AJCC 8 Implementation

January 1, 2018

Melanoma of the Skin

Suraj Venna

Personalized Medicine

AJCC 8th Edition This Time It’s Personal

• “Traditional” AJCC (TNM) – “population-based” analyses of large databases with 1000’s of cases – Simple to use – Clinically relevant because of overall survival data – Very limited with “factors” that are used to make such predictions

(melanoma: depth, MR, ulceration, nodal status)

• Precision Medicine Core: “Personalized Probabilistic Prediction Tool” – Help to refine a given individuals prognosis – Incorporate patient factors (age, sex) and other tumor-related (TILs,

growth phase, LVI) as well as molecular biomarkers – Provide accurate prognostic information (OS, recurrence) – “Conditional Survival” (p) of an event occurring over time – Web-based tools

AJCC 8th Edition, Jan 1, 2018 New International Melanoma Database

International melanoma database

• 10 cancer centers • 1/3 cases from Australia • 40,000 patients diagnosed with Stages 1 to 3 melanoma • First complete database in the “Sentinel Node” era • Most are SSM, NM (applied to DMM,LM,Acral) • Data over a 20 year period

Expert panel of 36 members Designed for more frequent updates

Gershenwald J et al. “Melanoma of the Skin.” In AJCC Cancer Staging Manual 8th Ed. 2017

Melanomas Not Staged Using the “Melanoma of the Skin” system……

These types of melanoma… Are staged according to… Melanoma of the conjunctiva Conjunctival melanoma Melanoma of the uvea Uveal melanoma Mucosal melanoma arising in Mucosal melanoma of the head and head and neck neck Mucosal melanoma of the No AJCC staging system urethra, vagina, rectum and anus

Gershenwald J et al. “Melanoma of the Skin.” In AJCC Cancer Staging Manual 8th Ed. 2017

AJCC – Goals

• Allow collection of standardized data to support clinical care

• Staging systems are based (sometimes) limited data, supplemented by expert opinion

• Classifies extent of disease based mostly on anatomic parameters – Primary tumor (T) – Regional nodal disease (N) – Distant metastases (M)

• Major challenge to TNM is the rapid evolution in cancer biology/molecular markers

Why is it important to Stage Our Patients?

– Prognosis – Management

• Sentinel lymph node biopsy • Adjuvant therapy • Treatment

– Clinical trials – Longitudinal follow up

• Frequency of clinical examination • Determining the type of follow up (medonc,surg,derm) • Frequency of additional testing

•1977 – First Melanoma Staging per AJCC

Breslow’s Depth <0.76mm 0.76-1.50mm 1.51-4.0mm >4mm •2001 – AJCC 6

Breslow’s Depth ≤1mm 1.01-2mm 2.01-4mm >4mm •2009 – AJCC 7 Breslow’s Depth ≤1mm 1.01-2mm 2.01-4mm >4mm

1. Breslow’s Depth 2. Clark’s level

1. Breslow’s Depth 2. Clark’s level 3. Ulceration

1. Breslow’s Depth 2. Ulceration 3. Mitotic rate replaced Clark’s level

Histologic Prognostic Marker Timeline

“T” (Tumor) Updates

AJCC 7th Edition T Categories Primary Tumor (T)

TX Primary tumor cannot be assessed (for example, curettage Or severely regressed melanoma) T0 No evidence of primary tumor Tis Melanoma in situ T Thickness Classification (mm) Ulceration Status/Mitoses T1 ≤ 1.0 a: w/o ulceration and mitosis < 1/mm2

b: with ulceration or mitoses ≥ 1/mm2

T2 1.01 – 2.0 a: w/o ulceration b: with ulceration T3 2.01 – 4.0 a: w/o ulceration b: with ulceration T4 > 4.0 a: w/o ulceration b: with ulceration

KEY CHANGES AJCC 8 Definition of Primary Tumor (T)

•All principal T-category tumor thickness ranges are maintained

•Tumor mitotic rate is removed as staging criterion for T1 tumors

•New “cut-point” for T1 tumors is 0.8mm

•For the first time there is a distinction between the clinical staging and pathologic staging of T1 melanomas

Gershenwald J et al. “Melanoma of the Skin.” In AJCC Cancer Staging Manual 8th Ed. 2017

Melanoma Institute Australia Data: 6270 Patients

With permission from Richard Scolyer MD

KEY CHANGES AJCC 8 Definition of Primary Tumor (T)

•T1a melanomas are < 0.8mm and non ulcerated (MR irrelevant)

•T1b melanomas are

0.8mm to 1.0mm regardless of ulceration

< 0.8mm with ulceration (MR irrelevant)

Gershenwald J et al. “Melanoma of the Skin.” In AJCC Cancer Staging Manual 8th Ed. 2017

KEY CHANGES AJCC 8 Definition of Primary Tumor (T)

• Tumor thickness now recorded to the nearest 0.1mm, not the

nearest 0.01mm

• Convention for rounding decimal values • Round down for those ending in 1 to 4 • Round up for those ending in 5 to 9

• “0.8mm tumor” are melanomas in the range of 0.75 to 0.84 (T1b)

• “1.0mm tumor” are melanomas in the range of 0.95 to 1.04 (T1b)

• The NEW T1b range is 0.75 to 1.04mm

Gershenwald J et al. “Melanoma of the Skin.” In AJCC Cancer Staging Manual 8th Ed., p568, 2017

i.e. 0.75mm will now be recorded as 0.8mm i.e. 0.54mm will now be recorded as 0.5mm

AJCC 8: Definition of Primary Tumor (T)

Definition of Primary Tumor (T):

T Category Thickness Ulceration Status

Tis (Melanoma in situ) Not applicable Not applicable T1 0.1 - 1.0/ ≤ 1.0 mm Unknown or unspecified T1a < 0.8 mm Without ulceration T1b 0.8 – 1.0mm Regardless ulceration status

< 0.8 mm With ulceration

T2 1.1 - 2.0/ > 1.0 - 2.0 mm Unknown or unspecified T2a > 1.0 - 2.0 mm Without ulceration T2b > 1.0 - 2.0 mm With ulceration

T3 2.1 - 4/ > 2.0 - 4.0 mm Unknown or unspecified T3a > 2.0 - 4.0 mm Without ulceration T3b > 2.0 - 4.0 mm With ulceration

T4 ≥ 4.1 / > 4.0 mm Unknown of unspecified T4a > 4.0 mm Without ulceration T4b > 4.0 mm With ulceration

Gershenwald J et al. “Melanoma of the Skin.” In AJCC Cancer Staging Manual 8th Ed. 2017

“N” (Nodal) Updates

AJCC 7: N Categories Regional Lymph Nodes (N) NX Patients in whom the regional nodes cannot be assessed

(for example, previously removed for another reason) N0 No regional metastases detected N1-3 Regional metastases based upon the number of metastatic Nodes and presence or absence of intralymphatic Metastases (in transit or satellite metastases) NOTE: N1-3 and a-c subcategories assigned as shown below: N No. of Classification Metastatic Nodes Nodal Metastatic Mass N1 1 node a: microstastasis1

b: macrostastasis2

N2 2-3 nodes a: micrometastasis1

b: macrometastasis2

c: in transit met(s)/satellite(s) without metastatic nodes N4 4 or more metastatic noses, or matted nodes, Or in transit met(s)/satellite(s) with metastatic node(s)

N3

N1 a,b,c N2 a,b,c N3 a,b,c

AJCC 8

STAGE III MELANOMA

AJCC 8: N – category

New Pathologic Group: Stage IIID T4 ulcerated with at least 4 nodes/matted/non- nodal+2nodes) “Microscopic” disease redefined as “Clinically occult” “Macroscopic” disease redefined as “Clinically detected” “Tumor burden” should be collected on all patients with Stage III

Gershenwald J et al. “Melanoma of the Skin.” In AJCC Cancer Staging Manual 8th Ed. 2017

AJCC 8: Non-nodal Locoregional Metastases

Microsatellite – microscopic cutaneous/subcutaneous metastasis adjacent or deep to a primary melanoma Satellite – recurrence within 2cm of the primary In-transit – recurrence > 2cm from the primary

Presence of microsatellites, satellites, in-transit now categorized as N1c,N2c, or N3c based on the # of involved nodes (0,1, ≥2 respectively)

Gershenwald J et al. “Melanoma of the Skin.” In AJCC Cancer Staging Manual 8th Ed. 2017

AJCC 8: N Categories N Number of tumor-involved regional lymph node In-transit,sat/microsat NX Regional nodes not assessed. Exception: pathological N

category is not required for T1 melanomas, use cN. No

N0 No regional metastases detected

No

N1 1 node or in-transit/sat/microsat, no tumor-involved nodes

N1a 1 clinically occult (i.e., detected by SLN biopsy) No N1b 1 clinically detected No N1c No regional lymph node disease Yes N2 2 or 3 nodes or in-transit/sat/microsat with 1 node N2a 2 or 3 clinically occult (i.e., detected by SLN) No N2b 2 or 3, at least one of which was clinically detected No N2c 1 clinically occult or clinically detected Yes N3 ≥4 nodes or in-transit/sat/microsat with ≥2nodes or matted

nodes without or with in-transit/sat/microsat N3a ≥4 clinically occult (i.e., detected by SLN biopsy) No N3b ≥4 at least one of which was clinically detected, or presence of

any number of matted nodes No

N3c ≥2 clinically occult or clinically detected and/or presence of any number of matted nodes

Yes

Gershenwald J et al. “Melanoma of the Skin.” In AJCC Cancer Staging Manual 8th Ed. 2017

Survival for N disease

Balch C M et al. JCO 2009;27:6199-6206

5 year survival ranges from 70% (N1a) to 39% (N3) disease

Survival spectrum in Stage III

Balch C M et al. JCO 2009;27:6199-6206

AJCC 7 Positive SLN ≤3 and any thickness non-ulcerated primary (T1a-T4a)

AJCC 8 Positive SLN ≤3 and limited to T1a/b and T2a

AJCC 8: New Stage IIID

“M ”(Metastasis) Updates

AJCC 7 : M Categories Distant Metastasis (M) M0 No detectable evidence of Distant metastases M1a Metastases to skin, subcutaneous, or distant lymph nodes M1b Metastases to lung M1c Metastases to all other visceral sites or distant metastases to any site combined with an elevated serum LDH NOTE: Serum LDH is incorporated into the M category as shown below: M Classification Site Serum LDH M1a Distant skin, subcutaneous, or nodal mets Normal M1b Lung metastases Normal M1c All other visceral metastases Normal Any distant metastasis Elevated

Elevated LDH defined M1c

CNS lumped in w/M1c

AJCC 8: M - categories

• New M1d designation to include CNS metastasis (regardless of other sites) – Poor prognosis associated with CNS spread – Frequent exclusion criteria from clinical trials

• Serum LDH to be recorded for all sites

– (0) for ‘not elevated’ – (1) for ‘elevated’ – Unknown

Gershenwald J et al. “Melanoma of the Skin.” In AJCC Cancer Staging Manual 8th Ed. 2017

AJCC 8: M Categories

M Category Anatomic site LDH Level M0 No evidence of distant metastasis Not applicable M1 Evidence of distant metasis See below M1a Skin, soft tissues including muscle,and or nonregional nodes Not recordered or

unspecified M1a(0) Not elevated M1a(1) Elevated M1b Lung with or without M1a sites of M1b(0) Not elevated M2b(1) Elevated M1c Non-CNS/Non-pulmonary, visceral sites Not recordered or

unspecified M1c(0) Not elevated M1c(1) Elevated M1d CNS with or without M1a, M1b, or M1c sites of disease Not recordered or

unspecified M1d(0) Normal M1d(1) Elevated

Gershenwald J et al. “Melanoma of the Skin.” In AJCC Cancer Staging Manual 8th Ed. 2017

Clinical versus Pathologic Staging

Clinical staging • Initial stage

• Microstaging of the primary

melanoma

• Should be used after biopsy of the primary melanoma

• Diagnostic biopsies to evaluate possible regional and/or distant metastasis are also included

Pathological staging • Definitive stage

• Microstaging of the primary

melanoma

• PLUS additional staging information from WLE and/or SLN and/or CLND

Gershenwald J et al. “Melanoma of the Skin.” In AJCC Cancer Staging Manual 8th Ed. 2017

Clinical (cTNM)

When T is… And N is… And M is… Clinical Stage Tis N0 M0 0 T1a N0 M0 IA T1b N0 M0 IB

T2a N0 M0 IB T2b N0 M0 IIA T3a N0 M0 IIA T3b N0 M0 IIB T4a N0 M0 IIB T4b N0 M0 IIC Any T, Tis ≥N1 M0 III Any T Any N M1 IV

Example: 0.7mm + ulceration : Stage 1B

Gershenwald J et al. “Melanoma of the Skin.” In AJCC Cancer Staging Manual 8th Ed. 2017

Pathological (pTNM)

When T is… And N is… And M is… Pathologic Stage Tis N0 M0 0

T1a N0 M0 IA

T1b N0 M0 IA T2a N0 M0 IB

T2b N0 M0 IIA

T3a N0 M0 IIA

T3b N0 M0 IIB

T4a N0 M0 IIB

T4b N0 M0 IIC

Example: WLE (-) and SLN (-) : Stage 1A

Gershenwald J et al. “Melanoma of the Skin.” In AJCC Cancer Staging Manual 8th Ed. 2017

BURDEN of T1 melanomas

Journal of Investigative Dermatology 2010 130, 793-797DOI: (10.1038/jid.2009.328)

Proportion of malignant melanomas by thickness: US 1988–2006

V. Criscione and M. Weinstock . Journal of Investigative Dermatology 2010 130, 793-797

T1 melanomas account for 70%

Tumor thickness Percentage No. of cases ≤1 70 91,174 1.01–2 16 20,424 2.01–4 9 11,702 >4 5 6,894 Total 130,194 Fatal melanomas ≤1 27 2,472 1.01–2 23 2,142 2.01–4 27 2,474 >4 22 2,041 Total 9,129

V. Criscione and M. Weinstock . Journal of Investigative Dermatology 2010 130, 793-797

About 30% of deaths from melanoma are patients initially diagnosed with a T1 melanoma

Nearly 30% of deaths from melanoma are patients initially diagnosed with a T1 lesion

~3%

~27%

1990-1994 1995-1999 2000-2004 2005-2009 ≤1mm 14%(112) 17.3%(169) 19.3%(219) 22.7%(296)

1.01–2.00 15.8%(126) 15.7%(153) 17.1%(194) 20.8%(272)

2.01–4.00 17.3%(138) 17.1%(167) 18.7%(212) 20.4%(267)

>4 11.3%(90) 13.2%(129) 14.5%(165) 14.2%(186)

More People Die from Thin Melanomas (≤1mm) than from Thick Melanomas (>4mm)

More People Die from Thin Melanomas (≤1mm) than from Thick Melanomas (>4mm) in Queensland,Australia. J of Investigative Dermatology(2015)135,1190-1193

Median (25%, 75%) duration between first melanoma diagnosis and death by thickness of first primary 1990-1994 1995-1999 2000-2004 2005-2009 TOTAL

≤1mm 5 (3–6) 6 (3–9) 7 (3–11) 7 (4–13) 6 (3–10)

1.01–2.00mm 4 (2–6) 4 (3–7) 4 (2–8) 5 (2–8) 4 (2–7)

2.01–4.00mm 2 (1–5) 3 (2–5) 3 (2–5.5) 3 (2–6) 3 (2–5)

>4 mm 2 (1–3) 2 (1–4) 4 (2–6) 2 (1–3) 2 (1–4)

More People Die from Thin Melanomas (≤1mm) than from Thick Melanomas (>4mm)

More People Die from Thin Melanomas (≤1mm) than from Thick Melanomas (>4mm) in Queensland,Australia. J of Investigative Dermatology(2015)135,1190-1193

About 3% of patients with T1 melanoma die of their melanoma on average, 7 years after the initial diagnosis

NCCN Recommendations for SLN V 1.2018 – published Oct 11, 2017

If risk of positive SLN is <5% “does not recommend” Clinical Stage 1A, T1a lesions <0.8mm, non-ulcerated, not transected and no other adverse features

If risk of positive SLN is 5-10%, “discuss and consider” Clinical Stage 1B, T1b

<0.8mm with ulceration or 0.8-1.00mm +/- ulceration Clinical Stage 1A, T1a

<0.8mm with adverse features (MR≥2; young age;LVI)

Study N Positive SLNB

N, %

Factors associated with (+) SLNB

Venna et al. , 2013 484 34 (7) Tumor thickness, Age, TILs, Site,

Wright et al,[46] 2008 631 31 (5) Age, Clark, Sex

Murali et al,[28] 2011 432 29 (6.7) Tumor thickness, LVI

Wong et al,[50] 2006 223 8 (3.6) None

Ranieri et al,[10] 2006 184 12 (6.5) Tumor thickness, Clark, MR

Kesmodel et al,[22] 2005 181 9 (5) Tumor thickness, MR

Stitzenberg et al,[48]

2004

146 6 (4) None

Oliveira Filho et al,[54] 77 8(10.4) Tumor thickness, MR, Ulceration,

Muller et al,[51] 75 0 (0) None

Bedrosian et al,[18] 71 4(5.6) Tumor thickness

Jacobs et al, [19] 2003 65 2 (3.1) None

Hershko et al,[52] 2006 64 5 (8) Tumor thickness, Clark

Cecchi et al,[53] 2007 50

2 (4)

Tumor thickness

Venna S, Thummala S, Nosrati M, Leong S, Miller J, Sagebiel R, Kashani-Sabet M. Analysis of sentinel lymph node positivity in patients with thin primary melanoma.JAAD 2013.

Studies with at least 50 patients with T1 melanomas who have undergone SLNB

Rate of Positive SLN in Thin Melanomas (≤1/mm2)

NCCN V 1.2018 – published October 11, 2017

Effect of Thickness on Rate of Positive SLN in Thin Melanomas (≤1mm)

NCCN V 1.2018 – published October 11, 2017

JAMA Dermatology July 2017 Association Between Patient Age and Lymph Node Positivity in Thin Melanoma.

Identify factors associated with positive SLN , T1 melanoma • Retrospective cohort using NCDB • 2010-2013 • N=8772 “T1” that had undergone SLN biopsy • (+) SLN in 333/8772 (3.8%) Multivariate analysis: independently associated with (+) SLN • Younger Age (<40) • Female Sex • Depth >0.76 • Mitoses • Clark’s (III,IV,V) • Ulceration • LVI

Authors: Sinnamon, A; Neuwirth M. Yalamuchi P, Gimotty P, Elder D, Xu X, Kelz R, Roses R, Chu E, Ming M, Fraker M, Karakousis G

Date of download: 10/2/2017 Copyright 2017 American Medical Association. All Rights Reserved.

From: Association Between Patient Age and Lymph Node Positivity in Thin Melanoma JAMA Dermatol. 2017;153(9):866-873. doi:10.1001/jamadermatol.2017.2497

Young patients with T1 mitogenic melanomas discuss/consider SLN

Classification Tree Analysis for SLN

non-mitogenic mitogenic MR info on 88.4%

Date of download: 10/2/2017 Copyright 2017 American Medical Association. All Rights Reserved.

From: Association Between Patient Age and Lymph Node Positivity in Thin Melanoma JAMA Dermatol. 2017;153(9):866-873. doi:10.1001/jamadermatol.2017.2497

How do the NCCN recommendations stack up?

OKOK X

?? OK OK

OK ?? X

From: Association Between Patient Age and Lymph Node Positivity in Thin Melanoma JAMA Dermatol. 2017;153(9):866-873. doi:10.1001/jamadermatol.2017.2497

Date of download: 10/2/2017 Copyright 2017 American Medical Association. All Rights Reserved.

*T1a tumors 0.50 to 0.75 mm not shown; nodal positivity rate was < 3% for all ages in this group

• SEER based analysis 2004-2009 • 5-year OS comparing SSM vs NM • We identified 5,011 patients with NM and 22,420 patients with

SSM. • Statistical tests: Chi-square test to compare proportions, and

the Kaplan-Meier method with Z-score to compare 5-year relative survival.

Five Year Survival in Patients with Nodular and Superficial Spreading Melanomas

in the US Population

Manuscript in preparation: Blair Saunders, BA, Shandiz Shahbazi, BS, Hongkun Wang, PhD ,Sekwon Jang, MD, Suraj Venna, MD

100.0% 93.5%

84.4% 77.0% 72.4% 69.0%

100.0% 100.0% 99.8% 99.2% 98.8% 98.3%

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5

Rel

ativ

e Su

rviv

al

Total NM (N = 5011)Total SSM (N = 22420)

5-year OS SSM vs NM

100.0% 94.2%

87.1% 80.5% 76.3%

70.8%

100.0% 100.0% 100.0% 99.9% 99.2% 98.5%

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5

T1b NM (N = 546)T1b SSM (N = 2783)

Nodular subtype is an adverse feature even in THIN melanomas

T1 Prognostic gap

• T1b is not an automatic recommendation for SLN

• When making decision about SLN in T1 patients, we need to

consider all the available clinical and pathologic factors

“Cutaneous melanoma is most unpredictable….two melanomas can have the same diameter, but vary considerably in depth…”. Alexander Breslow MD, 1970

1920-1980

Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg. 1970;172:90

Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg. 1970;172:90

“These criteria are not absolute and one can expect on occasion to find a lesion <0.76mm in maximal thickness which will recur and metastasize. I have seen such lesions at the National Cancer Institute…..these small lethal melanomas must represent a very small percent of lesions operated on” - Alexander Breslow MD, November 1970

Breslow A. Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Ann Surg. 1970;172:90