion: a meta-analysis

    Lancet Oncol

    (2004)
  • C. Voit et al.

    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

    (2007)
  • V. Kuenen-Boumeester et al.

    Ultrasound-guided fine needle aspiration cytology of axillary lymph nodes in breast cancer patients. A preoperative staging procedure

    Eur J Cancer

    (2003)
  • C.M. Balch et al.

    Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma

    J Clin Oncol

    (2001)
  • C.M. Balch 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)
  • U. Veronesi et al.

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

    N Engl J Med

    (1977)
  • F.H. Sim et al.

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

    Cancer

    (1978)
  • C.M. Balch et al.

    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

    (2000)
  • D.L. Morton et al.

    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

    (2003)
  • D.L. Morton et al.

    Technical details of intraoperative lymphatic mapping for early stage melanoma

    Arch Surg

    (1992)
  • D. Reintgen et al.

    The orderly progression of melanoma nodal metastases

    Ann Surg

    (1994)
  • R.J. Vuylsteke et al.

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

    J Clin Oncol

    (2003)
  • K.M. McMasters et al.

    Sentinel lymph node biopsy for melanoma: how many radioactive nodes should be removed?

    Ann Surg Oncol

    (2001)
  • S.H. Estourgie et al.

    Review and evaluation of sentinel node procedures in 250 melanoma patients with a median follow-up of 6 years

    Ann Surg Oncol

    (2003)
  • M.G. Statius Muller 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)
  • J.E. Gershenwald et al.

    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

    (1999)
  • J.F. Thompson et al.

    Single-dose isotope injection for both preoperative lymphoscintigraphy and intraoperative sentinel lymph node identification in melanoma patients

    Melanoma Res

    (1997)
  • J.H. de Wilt 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)
  • R.F. Uren 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)
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