1. Melanoma By Dr Abeer Elsayed Aly Lecturer of medical oncology SECI 19/03/2013

2. Melanoma Incidence and Mortality Incidence (US) – 59,580 new cases 33,580 new male cases 26,000 new female cases 12 per 100,000 population Mortality (US) – 7,770 total 4,910 males 2,860 females American Cancer Society, Cancer Facts and Figures. 2005.

3. Melanoma: risk factors Constitutional predisposition – Fair skin/hair color/ freckling – Burn vs tan – >20 benign nevi (moles) or >3 atypical nevi – Family history of dysplastic nevi – Increasing age – Immunosuppression – Xeroderma pigmentosum – H/O solar keratosis, squamous cell carcinoma

4. Melanoma: risk factors Risk behaviors – >3 sunburns – Episodic excessive sunlight exposure – Long term continuous sunlight exposure – UV exposure at tanning salons

5. Melanoma The challenge (historically): – Early detection – Rapid growth/high proliferation rate – Chemotherapy resistant – Radiation resistant – Short anticipated survival

8. Types of Melanoma Acral lentiginous Mucosal melanoma Superfical spreading melanoma Lentigo maligna melanoma Nodular melanoma

9. Superficial spreading most common head and neck, 50% 4th to 5th decade clinical mixture of brown/tan, pink/white irregular borders, biphasic growth irregular nests in epidermis underlying lymphoid infiltrate enlarged nests and single cells in all epidermal layers

10. Lentigo maligna 20% of head and neck longest radial growth phase >15 yrs elderly sun exposed areas clinical dark, irregular ink spot contiguous lintiginous proliferation, dyshesive, variable shape, atrophic epidermis, infundibular basal cell layer of hair follicles

11. Lentigo maligna

12. Nodular melanoma 30% of head and neck 5th decade aggressive monophasic growth sun-exposed and nonexposed areas well circumscribed blue/black or nodular with involution in irregular plaque downward tumorigenic growth, expand papillary dermis into reticular dermis

13. Nodular melanoma

14. Mucosal melanoma 8% head and neck histologic staging little use local control predicts survival neck dissection for clinical N+ XRT for histo N+ adjuvant interferon alpha 2-b

15. Biopsy techniques Excisional biopsy 1-3 mm margins avoid wider margins (accurate lymphatic mapping) Full thickness incisional/punch biopsy for large lesions lesions of the palms, soles, digits, face, ears Deep shave biopsies When suspicion for melanoma is low NCCN Guidelines 2005

16. Staging system

17. Clark staging Based upon histologic level of invasion Level I – Epidermis only (in situ) Level II – Invades the papillary dermis, but not to the papillary-reticular interface Level III – Invades to the papillary-reticular interface, but not into the reticular dermis Level IV – Into the reticular dermis Level V – Into subcutaneous tissue

19. Breslow staging Based upon absolute depth of invasion Stage I – < 0.75 mm Stage II – 0.76 – 1.5 mm Stage III – 1.51 – 4.0 mm Stage IV - > 4.0 mm

22. Work up Labs – LDH Radiology – CXR – Possible CT for metastasis – Possible CT abdomen, MRI brain – Possible Lymphoscintigraphy Excision – 2 cm margins Adjunctive Therapy – Possible elective neck dissection – Possible sentinel lymph node biopsy – Possible elective radiation

23. Prognostic indicators Thickness (Breslow depth) Nodal status Ulceration Mitosis Satellite lesions In transit lesions

24. Prognostic indicators Thickness (Breslow depth) Nodal status Ulceration Mitosis Satellite lesions In transit lesions

25. Prognostic indicators Thickness (Breslow depth) Nodal status Ulceration Mitosis Satellite lesions In transit lesions

26. Prognostic Indicators: Nodal status OS for patients with 1 positive sentinel node is 60% at 5 years OS for patients with a single palpable node is 40% at 5 years Gershenwald et al, 2001

27. Prognostic indicators Thickness (Breslow depth) Nodal status Ulceration Mitosis Satellite lesions In transit lesions

28. Mitotic Index N = 3661 from the Sydney Melanoma Database Correlated – clinical information (survival) – primary tumor thickness (Breslow depth) – ulcerative state (infiltrative, attenuative, and traumatic) – tumor mitotic rate (TMR) (at the invading front, deep border) Conclusion: TMR is a more powerful prognostic indicator than ulceration in patients with primary cutaneous melanoma Azzola et al, Cancer 2003

29. Prognostic indicators Thickness (Breslow depth) Nodal status Ulceration Mitosis Satellite lesions In transit lesions

30. Risk of In-Transit Metastasis In- transit metastasis – Cutaneous / subcutaneous tissue – Between the primary tumor – and the draining lymph node basin 5 yr survival rates: 12% - 37% Risk factors: – Thicker primary – Lower extremity – Regional LN metastasis

31. Other prognostic factors: LDH – Elevated levels correlate with: Early recurrence Shorter survival (Newcki et al, 2008) Serum S100 level – Early studies suggest: Shorter survival Early distant relapse Poorer response to treatment (Smith et al, 2008) Microvessel Density

32. Other prognostic factors: LDH – Elevated levels correlate with: Early recurrence Shorter survival (Newcki et al, 2008) Serum S100 level – Early studies suggest: Shorter survival Early distant relapse Poorer response to treatment (Smith et al, 2008) Microvessel Density

33. Other prognostic factors: LDH – Elevated levels correlate with: Early recurrence Shorter survival (Newcki et al, 2008) Serum S100 level – Early studies suggest: Shorter survival Early distant relapse Poorer response to treatment (Smith et al, 2008) Microvessel Density

38. Adjuvant treatment

48. Metastatic Melanoma

59. Dendritic cell T cell MHC B7 TCR CD28 Antigen CTLA4 Blocking Antibodies to CTLA4 Leach DR, et al. Science 1996;271:1734-1736.

62. Vaccine

63. Phase I GVAX: Melanoma VaxDTH Met Vasculopathy PreMet CD4 CD8

75. Adaptive Immune Therapy

85. BRAF Inhibitor