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  1. 1. MELANOMA
  2. 2. <ul><li>5th most common malignancy for men, 6th for women </li></ul><ul><li>Represents < 5% of skin cancers but accounts for 65% of deaths </li></ul><ul><li>Median age of diagnosis is 48 </li></ul><ul><li>#2 malignancy in loss of years of potential life (leukemia#1) </li></ul><ul><li>Incidence is rising significantly: #1 increasing malignancy in men, #2 in women (#1 is lung ca) </li></ul>
  3. 3. Melanocytes <ul><li>Originate from neural crest cells in the fetus which then migrate to skin at the dermalepidermal junction. </li></ul><ul><li>Also migrate to eyes (5%), meninges, upper esophagus, mucous membranes (1%) </li></ul><ul><li>Most common site for melanoma: women= legs, men= back </li></ul>
  4. 4. Risk Factors <ul><li>Previous skin cancer </li></ul><ul><li>Xeroderma pigmentosum </li></ul><ul><li>Dysplastic mole syndrome almost 100% risk of melanoma </li></ul><ul><li>Dysplastic, atypical, or large congentital nevi- 10% lifetime risk for melanoma </li></ul><ul><li>Family history of melanoma (10% are familial) </li></ul><ul><li>Fair complexion, intermittent/severe/ early Sunburns (severe childhood sunburns) </li></ul>
  5. 5. <ul><li>UVA radiation (320-400 nm)- penetrates deeper into the dermis. Responsible for sun-induced changes in dermal connective tissue and loss of elasticity (wrinkles, signs of aging) </li></ul><ul><li>UVB (290-320 nm)- causes sunburn </li></ul><ul><ul><li>increased melanin production in skin </li></ul></ul><ul><li>UVC(200-290nm)- absorbed by ozone </li></ul><ul><li>UVA and UVB carcinogenic </li></ul>
  6. 6. Pathology <ul><li>Small cluster of tumor cells in subepidermal lymphatics </li></ul><ul><li>Subepidermal zone showing inflammatory cells – mainly lymphocytes </li></ul>
  7. 7. Phases of Growth <ul><li>Radial Growth Phase- tumor cells proliferate at the dermal-epidermal junction. Tumor expands radially </li></ul><ul><li>– Lesions are confined to epidermis, may have superficial involvement of dermis </li></ul><ul><li>Vertical Growth Phase - lesion invades deeper into dermis, development of palpable nodule </li></ul><ul><li>– *Nodular type of melanoma </li></ul>
  8. 8. Lentigo maligna <ul><li>Best prognosis </li></ul><ul><li>least aggressive, present with minimal invasion, radial growth 1st </li></ul><ul><li>Flat ,darkly pigmented lesion with irregular margins </li></ul><ul><li>Usual age of onset 50-70’s </li></ul><ul><li>Sun-exposed skin (face) </li></ul><ul><li>Usually arise from large macular brown lesion, present for years </li></ul>
  9. 10. Superficial spreading <ul><li>Most common </li></ul><ul><li>Irregular margins with differing pigmentation </li></ul><ul><li>Initially flat </li></ul><ul><li>intermediate malignancy </li></ul><ul><li>originates from sun-exposed and non-sun -exposed (nevus) areas </li></ul>
  10. 12. Acral lentiginous <ul><li>very aggressive </li></ul><ul><li>poorer prognosis than other extremity sites independent of thickness </li></ul><ul><li>Prolonged radial growth phase </li></ul><ul><li>Commonly arises on palms, soles, subungual </li></ul><ul><li>More common among African-Americans </li></ul><ul><li>Also on mucous membranes- vulva, penis, anus, nasal sinus, oral mucosa (5 yr survival <20%) </li></ul>
  11. 13. <ul><li>Similar appearance to subungual hematoma </li></ul>
  12. 14. Nodular <ul><li>Most aggressive </li></ul><ul><li>Vertical growth phase first </li></ul><ul><li>most likely to have metastasized/ deepest growth at time of diagnosis </li></ul><ul><li>Well-circumscribed borders, uniform pigment, bluish-black </li></ul><ul><li>occurs anywhere on body </li></ul>
  13. 16. Amelanotic melanoma <ul><li>Amelanotic lesions appear as raised papules that can be pink, red, purple, or normal skin colors. </li></ul><ul><li>Atypical appearance frequently leads to a delay in diagnosis and therefore a poorer prognosis. </li></ul><ul><li>Desmoplastic melanoma is a specific type of amelanotic melanoma that commonly arises on the face and can be associated with lentigo maligna melanoma (LMM). </li></ul>
  14. 17. <ul><li>Desmoplastic melanomas exhibit neurotropism, which is also a poor prognostic factor. The prognosis appears to be worse because they are thicker lesions than nondesmoplastic lesions </li></ul>
  15. 18. Typical Presentation <ul><li>A = asymmetry </li></ul><ul><li>B = irregular borders </li></ul><ul><li>C = colour </li></ul><ul><li>D = diameter > 6mm </li></ul><ul><li>E = elevation </li></ul><ul><li>Advanced lesions- present with ulceration or itching/bleeding (invasion into the cutaneous nerve plexus/ superficial capillary bed) </li></ul>
  16. 19. Clinical management <ul><li>Biopsy- full-thickness excisional bx with 1-2 cm margins. (full-thick incisional or punch bx for palm, face, subungual,etc) </li></ul><ul><li>Orient bx with definitive treatment in mind </li></ul><ul><li>Pathology: Breslow thickness, ulceration, Clark’s level, margin status (deep and peripheral), satellite lesions </li></ul><ul><li>Lymph node exam </li></ul><ul><li>Complete skin exam </li></ul><ul><li>Family history of skin ca, melanoma </li></ul>
  17. 20. Prognostic Factors <ul><li>Localized disease: Breslow thickness,presence of ulceration, Clark level </li></ul><ul><li>Regional disease: </li></ul><ul><ul><li>tumor burden (# of positive nodes) </li></ul></ul><ul><ul><li>Macroscopic vs microscopic positive nodes </li></ul></ul><ul><ul><li>Extension into extranodal soft-tissue </li></ul></ul><ul><ul><li>Ulceration of primary tumor </li></ul></ul><ul><li>Other (worse prognosis): mucosal/ocular lesions, male, older age </li></ul>
  18. 21. Clark’s Levels for Melanoma <ul><li>I: Epidermis basement membrane intact </li></ul><ul><li>II: Papillary dermis through basement membrane </li></ul><ul><li>III: completely filling papillary dermis </li></ul><ul><li>IV: invadind reticular dermis </li></ul><ul><li>V: growth into subcutaneous fat </li></ul>
  19. 25. Melanoma Staging <ul><li>Stage 0: in situ </li></ul><ul><li>IA (low-risk primary): < 1 mm, no ulceration, Clark level II or III </li></ul><ul><li>IB, II (intermed & high-risk primary): <1.0 mm with ulcer or Clark level IV/V, or >1.0 mm with any characteristic, neg nodes </li></ul><ul><li>III (regional nodal disease): SLN pos., regional nodes <5mm in size or </li></ul><ul><li>III, in-transit disease </li></ul><ul><li>IV: any metastasis; distant soft tissue mets, nodes >5mm in size, >5 in-transit metastases, lung, other organs, elevated LDH </li></ul>
  20. 26. Treatment of Primary: Margins <ul><li>In-situ: wide excision with 0.5-1.0 cm margins, confirm neg margin! </li></ul><ul><li><1.0 mm (stage IA): 1cm margin </li></ul><ul><li>1.1-2.0 mm 1-2 cm </li></ul><ul><li>>2.0mm 2cm </li></ul><ul><li>*Margins of >2cm do not improve rate of local recurrence, disease-free survival, or overall survive </li></ul>
  21. 27. Perform SLN biopsy if: <ul><li>tumor is >1.0 mm thick (Stage IB) </li></ul><ul><li>OR </li></ul><ul><li>tumor is <1.0 mm thick with Clark’s level IV or V or ulcerated or demonstrates regression </li></ul><ul><ul><ul><li>AND physical examination and staging evaluation (CXR) show no evidence of metastatic disease in regional lymph nodes and distant sites </li></ul></ul></ul>
  22. 28. Lymphatic mapping and SLN Biopsy <ul><li>SLN bx identifies the 20% of patients w/ occult met disease and allows them to benefit from early completion lymphadenectomy </li></ul><ul><li>Provide more accurate staging information </li></ul><ul><li>Status of SLN reflects that of the entire regional basin </li></ul><ul><li>Isosulfan blue dye injection identifies SLN 85% of time </li></ul><ul><li>0.5-1.0 mCi of 99Tc-labeled sulfur colloid injected 1- 4 hrs pre-op, use gamma probe during surgery to identify SLN </li></ul><ul><li>Preop lymphoscintigraphy identifies multiple draining nodal basins, including non-standard sites (in-transit) </li></ul>
  23. 30. Preop Lymphoscintigraphy
  24. 31. In-transit Lymphatic Drainage
  25. 32. Treatment <ul><li>If SLN is positive (micrometastatic melanoma), perform completion lymphadenectomy of regional nodal basin (10- 30% have additional positive nodes) </li></ul><ul><li>Stage III: </li></ul><ul><ul><li>wide local excision w/ appropriate margins </li></ul></ul><ul><ul><li>full lymph node dissection </li></ul></ul><ul><li>Adequate LN dissection: inguinal= 10 nodes, axillary=15, neck=15 </li></ul>
  26. 33. Treatment: Metastatic intransit melanoma <ul><li>Resection of a single in-transit met- excision with SLN bx </li></ul><ul><li>Small, finite # of mets- perform complete excision with negative margins </li></ul><ul><li>Small, finite # of mets unable to excise: </li></ul><ul><ul><li>intradermal injections with interferon alfa-2b </li></ul></ul><ul><ul><li>CO2 laser ablation </li></ul></ul><ul><ul><li>hyperthermic isolated limb perfusion with melphalan. </li></ul></ul><ul><li>XRT poorly controls regional disease </li></ul><ul><li>Systemic therapy as part of clinical trial or after all other tx fail </li></ul>
  27. 34. Adjuvant Therapy <ul><li>frequently called biochemotherapy </li></ul><ul><li>combination of CVD(cisplatin, vinblastine, dacarbazine) , interferon, and interleukin-2 </li></ul><ul><li>No improvement in survival </li></ul>
  28. 35. Isolated Limb Perfusion <ul><li>ILP isolates limb from body and allows a much higher dose of cytostatic drug (melphalan) to be given without systemic exposure and toxic effects </li></ul><ul><li>Technique: Clamp main artery/vein, ligate collaterals, apply tourniquet at base, cannulate artery and vein, extracorporeal bypass with cytostatic drug (isolated circuit), rinse, remove cannula and repair vessels </li></ul><ul><li>Controversial despite >35 yrs of use </li></ul><ul><li>Treatment of choice only for those with locally inoperable limb melanomas </li></ul>
  29. 36. <ul><li>Causes complete disappearance of macroscopic tumor in majority of patients- palliates sx, prevents need for amputation </li></ul><ul><li>But there is a high rate of recurrence of disease and short duration of response </li></ul>
  30. 38. Treatment: Stage IV <ul><li>Single lesion- resect if possible </li></ul><ul><li>Unable to resect and/or other sites of disease: </li></ul><ul><li>– clinical trial </li></ul><ul><li>– single-agent systemic therapy (IL-2, dacarbazine, or temozolomide </li></ul><ul><li>– Dacarbazine-based combination therapy, chemotherapy, and/or immunotherapy </li></ul><ul><li>– best supportive care </li></ul>
  31. 40. Surveillance <ul><li>optimal duration of follow-up is controversial </li></ul><ul><li>Most recurrence <5 yrs, however well documented late recurrence (>10 yrs) </li></ul><ul><li>Stage 0 : yearly skin exams (consider monthly skin and nodal exams by patient) </li></ul><ul><li>Stage IA : comprehensive H&P q 3-12 months as clinically indicated, in addition to yearly skin exams </li></ul><ul><li>IB-IV : H&P every 3-6 months for 3 yrs, 4-12 months for 2 yrs, then yearly; yearly skin exams; consider CXR , LDH, CBC q3-12 months </li></ul>
  32. 41. Recurrence <ul><li>confirm by FNA or biopsy </li></ul><ul><li>Any patient with recurrent disease rendered free of disease by surgery- appropriate to consider adjuvant (clinical trial preferred, alfa interferon second choice) </li></ul><ul><li>inadequate excision (locally persistent disease)- better prognosis after re-excision, SLN, etc </li></ul><ul><li>Local scar recurrence (dermal lymphatic disease)= like stage III (excise, SLN, consider adjuvant) </li></ul><ul><li>In-transit recurrence: re-excise with neg margins, SLN </li></ul><ul><li>Unresectable- interferon alfa-2b, CO2 laser, radiation, adjuvant, etc </li></ul>
  33. 42. <ul><li>Nodal recurrence- confirm with FNA, complete lymphadenectomy (if not already performed), and wide excision with neg margins. Consider radiation, especially head and neck </li></ul><ul><li>Systemic- solitary, asymptomatic recurrence may watch for 3 months with repeat scans to detect if other recurrences; or just resect; if sx= resect; </li></ul><ul><li>Unresectable but no brain involvement: 1- clinical trial </li></ul><ul><li> 2- dacarbazine </li></ul><ul><li> 3- IL-2 </li></ul><ul><li> 4- dacarbazine based combination therapy or immunotherapy </li></ul><ul><li> 5- temozolomide </li></ul><ul><li>Brain mets- surgery or XRT, palliation </li></ul>