EPIDEMIOLOGY AND TREATMENT Hazard ARH Regional Medical Center Melanoma EPIDEMIOLOGY AND TREATMENT DANIEL KENADY, M.D. Hazard ARH Regional Medical Center

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Epidemiology of Melanoma IN1968B

Estimated New Melanoma Cases & Deaths: US, 2016 70000 60000 50000 40000 Cases 76380 30000 Deaths 20000 46870 29900 29510 10000 6750 10130 3380 Total Male Female American Cancer Society. Cancer Facts & Figures 2004.

Lifetime Risk of Developing Cutaneous Melanoma in the US 1:74 1:100 1:150 1:250 1:600 1:1500 1935 1960 1980 1985 1993 2000 Rigel DS, Carucci JA. CA Cancer J Clin. 2000;50:215–236.

Melanoma Mortality Rates: US, 1975-2000 White Men All Men Overall Women Ries LAG, et al, eds. SEER Cancer Statistics Review, 1975–2000. Bethesda, MD: National Cancer Institute; 2003: Tables XVI-1–9.

Melanoma Diagnosis: Identifying Populations at High Risk Factors known to increase risk Familial History of malignant melanoma Skin type and color Environmental 3 blistering sunburns before age 20 Outdoor summer jobs for 3 years in adolescent years Use of sunlamps, tanning beds Other Actinic keratosis, elastosis Marked freckling on upper back Large number of normal nevi Atypical nevi, congenital giant nevi Each risk factor increases risk additively CA Cancer J Clin. 2000;50:215–236.

NEJM 355:51,2006

Cutaneous Melanoma: Early Recognition and Diagnosis

The ABCDEs of Melanoma Diagnosis Asymmetry One half of the lesion is shaped differently than the other The border of the lesion is irregular, blurred, or ragged Border Color Inconsistent pigmentation, with varying shades of brown and black >6 mm, or a progressive change in size Diameter Evolution History of change in the lesion Photos courtesy of the American Cancer Society.

Morphologic Types of Melanoma Superficial 60%-70% Flat during early phase; notching, spreading scalloping, areas of regression Nodular 15%-30% Darker and thicker than superficial spreading, rapid onset; commonly blue-black or blue-red (5% amelanotic) Lentigo ~5% Enlarge slowly; usually large, flat, tan maligna or brown Acral Uncommon On soles, palms, beneath nail beds; lentiginous Asians (46%), usually large, tan or brown; irregular Blacks (70%) border; subungual melanoma more common in older, dark-skinned people Desmoplastic 1.7% Rare, locally aggressive, occur primarily on head and neck in elderly Data from Lotze MT, et al. Cutaneous Melanoma. In: DeVita VT Jr,. et al, eds. Cancer: Principles & Practice of Oncology. 6th ed. Philadelphia, PA: Lippincott-Raven; 2001.

Seborrheic Keratosis

Basal Cell Carcinoma

Hemangioma

Melanoma

Images courtesy of Kenneth Tanabe, MD

2010 AJCC Melanoma Staging System: T Classification Depth Ulceration* Stage T1 T2 T3 T4 1.0 mm 1.01-2.0 mm 2.01-4.0 mm 4.0 mm a† b‡ a b IA IB IIA IIB IIC *a, no ulceration; b, ulceration †Clark’s level II/III ‡ulceration or Clark’s level IV/V J Clin Oncol. 2001;19:3635-3648.

2010 AJCC Melanoma Staging System: N Classification Number Type Stage* N1 N2 N3 1 2-3 4+ and/or matted, in-transit, satellite or ulceration a micro b macro c in-transit or satellite, no + nodes IIIA/B IIIB/C IIIB IIIC *reflects effects of ulceration J Clin Oncol. 2001;19:3635-3648.

2010 AJCC Melanoma Staging System: M Classification Location Stage Mx M0 M1 Unassessable No distant metastases Distant metastases IV a: Skin, subcutaneous tissues, distant lymph nodes b: Lung c: All other distant sites or at any site with  LDH* *LDH = lactate dehydrogenase J Clin Oncol. 2001;19:3635-3648.

AJCC Staging Criteria: T Stage 5-Year Survival* Ulceration Depth – + <1.0 mm 1.01-2.0 mm 2.01-4.0 mm >4.0 mm 95% 89% 78% 67% 91% 77% 63% 45% *10-year survival was 10-15% less in each category J Clin Oncol. 2001;19:3635-3648.

5-Year Survival by Node Class + Nodes Microscopic Macroscopic 1 61% 46% 2 56% 37% 3 56% 27% 4 36% 24% >4 35% 24% J Clin Oncol. 2001;19:3622-3634.

5-Year Survival in Stage III Melanoma Microscopic Macroscopic J Clin Oncol. 2001;19:3622-3634.

Surgical Management and Sentinel Lymph Node Biopsy in Cutaneous Melanoma

Diagnostic Biopsy in Primary Melanoma Narrow excisional biopsy (2-3 mm) Goals Rule out lesions with potentially similar features seborrheic keratosis pigmented basal cell cancer solar lentigines atypical nevi Determine depth and level of invasion Identify other prognostic features of the 1º lesion Am J Clin Dermatol. 2002;3:401-426. Cancer Principles & Practice of Oncology, 6th ed. 2001:2012-2069. Guidelines of Care for Primary Cutaneous Melanoma. American Academy of Dermatology. 2001:1-11.

Diagnostic Biopsy in Primary Melanoma Lesion Too Large for Excision/Closure Incisional biopsy or punch biopsy Must be full thickness through thickest part of lesion clinically No shave biopsy

Wide Excision: Prospective Randomized Trials Surgical Trial n Tumor Thickness Arms

Intergroup Trial Results: Surgical Margins Local Recurrence Survival Skin Graft 2 cm 4 cm 2.1% 2.6% 70% 77% 11% 46% These data are not reflected in the Balch Intergroup Trial reference (2001, Ann Surg Oncol), which also does not include skin graft data. The data for a smaller group of patients, however (reported in Balch, et al. Ann Surg 1993), are reflected here. Should this slide and its data be changed to reflect the 2001 report, or should the previous slide (#3) be changed to correlate with the data reported here? Ann Surg. 1993;218:262–267. Ann Surg Oncol. 2001;8:101–108.

Surgical Excision for Localized Cutaneous Melanoma: Recommended Margins Melanoma Thickness Margin* 1 mm 1.01–2.00 mm 2.01–4.00 mm >4 mm 1 cm 1–2 cm† 2 cm Margins may be modified to accommodate individual anatomic or cosmetic considerations For clinically ill-defined lentigo maligna pattern lesions of the head and neck, pathological confirmation of negative peripheral margin is important *Maximal achievable with 1 closure †Where anatomically feasible NCCN Practice Guidelines: Melanoma.

Rationale for Lymphadenectomy Improve regional disease control Enhance accuracy of staging Improve odds of survival

Intergroup Melanoma Surgical Program: All Patients 100 Overall Survival (%) Regional Node Dissection (n = 379) 90 80 70 Observation (n = 361) 60 Arm ELND* Obs 5-yr Survival 86% 82% 50 P = 0.25 40 1 2 3 4 5 6 7 8 9 10 11 12 Years *Elective regional lymph node dissection Ann Surg. 1996;224:255–66.

Techniques in SLN Mapping and Biopsy Preoperative injection of radiocolloid + intraoperative blue dye improves accuracy of lymphatic mapping Identification of SLN occurs both by sight and with a handheld gamma probe Lymphatic drainage does not always match classic anatomical patterns Excision of primary lesion Should be performed at the time of SLN biopsy or thereafter Recent studies have shown no significant decrement in ability to identify SLN when mapping and biopsy are performed after wide excision Am J Clin Dermatol. 2002;3:401–426. Ann Surg. 1999;230:453–465. Ann Surg Oncol. 2003;10:196–200. Ann Surg Oncol. 2003;10:416–425.

Sentinel Lymph Node (SLN) Mapping and Biopsy Lymphatic metastases from tumor spread first through afferent channels SLN is first node along those channels SLNs are immuno- suppressed and proven to be sites of early metastases SCOTT/AU: The photograph of the lymph node on the slide does not appear in the Morton reference. Ann Surg. 1999;230:453–465.

Surgical Management of Clinical Stage I and II Melanoma SLN identified Evaluate by hematoxylin/eosin & immunohistochemistry, stepped sections Node negative Node positive Observation En bloc dissection Adjuvant therapy Arch Surg. 1992;127:392–399.

…or is it?

Potential Candidates for SLN Biopsy Risk of nodal metastasis varies with tumor thickness <5% for tumors 1 mm w/o ulceration, other adverse factors 20% for tumors 1–4 mm 35% for tumors 4 mm SLN biopsy should be discussed with all patients with invasive melanoma Patients with primary melanomas 1 mm are appropriate candidates for SLN biopsy Some patients with thinner primary melanomas may also be appropriate candidates for SLN biopsy Ulceration, Clark level IV invasion, truncal location, and mitoses should be considered Patients with nevomelanocytic lesions assessed by biopsy in which biology is uncertain (eg, atypical Spitz nevus) Evaluate each patient individually Arch Dermatol. 2001;137:1217-1224. J Surg Oncol. 2003;82:209-216. NCCN Practice Guidelines: Melanoma.

Surgery >4 mm or node + (ELND) followed by randomization (n = 287) E1684: Study Design Observation Arm A 52 Weeks Surgery >4 mm or node + (ELND) followed by randomization (n = 287) IFN-a2b Induction Maintenance Arm B 4 Weeks 48 Weeks Induction: 20 MIU/m2 IV 5x weekly x 4 weeks Maintenance: 10 MIU/m2 SC TIW x 48 weeks J Clin Oncol. 1996;14:7-17.

E1684: Estimated Relapse-Free Survival 1.0 Arm IFNa2b Obs Median RFS 1.72 yr 0.98 yr 0.9 0.8 0.7 0.6 Probability of relapse-free survival 0.5 0.4 IFN-a2b (n=143) 0.3 Observation (n=137) 0.2 0.1 1 2 3 4 5 6 7 8 Years P=0.0023 J Clin Oncol. 1996;14:7-17.

E1684: Estimated Overall Survival 1.0 Arm IFNa2b Obs Median OS 3.82 yr 2.78 yr 0.9 0.8 0.7 0.6 Probability of survival 0.5 IFN-a2b (n=143) 0.4 Observation (n=137) 0.3 0.2 0.1 1 2 3 4 5 6 7 8 P=0.0237 J Clin Oncol. 1996;14:7-17.

Recommendations for Adjuvant Therapy For patients with IIB, IIC or III: 2B recommendations-clinical trial vs observation vs HD IFN (4 weeks) followed by 48 weeks of LD IFN. Many caveats and contra-indications to HD IFN. Careful adherence to standards of supportive care nearly always prevent serious complications of the therapy.

FUTURE ADJUVANT THERAPIES * VEMURAFENIB –BRAF-mutant cases * IPILIMUMAB ( anti-CTLA-4 ANTIBODY) * NIVOLUMAB ( anti-PD-1 antibody)

ANIMAL SLIDE