melanoma update - Oregon Academy of Family Physicians

MELANOMA UPDATE
MAERAN CHUNG LANDERS MD PHD
ADVANCED DERMATOLOGY OF OREGON
OAFP CONFERENCE
APRIL 25, 2014
Disclosures
 I have no relevant disclosures.
Overview of melanoma
 Epidemiology of melanoma
 Discuss the clinical and histological features of the primary
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types of melanomas
Examine biopsy techniques and review pathology of
melanomas
Review staging of melanoma
Treatment options for melanoma: surgical, chemotherapy,
immunotherapy, and radiation therapy for metastatic
melanoma
Review the long term follow up of patients with previous
history of melanoma
Screening techniques for detections of melanoma, rationale
both for and against screening in both low risk and high risk
populations
Melanoma in US
•Rising incidence of melanoma (1970-2009)
•800% increase in women
•400% increase in men
•One person dies of melanoma every hour.
•An estimated 76,690 new cases of invasive melanoma will be
diagnosed in the US in 2013.
•45,060 men
•31,630 women
•An estimated 9,480 people will die of melanoma in 2013.
•6,280 men
•3,200 women
•Melanoma accounts for less than five percent of skin cancer cases,
but the vast majority of skin cancer deaths.
•Of the seven most common cancers in the US, melanoma is the
only one whose incidence is increasing. Between 2000 and 2009,
incidence climbed 1.9 percent annually.
Melanoma in US
•1 : 50 lifetime risk of melanoma
•Age < 40 yo, women>men
•Age >40 yo, men>women
•1:35 men will develop melanoma
•1:54 women will develop melanoma
•About 86 percent of melanomas can be attributed to exposure to
ultraviolet (UV) radiation from the sun.
•Melanoma is one of only three cancers with an increasing mortality
rate for men, along with liver cancer and esophageal cancer.
•9X risk of melanoma survivors developing a new melanoma in
comparison to the general population
www.Skin cancer.org
Melanoma in US
Women aged 39 and under have a higher
probability of developing melanoma than
any other cancer except breast cancer.
The majority of people diagnosed with
melanoma are white men over age 50.
Melanoma in the US
 Doctors are required by law to report
melanomas to central cancer registries, but
many dermatologists reported being
unaware of reporting requirements.
 Plescia M, Protzel Berman P, White MC.
Melanoma surveillance in the United States.
Journal of the American Academy of
Dermatology 2011;65(5 S1):S1–S2.
Impact of melanoma in males
(#5 cancer)
U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2009
Incidence and Mortality Web-based Report. Atlanta: U.S. Department of Health
and Human Services, Centers for Disease Control and Prevention and National
Cancer Institute; 2013. Available at: www.cdc.gov/uscs.
Impact of melanoma in females
(#7 cancer)
U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2009
Incidence and Mortality Web-based Report. Atlanta: U.S. Department of Health
and Human Services, Centers for Disease Control and Prevention and National
Cancer Institute; 2013. Available at: www.cdc.gov/uscs.
Source: Journal of the American Academy of Dermatology 2011; 65:S6.e1-S6.e12 (DOI:10.1016/j.jaad.2011.04.037 )
Copyright © 2011 American Academy of Dermatology, Inc. Terms and Conditions
A 70 year patient presents with the following lesions on
his back? Which one is the melanoma?
A
B
C
D
Answer:
 C and D are superficial spreading melanomas
 A is an atypical nevus
 B is a seborrheic keratosis
Types of melanoma
Types of Melanoma
 Superficial spreading melanoma
 Nodular melanoma
 Lentigo maligna
 Acral lentiginous melanoma
 Subungual melanoma
 Desmoplastic melanoma
 Metastatic melanoma
 Ocular melanoma
Superficial spreading melanoma
Superficial spreading
melanoma
Nodular melanoma
Lentigo maligna
Nodular melanoma with
lentigo maligna
Lentigo maligna
Amelanotic melanoma
Areas of regression
Acral lentiginous
Subungual melanoma
Desmoplastic melanoma
What is your diagnosis?
• 56 yo male patient presents
with a nonhealing sore on his
buttock and new cysts on his
shoulder.
Metastatic Melanoma
Metastatic melanoma
Subcutaneous metastatic
melanoma
Metastatic melanoma
What type of biopsy would
you perform?
 A. 6 mm Punch
 B. Saucerization
 C. Shave
 D. Incisional
 E. All the above
4 mm
Answer:
 A-C are correct if you can clear the peripheral
and deep margins.
 Incisional biopsy is incorrect.
What type of biopsy would
you perform?
 A. Punch
 B. Saucerization
 C. Shave
 D. Excisional
 E. Incisional
Answer:
 B-D are correct if you can clear the peripheral
and deep margins.
 Punch and Incisional biopsy are incorrect.
AAD Guidelines of Care:
___Biopsy Technique___
• Excise with narrow margins (2-3 mm)
• Incisional biopsy if necessary
• Repeat biopsy if initial specimen is
inadequate or does not correlate with
clinical suspicion.
• FNA should not be used for initial biopsy
• Biopsy read by physician experienced in
diagnosis of pigmented lesions
(dermatopathology)
Dermablade for saucerization
or shave biopsy
Shave and saucerization
biopsies
 Pearls to remember:
 Be sure to go through at least the deep
dermis or subcutaneous fat if you are
suspecting a melanoma
 If clinical suspicion is low, this is a great
technique especially in cosmetically
important areas such as the face
Punch biopsy of melanoma
Key pearls for the punch
biopsy
 Add 2 mm around the entire periphery of the
lesion
 For a 4 mm pigmented lesion, perform a 6 mm
punch – 8 mm punch biopsy. Do not do a 4 mm
punch biopsy.
 Use deep and superficial suture for punch
biopsies greater than 6 mm in diameter
 Do not squeeze the specimen with your
forceps
 Go down to the SC fat
What type of biopsy?
 A. Punch
 B . Saucerization
 C. Shave
 D. Excisional
 E. Incisional
Answer: Incisional biopsy is best due to the
size of the lesion and acral location
Incisional biopsy
 Consideration:
 Facial
 Acral
 Low clinical suspicion
 Uncertain diagnosis
 Very large broad lesion
Goals for biopsy techniques
 Entire lesion
 Don’t transect the lesion at the deep margin
 Narrow excisional biopsy for entire breadth of
lesion with clinically negative margins to
deep margin
 1-3 mm margins for clear subclinical margins
 Orient narrow excisional biopsies along the
longitudinal axis of extremities (optimal for
secondary WLE and SLN)
Histology of melanoma
What is Breslow thickness?
Essentials of pathology
report for melanoma
 Age, sex of patient
 Type and size of biopsy
 Permanent paraffin sections (no frozen
sections)
 Pathologic features
 Breslow thickness
 +/- microscopic ulceration
 Mitotic rate (# dermal mitoses per mm2)
 Peripheral and deep margins
AAD Guidelines of Care:
___Pathology Report___
• Mandatory required elements
– Diagnosis, identifying features,
microscopic description
– Thickness in millimeters
– Ulceration
– Mitoses
– Margin involvement
Evaluation of Melanoma patients
 Complete examination: skin, lymph nodes,
lung, liver, spleen
 Complete ROS
 Biopsy:
 Narrow excision best
 Incisional if necessary
 Optional CXR and LDH
Table II. 2010 American Joint Committee on Cancer TNM definitions
Primary tumor (T)
Primary tumor cannot be assessed (eg, curettaged or severely
regressed melanoma)
T0
No evidence of primary tumor
Tis
Melanoma in situ
T1
Melanomas ≤1.0 mm in thickness
T2
Melanomas 1.01-2.0 mm
T3
Melanomas 2.01-4.0 mm
T4
Melanomas >4.0 mm
Note: a and b subcategories of T are assigned based on ulceration and No. of mitoses per mm2
as shown below:
TX
T classification
Thickness, mm
T1
≤1.0
T2
1.01-2.0
T3
2.01-4.0
T4
>4.0
Ulceration status/mitoses
a: Without ulceration and <1
mitosis/mm2
b: With ulceration or ≥1
mitosis/mm2
a: Without ulceration
b: With ulceration
a: Without ulceration
b: With ulceration
a: Without ulceration b: With
ulceration
Regional lymph nodes (N)
Patients in whom regional lymph nodes cannot be assessed (eg,
previously removed for another reason)
N0
No regional metastases detected
Regional metastases based on No. of metastatic nodes and
N1-3
presence or absence of intralymphatic metastases (in transit or
satellite)
Note: N1-3 and a-c subcategories assigned as shown below:
NX
N classification
No. of metastatic nodes
Nodal metastatic mass
N1
1 Node
a: Micrometastasis
b: Macrometastasis†
N2
2-3 Nodes
a: Micrometastasis
b: Macrometastasis†
c: In transit met(s)/satellite(s)
without metastatic nodes
N3
≥4 Metastatic nodes, or matted
nodes, or in transit
met(s)/satellite(s) with
metastatic node(s)
Micrometastases are diagnosed after sentinel lymph node biopsy and completion lymphadenectomy (if performed).
†Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when
nodal metastasis exhibits gross extracapsular extension.
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 elevated serum LDH
Note: Serum LDH is incorporated into 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
Any distant metastasis
Normal
Elevated
Table III. 2010 American Joint Committee on Cancer anatomic stage/prognostic
groups
.
M0
Pathologic staging†
0
Tis
N0
M0
N0
M0
IA
T1a
N0
M0
T1b
T2a
T2b
T3a
T3b
T4a
N0
N0
N0
N0
N0
N0
M0
M0
M0
M0
M0
M0
IB
T1b
T2a
T2b
T3a
T3b
T4a
N0
N0
N0
N0
N0
N0
M0
M0
M0
M0
M0
M0
Stage IIC
T4b
N0
M0
IIC
T4b
N0
M0
Stage III
Any T
≥N1
M0
IIIA
T1-4a
N1a
M0
T1-4a
T1-4b
T1-4b
T1-4a
T1-4a
T1-4a
T1-4b
T1-4b
T1-4b
Any T
N2a
N1a
N2a
N1b
N2b
N2c
N1b
N2b
N2c
N3
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
Any T
Any N
M1
Clinical staging
Stage 0
Tis
N0
Stage IA
T1a
Stage IB
Stage IIA
Stage IIB
IIA
IIB
IIIB
IIIC
Stage IV
Any T
Any N
M1
IV
Stage Specific Survival Rates
STAGE
TNM
DEPTH
IA
T1a
1mm
IB
T1b/T2a
IIA
T2b/T3a 1-2/2-4mm
IIB
T3b/T4a
IIC
T4b
1/1-2mm
ULCER
no
NODES
1-YEAR OS
5-YEAR OS
0
99
95
yes/no
0
99
90
yes/no
0
98
78
2-4/>4mm
yes/no
0
95
65
>4mm
yes
0
90
45
1/2-3*
94
66
IIIA
N1a/N2a
any
no
IIIB
N1a-2a/
N1b-2b/N2c
any
yes
no/any
1/2-3**
77-93
46-53
IIIC
N1-2b/N3
any
yes/any
1-4**
71-78
24-29
IV
M1a/b/c
any
41-60
7-19
any
Adapted from Balch et al. Final AJCC Staging-Melanoma;
Table 3. J Clin Oncol. 2001:19;3635-48.
any
*Micro
**Micro or Macro
Surgical recommendations for primary
cutaneous melanoma
Tumor thickness
Clinically measured surgical
margin
In situ
0.5-1.0 cm
≤1.0 mm
1 cm
1.01-2.0 mm
1-2 cm
>2.0 mm
2 cm
Wider margins may be necessary for lentigo maligna subtype.
Use a wood’s light for greater clinical margins
Excise to deep fat to fascia
Recommendations for staging workup and
follow-up
No baseline laboratory tests and imaging studies required < 1 mm depth, asymptomatic
melanoma patients.
At least annual history and physical examination with attention to skin and lymph nodes is
recommended for detecting recurrent disease or new primary melanoma. Emphasize monthly selfexaminations.
Directed studies to detect local, regional, and distant metastasis based on history and PE.
Surveillance laboratory tests and imaging studies in asymptomatic patients with melanoma have
low yield for detection of metastatic disease and are associated with relatively high false-positive
rates.
Recommendations for sentinel lymph node biopsy
Most sensitive & specific staging test for detection of
micrometastatic melanoma
Status of SLN is most important prognostic indicator for disease-specific survival in
patients with primary cutaneous melanoma; impact of SLNB on overall survival remains
unclear.
SLNB is not recommended for patients with melanoma in situ or T1a melanoma.
SLNB should be considered in patients with melanoma >1 mm in tumor thickness.
In patients with
-T1b melanoma, 0.76-1.00 mm in tumor thickness, SLNB should be discussed;
- T1b melanoma, with tumor thickness ≤0.75 mm, SLNB should generally not be
considered, unless other adverse parameters in addition to ulceration or increased
mitotic rate are present, such as angiolymphatic invasion, positive deep margin, or
young age.
Indications for SLN Biopsy
•SLN biopsy appropriate
–Ulcerated lesions of any depth
–Lesions greater than 1.0 mm
•SLN biopsy uncertain
–Lesion 0.76-1.0 mm
–If + mitoses, ulceration, angiolymphatic
invasion, positive deep margin, young age
•SLN biopsy inappropriate
–Lesion less than 0.76 mm, unless ulcerated
Management options for resected Stage III
melanoma (mets to LN, in-transit disease,
or satellite mets)

Management
options
Details
Key points
Observation
Q3-6 month x 2 years
Then Q3-12 months x 3
years
ID regional recurrence
ID new primary
melanoma
Interferon alpha-2b
Only FDA approved
Induction IV Mon-Fri x 4
weeks
Maintenance SC dose 3 x
per week x 11 months
RFS on IFN is 1.72 v. 0.98
years
OS increased by 1 year
Estimated 5 year RFS
rate 37% for IFN v. 26%
with observaion
No clear OS benefit
Clinical trials
E1609: ipilimumab v.
interferon
Ipi with OS adv for stage
IV paients
Adjuvant XRT
Directed at nodal basin
after lymphadenectomy
Higher risk of
lymphedema
Reduction of LN field
relapse among patients
treated with XRT + LN v.
observation
No clear OS benefit
Journal of the American Academy of Dermatology
Volume 68, Issue 1 , Pages 1.e1-1.e9, January 2013
Patient
selection
Contraindication: Afib,
depression,
autoimmune, poor
baseline health
Best for young highly
motivated patients
For high risk nodal
relapse patients
Extracapsular nodal
extension or high # of
nodes positive for mets
histologically
Best for H&N areas
Management options for patients with distant metastatic melanoma
(Stage IV disease)
Management options
Details
Key points
Patient selection
Metastasectomy
Observation and PET/MRI
Removal of isolated foci of
metastatic disease
For patients with limited,
resectable metastases
Ipilimumab: monoclonal Ab
against CTLA-4; blocks inhibitory
signal of CTLA-4 to T cells;
enhacing T cell activation and
cytokine production
FDA-approved immune therapy
-Outpatient IV every 3 weeks x 4
-SE: fatigue, nausea, rash,
diarrhea, immune-related toxicity
Overall response rate
7% of all treated patients had
minimum 2 year response
Consider for patients with
unresectable or disseminated
disease
Contraindication: patient with
autoimmune disease
Vemurafenib, Tafinlar (dabrafenib)
and Mekinist (trametinib)
FDA-approved “targeted” therapy
-Only if BRAF V600 mutation
positive
-PO dosing; continuous
-SE: pain, rash, photosensitivity,
SCC
OS advantage compared with
DTIC: average duration of response
6-7 months
Consider with BRAF mutation
positive unresectable or
disseminated disease
Consider when rapid response is
paramount
FDA-approved immune therapy
-Inpatient; Mon-Sat 1 week off
then repeat Mon-Dat
-SE: toxic, flu like sx, hypotension,
arrhythmia, capillary leak/edema,
hepatorenal toxicity
Chance of response: 16%
Chance of complete response 6%
Occasional long-term remission
Consider for younger patients with
unresectable or disseminated
disease with high pretreatment
performance status
Best results for patients with
distant cutaneous or
subcutatneous mets or mets to LN
or lung
Chance of response 10-15%
Consider for patients with
unresectable or disseminated
disease
The name "vemurafenib" comes
from V600E mutated BRAF
inhibition. It causes apoptosis of
melanoma cells. Vemurafenib
interrupts the B-Raf/MEK step on
the B-Raf/MEK/ERK pathway
High-dose IL-2
DTIC or temozolomide
DTIC: FDA-approved
chemotherapy; IV every 3 weeks
(outpatient)
Temozolomide: PO x 5 days every
4 weeks
-SE: well tolerated, nausea,
fatigue, constipation,
Journal of the American Academymyelosuppression
of Dermatology
-Duration
treatment; indefinite,
Volume 68, Issue 1 , Pages 1.e1-1.e9, Januaryof2013
A, Computed tomographic (CT)
scan of the abdomen of a
patient with stage IV melanoma
with multiple liver
metastases, each highlighted
by an asterisk. B, CT scan of
the abdomen of the same
patient after 8 months of
treatment with ipilimumab.
Note the resolution of the
liver metastases
Journal of the American
Academy of Dermatology
Volume 68, Issue 1 , Pages
13.e1-13.e13 , January 2013
Immunotherapy for metastatic
melanoma
vemurafenib
FIGURE 7 | PET scans of patients treated with vemurafenib.
From the following article:
Vemurafenib: the first drug approved for BRAF-mutant cancer
Gideon Bollag, James Tsai, Jiazhong Zhang, Chao Zhang, Prabha Ibrahim, Keith
Nolop & Peter Hirth
Nature Reviews Drug Discovery 11, 873-886 (November 2012)
Advanced melanoma.
Significant and rapid
reduction in tumor burden
from baseline (A) to after 3
months of treatment with
vemurafenib (B).
Journal of the American
Academy of Dermatology
Volume 68, Issue 1 , Pages
13.e1-13.e13 , January 2013
A, Magnetic resonance
imaging (MRI) scan of
the brain of a patient
with melanoma with
intracranial metastasis.
The metastatic lesion is
marked by an asterisk.
B, MRI scan of the brain
of the same patient
after 8 months of
treatment with
vemurafenib. Note the
significant improvement
in metastat
Journal of the American
Academy of Dermatology
Volume 68, Issue 1 ,
Pages 13.e1-13.e13 ,
January 2013ic disease
Management options for patients with distant
metastatic melanoma (Stage IV disease)
Management options
Details
Key points
Patient selection
Radiotherapy for CNS mets
Includes both SRS and WBRT
Stereotactic radiosurgery
Whole brain radiation therapy
WBRT after surgical resection of
brain mets reduces recurrence at
resection sites and prolongs
disease free survival
-SRS yields 1 year local contraol
rates 49-79%
-Radiosurgery (SRS, gamma knife)
or conventional surgery considered
for patients with 1-3 brain mets and
low systemic burden
-WBRT considered after surgical
resection of single brain met
-WBRT considered as first line
treatment for patients with brain
mets and extensive extracranial
disease, poor surgical candidates
or those with >3 brain mets.
Management of Melanoma
Stage
Criteria
Management and
follow-up
I
< 1 mm
1 cm resection
Q4-6 month skin exam
II
> 1 mm – 4 mm
2 cm resection
Q4-6 month skin exam
PET/CT
III
4 mm
Positive lymph node
2 cm resection
Q4-6 month skin exam
PET/CT
IV
Any depth,
Metastatic disease
Resection
Chemotherapy/XRT
Q4-6 month skin exam
PET/CT
AAD Guidelines of Melanoma Care
_______Summary_______
 Work-up/Follow-up
 Routine labs/imaging not required
 CXR and LDH optional
 Patient education on skin/lymph node exam
 Routine follow-up exam at least annually
Screening of melanoma patients
 1x/year low risk: as needed and referred by
PCP or other physician
 2x/ year intermediate risk: Fhx MM, fair,
numerous sunburns, atypical nevus
syndrome, >100 nevi
 3-4x/year high risk: previous history of any
skin cancer, melanoma
How often do you screen this 20 yo
for skin cancer?
A. Never
B. Every 6
months
C. Yearly
D. Monthly
E. Once and then
for changing and
new lesions only
Answer
 B is probably the best answer.
 If there is a family history of melanoma,
definitely every 6 months rather than just
annually.
 Self skin examinations should be performed
monthly.
What is your diagnosis?
 A. melanoma
 B. Spitz nevus
 C. atypical nevus
 D. benign nevus
 E. Not sure just do the biopsy because
it is strange looking
Answer : B. Spitz nevus
What is the diagnosis of
these lesion?
Acral nevus and benign nevus on the R thumb nail
What is your diagnosis?
Seborrheic keratosis
Which one is the melanoma?
A
B
C
D
A is a nodular melanoma; B-D are superficial spreading melanomas
What is your diagnosis?
 A. angioma, traumatized
 B. pyogenic granuloma
 C. amelanotic melanoma
 D. spider bite
 E. Not sure just do the biopsy because
it is strange looking
Answer : C. amelanotic melanoma
What is the diagnosis?
Blue Nevus
What is your risk of
melanoma?
 A. 2X
 B. 4X
 C. 5x
 D. >10X
Answer : Atypical nevus syndome patients
Have a >10X increased risk for melanoma.
Which of these benign nevi
is most often confused with
Spitz nevus
melanoma?
Dark skin with dark nevi
Blue nevus
Spindle cell nevus of Reed
Recurrent nevus
Which of these lesions are
benign?
B
A
E
C
D
All of the above
What is your diagnosis?
 A. melanoma
 B. Spitz nevus
 C. atypical nevus
 D. benign nevus
 E. hemangioma
Answer : A. nodular melanoma
Melanoma
 Know your ABCD’s
 A asymmetry
 B border
 C color variegation
 D diameter
 E evolution and/or elevation
Take Home Lessons on melanoma
1.
2.
3.
4.
5.
6.
7.
8.
Wear sunscreen (broad spectrum SPF at least 30)and/or sun protective clothing
every day
See a dermatologist for a full skin examination annually if you are at risk
Melanoma is potentially life threatening and increasing in incidence. Look for it
on every patient.
Not every melanoma is dark and black.
Biopsy technique and dermatopathology matters!
If melanoma is diagnosed early, it is truly treatable and often curable at 98%.
Consider a SLN biopsy for detection of microscopic metastasis which can
extend remission. It does not appear to affect long term outcome.
Extensive research and new immunologic therapies for late stage melanomas
are demonstrating promising and ground breaking results.
Thank you for your attention
 Maeran Chung Landers MD PhD
 Advanced Dermatology of Oregon
 19255 SW 65th Ave Suite 260 Tualatin OR
97062
 Office 503-692-9525
 www.advanceddermor.com
 Don’t hesitate to call me if you have any
questions.