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Melanoma
Jason P. Sulkowski MD
www.downstatesurgery.org
Question 1 • In which of the following cases should a sentinel
lymph node biopsy be performed?
– A. 0.7 mm melanoma over right tibia with clinically negative right groin
– B. 1.0 mm melanoma overlying the left groin
– C. 1.5 mm melanoma of RUE and clinically negative right axilla
– D. 1.7 mm melanoma of left thigh with palpable adenopathy of left groin
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Question 2 • Melanoma
– A. Incidence is decreasing in the U.S.
– B. Most commonly presents as the nodular subtype.
– C. Is best biopsied using a shave technique.
– D. Should be excised with a 2 cm margin if >2 mm
thick.
– E. Rarely spreads to lymph nodes.
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Case - AM • HPI: 27y F presented with pre-existing mole on
RLE that became raised, multi-color, crusted. 1 month prior had excisional biopsy in dermatology office.
• PMH: significant sun exposure, multiple sun burns in past
• Medications/Allergies: none
• Family Hx: no history of skin cancer
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Case - AM
• Physical Exam: – Vitals: wnl – HEENT: wnl – CV: wnl – Pulm: wnl – Abd: wnl – LNs: no cervical axillary or inguinal
lymphadenopathy
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Case - AM
• Physical Exam: – RLE: 4 cm well-healing
incision on posteromedial calf
– LLE: no abnormal lesions
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Case - AM
• Pathology (1): – Malignant melanoma – 1.9 mm thick – Tumor within 1 mm of margin
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Case - AM
• Lymphoscintigraphy: – Three sentinel lymph nodes identified in
right inguinal region
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Case - AM • Procedure:
– Wide local excision (WLE) of melanoma site • Elliptical incision, 2 cm margins, dissection down
to fascia
– Sentinel lymph node biopsy (SLNB) of right groin
• Radiocolloid only • One node excised • All other nodes had <10% signal • Frozen section negative for malignancy
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Case - AM
• Pathology (2): – No residual melanoma cells
– One of one lymph nodes negative for
malignancy • Negative for S100 and HMB45 immunostains
– T2a N0 M0 Stage Ib
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Management of Melanoma • Epidemiology • Diagnosis • Staging & Work-Up • Surgical Management
– WLE – SLNB
• Adjuvant Therapy • Follow-Up • Outcomes
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Epidemiology
• Incidence increasing – Men
• 28.2 per 100,000
– Women • 16.8 per 100,000
– #6 most common (incidence)
Source: seer.cancer.gov
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Epidemiology
• Reasons for increase? – Increased number of skin biopsies
– Increased screening
– Increased sun exposure
• Duration • Ultraviolet radiation levels
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Epidemiology • Risk factors
– Sun exposure • Fair skin • Geography • Tanning beds • Peeling sunburns
– Genetics (10-15%)
• CDKN2A – most common mutation • Familial atypical multiple mole melanoma
syndrome (FAMMM) • Xeroderma pigmentosa
previsecare.wordpress.com
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Melanocytes
• Neural crest derived
• Located at basal layer of epidermis
• Produce melanin
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Melanin Transport
qsystem.gblifesciences.com
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Melanin Transport
• Produces skin pigment
apple.com
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Malignant Transformation • MAP Kinase
– Constitutive activation leads to activation of NFκB
– Result: aggressive growth
• ras oncogene – Mutation leads to malignant
transformation in human melanocytes Baskaran Govindarajan et al. J. Biol. Chem. 2003
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Diagnosis
• Asymmetry
• Border
• Color
• Diameter
• Evolving skincancer.org
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Diagnosis • Biopsy techniques
– Excisional • Small lesions • Incision oriented longitudinally
– Incisional, punch or
saucerization • Large lesions, cosmetically
sensitive area • Must include base of lesion
– Do not perform shave biopsy
• e.g. Mohs us.vwr.com
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Superficial Spreading
• 70% • Arises from pre-
existing nevus • Exhibits classic
melanoma features – ABCD
cancernetwork.com, ispub.com
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Lentigo Maligna Melanoma
• 10-15% • Sun exposed areas • Growth beyond
clinical lesion • Often preceded by
lentigo maligna – In situ melanoma
skincareguide.ca
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Nodular
• 15-30% • Most aggressive
– Vertical growth • Often without classic
melanoma features – Evolution
malignant-melanoma.org
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Acral Lentiginous
• 35-60% in non-white • Feet, hands, subungual • Later diagnosis
– Lower suspicion – Location not easily or
frequently examined
cancer-network.org, healthh.org
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(Other) • Mucosal • Anal • Vulvovaginal • Desmoplastic • Amelanotic
• All have worse
outcomes – Atypical presentation delayed identification dermis.net, ilmelanoma.net, melanoma.org
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Staging • TNM system
• 7th Ed American Joint Committee on
Cancer Staging Manual
• J Clin Oncol 2009; 27:6199-6206
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Tumor
aboutcancer.org
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Tumor www.downstatesurgery.org
Node www.downstatesurgery.org
Metastasis www.downstatesurgery.org
Staging www.downstatesurgery.org
Laboratory Studies • Pre-Op Labs
• LDH
– Elevated LDH 1 year survival 32% (vs. 65% for normal level) in Stage IV disease
• S-100B
– Elevated pre-op S-100B 2.6x more likely to have
recurrent disease
Ann Surg Oncol 2009, 16:3455-3462
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• Stage II and III patients
• Serial LDH & S-100B levels
• S-100B first sign of distant mets – >50% of patients
• S-100B > LDH
Melanoma Research 2009, 19:31-35
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Radiographic Studies • Chest X-ray
– Stage Ib & II, optional
• CT chest & abdomen/pelvis – Stage IIC and higher – Symptoms – Anemia – LDH – Clinically positive inguinal nodes
• CT/MRI brain
– Stage IV – Stage III, optional
• PET
– Increases accuracy of CT/MRI
Source: Annals of Oncology 2009, 20 (Supp 6): vi14-vi21
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Surgical Management • Wide local excision
• Melanoma in situ
– To mid subcutaneous tissue
• Melanoma (T1-3) – To fascia
• Melanoma (T4)
– Beyond fascia or into muscle
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Margins
Breslow Depth of Primary Pathologic Margin
in situ 5 mm
≤ 1 mm 1 cm
1.01 – 2 mm 1 – 2 cm
2.01 – 4 mm 2 cm
> 4 mm ≥ 2 cm Source: Current Surgical Therapy, 11th Ed.
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Wound Closure • Elliptical incision
– 3:1 length to width
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Wound Closure • Elliptical incision
– 3:1 length to width
• Local advancement flaps
Current Surgical Therapy, 11th Ed.
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Wound Closure • Elliptical incision
– 3:1 length to width
• Local advancement flaps
• Other skin flaps – Rotational rhomboid – VY – Z-plasty
intechopen.com, thefreedictionary.com
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Wound Closure • Elliptical incision
– 3:1 length to width
• Local advancement flaps
• Other skin flaps – Rotational rhomboid – VY – Z-plasty
• Skin grafts
– Split-thickness – Full-thickness
dermnetnz.org, openi.nlm.nih.gov
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Sentinel Lymph Node Biopsy
• Node status: most important survival predictor
• Indicated for all tumors > 1 mm thick – Clinically negative nodes
• Premise: If the sentinel node is
negative, the entire basin is negative
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SLNB: Contraindications
• T1 (< 1 mm)
• High risk histology – Ulceration, high mitotic rate (“b”) – Positive deep margin (e.g. shave biopsy) – Clark level IV depth
• Clinically positive nodes
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SLNB: Technique
Sulfur Colloid and/or Vital Blue Dye
Current Surgical Therapy, 11th Ed.
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Vital Blue Dyes: Truly Vital? • Methylene blue • Isosulphan blue (aka lymphazurin)
• Addition of blue dye provided only 1.8%
localization advantage – Study of Stage I/II breast CA – Surgery, 2008; 144:606-610
• Blue dye downsides:
– Allergic reaction/anaphylaxis (0.5-3%) – Skin staining – Increased cost to provider (Medicare does not
reimburse!)
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Ann Surg 2015, Epub ahead of print
• 215 patients
• 100% localization with radiocolloid only – No comparison group
• 6/175 (3.4%) with negative SLNB had
recurrence in regional nodes – Negative predictive value: 96.6%
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MSLT-1 • Multicenter Selective Lymphadenectomy
Trial – NEJM 2006; 355:1307-17
• ~1300 patients with intermediate
thickness melanoma (T2-T3) – Survival out to 5 years
• WLE & nodal observation • WLE & SLNB
– Lymphadenectomy for + SLNB
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MSLT-1 • In SLNB group, + node:
– 2.48 HR for death – 3.04 HR for recurrence
• Mortality in those with lymphadenectomy:
– SLNB: 26.2% – Observation: 48.7%
• Nodal stage 1 after lymphadenectomy:
– SLNB: 70.5% – Observation: 39.2%
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MSLT-1 • Final report – 10 year outcomes
– NEJM 2014; 370: 599-609
• In SLNB group, + node: – 2.40 HR for death – 2.64 HR for recurrence
• Mortality in those with lymphadenectomy:
– SLNB: 37.9% – Observation: 58.5%
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MSLT-2
• Ongoing trial, enrollment closed – NCT00297895
• All patients receive SLNB
• Randomized to:
– Completion lymphadenectomy – Observation with nodal ultrasound
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Metastatic Disease • Most common sites:
– Lung – Brain – Liver – Bone
• More commonly presents as disease
recurrence – Time to recurrence inversely related to
disease stage at initial diagnosis
Source: J Oncology 2012; vol 2012: 1-9.
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Metastatic Disease • Metastasectomy indicated in selected patients
– Slow progression (doubling time > 40 days) – Extent (single vs multiple sites) – Resectability
• Improved survival in patients who were able to
undergo metastasectomy
• Most cases will be palliative, not curative – Bleeding GI metastases – Ulcerated cutaneous metastases – Symptomatic brain metastases
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In Transit Disease • Spread via dermal or sub-
dermal route – Difficult to manage – Poor prognosis
• Local
– Intralesional • BCG, IFN α-2b, IL-2
– Electrochemotherapy • Regional
– Isolated limb perfusion – Isolated limb infusion
• Both use melphalan
www.intochopen.com, Current Surgical Therapy, 11th Ed.
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Adjuvant Therapy
• Radiation – Some benefit in poor prognosis Stage III – Large (>3 cm) or numerous (>5) nodal
mets
• Chemotherapy – Dacarbazine
• Poor results, significant toxicity
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Adjuvant Therapy • Immune Therapies
– Interferon α-2b – IL-2 – Vaccines – Activated cytotoxic T-lymphocytes
• Molecular targeted therapies
• Modulators of MAP kinase pathway – BRAF inhibitors (vemurafenib, dabrafenib) – MEK inhibitors (binimetinib) – CKIT inhibitors (imatinib)
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Follow-Up • Clinical exam, labs (LDH, S-100B)
• Thin primary, negative nodes
– q6 months, x3 years – q1 year, x2 years
• Moderate/thick primary, positive nodes
– q3 months, x3 years – q6 months, x2 years – q1 year, indefinitely
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Outcomes
• 5-year survival (all) 91.5% – Source: SEER, 2005-2011
Stage 5 year survival (%)
I 89 - 95
II 45 - 78
III 24 - 69
IV 6 - 18 Source: ACS Surgery 7
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Management of Melanoma • Epidemiology: Incidence is increasing • Diagnosis: ABCD(E) • Staging: Breslow thickness, Nodal status • Surgical Management
– WLE – SLNB
• Adjuvant Therapy: Select patients • Follow-Up: Evaluate for recurrence • Outcomes: 91% overall, <20% Stage IV
www.downstatesurgery.org
Question 1 • In which of the following cases should a sentinel
lymph node biopsy be performed?
– A. 0.7 mm melanoma over right tibia with clinically negative right groin
– B. 1.0 mm melanoma overlying the left groin
– C. 1.5 mm melanoma of RUE and clinically negative right axilla
– D. 1.7 mm melanoma of left thigh with palpable adenopathy of left groin
www.downstatesurgery.org
Question 1 • In which of the following cases should a sentinel
lymph node biopsy be performed?
– A. 0.7 mm melanoma over right tibia with clinically negative right groin
– B. 1.0 mm melanoma overlying the left groin
– C. 1.5 mm melanoma of RUE and clinically negative right axilla
– D. 1.7 mm melanoma of left thigh with palpable adenopathy of left groin
www.downstatesurgery.org
Question 2 • Melanoma
– A. Incidence is decreasing in the U.S.
– B. Most commonly presents as the nodular subtype.
– C. Is best biopsied using a shave technique.
– D. Should be excised with a 2 cm margin if >2 mm
thick.
– E. Rarely spreads to lymph nodes.
www.downstatesurgery.org
Question 2 • Melanoma
– A. Incidence is decreasing in the U.S.
– B. Most commonly presents as the nodular subtype.
– C. Is best biopsied using a shave technique.
– D. Should be excised with a 2 cm margin if >2 mm
thick.
– E. Rarely spreads to lymph nodes.
www.downstatesurgery.org
Textbook References • Leung AM, Faries MB, Morton DL. “The Management
of Cutaneous Melanoma.” From: Current Surgical Therapy – 11th Ed. Editors: Cameron JL, Cameron AM. 2014.
• Wargo JA, Tanabe K. “Surgical Management of Melanoma and Other Skin Cancers.” From: ACS Surgery 7. Editors: Ashley SW, Cance WG, et al. 2014.
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Questions? www.downstatesurgery.org