Malignant Melanoma Tommy Busick MD Residents Conference November

Malignant Melanoma Tommy Busick, MD Resident’s Conference November 2, 2004

Melanoma Rising Incidence n n n Lifetime risk in 1979 1: 250 Today 1: 64 Rank among cancers in 1979 Women 10 th Men 11 th Today Women 7 th Men 5 th Total incidence 1979 13, 600 Today 55, 100 Total deaths in 1979 4, 300 Overall survival 75% Today 7, 910 Est. survival 90% Rise in new cases only exceeded by lung CA in women

Why the Changes? n n Actual increase in the incidence of disease due to increased recreational sun exposure. Greater public awareness/surveillance so more cancers are found. Incidence has actually leveled off starting in the 90’s due to this increased awareness. Cancers are detected earlier, thus the lower mortality rates. Average Breslow depth 1979 2 mm Today 1 mm

ABCD’s n n n A = Asymmetry B = Border irregularity: a jagged or "coast of Maine" type border represents horizontal extension of malignant cells C = Color: blue-black, white, red and grey-brown coexist, reflecting the presence of malignant extension D = Diameter: greater than 6 mm is suspicious for pigment cell atypia Amelanotic melanomas do occur and can present as rapidly growing flesh-colored or nonpigmented tumors

RF’s for Melanoma: MMRISK n. M n. R n. I n. S n. K Moles: atypical/dysplastic (>5) Moles: common moles (>50) Red hair and freckling Inability to tan: skin types I and II Sunburn: severe sunburn especially in/before adolescence Kindred: family history of melanoma

Sun Exposure and Melanoma (ORs) Exposure Summary Intermittent Occupational Total exposure Adult/lifetime sunburn Adolescence sunburn Childhood sunburn result (95% CI) 1. 87 (1. 67– 2. 09) 0. 76 (0. 68– 0. 86) 1. 20 (0. 00, 1. 44) 1. 91 (1. 69, 2. 17) 1. 95 (1. 60, 2. 36) 1. 62 (1. 35, 1. 95) Significant positive association for intermittent exposure and positive associations for sunburn in adolescence and sunburn in childhood

Genetics of Melanoma n n n Approximately 10% of melanomas are familial Familial Atypical Multiple Mole Melanoma (FAMMM) Syndrome (>50 -100 melanocytic nevi and melanoma in at least 1 first degree relative) CDKN 2 A tumor suppressor down regulates p 53 CDK 4 oncogene MC 1 R - melanocortin 1 receptor BRAF - gain of function in a protein kinase HRAS - implicated in acral melanomas

Gender Differences n n n Males are more likely to get melanoma 19/100, 00 than females 14/100, 000 Males most common site is trunk Females most commonly lower extremity Both can get melanoma anywhere Difference most likely related to clothing differences Studies have shown that intermittent sun exposure on unexposed skin is important in the etiology of melanoma

Ethnicity Incidence of melanoma among whites is approximately 20 times higher than among blacks n Hispanics in LA have melanoma 2– 3 per 100, 000 n Whites 11 per 100, 000 n For basal cell and squamous cell carcinoma, rates among blacks are 1/80 of the rates among whites n

Types of Melanoma n n n n Superficial spreading melanoma Lentigo maligna melanoma Melanoma arising in dysplastic nevus Nodular melanoma Acral lentiginous melanoma Nonpigmented/amelanotic Melanoma of mucous membranes Desmoplastic (Spindle Cell) Melanoma

Superficial Spreading Melanoma n These lesions tend to exhibit horizontal growth for variable periods prior to vertical growth n 70% of melanomas are of this type

Lentigo Maligna n Broad macular lesion usually on the face of elderly individuals n 5% of melanomas present in this fashion

Dysplastic Nevus n Melanoma can arise from these in congenital lesions but more commonly from nevi acquired later in life

Nodular Melanoma n Nodule or tumor often extending above the surface of the skin n Thought to have an abbreviated radial growth phase and accounts for 15% of all melanomas n Worst prognosis as early metastasis

Acral Lentiginous Melanoma n Lesions are by definition isolated to the distal extremities often occurring in the subungual or periungual regions n Representing 5% of melanomas n Most frequent melanoma in dark skinned individuals

Clark Level n n n Level of invasion based on cutaneous anatomy. Deeper invasion correlates with worse prognosis, but not as well as Breslow depth. A. Clark level I: Involvement of the epidermis only. B. Clark level II: Invasion into but not filling of papillary dermis C. Clark level III: The papillary dermis is filled with neoplastic cells D. Clark level IV: Invasion into the reticular dermis E. Clark level V: Invasion into the subcutaneous fat

Breslow Depth n n n n Vertical distance in mm from the base of the granular layer in the overlying epidermis to the deepest melanoma cell in the subepidermal tissues. Best prognostic indicator available TIS In Situ Near 100% Survival TI <1 mm T 2 1. 01 -2. 0 mm T 3 2. 01 -4. 0 mm T 4 >4 mm 45 -63% if node negative

Surgery for Melanoma Up until the 1970 s, margins of excision ranging from 3 to 5 cm were the standard n Current recommendations from 4 randomized prospective trials n 1 -cm radial margins for primaries up to 1 mm thick n 2 -cm margins for primaries up to 4 mm thick n

Excision should include skin and underlying subcutaneous adipose down to the muscle fascia n Excision of the muscle fascia has not been shown to improve disease control n Limited margins of excision reduce the need for skin grafts, complex tissue closures, and ultimately the costs and morbidity of patient care n

Likelihood of Recurrence Primary tumor thickness n Ulceration n Increasing patient age n Anatomic site: head, feet, and hands n Unfortunately, most patients with local recurrences eventually die of distant disease n

Elective Lymph Node Dissection Considered a valuable staging procedure in past n Cost, morbidity, and overall low yield of tumor -containing nodes have led most surgeons to abandon this procedure as a routine part of patient care n Tumor status of the regional lymph nodes has become exceedingly important for determining patient prognosis and directing the use of adjuvant therapy n

Sentinel Node Biopsy n n n Technetium 99 m and sulfur colloid Scintillation camera is used to document the drainage pattern Isosulfan blue dye injected at the site of the primary melanoma Handheld gamma probe used to determine the radioactive counts over the blue nodes Excise “hottest” node If positive, sentinel complete lymph node dissection

Immunohistochemical Staining Detect micrometastatic disease in nodes n Specific antibodies to melanoma-associated proteins n S-100, HMB-45, Melan-A, and NKI/C 361 n S 100 highly sensitive but limited by low specificity n HMB-45 most widely used because higher specificity, but has false negative in 10 -15% n

Radiation No great studies on this n Radiotherapy as primary treatment for cutaneous melanoma is rarely indicated n Exception is the case of extensive facial lentigo maligna melanoma n Large tumors difficult to resect n Reasonable tumor control and good to excellent cosmesis n

n n n Very few series supporting the routine use of adjuvant local irradiation In general, indications for adjuvant radiation include head and neck desmoplastic primaries, thick or ulcerated primaries, those with close or positive resection margins, and locally recurrent disease Despite a lack of randomized clinical trial data, generally recommend adjuvant axillary irradiation when either extracapsular extension is noted histologically, involved lymph nodes are ≥ 3 cm in size, four or more lymph nodes are involved, or disease is recurrent after initial surgical resection

Metastases n n n n Notorious for late metastasis Once melanoma has spread to a distant site median survival is 7 to 8 months and 5 -year survival is less than 5% Survival worse with early metastasis and multiple sites Grim prognosis has remained relatively unchanged for 30 years Response to conventional chemotherapy is rarely complete Metastasectomy can improve survival in carefully selected patients as it can rapidly render a patient disease-free Complex imaging techniques help select these patients with fewer mets No general recommendations for these surgeries

Survival After Metastsis Site Survival (mos) Skin, nodes 15 GI tract 11 Lung 8 Bone 6 Liver 4 Brain 4 All sites 7. 5 2 years 29± 3% 28± 5% 12± 1% 9± 3% 6± 1% 8± 2% 14± 1% 5 years 14± 2% 12± 4% 4± 1% 4± 2% 2± 1% 3± 1% 6± 1%

Chemotherapy n n Chemotherapy in the treatment of melanoma is usually reserved for metastatic disease Dacarbazine is the most active single-agent with response rate of 20% that last 6 months and only 2% of patients with sustained remission Cisplatin, nitrosoureas, taxanes, and vinblastine have been tried with response rates of 10 -20% and significant toxicity Combination chemotherapy (CVD most common) has been extensively explored with greater toxicity and no improvement in overall survival

Biochemotherapy n n Interferon-alfa alone failed to demonstrate a significant improvement in overall response and survival with increased toxicity Interleukin-2 also does not seem to improve responses rates or survival IL-2 may interact synergistically with cisplatin and multiagent regimens with this combination are currently being explored Chemotherapy in combination with INFa and IL-2 is considered in the classic biochemotherapy regimen

Novel Agents n n n Temozolomide new alkylating agent G-3139 (Augmerosin) - BCL-2 antisense protein PS-341 is a proteasome inhibitor being investigated as a single agent and in combination therapy possibly as a sensitizer to chemo Epothilone (BMS – 277550) is a novel antitubulin chemotherapy Several other innovative treatment options also under investigation, such as novel vaccines, fusion proteins, and dendrite cell vaccines

Bottom Line n The early diagnosis and surgical treatment of melanoma are the only approaches to date that have increased survival.

Skin Cancer Preventive Behavior n n n Minimize exposure to the sun during peak hours (10 a. m. -4 p. m. ) Seek shade from the midday sun (10 a. m. - 4 p. m. ) Wear clothing, hats, and sunglasses that protect the skin Use a broad-spectrum sunscreen (UV-A and UV-B protection) with a sun-protection factor of ≥ 15 Avoid sunlamps and tanning beds

Benign or Malignant

References n n n n Ballo M, Ang K. Radiation therapy for malignant melanoma. Surgical Clinics of North America 2003; 83. Essner R. Surgical treatment of malignant melanoma. Surgical Clinics of North America 2003; 83. Glanz K, Saraiya M, Wechsler H. Guidelines for School Programs To Prevent Skin Cancer. Morbidity and Mortality Weekly Report 2002; 51. Pavlick A. Chemotherapy approaches to melanoma. Dermatologic Clinics 2002; 20. Schaffer J, Rigel D, Kopf A, Bolognia J. Cutaneous melanoma-past, present and future. J Am Acad Derm 2004; 51. Rogers G, Braun S. Prognostic factors. Dermatologic Clinics 2002; 20. Johns Hopkins Dermatology Website. http: //dermatlas. med. jhmi. edu University of Iowa Dermatology Website. http: //tray. dermatology. uiowa. edu/Derm. Imag. htm