Update on Lymph Node Management in Melanoma - John T. Vetto MD, FACS Professor of Surgery Division of Surgical Oncology Oregon Health & Science ...
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Update on Lymph Node
Management in
Melanoma
John T. Vetto MD, FACS
Professor of Surgery
Division of Surgical Oncology
Oregon Health & Science University
Portland, OregonLymph Nodes in Melanoma
Outline
• Can we better predict who is sentinel lymph node
(SLN) positive?
• Can we predict who has tumor in the
non-sentinel nodes (NSLNs)
Heraclitus
• Is there still a role for CLNDx?Halstedian Model
Primary (T) Nodal (N) Distant (M)
Non-Halstedian Model
Primary
Nodal DistantOHSU Prospective SLN Database:
Adults SLN+ Rate=12% (T1-T4)-16% (T2-T4)
SLN-
• Predictors of survival
SLN+ • SLN status
• Ulceration
• Gender
p1500 cases 4Can We Better Predict Who is SLN Positive?
• 6 of 7 (all T stages) or 5 of 6 (MSLT-1; T2-T4) sentinel nodes are negative
• Clinical Factors:
Thickness Chance of a + SLN
(nonulcerated-
ulcerated)
4.0 34-54%
• For T1: Breslow thickness ≥ 0.75 mm, Clark level ≥ IV, and ulceration
Han D, et al. Clinicopathologic predictors of sentinel lymph node metastasis in thin melanoma. J
Clin Oncol. 2013 Dec 10;31(35):4387-93NCCN Version 3.2 (2018) Recommends SNB
Should be Based on “Risk” of a +SLN
Risk Recommendation Examples
5%< Do not recommend T1a with no negative features*
5-10% Discuss and Consider T1a with negative features
or T1b with no negative features
>10% Discuss and Offer T1b with negative features
or >T2a
• Negative features: young age, mitoses >2/mm2, LVI, transection
• https://www.nccn.org/professionals/physician/melanomaCellular Functions Represented in the
DecisionDx-Melanoma Signature
Migration/chemotaxis/ CXCL14 Differentiation/ CRABP2
metastasis SPP1 proliferation SPRRIB
CLCA2 BTG1
S100A9
Cell surface receptors TACSTD2
S100A8
CLCA2
BAP-1
ROBO1
Chemokine/secreted CXCL14 CST6
Structural proteins
molecules MGP KRT6B
SPP1 KRT14
Gap junction/cellular GJA1 Immune response LTA4H
adhesion DSC1 S100A8
PPL S100A9
TYRP1
Extracellular matrix MGP ARG1
protein ARG1 CXCL14
Transcription factor TRIM29 Other SAP130
ID2 EIF1B
AQP1
Gerami et al, Clin Cancer Res; 21(1), 2015 RBM23DecisionDx-Melanoma Test Workflow
CM
tumor RNA isolation
tissue
cDNA generation and amplification (14X)
Microfluidics PCR gene card
28 discriminant gene targets and 3 control genes
Analysis of GEP with a proprietary algorithm
to determine class and metastatic risk
Class 1 Class 2
low metastatic risk high metastatic riskRisk prediction for Stage I/II patients is refined using sub-classification
Class 1 Class 2
Low Risk High Risk
0 0.41 0.5 0.59 1
Probability score
Class 1A Class 1B Class 2A Class 2B
Recurrence-Free Survival (n=356)Can We Use the GEP Score to Determine Risk of +SLN?
Zager et al. BMC Cancer 2018
Vetto et al. Amer Acad Derm Meeting 2018
NCCN Thresholds for SLNB
(2.2018) Develop Optimal Algorithm: Independently Validate:
SLN+
Guideline Model development with
(positivity) rate
retrospective cohort totaling
Discuss and 946 patients1-3 Two prospective, multicenter
>10%
offer cohorts totaling 1,421
Discuss and Class 1 patients
5% to 10% Breslow’s depth ≤2mm and
consider
Age
Do notDemographics for prospective validation cohort (#1 and #2) for SLNB guidance
Cohort #1 (n= 584) Cohort #2 (n=837)
Attribute Castle prospective Independent prospective
multi-center studies1,2 multi-center study3
Age (years)
Median (range) 61 (18 – 100) 63 (12 -101)
Breslow depth (mm)
Median (range) 1.2 (0 – 18) 1.16 (0 - 60)
Ulceration present 18% 24%
Mitotic rate ≥1/mm2 65% 64%
Node status positive 14% 12%
T Stage
T1 44% 42%
T2 31% 32%
T3 17% 17%
T4 7% 9%
GEP Class 2 25% 29%
1Hsueh et al. J Hematol Oncol 2017 ; 2Dillon et al. SKIN J Cutan Med 2018; 3Vetto et al. AAD Meeting 2018GEP subclass can predict SLNB positivity risk for
patients with T1-T2 tumors and inform SLNB guidance
30% NCCN Recommendations Probability of a Positive Sentinel Lymph
for SLNB (v3.2018) Node for T1-T2 Patients
20%Completion Lymph Node
Dissection
• Historically the standard of care for patients
with positive sentinel nodes.
• MSLT-II: Associated with increased
disease-fee overall survival.
• Non-sentinel node status is an important
prognostic factor (hazard ratio for death:
1.78).
Faries, M. B., et al. New England Journal of Medicine 2017:23:
2211-2222.MSLT-2: Three Questions •Would an improved OS survival be seen in arm contained only patients with +NSNs? •What will happen to +NSNs left in patients (in the era of new adjuvant therapies)? •Can we predict which patients have +NSNs?
Results
Overall Incidence of Positive NSNs in CLND Specimens
17.6%
82.4%
Schuitevoerder D, Am J Surg, 2018, in pressFindings
• Increased tumor thickness and anatomic location (neck,groin)
of the nodal basin were associated with metastasis in NSNs.
• Higher numbers of harvested NSNs were associated with higher
rates of NSN positivity (13 vs. 20, p=0.005).
• Supports other studies: plus SLN tumor burden, GEP score (SSO
abstract).
Schuitevoerder D, Am J Surg, 2018, in pressHalstedian Model
Primary (T) Nodal (N) Distant (M)
Non-Halstedian Model
Primary
Nodal DistantOHSU Multidiciplinary Melanoma Team
Shared Beliefs
• Patient –centered care; Platinum Rule
• Decisions are shared
• Consider clinical trials at every step of the way
• Exciting time for melanoma patients and providersShameless Plug: OHSU/Knight Multidisciplinary Melanoma Conference (Thursdays, &am, 3rd floor CHH) • Surgical Oncology • Medical Oncology • Radiation Oncology • Dermatology • Nuclear Medicine/Radiology • Dermatopathology • Surgical Pathology • Medical Genetics • Clinical Trial staff • Data Managers
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