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

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

8. Why the Changes?
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 mm
Today 1 mm

9. ABCD’s
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

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

12. Sun Exposure and Melanoma (ORs)
Exposure Summary result (95% CI) Intermittent (1.67–2.09) Occupational (0.68–0.86) Total exposure (0.00, 1.44) Adult/lifetime sunburn (1.69, 2.17) Adolescence sunburn (1.60, 2.36) Childhood sunburn (1.35, 1.95)
Significant positive association for intermittent exposure and positive associations for sunburn in adolescence and sunburn in childhood

13. Genetics of Melanoma Approximately 10% of melanomas are familial
Familial Atypical Multiple Mole Melanoma (FAMMM) Syndrome (> melanocytic nevi and melanoma in at least 1 first degree relative)
CDKN2A tumor suppressor down regulates p53
CDK4 oncogene
MC1R - melanocortin 1 receptor
BRAF - gain of function in a protein kinase
HRAS - implicated in acral melanomas

14. Gender Differences
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

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

16. Types of Melanoma 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

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

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

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

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

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

30. Clark Level
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

32. Breslow Depth
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 mm
T mm
T >4 mm % if node negative

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

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

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

38. Elective Lymph Node Dissection
Considered a valuable staging procedure in past
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
Tumor status of the regional lymph nodes has become exceedingly important for determining patient prognosis and directing the use of adjuvant therapy

39. Sentinel Node Biopsy Technetium 99m 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

40. Immunohistochemical Staining
Detect micrometastatic disease in nodes
Specific antibodies to melanoma-associated proteins
S-100, HMB-45, Melan-A, and NKI/C361
S100 highly sensitive but limited by low specificity
HMB-45 most widely used because higher specificity, but has false negative in 10-15%

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

43. 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

44. Metastases 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

46. Survival After Metastsis
Site Survival (mos) years years
Skin, nodes ±3% ±2%
GI tract ±5% ±4%
Lung ±1% ±1%
Bone ±3% ±2%
Liver ±1% ±1%
Brain ±2% ±1%
All sites ±1% ±1%

47. Chemotherapy
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

48. Biochemotherapy
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

49. Novel Agents 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

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

51. Skin Cancer Preventive Behavior
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

52. Benign or
Malignant

61. References
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.
University of Iowa Dermatology Website.