Pathophysiology of Melanoma:New insights into Genetics, Markers, Staging, and Treatment Ritu Saini, MD NY Medical Skin Solutions New York University Langone Medical Center
Epidemiology • 114,900 cases diagnosed in 2010 • 1/39 caucasian man, 1/58 caucasian woman • Most common cancer in 25-29 year olds • 1 of only 3 cancers with an increasing mortality rate for men (liver and esophageal) • <5% of skin cancers > 75% skin cancer deaths • Incidence increasing in Caucasian men over 65 by 8.8% since 2003 • 65 % due to UV sun exposure • Survival with melanoma increased from 49 percent (1950 – 1954) to 92 percent (1996 – 2003)
Risk Factors • Fair Skin • History of Sunburn • Excessive Ultraviolet light exposure • Living closer to the equator or at high elevation • Having many moles/dysplastic nevi • Weakened immune system • Advancing age • Genetics- Family history of melanoma
Genetics • Family history in 10% ~2-fold increased risk • One relative with melanoma frequent (8%) • Low-risk susceptibility genes in these families • Multiple relatives with melanoma (0.4%) • High-risk susceptibility genes in these families Rutte JL et al. Cancer 2004;101(12):2809–16
Genetics Udayakumar D and Tsao H. Heme/onc clin north america. 2009; 23(3): 383-95.
Genetics – High-risk alleles • Multiple cases of melanomas in several generations on one side of the lineage • Multiple primary melanomas in a given individual • Early onset of the disease • Hereditary melanoma Autosomal dominant
CDKN2A (High-risk allele) • Deleterious germline mutations in CDKN2A among a subset of melanoma prone families • 4 exons p16/Ink4a and p14/Arf • Both are tumor suppressors cell cycle and apoptosis regulation
CDKN2A/CDK4 (High-risk allele) p16/Ink4a p14/Arf • Binds Cdk4 Phosphorylation of Rb • Binds to HDM2 Interaction with p53 E2F1 Up regulation of p53 Synthesis of S phase genes /cell cycling
Udayakumar D and Tsao H. Heme/onc clin north america. 2009; 23(3): 383-95.
Phenotypic Features- CDKN2A • Study of 385 families by international melanoma genetics consortium GenoMEL • 39% of families had mutations • 20% in Australia • 45% in North America • 57% in Europe • >number of affected in a family > mutation rate • 72% had one family member with pancreatic cancer • 81% had two family members with pancreatic cancer • Rates variable- another study showed rates 1.2% • Associated with a younger age of diagnosis Goldstein AM et al. J Med Genet 2007;44:99–106. Berwick M et al. Cancer Epidemiol Biomarkers Prev 2006;15:1520–5.
2 SignallingPathways Mitogen-Activated protein kinase (MAPK) Phosphotidylinositol-3-kinase-PTEN (PI3K/AKT/PTEN/mTOR) • Regulates cell growth Growth Factors • Regulates cell death Ras or paracrine/autocrine growth factors Cell surface receptors Ras PI3K PTEN A-RAF, BRAF, CRAF AKT MAP Kinase mTOR
2 Signaling Pathways Mitogen-Activated protein kinase (MAPK) Phosphotidylinositol-3-kinase-PTEN (PI3K/AKT/PTEN/mTOR) • >90 % of clinical melanoma specimens have MAPK hyperactivity • The most common mutation reported in melanoma is in BRAF (60%) • May contribute to metastasis • May allow melanoma to escape immune surveillance • May not be as relevant in other subtypes of melanoma (Acral-lentiginous) • 50% of melanomas has upregulation of AKT • Loss of expression and/or mutation of PTEN in up to 30% of melanomas • Allelic loss of PTEN may occur in at least 58% melanoma metastases
Genetic Testing • Current commercial testing focused on coding regions of p16/Ink4a transcript • Does not include CDK4, exon 1b of p14/Arf, or deep intronic regions Some mutations will be missed • If affected member tests positive increased risk of second melanoma • If affected member tests negative cannot rule out the possibility of hereditary melanoma other unknown high-risk alleles • Given pancreatic cancer risk, those testing + should see gastroenterologist
Low-risk Alleles • Phenotype is more related to general pigmentary traits • Skin color • Hair color • Sun sensitivity
MC1R (Low-risk alleles) • Melanocortin – 1 – Receptor • Seven-transmembrane protein Binds to α – MSH G-Protein Adenylate cyclase Intracellular cAMP Dark eumelanin over red pheomelanin
Udayakumar D and Tsao H. Heme/onc clin north america. 2009; 23(3): 383-95.
Phenotypic Features (Mc1R) • Germline variants in 80%of the individuals with red hair color and/or fair skin • < 20 % brown or black hair • < 4 % in those with good tanning response • Study- 395 subjects from 16 American CDKN2A families • All those with multiple primary melanomas (MPM) had at least one Mc1R variant • 65% of MPMs and only 17% single melanoma had two variants • Other low risk alleles exist Goldstein AM et al. J Med Genet 2007;44:99–106
Markers • May help to identify patients with early stage melanoma who are likely to develop advanced disease and would benefit from treatment • Can identify sub-clinical disease • Personalized management strategies • Identify molecular pathways that could be targeted therapeutically • 681 patients <0.76 mm in thickness 4.8% progressed to metastatic disease
Markers of Prognostic Significance • Predict prognosis independent of • Breslow thickness • Clark’s Level • Ulceration • Diameter • Anatomic Site • Sentinel lymph node status
Markers of Prognostic Significance • Microtubule-associated protein 2 (MAP2) • Neuron-specific protein involved in mitotic spindle assembly during cell division • Stabilizes microtubules in the dendrites of post-mitotic neurons • Induced in primary cutaneous melanomas • Absent in metastatic melanomas • Study of 37 patients • 5 year follow up- those with MAP2 –improved survival • Independent predictor of metastasis Fang D et al. Am j Pathol 158: 2107-15
Markers of Prognostic Significance • Melanoma Cell Adhesion Molecule • Important in cell-cell and cell-matrix interactions • More strongly expressed in melanoma than benign nevi • Pacifico et al prospectively evaluated 76 specimens • Found to be stronger predictor of prognosis than Breslow thickness • Previous study of 386 specimens showed it not to be independent prognostic predictor Pacifico et l. Plast Reconstr Surg 2005. 115: 367-75
Markers of Prognostic Significance • Dysadherin • Downregulates expression of cellular adhesion molecule- E-Cadherin • E-Cadherin mostly seen in metastatic melanoma • Rarely in benign nevi and primary melanoma • Study of 115 specimens – 55% acral-lentiginous • Dysadherin correlated with reduced survival after adjustments for other prognostic indicators • Large scale studies needed to see its role in other melanoma subtypes Nishiwaza et al. Cancer 2005. 103:1693-1700
Markers of Prognostic Significance • Β – catenin • Cellular adhesion through E-Cadherin • Functions as a transcription factor and activates genes involved in tumorigenesis • Study of 133 primary melanomas, 58 metastases, and 32 benign nevi • Associated with poorer prognosis after adjustment • Previous study did not show poor prognosis when studied in acral melanoma samples Bachmann IM et al. Clin Cancer Res. 2005 11:8606-14
Markers of Prognostic Significance • Microphthalmia- associated Trascription Factor • Involved in differentiation of neural-crest derived melanocytes • Mutations associated with depigmentation of skin • Amplification found in 15-20% metastatic melanoma • Associated with decreased 5-year survival
Melanoma Staging • Updated last year by American Joint Committee on Cancer (AJCC) • Tumor thickness • Is there ulceration? • Metastatic lymph nodes? How many? Micro or macrometastasis? • Number of mitoses • The site of distant metastasis • Level of serum LDH
Melanoma Staging-TNM System • T: the features of the primary tumor • thickness, mitoses, and ulceration. • Tumor thickness (also known as Breslow depth) is measured in millimeters (mm). • 1 mm = .04 inch, or less than 1/16 inch (about equal to the edge of a penny) • 2 mm = between 1/16 and 1/8 inch (about equal to the edge of a nickel) • 4 mm = between 1/8 and 1/4 inch (about equal to the edges of two nickels) • N: the presence or absence of tumor spread to nearby lymph nodes • M: the presence or absence of metastasis to distant sites
Updated Staging • Methods • Multivariate analysis of 30,946 patients with stage I, II, and III • 7,972 patients with stage IV • Findings • In localized melanoma, tumor thickness, mitotic rate, and ulceration most important prognostic factors • Mitotic rate replaces level of invasion (clark level) for primary criteria of T1b melanoma Balch, C et al. JCO December 20, 2009 vol. 27 no. 36 6199-6206
Updated Staging • 3,307 patients with regional metastasis • Number of metastatic nodes, tumor burden, and ulceration of primary melanoma defined N • All patients with microscopic nodal metastasis are Stage III • The site of distant metastasis (nonvisceral vs. lung vs. visceral) and an elevated LDH define the M category.
Sentinel Lymph Nodes (SLN) >1 mm and < 4 mm + Complete Lymph node dissection • Gray area : < 1mm and > 4 mm • < 1mm • Risk of node metastasis < 5% and < 2% for tumor <0.76 • Metanalysis of 3651 patients with thin melanoma • SLN positive in 5.6% and had tumor ulceration, regression • Mitotic rate is a predictor SLN positivity in thin melanomas • Nodal status not an important predictor of overall survival Warych MA et al. Cancer 2009;115:869-79.
Sentinel Lymph Node • > 4 mm- differing opinions • High risk of occult disease so treatment of regional nodes not justified • 152 patients > 4mm with SLN biopsy • 5 year survival + 37.5 +/- 8.1 % , if – 67.6 +/- 6.7% • Most important prognostic paramater • New AJCC Recommendations for SLN biopsy • ≤ 1 mm if there is also ulceration and at least 1 mitosis/mm2 • > 4 mm if there are clinically or radiographically univolved regional lymph nodes Gutzmer et al. J Dtsch Dermatol Ges 2008;6:198-203. 2009 AJCC Cancer Staging Manual,
Sentinel Lymph Nodes • Is there a survival benefit in those patients who undergo biopsy? • Retrospective study of 213/1049 SLN + patients • 176 had complete lymph node dissection (CLND) • Remaining 37 refused • 26 of 176 (14.8%) showed metastases in their NSLN • These correlated with: • ***an increasing tumor thickness -< 1mm no metastatic NSLNs. • Ulceration • Regression • Nevus association • * Low Sample size* Kunte et al. J Am Acad Dermatol. April 2011 64(4):655-62
Treatment • Localized melanomas (<2 mm) • Surgical Excision • Melanoma in situ with 0.5 cm margins • Melanoma < 2mm with 1 cm margins • Thicker melanomas > 2 cm margins • Margin control for preservation of certain anatomic areas (Mohs or slow mohs, square or spaghetti procedure in thin melanomas) • Routine elective lymphadenectomy or regional node irradiation is not recommended.
Treatment • No generally accepted adjuvant therapy for high risk primary melanoma or completely resected lymph nodes metastases(stage III) • Clinical trials with Interferon in micrometastases promising • Experimental immunotherapy with IL-2 • Radiotherapy for local tumor in case of inadequate surgical margins for lentigo maligna
Treatment • Locoregional Metastatic Disease • Surgical removal of regional lymph nodes • CT or PET scan for CNS metastases prior to surgery • Adjuvant chemotherapy after complete resection • Radiation when metastases or primary tumors non-resectable • Systemic metastatic disease • Palliative therapy • Combination chemotherapy with cytokines- controlled clinical trials (Dacarbazine and IL-2)
New Treatments • Yervoy- Ipilimumab – Bristol-Myers Squibb • FDA Approved • First Metastatic Melanoma drug to clearly demonstrate that patients live longer after treatment • Study based on 676 end-stage (stage III and stage IV unresectable) patients • Patients received drug plus peptide vaccine (glycoprotein 100) • Median survival of 10 months, compared with 6.4 months in those receiving vaccine alone N Engl J Med. 2010:363;711-723