II. Epidemiology
-
Incidence 2016 to 2020 U.S.
- Male: 27 per 100,000 (59,000 U.S. men in 2024)
- Female: 17 per 100,000 (41,000 U.S. women in 2024)
- Prevalanence U.S.
- U.S. Prevalence in 2021: 1.45 Million
- Lifetime Prevalence: 2.2%
-
Incidence by Fitzpatrick Skin Type
- Males with Fitzpatrick Skin Types I and II: 38 per 100,000
- Females with Fitzpatrick Skin Types I and II: 25 per 100,000
- Fitzpatrick Skin Types V and VI: 1 per 100,000
- However, when Melanoma is diagnosed in darker skin, it is often advanced with worse outcome
- Age at diagnosis
- Overall Mean: 65 years (regardless of Fitzpatrick Skin Type)
- Women age 25 to 34 years old: 17 per 100,000 (twice the Incidence of men in this age group)
- Melanoma is among the top two cancers in U.S. women in this age group
- Deaths: 8200 per year in United States predicted 2024
- Melanoma mortality has dramatically fallen since 2000 (related to treatment)
- Melanoma represents only 1% of Skin Cancers, but accounts for 75% of deaths from Skin Cancers
- Increasing Incidence
III. Pathophysiology
- Melanocyte (Melanin producing cells) malignant transformation
- BRAF Mutation (esp. V600) is found in 50% of cases
- Allows for specific targeted Immunotherapy (Ipilimumab, Nivolumab)
IV. Risk Factors
- See Melanoma Risk Factors
- Precursor Lesions
- Lentigo maligna
- Congenital neoplastic nevi
- Clark's melanocytic nevi (Dysplastic Nevus)
V. Exam
VI. Diagnosis: Biopsy
- See Atypical Nevus for biopsy guidelines
- Biopsy all suspicious pigmented lesions (and take images for EMR prior to biopsy)
- Obtain full thickness sample with 1-3 mm margins (via Punch Biopsy, Fusiform Excision or deep saucerization)
- Allows for Breslow Depth measurement (maximal thickness of primary lesion rounded to nearest 0.1 mm)
VII. Classification
- Precaution: Melanoma is Melanoma (manage all types aggressively)
- Melanoma in Situ (Up to 50% of Melanomas)
- Malignant Melanocytes are confined to the Epidermis
- Excision is typically curative with 5 mm to 10 mm margins (with clear margins confirmed on pathology)
- Superficial spreading Melanoma (SSM, up to 70% of Melanomas)
- More common at age 30-50 years, often on the trunk in men, and legs in women
- Most common Melanoma in fair skin
- Initially brown to black lesions develop blue, red, white color variations
- Form irregular, unusual shapes
- Initially flat, >6 mm, with radial growth for months to years
- When >2.5 cm vertically grow into Nodules
- Nodular Melanoma (NM, 15-20% of Melanomas)
- More common at age 40-60 years and twice as common in men
- No horizontal growth phase and rapid vertical growth over weeks to months
- Involves trunk, head or neck most often
- Firm, raised, dome shaped lesions which may itch or bleed more easily
- Colors vary from brown or black to red or purple
- May appear flesh colored (amelanotic nodular Melanoma) and appear more like Basal Cell Carcinoma
- Most frequently misdiagnosed Melanoma (see differential diagnosis below)
- May be misdiagnosed as acne, Furuncles, Skin Ulcers
-
Lentigo maligna Melanoma (LMM, 5-15% of Melanomas)
- More common at age 50-80 years, especially with sun-damaged skin
- Develops on the face in 90% of cases
- Develops from the precursor lesion Lentigo maligna (Hutchinson's Freckle)
- Tumors develop in center of Lentigo maligna
- Typically invades after >5 cm in diameter
- Invasion can not be determined by external skin exam
- Amelanocytic Melanoma (<5% of Melanomas)
- Nonpigmented Melanoma (red or pink coloration)
- Broad differential diagnosis: Eczema, fungal dermatitis, Basal Cell Carcinoma, Squamous Cell Carcinoma
- Delay in diagnosis is common and often diagnosed at a more advanced stage with lower 5 year survival
-
Acral Lentiginous Melanoma (ALM, 2-8% of Melanomas)
- Represents up to 75% of Melanomas in non-caucasian patients (black or asian ethnicity)
- Least related to UV radiation and more to shearing forces with increased cellular genetic mutations
- Occurs on acral surfaces
- Palms, soles, distal digits (knuckles, fingertips), elbows, knees, ears and mucous membranes
- Diagnosis often delayed (presenting at more advanced stage with worse outcomes)
- Include foot exam with skin exam, especially in non-caucasian patients
- Biopsy from most nodular lesion (most accurate, predictive breslow depth)
- Represents up to 75% of Melanomas in non-caucasian patients (black or asian ethnicity)
-
Subungual Melanoma (up to 3.5% of Melanomas)
- Hutchinson Sign is a pigmented longitudinal band under nail plate (Longitudinal Melanonychia)
- Very aggressive tumor with early metastases even from small lesions
- Biopsy of lesion including the nail matrix (typically by dermatology)
- Affects great toe or thumb in >90% of cases
- Most common Melanoma in black, asian and hispanic patients
VIII. Differential Diagnosis
- Melanoma look-alikes in general
- Seborrheic Keratosis
- Irritated nevus
- Pigmented Basal Cell Carcinoma
- Lentigo
- Blue Nevus
- Angiokeratoma (red to blue vascular lesions)
- Traumatic Hematoma
- Venous lake (Phlebectases: soft, blue purple lesions on face, especially lips and ears)
- Hemangioma
- Pigmented Actinic Keratosis
- Nodular Melanoma
- Dermatofibroma (amelanotic)
- Basal Cell Cancer (amelanotic)
- Hemangioma
- Seborrheic Keratosis
- Pyogenic Granuloma
IX. Labs: Histology
- Clark's Level
- Five-year survival related to tumor depth
- Thin breslow thickness (=1.0 mm) has significantly better prognosis than thicker breslow >1.0
- Stephens (2024) J Surg Res 301:24-8 +PMID: 38908355 [PubMed]
X. Staging (AJCC)
- In-Situ
- Stage 0 (TisN0M0)
- Confined to Epidermis (99-100% five and ten year survival)
- Stage 0 (TisN0M0)
- Localized
- Stage IA
- Thickness <0.8 mm and not ulcerated (T1aN0M0)
- Survival: 99% five year survival and 98% ten year survival
- Stage IB
- Thickness <0.8 with ulceration or 0.8 to 1.0 mm with or without ulceration (T1bN0M0)
- Thickness 1.1 to 2 mm without ulceration (T2aN0M0)
- Survival: 97% five year survival and 94% ten year survival
- Stage IIA
- Thickness 1 to 2 mm and ulcerated (T2bN0M0) or 2.1 to 4 mm and not ulcerated (T3aN0M0)
- Survival: 94% five year survival and 88% ten year survival
- Stage IIB
- Thickness 2 to 4 mm and ulcerated (T3bN0M0) or >4 mm and not ulcerated (T4aN0M0)
- Survival: 87% five year survival and 82% ten year survival
- Stage IIC
- Thickness >4 mm and ulcerated (T4bN0M0)
- Survival: 82% five year survival and 75% ten year survival
- Stage IA
- Metastatic
- Stage III: Regional node metastases (Any T, N>=1, M0)
- Stage IIIA - Survival: 93% five year survival and 88% ten year survival
- Stage IIIB - Survival: 83% five year survival and 77% ten year survival
- Stage IIIC - Survival: 69% five year survival and 60% ten year survival
- Stage IIID - Survival: 32% five year survival and 24% ten year survival
- Stage IV: Distant metastases (Any T, any N, M1)
- Survival: 32% five year survival and 10-15% ten year survival
- Stage III: Regional node metastases (Any T, N>=1, M0)
XI. Evaluation: Melanoma Metastases
- Lymph Node exam
- Full skin exam
- Chest XRay
- Labs considered above stage IA (and in all cases of Stage III and IV)
- Complete Blood Count (CBC)
- Comprehensive Metabolic Panel (includes Electrolytes and hepatic panel)
- Lactate Dehydrogenase (LDH)
- Common genetic mutations (e.g. BRAF)
- Advanced imaging (indicated for stage III, IV)
XII. Management: Surgical Excision
- Lesions <=0.8 mm Diameter: Local excision with clear margins
- Melanoma in situ: Margin 0.5 to 1.0 cm
- Breslow thickness <=1 mm: Margin 1 cm
- Breslow thickness >1 to 2 mm: Margin 1-2 cm
- Breslow thickness >2 mm: Margin 2 cm
- Lesions >0.8 mm Diameter: Refer
- Refer to surgery or surgical oncology for wide local excision
- Sentinel Node biopsy often performed at same time
-
Lymph Node biopsy indicated if Breslow thickness >1mm
- Sentinel Node biopsy for staging when Breslow thickness >1 to 4 mm (consider for 0.8 to 1)
- Complete Lymph Node dissection is no longer recommended (does not improve survival)
- Mohs Micrographic Surgery indicated where surgical margins are difficult to detect
XIII. Management: Neoadjuvant Chemotherapy and Immunotherapy
-
General
- Targeted therapies are available for gene mutations BRAF and MEK
- Targeted neoadjuvant therapy has significantly improved relapse-free 5 year survival
-
Immune Checkpoint Inhibitors (intravenous agents)
- PD-1 Inhibitors
- PD-L1 inhibitors
- CTLA-4 inhibitors
- LAG-3 inhibitors
- Relatlimab
-
Tyrosine Kinase Inhibitors (oral agents)
- BRAF Inhibitors
- Vemurafenib (Zelboraf)
- Debrafenib (Tafinlar)
- MEK Inhibitors
- BRAF Inhibitors
-
Interferon Alfa-2B (Intron A)
- Cytokine effective in increasing relapse-free survival
- Wheatley (2003) Cancer Treat Rev 29:241-52 [PubMed]
- Tumor-infiltrating Lymphocyte (TIL) Therapy
- Lifileucel (Amtagvi)
- Oncolytic Virus
- Indicated in nonresectable Melanoma
- Intralesional injection of virus Talimogene Laherparepvec (Imlygic)
- Immune Stimulators
XIV. Precautions: Defusing Myths
- Hairy moles do NOT differentiate benign from malignant
- Do not prophylacticly biopsy benign appearing moles
- Incisional Biopsy into Melanoma does NOT spread tumor
XV. Prevention
- See Melanoma Prevention
- Follow-up Immediately for:
- Pruritic nevus
- Atypical Nevus Signs
- Frequent History and physicals (with comprehensive skin exams) for high risk or Melanoma history
- Stage 0: Melanoma in situ (confined to Epidermis)
- Follow-up with full skin check, recurrence evaluation every 3 to 12 months for 1 to 2 years
- Stage I: Thickness <1 mm and no Atypical Nevus syndrome or FHx
- Follow-up with full skin check, recurrence evaluation every 3 to 12 months for 2 years
- Stage II: Thickness >1 mm or Clark's Level IV
- For Stage IIa, follow-up as per Stage I
- For Stage IIb
- Follow up every 3-6 months for first 2 years, then
- Follow up every 6-12 months for next 3 years, then
- Follow-up annually as indicated
- CBC, chemistry panel, LDH every 6 months (or per oncology recommendations)
- Consider Chest XRay and other imaging as per oncology recommendations
- No further repeat imaging indicated after the first 3-5 years disease free
- Stage III: Regional Metastases
- Diagnostics
- CBC, chemistry panel, LDH every 3-6 months (or per oncology recommendations)
- PET/CT Scan and/or CT Scan every 4 to 12 months (or per oncology recommendations)
- Consider yearly Brain MRI
- No further repeat imaging indicated after the first 3-5 years disease free
- Follow-up
- Follow up every 3-6 months for first 2 years, then
- Follow up every 6-12 months for next 3 years, then
- Follow-up annually
- Diagnostics
- Stage IV: Distant Metastases (or per oncology recommendations)
- Chest XRay, CBC, Liver Function Tests every 3 months (or per oncology recommendations)
- PET Scan and/or CT Scan every 2-4 months for first 5 years and then annually
- Consider yearly Brain MRI
- Follow-up every 3-6 months for 2 years
- Next every 6 to 12 months for 3 years
- Next follow-up yearly
- Stage 0: Melanoma in situ (confined to Epidermis)
- References
XVI. Prognosis
- See Histology and Staging above
- Survival rates are better in women
-
Relative Risk of developing a second primary tumor: 10
- Second primary cancer develops in 4-8% of Melanoma survivors
- Melanoma recurrence may occur more than 10-20 years after the initial Melanoma management
XVII. References
- Fauci (1998) Harrison's Medicine, 14th ed., McGraw-Hill
- Goldstein (2001) Am Fam Physician 63(7): 1359-68 [PubMed]
- Houghton (1998) Oncology 12:153-77 [PubMed]
- Landis (1999) CA Cancer J Clin 49:8-31 [PubMed]
- Lauters (2024) Am Fam Physician 110(4): 367-77 [PubMed]
- Rager (2005) Am Fam Physician 72:269-76 [PubMed]
- Shenenberger (2012) Am Fam Physician 85(2): 161-8 [PubMed]
- Wilbur (2014) Am Fam Physician 91(1):29-36 [PubMed]
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Related Studies
Definition (MEDLINEPLUS) |
Melanoma is the most serious type of skin cancer. Often the first sign of melanoma is a change in the size, shape, color, or feel of a mole. Most melanomas have a black or black-blue area. Melanoma may also appear as a new mole. It may be black, abnormal, or "ugly looking." Thinking of "ABCDE" can help you remember what to watch for:
Surgery is the first treatment of all stages of melanoma. Other treatments include chemotherapy and radiation, biologic, and targeted therapies. Biologic therapy boosts your body's own ability to fight cancer. Targeted therapy uses substances that attack cancer cells without harming normal cells. NIH: National Cancer Institute |
Definition (NCI) | A malignant, usually aggressive tumor composed of atypical, neoplastic melanocytes. Most often, melanomas arise in the skin (cutaneous melanomas) and include the following histologic subtypes: superficial spreading melanoma, nodular melanoma, acral lentiginous melanoma, and lentigo maligna melanoma. Cutaneous melanomas may arise from acquired or congenital melanocytic or dysplastic nevi. Melanomas may also arise in other anatomic sites including the gastrointestinal system, eye, urinary tract, and reproductive system. Melanomas frequently metastasize to lymph nodes, liver, lungs, and brain. |
Definition (NCI_NCI-GLOSS) | A form of cancer that begins in melanocytes (cells that make the pigment melanin). It may begin in a mole (skin melanoma), but can also begin in other pigmented tissues, such as in the eye or in the intestines. |
Definition (NCI_CDISC) | A malignant neoplasm composed of melanocytes. |
Definition (MSH) | A malignant neoplasm derived from cells that are capable of forming melanin, which may occur in the skin of any part of the body, in the eye, or, rarely, in the mucous membranes of the genitalia, anus, oral cavity, or other sites. It occurs mostly in adults and may originate de novo or from a pigmented nevus or malignant lentigo. Melanomas frequently metastasize widely, and the regional lymph nodes, liver, lungs, and brain are likely to be involved. The incidence of malignant skin melanomas is rising rapidly in all parts of the world. (Stedman, 25th ed; from Rook et al., Textbook of Dermatology, 4th ed, p2445) |
Definition (CSP) | malignant neoplasm derived from cells that are capable of forming melanin, which may occur in the skin of any part of the body, in the eye, or, rarely, in the mucous membranes of the genitalia, anus, oral cavity, or other sites; occurring mostly in adults and may originate de novo or from a pigmented nevus or malignant lentigo; frequently metastasize widely, and the regional lymph nodes, liver, lungs, and brain are likely to be involved. |
Concepts | Neoplastic Process (T191) |
MSH | D008545 |
ICD10 | M8720/3 |
SnomedCT | 2092003, 154501005, 189749008, 269503007, 269577007, 309331000009104, 372244006 |
LNC | LA14279-6 |
English | Malignant Melanoma, Melanoma, Melanomas, MELANOMA MALIGNANT, Malignant Melanomas, Melanoma, Malignant, Melanomas, Malignant, Melanoma malignant, [M]Malignant melanoma NOS, Malignant melanoma NOS, Malignant melanoma, no ICD-O subtype, Melanoma [Disease/Finding], malignant melanomas, melanosarcoma, melanoma syndrome, nevocarcinoma, cutaneous melanoma, melanomas, melanocarcinoma, melanoma malignant, Melanoma - malignant, [M]Naevocarcinoma, [M]Melanoma NOS, [M]Melanosarcoma NOS, [M]Melanocarcinoma, [M]Malignant melanoma NOS (morphologic abnormality), [M]Malignant melanoma NOS or melanocarcinoma or melanoma NOS (disorder), [M]Malignant melanoma NOS or melanocarcinoma or melanoma NOS, Melanoma (disorder), Malignant melanoma, no ICD-O subtype (morphologic abnormality), Malignant melanoma, no International Classification of Diseases for Oncology subtype (morphologic abnormality), Malignant melanoma, no International Classification of Diseases for Oncology subtype, MALIGNANT MELANOMA, MELANOMA, MALIGNANT, malignant melanoma, malignant melanoma (diagnosis), malignant neoplasm melanoma, Melanosarcoma, Malignant melanoma, MM - Malignant melanoma, Malignant melanoma (disorder), Malignant melanoma, NOS, Melanoma, NOS, Malignant melanoma (morphologic abnormality), Malignant melanoma, morphology (morphologic abnormality), melanoma |
Portuguese | MELANOMA MALIGNO, Melanoma maligno, Melanoma Maligno, Melanoma |
Spanish | MELANOMA MALIGNO, melanoma maligno, no clasificado como subtipo en CIE-O (anomalía morfológica), melanoma maligno, sin subtipo en la CIE O (anomalía morfológica), melanoma maligno, no clasificado como subtipo en CIE-O, melanoma maligno, sin subtipo en la CIE O, melanoma maligno, morfología, [M]melanoma maligno, SAI (anomalía morfológica), [M]melanoma maligno, SAI, melanoma maligno (anomalía morfológica), melanoma maligno (trastorno), melanoma maligno, melanoma, Melanoma maligno, Melanoma, Melanoma Maligno |
Dutch | melanoom maligne, melanoom, maligne melanoom, Maligne melanoom, Melanoom |
German | Melanom boesartig, MELANOM MALIGNE, boesartiges Melanom, Melanom, Bösartiges Melanom |
Swedish | Melanom |
Japanese | アクセイコクショクシュ, コクショクシュ, 黒色腫, 悪性黒色腫, メラノーマ, メラノーム, 黒色癌腫, 黒色肉腫, 黒色癌 |
Czech | melanom, Melanom, Maligní melanom, maligní melanom |
Finnish | Melanooma |
Italian | Melanoma maligno, Melanoma |
Russian | MELANOSARKOMA, MELANOMA ZLOKACHESTVENNAIA, MELANOMA, MELANOBLASTOMA, МЕЛАНОБЛАСТОМА, МЕЛАНОМА, МЕЛАНОМА ЗЛОКАЧЕСТВЕННАЯ, МЕЛАНОСАРКОМА |
French | MELANOME MALIN, Mélanome, Mélanome malin |
Croatian | MELANOM |
Polish | Czerniak, Czerniak złośliwy |
Hungarian | Rosszindulatú melanoma, Melanoma, Melanoma malignum |
Norwegian | Malignt melanom |
Ontology: Cutaneous Melanoma (C0151779)
Definition (NCI) | A primary melanoma arising from atypical melanocytes in the skin. Precursor lesions include acquired and congenital melanocytic nevi, and dysplastic nevi. Several histologic variants have been recognized, including superficial spreading melanoma, acral lentiginous melanoma, nodular melanoma, and lentigo maligna melanoma. |
Concepts | Neoplastic Process (T191) |
MSH | C562393 |
ICD9 | 172.9, 172 |
ICD10 | C43 , C43.9 |
SnomedCT | 190105009, 269577007, 154501005, 154506000, 188082007, 321031000009106, 93655004 |
LNC | LP36756-2, MTHU019305 |
English | MM-Malignant melanoma of skin, Mal melanoma/skin,unspecfd, Malignant melanoma of skin NOS, Malignant melanoma of skin, unspecified, [X]Mal melanoma/skin,unspecfd, [X]Malignant melanoma of skin, unspecified, Cutaneous Melanoma, FAMMM, DYSPLASTIC NEVUS SYNDROME, HEREDITARY, CMM, MELANOMA, FAMILIAL, FAMILIAL ATYPICAL MOLE-MALIGNANT MELANOMA SYNDROME, DNS, MLM, malignant melanoma of skin (diagnosis), malignant melanoma of skin, Melanoma of skin (malignant), Malignant melanoma of skin stage unspecified, Melanoma skin, Skin melanoma, Malig melanoma skin NOS, Melanomas of skin, Melanoma (malignant) NOS, melanomas of skin, skin cancer melanoma, cutaneous malignant melanoma, melanoma skin cancer, skin melanomas, skin melanoma cancer, malignant melanoma skin, malignant cutaneous melanoma, melanoma skin, skin malignant melanoma, cancer melanoma skin, skin melanoma, MELANOMA, CUTANEOUS MALIGNANT, Cutaneous melanoma, Melanoma, Cutaneous Malignant, Dysplastic Nevus Syndrome, Hereditary, Melanoma, Familial, Fammm, Familial Atypical Mole-Malignant Melanoma Syndrome, [X]Malignant melanoma of skin, unspecified (disorder), Malignant melanoma of skin NOS (disorder), Melanoma of skin (disorder), Melanoma of skin, Malignant melanoma of skin, Cutaneous malignant melanoma, MM - Malignant melanoma of skin, Malignant melanoma of skin (disorder), cutaneous melanoma, melanoma, cutaneous, Skin cancer, melanoma, melanoma; skin, skin; melanoma, Malignant melanoma of skin, NOS, Malignant Cutaneous Melanoma, Malignant Melanoma (of Skin), Stage Unspecified, Malignant Melanoma of Skin Stage Unspecified, Malignant Melanoma of Skin, Melanoma of Skin, Melanoma of the Skin, Skin Melanoma, Skin, Melanoma, Melanoma of skin, site unspecified |
Dutch | melanoom van de huid, plaats niet-gespecificeerd, melanoom van de huid (maligne), maligne melanoom van de huid, melanoom huid, melanoom van de huid maligne niet-gespecificeerd stadium, huidmelanoom, huid; melanoom, melanoom; huid, Maligne melanoom van huid, niet gespecificeerd, Maligne melanoom van huid |
French | Mélanome cutané (malin), Mélanome malin cutané stade non précisé, Mélanome cutané, Mélanome cutané malin, Mélanome cutané, site non précisé |
German | Melanom der Haut (boesartig), Melanom der Haut, Stelle unspezifisch, Hautmelanom, Melanom Haut, boesartiges Melanom der Haut, boesartiges Melanom der Haut Stadium unspezifisch, Boesartiges Melanom der Haut, nicht naeher bezeichnet, Boesartiges Melanom der Haut |
Italian | Melanoma cutaneo (maligno), Melanoma maligno della cute stadio non specificato, Melanoma cutaneo, sede non specificata, Melanoma della cute, Melanoma maligno della cute, Melanoma cutaneo |
Portuguese | Melanoma cutâneo maligno, Melanoma cutâneo, Melanoma cutâneo de localização NE, Melanoma maligno da pele, Melanoma maligno cutâneo estádio NE |
Spanish | Melanoma maligno de piel en estadio no especificado, Melanoma de piel, zona no especificada, Melanoma maligno de la piel, Melanoma de piel (maligno), Melanoma de piel, Melanoma cutáneo, melanoma maligno cutáneo, SAI, melanoma maligno de piel, SAI (trastorno), [X]melanoma maligno de piel, no especificado (trastorno), Malignant melanoma of skin NOS, melanoma maligno de piel, SAI, [X]melanoma maligno de piel, no especificado, melanoma maligno de la piel (trastorno), melanoma maligno de la piel |
Japanese | 皮膚悪性黒色腫、病期不明, 皮膚の悪性黒色腫, ヒフアクセイコクショクシュビョウキフメイ, ヒフノアクセイコクショクシュ, ヒフコクショクシュアクセイ, ヒフコクショクシュ, 皮膚黒色腫(悪性), 皮膚黒色腫 |
Czech | Melanom kůže blíže neurčené lokalizace, Maligní melanom kůže, Melanom kůže (maligní), Melanom kůže, Maligní melanom kůže blíže neurčeného stadia, Kožní melanom |
Korean | 상세불명의 피부의 악성 흑색종, 피부의 악성 흑색종 |
Hungarian | Bőrmelanoma (malignus), Bőrmelanoma, Bőr malignus melanomája, Bőr nem meghatározott stádiumú malignus melanomája, Bőr nem meghatározott helyű melanomája, Bőr melanomája |