melanoma

see also:

• skin cancer
• neoplasia / cancer / tumours

• melanoma is the skin cancer which causes the most deaths as it tends to metastasize early and has proven difficult to treat once it has spread
• 90% of melanomas are caused by sporadic damage to the genes which occurs by chance exposure to environmental agents such as UV light
• certain people are at higher than normal risk of melanoma even without UV exposure, in particular, fair-skinned red-heads such as those of Celtic origin
• there are other much less common familial cases
• it appears infection with Candida albicans increases the aggressiveness of melanomas by activating signalling pathways (p38-MAPK/c-Fos/AP-1 and HIF-1/HIF-1α/c-Fos/AP-1 pathways) in the melanoma cells, and, as a result, creates an environment that helps to reprogram angiogenesis and metabolism ¹⁾

• UV light exposure especially UVB
  • “DNA comprises four chemical bases that exist in pairs – adenine (A) and thymine (T), and cytosine (C) and guanine (G). Different sequences of these pairs encode all of the instructions for life. In melanoma, the problem occurs when UVB radiation from the sun hits certain sequences of bases – CC, TT, TC and CT – causing them to chemically link together and become unstable. The resulting instability causes a chemical change to cytosine that transforms it into uracil, a chemical base found in the messenger molecule RNA but not in DNA. This change, called a “premutation,” primes the DNA to mutate during normal cell replication, thereby causing alterations that underlie melanoma.”²⁾
• dysplastic nevi
• PH melanoma
• age - median age is 50yrs
• family history and known genetic mutations
  • If a person has a close relative (parent, brother, sister, or child) who has been diagnosed with melanoma, his or her risk of developing melanoma is 2 to 3 times higher than the average risk
  • Caucasians - white people have 20x risk compared to black people
• fair skin with tendency to freckling, blonde or red hair, blue eyes phenotype in who their skin tends to burn rather than tan
• immunosuppression
• rare disorders that have increased risk of melanoma:
  • xeroderma pigmentosum (XP)
  • retinoblastoma
  • Li-Fraumeni syndrome
  • Werner syndrome
  • BRCA2 breast cancer gene increases risk mildly

• 8% have a first degree family member with melanoma
• 1-2% have 2 or more close relatives with melanoma
• individuals in melanoma-prone families frequently have moles called dysplastic nevi
• those with familial melanoma tend to be diagnosed earlier in their 30's compared to 50's in the general population
• within melanoma-prone families with known genetic mutations, dysplastic nevi (moles) and sun exposure are independent risk factors for melanoma.
• familial melanoma tends to occur in an autosomal dominant manner
• genes have been linked familial melanoma but these only occur in a minority of cases of familial melanoma:
  • CDKN2A
    • risk of melanoma in CDKN2A mutation carriers is approximately 14% by age 50 years, 24% by age 70 years and 28% by age 80 years.
  • MDm2 gene
    • an essential negative regulator of the p53 tumour suppressor protein
    • mutations in the MDm2 gene predispose women, but not men, to develop melanoma at a younger age
  • CDK4
  • RB1 gene
    • germline mutations in the retinoblastoma gene (RB1) itself, in the INK4A–CDK4/6–RB pathway, could lead to a 4-fold to 20-fold increased risk of melanoma
  • MC1R gene alters the risk of melanoma and variations are associated with freckling and red hair.
    • people who have olive and darker skin and who carry one or more variations of this gene have a higher than average risk for melanoma.
  • TYR, TYRP1, and ASIP genes
  • 0.5% have AD POT1 mutation and this is associated also with lymphomas - accounts for 2.4-4% of familial melanoma cases ³⁾

• see also: https://dermnetnz.org/topics/genetics-of-melanoma/
• 40-60% have an abnormal serine-threonine protein kinase (BRAF) which is involved in activation of mitogen-activated extracellular signal regulated kinases (MEK1 and 2) which are part of a pathway that regulates cell proliferation
  • trametinib is a kinase inhibitor which reversibly blocks MEK1 and 2 in melanoma cells with the BRAF mutation and appears to improve 6 month survival from 67% to 81% compared with chemotherapy using dacarbazine or paclitaxel, and when added to dabrafenib, 6 month survival improved from 5.8 months to 9.4 months compared with dabrafenib alone, while induction of squamous cell carcinomas decreased from 19% to 7%.
• in 2013, a report of familial melanoma in an Indian family suggested that an identical mutation in the gene for telomerase was responsible
• most tissue samples of the much more common, sporadic non-inherited melanoma shows alterations in the telomerase gene switch resulting in over-active telomerase

• ASSYMETRY
• BORDER irregularity
• COLOUR variation
• DIAMETER > 6mm or growing
• EVOLVING
  • Changes in size, shape, colour, elevation, or another trait (such as itching, bleeding or crusting).(This last point is likely the strongest of all of the warning signs)

• dermoscope is a tool giving 10x magnification with a light source at 20deg allowing visualisation of the dermoscopic characteristics resulting from the presence of melanin and haemoglobin in the different skin layers.
• using this tool with training, diagnostic accuracy may increase from 58% to 76% compared to naked eye
• it will NOT detect featureless melanoma but these may be suspected from recent changes in size, shape, and/or color and this is the potential benefit of sequential dermoscopy (mole mapping)
  • any of the following lesions should be considered for biopsy unless unequivocal diagnosis of seborrhoeic keratosis can be made:
    • any changing lesion on an adult
    • any lesion on the head or neck with dermatoscopic grey appearance
    • any nodular pigmented lesion
    • any acral lesion with a parallel ridge pattern
• Fed Pract. 2018 Using Dermoscopy to Identify Melanoma and Improve Diagnostic Discrimination
• https://www.racgp.org.au/afp/2012/july/dermatoscopy-in-routine-practice/

• developed in 1998 by Argenziano et al
• concerning for melanoma if total score ≥ 3 points
• major criteria (2 points each):
  • atypical pigment networks
    • pigmented lines and hypopigmented holes in a grid network
    • sens. 21-100%
  • blue-white veil
    • blue pigmentation with a glassy haze
    • sens. 11-94% spec. 74-99% odds ratio 1.7-13
  • atypical vascular pattern
• minor criteria (1 point each):
  • atypical dots and globules of color
    • black, brown, or blue-gray round structures
    • sens. 13-39% spec. 74-92% odds ratio 1.7-4.8
  • irregular streaks
    • black or brown radial projections at the border of the lesion
    • sens 5-58%
  • regression structure
    • depigmented region similar to a scar that may present with gray peppering
    • sens. 11-79%; spec. 63-99% odds ratio 2-18.3
• other:
  • negative network
    • serpiginous lines of hypopigmentation surrounded by globular structures
    • sens. 22-34% spec. 77-95% odds ratio 1.4-1.8

• developed by Menzies et al in 1996
• Highly suggestive of melanoma if absence of pattern symmetry AND color uniformity, AND at least one of the following:
  • Blue-white veil
  • Multiple brown dots
  • Pseudopods
  • Radial streaming
  • Scarlike depigmentation
  • Peripheral black dots/globules
  • 5–6 colors
  • Multiple blue/gray dots
  • Broadened network

• developed by Stolz and colleagues in 1994
• Total dermoscopic score ≥ 5.45 is highly suggestive of melanoma;
• Total dermoscopic score = 1.3 (A score) + 0.1 (B score) + 0.5 (C score) + 0.5 (D score).

• developed by Henning et al in 2006 with the intention of assisting less experienced dermoscopy users
• Highly suggestive of melanoma if total score ≥ 8 points.
• Color (1 pt each):
  • Light brown
  • Dark brown
  • Black
  • Red
  • White
  • Blue
• Architectural disorder (0–2 points)
• Symmetry (0–2 points)
• Homogeneity (1 point each)
  • Atypical network
  • Dots/globules
  • Streaks/pseudopods
  • Blue-white veil
  • Regression structures
  • Blotches
  • Polymorphous blood vessels

• developed by Rogers et al in 2016
• “Does the lesion exhibit clear dermoscopic evidence of an angioma, dermatofibroma, or seborrheic keratosis?”
  • if NO, “Does the lesion exhibit architectural disorder?”
    • if YES then biopsy
    • if NO, “Does the lesion contain any starburst patterns, blue-black or gray coloration, shiny white structures, negative networks, ulcers or erosions, and/or vessels?”
      • if YES then biopsy

• Exceptions which should be biopsied: changing lesions on adults, dermatoscopic grey on head or neck, pigmented nodular lesions, parallel ridge pattern (palms or soles)
• pigmented skin lesion
  • is chaos present?
    • NO ⇒ no intervention
    • YES
      • is clue present?
        • NO ⇒ no intervention
        • YES ⇒ biopsy
• Chaos:
  • asymmetry of structure or colour
• Clues:
  • 1 – eccentric structureless
  • 2 – thick lines reticular
  • 3 – grey dots
  • 4 – black dots, peripheral,
  • 5 – radial lines, segmental
  • 6 – white lines
  • 7 – polymorphous vessels
  • 8 – parallel ridge pattern

• superficial spreading melanoma
  • most common form accounting for 70% of melanomas in Caucasians
  • may grow for several years along the outer layer of the skin.
• nodular melanoma
  • 15% of melanomas
  • around a quarter are skin coloured and thus are harder to diagnose early
  • accounts for most of melanoma deaths!
• acral-lentiginous melanoma
  • may be found on the palms of the hands, soles of the feet and under the nails
  • accounts for up to 70% of melanomas in African Americans and 46% of all cases in Asians
• lentigo maligna melanoma
  • the most common form of melanoma in Hawaii
  • prevalence increases with age and prolonged sun exposure
• amelanotic melanoma
  • rare, difficult to Dx as lacks pigment
• desmoplastic melanomas
  • rare, usually found on head and neck of elderly patients
• ocular melanoma
  • account for 3% of melanomas and usually arise in the iris