Clinical relevance of melanoma micrometastases (<0.1 mm) in sentinel nodes: are these nodes to be considered negative?

Abstract

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.

Stage migration after minor changes in histologic estimation of tumor burden in sentinel lymph nodes

“…[32][33][34] Recently, there has been increasing focus on the prognostic value of metastasis size in melanoma, and some centers advocate avoiding a completion lymph node dissection (CLND) in situations in which only very small metastases (< 0.1 mm) are detected. 15 In breast cancer, distinct metastasis diameter cutoff points are used to determine the treatment for the individual patient in cases in which the primary tumor characteristics would not result in adjuvant treatment. For example, the Danish national guidelines for breast cancer state that the presence of only isolated tumor cells or clusters (<0.2 mm) is an indication for CLND alone, and patients with micrometastases ( 2 mm) should be treated with both CLND and adjuvant chemotherapy, whereas patients with macrometastases (>2 mm) should receive additional local radiotherapy to the axilla.…”

“…15 We also measured the centripetal depth of metastatic invasion, according to the S-classification, as proposed by Starz et al (Group 1: <0.3 mm; Group 2: 0.3-1 mm; and Group 3: > 1 mm). 23 Finally, we recorded the microanatomic location of the tumor deposits, according to the classification proposed by Dewar et al (subcapsular, parenchymal, combined, multifocal, or extensive).…”

“…Similarly, in melanoma, increasing evidence is emerging to support the view that SLN metastasis size is of prognostic significance. [15][16][17][18][19][20] We have shown that stereology-based volume estimates of melanoma metastases in SLNs more accurately predict disease-free survival than measuring the maximum metastasis diameter. 21 Volume estimates based on the Cavalieri principle 22 require complete serial step-sectioning of the SLNs, a procedure not included in most SLN histologic protocols.…”

“…21 Volume estimates based on the Cavalieri principle 22 require complete serial step-sectioning of the SLNs, a procedure not included in most SLN histologic protocols. Other estimates of metastasis burden that can be performed using more limited sectioning protocols, such as the maximum metastasis diameter, 15 the centripetal depth of metastatic invasion, 23 or the microanatomic 24 location of the metastases present in the levels examined, have been more widely applied.…”

Interaction of tumor cells and lymphatic vessels in cancer progression

“…64 In the case of melanoma, treatment follow-up studies indicate that metastases under 0.1 mm in diameter might not have an impact on prognosis. 67 However, larger size metastatic melanoma lesions in lymph nodes correlate with shorter progression-free survival (reviewed in Leong et al 64 ). Thus, lymphatic metastasis is common, at least in selected cancer types, and is associated with increased lethality.…”