MELANOMA
Sentinel Lymph Node Evaluation:
Update
Kim James Charney, MD
Conflict of Interest
None
Objectives





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Sentinel lymph node (SLN) biopsy concept
and technique
Impact of SLN metastasis on recurrence and
survival in melanoma
Implication of isolated SLN tumor cells in
melanoma
SLN tumor burden
Necessity of completion lymph node
dissection (CLND)
Candidates for SLN biopsy
Stage I & II

85% of newly diagnosed patients
Surgical Management of Stage I and II
Goals



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Accurate Staging
 Assess risk for recurrence
 Recommendation for therapy
Durable Local/Regional Control
Cure
Minimize Morbidity
Stage I and II Primary Melanoma
Components of Treatment
Wide Excision
Margins appropriate for thickness
Regional Nodes?
Lymph Node Involvement and
Melanoma

Regional nodes, most common site of first
recurrence


>50% chance for distant relapse
15-50% chance for in-basin failure after lymph node
dissection for palpable disease
Approach to the Clinically Negative
Regional Basin

Observation-----------------------Therapeutic Dissection

ELND


Intermediate thickness
Selective lymphadenectomy


Lymphatic mapping and sentinel lymph node biopsy
Only pt’s with metastases are dissected
Morton, DL, et al. Arch Surg. 1992; 127:392-399
Sentinel Node Biopsy
Published Findings

SLN identification rate: 99%

Dual modality technique
Blue dye
 Radio-colloid injections and gamma probe


Accurately stages regional nodal basin
Concomitant ELND:FNR < 5%
 Follow-up of SLN-neg. patients: ~3% will develop nodal
disease
 Facilitates the use of sensitive pathologic techniques

Sentinel Node Biopsy
Goals

Improve disease outcome for node positive
patients
Regional control
 Survival
Prevent the development of clinical nodal involvement


Minimally invasive approach to nodal staging
Staging
Prognostic Relevance
2010 AJCC Staging
Changes

Stage I and II (clinically localized)

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Stage III (regional)


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
Thickness
Ulceration
Mitotic Rate >1/mm2
SLN status?
Nodes
In-transit disease
Ulceration
Stage IV (distant)


Site
LDH
AJCC MELANOMA STAGING DATABASE
Survival Curves for Stage I & II
1.0
0.9
(1)
(2)
Proportion Surviving
0.8
Ia
Ib
0.7
(3)
(4)
(5)
0.6
IIa
(7)
0.5
(6)
0.4
(8)
0.3
0.2
IIb
IIc
Non-ulcerated
Ulcerated
0.1
0
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15
Survival, years
Balch CM, et al. J Clin Oncol. 2001;19(16):3622-3634.
Incidence of SLN Metastases
MDACC Database
Tumor
Thickness
(mm)
< 1.00
1.01-2.00
2.01-4.00
4.01+
Total
Total No.
Patients
(N)
326
490
310
190
1316
All
(%)
4.2
11.4
28.5
45.5
17.4
Positive SLN
non-Ulcerated
(%)
3.9
10.8
23.1
34.2
11.9
ulcerated
(%)
12.5
21.2
37.0
55.4
37.0
Ross, MI. Clin Cancer Res. 2006;12: 2312s-2319s.
2008 AJCC Melanoma Database Stage I
Survival Rates for T1 Patients (0.01-1.00 mm)
According to MR (per mm2)
Survival Rate
Thickness
MR
5-Year
10-Year
n
(mm)
0.01-0.50
0.01-0.50
0.51-1.00
0.51-1.00
<1.0
>1.0
<1.0
>1.0
99%
97%
98%
94%
97%
95%
93%
87%
1,194
327
1,472
1,868
2009 staging rule: T1b melanomas defined as
≤1.0 mm with ulceration or >1 mitosis / mm2
The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010)
published by Springer Science and Business Media LLC, www.springerlink.com.
Impact of MR on SLN Positivity



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Currently, the T1b designation is used for staging in
terms of survival

Is not itself a criterion to perform SLNB
Evolving data suggests that MR may be predictive of
occult regional nodal disease
Andtbacka RH et al: SLNB in thin melanoma

Suggests that SLNB is appropriate for patients with T1b
melanomas, including those defined by MR
Await publication of a larger analysis of patients with
thin melanoma
Andtbacka RH, Gershenwald JE. JNCCN. 2009;7:308-317.
Prognostic Factors Influencing
Disease-Specific Survival
_____________________________________________________________________________
Multiple covariate
Prognostic Factor
Univariate
Hazard Ratio
p-value
Age
NS
NS
Sex
NS
NS
Axial location
.03
NS
Tumor thickness
<.0001
1.1
.04
Clark level > III
.001
2.3
.01
Ulceration
<.0001
3.3
<.0001
SLN status
<.0001
6.5
<.0001
_____________________________________________________________________________
Several large single institution and multi-center databases provide consistent findings
Disease-Specific Survival by
SLN Status
Most powerful predictor of survival
Morton DL, et al. N Engl J Med. 2006; 355: 1307-1317
Does early treatment of lymph node
disease improve survival?
Randomized Surgical Trials Comparing
ELND vs. Nodal Observation
Pt’s.
Thickness
Site
WHO Program
Trial #1
Trial #14
533
227
All
>1.5mm
Extremities
Trunk
Mayo Clinic
171
All
Extremities
Trunk
Intergroup Melanoma Trial
737
1-4mm
All
Not all patients benefit
Long Term Results of ELND Trials
2 contemporary ELND trials with survival benefits for patients with
microscopic disease
Survival According to Status of Regional Nodes
Cascinelli. Lancet 1998
German Retrospective Review
Impact of Sentinel Node Biopsy on Survival
for Node-Positive Patients
SLNE: Sentinel Lymph Node positive Elective node dissection
DLND: Delayed Lymph Node Dissection
Kretschmer et al, Eur J Cancer. 2004; 212-218.
ELND Trial Outcomes
Conclusions


No overall survival benefit

Early dissection has no impact on the natural history of primary
melanoma

Incidence of node positive patients too low to adequately test the
hypothesis
Survival benefit observed in the node positive and other stratified
subgroups
MSLT-I: Immediate vs. Delayed CLND
for Nodal Metastases
Biopsy-proven Melanoma > 1mm
Randomized
60%
40%
WEX + SNB
WEX + Watch & Wait Observation
A: Comparison of all randomized patients
SN(-)
Observation
SN(+)
Immediate CLND
Nodal
Recurrence
Delayed CLND
B: Comparison of randomized patients with
SN occult vs. palpable nodal metastases
Morton DL, et al. N Engl J Med. 2006; 355: 1307-1317
MSLT-1
5-year Survival Benefit Estimates


Based on previous trial observations

WHO: 20% survival advantage in the microscopic node positive

German multi-center trial: 15% benefit in SLN positive group
Assuming 20% incidence of node positivity

Overall 3%-4% survival benefit
Morton DL, et al. N Engl J Med. 2006; 355: 1307-1317
Impact of Sentinel Node Biopsy on
Relapse-Free Survival
5-year disease-free survival
•
•
•
73.1% vs 78.3%, p=0.009
Median follow-up 59.8 months
26.8% patients on observation arm with relapse at any
site
20.7% patients on sentinel node biopsy arm with
relapse at any site
Morton et al. N Engl J Med. 2006;355:1307
MSLT-I: Immediate vs. Delayed CLND
for Nodal Metastases
Biopsy-proven Melanoma > 1mm
Randomized
60%
40%
WEX + SNB
WEX + Watch & Wait Observation
A: Comparison of all randomized patients
SN(-)
Observation
SN(+)
Immediate CLND
Nodal
Recurrence
Delayed CLND
B: Comparison of randomized patients with
SN occult vs. palpable nodal metastases
Morton DL, et al. N Engl J Med. 2006; 355: 1307-1317
Stage Progression to More Advanced Nodal Disease
Among “Watch and Wait” Patients vs. SNB
70%
4
3.4
Mean # Pos. Nodes
3
2
1.6
SNB
1
% SNB (+) or Nodal Recur.
Watch
60%
67%
SNB
P=0.0001
50%
41%
40%
Watch
32%
28%
30%
27%
Watch
SNB
Watch
20%
5%
10%
SNB
0%
0
Rx
1 Node
N1
2-3 Nodes
N2
AJCC N Stage
> 4 Nodes
N3
MSLT-I: Impact of Sentinel Node Biopsy on
Survival for Node-Positive Patients
All 2001 Patients
Randomization
SLNB
+
OBS
-
-
Early TLND
72% 5-year survival
+
Delayed TLND
52% 5-year survival
P= 0.004
multivariate model adjusted for known prognostic factors
Morton DL, et al. N Engl J Med. 2006; 355: 1307-1317
MSLT-1 Node + Subgroups
Reasons for Survival Differences

False positive SLN's

SLN group prognostically more favorable

Early dissection prevents regional progression and
distant dissemination
False Positive SLN?
% Node (+) or Nodal Recurrence
Incidence of SN Metastases at SNB vs. Clinical Nodal
Recurrence following “Watch and Wait”
40.0%
35.2
35.5
P=0.8329
30.0%
19.8
20.0%
16.2
20.3
16.4
SNB
Watch
10.0%
0.0%
1.2-3.5
>3.5
Overall
Breslow Thickness (mm)
Cumulative Incidence of Regional
Node Metastasis
Morton et al. N Engl J Med. 2007;356:418-421
AJCC 2009 Stage III Changes

Concept of ITCs as node-negative disease [N0(i+)] no longer used

Scheri et al: 214 SLN+ patients, 57 had ITCs (≤ 0.2 mm)


Akkooi et al: 388 SLN+ patients, 40 (10%) had metastases <0.1 mm


CLND 6 (12%) additional + nodes, 5-yr melanoma-specific survival LOWER
in ITC+ patients than SLN- patients (89% vs 94%, P=.02)
1 (3%) with additional + nodes, 5-yr OS 91% = to SLN- patients
Bottom line: It remains unclear whether ITCs in the regional
nodes are of clinical significance

BUT, concept of “clinically insignificant nodal disease” unproven
Scheri RP et al. Ann Surg Oncol. 2007;14:2861-2866.
van Akkooi ACJ et al. Ann Surg. 2008;248:949-955.
Microscopic metastases will become
Macroscopic
Do the AJCC staging criteria apply to
patients with microscopic SLN tumor
burden?
Revised AJCC Staging System
Stage III Changes
Independent Prognostic Factors
AJCC Cox Model – 1151 Stage III Patients
Variable
Number of (+)
Chi Square
P-Value
Risk Ratio
57.6
<0.00001
1.26
Tumor Burden
40.3
<0.00001
1.79
Ulcer +
23.3
<0.00001
1.58
Nodes
6th Edition - 2002
Balch CM et al. J Clin Oncol. 2001; 19(16):3622-3634.
Disease-Specific Survival Total # Positive Nodes
SLN Positive Patients Only
Gershenwald JE et al. WHO 6th World Congress on Melanoma; September 2005; Vancouver, BC.
Disease-Specific Survival by Ulceration
SLN Positive Patients Only
Gershenwald et al, Ann Surg Oncol. 2000;7:160
Disease-Specific Survival by Tumor Burden
Largest Focus SLN-Positive Patients Only
Gershenwald JE et al. WHO 6th World Congress on Melanoma; September 2005; Vancouver, BC.
Survival According to Tumor Burden in
SLN’s
Ross MI. New AJCC Recommendations for Melanoma Staging. Presented at: 33rd ESMO Congress Satellite
Symposium: Current Trends in Melanoma Management; September 14, 2008; Stockholm, Sweden.
Prognostic Factors Influencing DSS
SNL Positive Patients Only
Prognostic Factor
Ulceration
Total Positive Nodes
1
2
3+
Largest SLN metastatic focus
< 2mm
>2 & < 8mm
> 8mm
Multiple covariate
Hazard Ratio
p-value
2.04
.01
1.0
1.46
2.10
.25
.045
1.0
2.51
2.91
.004
.01
Fifteen-year Survival Curves for the Stage Groupings of Patients with Regional
Metastatic Melanoma (Stage III)
From Balch, C. M. et al.
CA Cancer J Clin 2004;54:131-149.
Copyright ©2004 American Cancer Society
Completion Node Dissection for
Positive Sentinel Nodes:
Is it necessary?



Staging
Survival
Regional Control
Regional Recurrence After Surgery
Alone
Reference
Regional
Failure Rate
Fuhrmann,2001
Kretschmer, 2001
Lee, 2000
Shen, 2000
Hughes, 2000
Monsour, 1993
28%
34%
30%
14%
25%
52%
Miller, 1992
12%
O’Brien, 1991
Calabro, 1989
Bowsher, 1986
Byers, 1986
24%
17%
15%
16%
Weighted average:
692 failures/3350 patients=
21%
Risk Factors for Regional Recurrence
After Surgery Alone
Regional
Failure Rate
Characteristic
References
Extracapsular extension
31% - 63%
Lee, Calabro, Shen, Monsour
>4 involved lymph nodes
22% - 63%
Lee, Calabro, Miller, Kretschmer
Lymph node >3 cm
42% - 80%
Lee
Cervical ln location
33% - 50%
Lee, Bowsher, Monsour
30% - 50% if high-risk features present
In-Basin Failure
% Nodal Failure
Selective Lymphadenectomy vs. ELND
(Node Positive Only)
9
8
7
6
5
4
3
2
1
0
ELND
Slingluff, 1994
SLN
MDACC Study, 2003
Rational For Completion Dissection



Avoid the development of palpable nodal disease
- residual microscopic disease in non-sentinel nodes
Staging
- total number of nodes involved prognostically relevant
- may influence recommendations for adjuvant therapy
Incidence of non-sentinel node involvement under-estimated
- based on routine pathologic techniques
Reasons Against Routine Use of
Completion Dissections

Incidence of non-sentinel node involvement is only 10%-20%
- unnecessary cost and morbidity in patients without additional
microscopic disease

No proven survival benefit for node dissection

Incidence of nodal failure after SLN biopsy
A selective approach to completion
dissection is rational.
Recommendations


CLND for a positive SLN is the standard of care
Omission of CLND should only occur as part of a
clinical trial
SLN Biopsy
Indispensable Staging Procedure?

Effectively identifies microscopic disease/Promotes early node
dissection




Identifies patients who benefit most with adjuvant therapy
Facilitates careful pathologic scrutiny


survival benefit
optimizes regional control
Node negative patients spared toxicity
Critical prognostic information

Stratification criteria for clinical trials
Candidates for SLN Biopsy
Incidence of Positive SLN:
AJCC Stage Grouping
55.4%
Percent Positive SLN
60
50
40
35.3%
30
22.1%
20
11.4%
10
3.9%
0
Ia
Ib
IIa
AJCC Stage
IIb
IIc
Melanoma Lymphatic Mapping
Preoperative Eligibility

Primary tumor criteria


> 1mm Breslow thickness
< 1mm

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
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MR: present (Ib)
Ulceration (Ib)
Clark Level IV/V
Vertical growth phase?
Age?
After a wide excision?
Ambiguous diagnosis of melanocytic lesion?
Pure Desmoplastic melanoma?
National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for
Melanoma. V1.2010
Balch CM et al. J Clin Oncol. 2009;27(6):6199-6206.
Who Should Undergo SLNB?

National Comprehensive Cancer Network, 2011



Consider SLNB for high risk Ia melanoma
Discuss and offer SLNB for stage Ib, stage II CM
SLNB important staging tool, but impact on overall survival
unclear

AJCC Recommendations


Microstaging of all primary melanomas
Pathologic nodal staging for stage Ib-IIc
National Comprehensive Cancer Network Clinical Practice Guidelines
in Oncology Melanoma. V. 3.2011
AJCC Cancer Staging Manual, Seventh Edition (2010) published
by Springer Science and Business Media LLC, www.springerlink.com.
SLN Biopsy
Standard of Care?
Discuss with patients:
 accuracy of SLN biopsy
 predicted risk for microscopic nodal disease
 potential risks and benefits
 how the information will impact therapy
Currently offered as standard of care for patients
with Ib-IIc and selectively for Ia.
Thank You