Melanoma History John Hunter



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Melanoma
History
John Hunter (1728-1793)

  • first published account of a patient with melanoma (a secondary deposit) 1787 – but was not known as “melanoma”, histological confirmation only in 1968 by Bodenham described as “melanocytic sarcoma cells”

Rene Laennec (1781-1826)

  • First to describe melanoma as a disease entity in a publication

  • Others claim Dupuytren was the first to describe it in lectures as “cancer noire”

  • First coined the word melanosis in 1812

  • Described metastatic deposits throughout the body in post mortems

William Norris (1792-1877)

  • First to describe melanoma in English literature 1820 and study it in depth

  • First noted hereditary tendency

  • Also described metastatic deposits in 1857

  • English general practitioner in Stourbridge for 60 years

  • Published the first comprehensive study of case series of patients with “melanosis”

  • Norris alluded to several principles on melanoma:

    • Epidemiological features (moles & melanomas, industrial > rural, light coloured, hereditary disposition, trauma accelerate growth)

    • Pathological features (colour, variable pigmentation, satellite tumours, subcutaneous deposits, widespread dissemination)

    • Clinical features (smokers, men, usually in good health until late stage)

    • Management (recurrence, wide excision, no effective treatment for disseminated disease)

Jonathan Hutchinson (1828-1913)

  • First described subungual melanoma in 1857

  • Described a series of cases of “Hutchinson’s melanotic freckle” in 1892

  • An English Generalised Specialist, wrote the Journal: Archives of Surgery for over 11 years

Other notable individuals in 19th and early 20th century

  • Robert Carwell in 1834 used the term melanoma as a synonym for melanosis and then described it in his book in 1838

  • David Williams in 1834 described the horizontal and vertical growth phases of a superficial spreading melanoma

  • Samuel Cooper in 1840 described enucleation of a an eye for melanosis

  • James Paget 1853 described a large series of 25 patients

  • Oliver Pemberton collected 60 patients, published 25 cases 1858, also described the first case of melanoma in a black man

Late 19th century - WLE of 1O melanoma accepted but controversies regarding ELN dissection began - Snow in 1892 wrote as proponent for elective lymph node dissections in Lancet

Early 20th century - proponents of ELN dissection and WLE

- also greater awareness that melanoma arose out of both moles and clear skin



William Sampson Handley (1872 – 1962)

  • 1907 recommendations in lectures (based on a single autopsy!)  extensive excisions (an inch margin, to fascia) +/- amputation, regional lymph node dissection

  • Formed the basis for melanoma treatment for the following 50 years!

Sophie Spitz (1910 – 1956)

  • With Allen delineated in 1948 the “benign juvenile melanoma”  better diagnosis in children and avoided unnecessary surgery (named “Spitz naevus” in 1967 by McGovern)

  • Also recognised ulceration in melanoma as a major adverse prognostic factor

  • Both were staff pathologists at Memorial Hospital

Vincent McGovern (1915 – 1983)

  • Pathologist in Australia

  • Published 100 articles and 3 books on melanoma

  • Organised, chaired international consensus on classification and melanoma reporting

  • 1972 – first international consensus meeting on melanoma  1972 classification

  • Revised in 1982 at a second international pathologist meeting

  • First to associated sunlight to development of melanoma

  • First to delineated prognostic histopathological features

  • First to describe regression in melanomas

  • Documentation of tumour thickness as an independent prognostic factor using work from Sydney Melanoma Unit database

Alexander Breslow (1928 – 1980)

  • Professor of pathology at George Washington University Medical Centre

  • Delineated primary melanoma thickness as easy prognostic indicator for risk of local recurrence and metastasis – results reproducible.

  • First paper published in 1970 – later increase in a series of 138 patients

  • All those with 0.75mm survived, then staged as multiples of 0.75mm as prognostic thresholds

  • 248 patients – results showed that tumour thickness was a better predictor of metastases & survival than level of invasion or any other parameter!

  • Subsequently examined margins of resection

Wallace H. Clark Jr (1924 – 1997)

  • Physician at MGH, and University of Pennsylvania

  • 1969 described the “Clark levels” of invasion  prognostication

  • Also described superficial spreading form of melanoma

  • Described the B-K mole (i.e. dysplastic nevus or “Clark’s nevus) as a precursor or marker of increased risk

  • Developed concept of radial growth phase (no metastatic capacity) and vertical growth phase (metastatic capacity)

  • Described other prognostic factors: tumour site, patient sex, tumour thickness, mitotic rate, regression and degree of host response (lymphocytic infiltration)



Epidemiology
Incidence

  • Increasing () incidence in all Caucasian populations, ~5% per year

Racial Difference

  • 2x  in Hispanic from 1.5/100,000 (1986) to 3.0/100,000 (1996) with higher mean age than Caucasian population (~60 y.o.)

  • Extremely low rates in Asians, ~0.2/100,000, slight  in women (Japan 1987)

  • African-Americans have a male preponderance 4:1, majority are acral lentiginous

The Epidemiological Data

  • Incidence Trends

    • Melanoma risk is high in those born before 1950

    • Melanoma incidence is / for those born after 1950

    • Melanoma incidence is  for females born after 1960

  • Anatomic Site trends studied in Canada and NZ – both showed rates for upper limb and trunk in both sexes

  • Age & Sex

    • Mean age of diagnosis range 50 – 58 years (10 years earlier than other common tumours)

    • Ratio of male:female varies by country

    • NSW, Australia study show: younger age groups are  (males) and  (females), continuing to  in those over 65

    • USA, males under 60 rates are  or , but for over 60 rates are 

    • USA, age specific rates show sharp  in incidence in males over 45

  • Thickness of tumour – largest  incidence is in thin melanomas (<0.75mm)

    • ANZ –  in thick (>0.75mm) lesions in <65 y.o.,  in thick lesions >75 y.o., all age group show  in thin lesions except men <34 and women <49 y.o., no change in median tumour thickness

    • Europe – median tumour thickness  1.2mm to 0.8mm,  in thin melanomas (esp. females),  incidence of thick melanomas, invasive melanoma  during 1980’s then  after 1989

    • USA –  in thin lesions (<1.00mm) in <65 y.o.,  in thick lesions in >65 y.o., Lee found in situ tumours were in older patients c.f. invasive tumours, incidence of in situ melanoma has a greater  in incidence

World Incidence

  • Incidence rate in the world range from 0.2/100,000 (China) to 40.5/100,000 (Males in Australia)

  • Australia Ranks no.1 for male (male 40.5/100,000 and female 31.8/100,000)

  • New Zealand Ranks no.1 for female (male 36.7/100,000 and female 34.9/100,000)

Mortality



  • Rates are 5x lower than incidence rates

  • Female have better survival rates after diagnosis (?earlier detection or tumour biology)

Australia

  • 3rd most common cancer in Australia

  • Risk <75 y.o. Male 1 in 25, Female 1 in 36

  • Peak risk in 4th decade of life

  • Most common sites is face and ears in both sexes

  • 52% at diagnosis is <0.75mm

(Baade; Trends in melanoma mortality in Australia: 1950-2002 and their implications for melanoma control. Aust N Z J Public Health. 2005 Aug)


  • significant decreases in mortality rates for men and women younger than 55 years (percentage change per year, men 35-55 years: -2.4%; women: -2.9%)

  • For ages 55-79 years, rates are now stable for both men

  • men and women 80 years or older, rates have continued their statistically significant increase of 3-4% per year

  • most likely cause of the recent statistically significant decreases in mortality is early detection.

Western Australia



  • Increasing incidence of 4-5% per year

  • Most common cancer from 15-39 y.o.

  • In WA 2000, 70% melanoma <1mm, median thickness is 0.6mm

  • Melanoma diagnosed in older persons are thicker and more invasive at time of diagnosis (up to 25% of diagnosed in >75y.o.)

Summary

  • Incidence of melanoma continues to  esp. in older males

  • The  incidence is highest in thin lesions

  • Different countries are at different points along the melanoma epidemic in incidence and mortality (Australia/Nordic/USA ing  UK/Canada just started   France/Italy/Eastern Europe still ing)

  • Evidence still not convincing that changed sun exposure patterns has led to ing incidence in countries such as Australia


Pathogenesis, Risk Factors, Prevention & Screening
Pathogenesis (Hypothesis)

  • Melanocytes on basal membrane in epidermis produce melanin  distributed to surrounding keratinocytes by dendritic projections

  • Melanin absorbs UV energy and free radicals produced by UV radiation (which would normal act on membrane lipids and other cellular chromophores)

  • Melanin is distributed within cells as supranuclear caps which protect cell nucleus from injury

  • Tanning  increased rate of melanogenesis within melanocytes  absorbs more UV radiation (SPF ~3-5), epidermal melanocytes increase in number within 1-2 weeks but limited in proliferative ability

  • Melanocytes are more resistant apoptosis, after severe sun exposure, substantial damage to DNA in both melanocytes and keratinocytes occur with keratinocytes undergo apoptosis but melanocytes do not undergo apoptosis so melanocytes undergo DNA repair (limited ability in melanocytes)  accumulation of minimal damage  eventually lead to malignant change and melanoma

Environmental Risk Factors

  1. Sun exposure

  • Principal risk factor for melanoma, 2/3 of cases strongly assoc. with history

  • Early intermittent exposure more at risk than chronic exposure (but not shown in Australian studies), supported in European studies and also because disease seen in higher socioeconomic class

  • Body site incidence assoc. with greater sun exposure areas

  • Migrant study: childhood immigrant arriving >15y.o. has ¼ of the risk of residing population, but those arriving earlier has higher risk than those arriving later

  • Latitude variation (higher incidence in USA and Australia with closer to equator) – but confounded by racial/skin colour difference in Europe, Nordic countries has higher rates than southern Europe

  • UVA is major component of sun exposure, cause oxidative DNA damage, in animals can induce melanomas, also the ray used in tanning facilities

  • Long latent period from exposure to disease

  • Sunlight damage is cumulative (D. Holman & P. Heenan)

  1. Tanning Booths and Sunbeds

  • UVA radiation delivery may be a risk factor but studies have been inconsistent

  1. Ozone Layer depletion:

  • Loss ability in blocking UVB, thus more reaches earth’s surface

  • For each % decrease in amount of ozone, melanoma incidence increases by 1%

Some data not supporting sun exposure

  • Higher incidence in countries further from equator  racial/ethnic influence

  • Almost 50% of cases worldwide occur on parts of the body not routinely exposed to sunlight  intermittent exposure theory?

Genetic Risk Factors

  • Very small increase in melanoma incidence in families with member diagnosed

  • 10% cases have FHx = family clusters with younger age onset

  • 2% of all cases have genuine inheritance of susceptibility genes (e.g. CDKN2 tumour suppressor gene on 9p21)

  • Risk associated with one affected first degree relative is 2.2

  • Genetic disorders assoc with increased melanoma incidence:

    • Xeroderma pigmentosum (3% will develop melanoma, RR 100 in < 20 y.o.)

    • BK (dysplastic) mole syndrome (described by Clarke 1975) or familial atypical mole and melanoma (FAMM) syndrome – multiple large dysplastic naevi (described by Lynch in 1978)

Other Associated Risk Factors




  • Fair complexion, inability to tan, freckles, solar lentigines, light coloured eyes, fair or red hair – increase in relative risk 2-4x (accounts for incidence difference in racial groups)

  • Past Hx of non-melanoma skin cancers = index of sun exposure RR 2.4-3.6

  • Past Hx of melanoma – 4.5% within 5 years

  • Freckles – strongly associated with melanoma, but reflective of skin type and ethnic background

  • Number of nevi - >20 nevi on arm increases risk 10-20x.

  • Multiple dysplastic naevi

  • Large congenital melanocytic naevi

  • Immunodeficiency states (studied in renal transplant patients)

  • PUVA treatment (for psoriasis)  studies inconsistent but relative increase of melanoma incidence, and BCC has been shown in some long-term studies






Risk Factors NOT Associated with Melanoma

  • Smoking

  • Diet

  • Hormones

Prevention

Recommendation by the Australian Cancer Society



  • Physical protection should be the primary preventive measure

    • Avoidance of direct sunlight (esp two hours on either side of solar noon)

    • Use of shade structures

    • Wearing sun protective clothing, hats

  • Sunscreens (only as an adjunct to above!)

    • Min SPF of 15, broad spectrum

    • These are filters only, not blocks, some sunlight damage still continues

    • Studies on its effect is equivocal – but assoc. w greater sun exposure in subjects who use sun-screen!

    • Reapply at intervals, water-proofing

  • Advise against tanning salons

Screening

  • No data to show screening of general population to be effective in controlling mortality

  • Surveillance of high risk group has been shown to detect disease at an earlier stage

  • All those at high risk should be advised re:

    • Education and self-examination

    • Appropriate prevention

    • Regular follow-up

    • Baseline photography

  • High Risk Groups requiring Surveillance:

  1. Multiple dysplastic naevi

  2. Families with history of multiple dysplastic naevi syndrome or melanoma (1st degree relative)

  3. Large congenital melanocytic naevus


Moles and Precursor Lesions
Superficial spreading melanoma is thought to arise from:
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