Cutaneous Malignant Melanoma

Cutaneous Malignant Melanoma
The science behind the guidelines
For decades the frequency of cutaneous melanomas worldwide has been
increasing faster than any other cancer. Melanomas cause about 90 percent
of skin cancer mortality. Even seemingly small lesions can be life-threatening
because just a few millimeters in depth of invasion can effectively make the
difference between life and death.
Melanomas are malignant tumors which derive from certain melanincontaining cells in the body and pre-dominantly manifest on the skin. In rare
cases, melanomas may also appear in the eye (choroid, conjunctiva or uvea),
in the meninges or on mucosal surfaces in different locations. In relation
to their size, melanomas have a very high tendency to metastasize, which
leads to an unfavorable prognosis. Melanomas therefore cause about 90
percent of skin cancer-associated mortality, although other skin cancers are
considerably more common clinically. Despite this, melanomas are usually
curable if recognized and treated at an early stage. Today, about 90 percent of
melanomas are without obvious metastasis at the time of diagnosis.
Epidemiology
Sun exposure during childhood
is an important risk factor for
developing melanomas.
The incidence of melanomas has steadily increased in the white population
worldwide over the last few decades, especially in areas with high sun
exposure. At an average of 6 percent per year, the increase of melanomas over
the last 50 years has been faster than for any other cancer. In central Europe,
the incidence averages about 10 to 12 cases per 100,000 inhabitants per
year, in the United States 10 to 25 cases, and the highest incidence rates are
reported from Australia, with 50 to 60 cases per 100,000. In ethnic groups
with stronger pigmented skin, like native African and Asian populations,
melanomas are very rare but no less serious.
Graph 1: Melanoma incidence in the white U.S. ­population over 1970-201011
Melanoma incidence rate per 100,000 USA (white population)
30
25
20
15
10
Source: seer.cancer.gov/faststats/
5
1970
1975
1980
1985
1990
1995
2000
2005
2010
Munich Re
Cutaneous Malignant Melanoma.
Page 2/4
Risk factors for developing melanomas
It is generally accepted that sun exposure plays a major role in the develop­
ment of melanomas. Only 5–10 percent of melanomas are related to hereditary
factors. Sun exposure during childhood seems to have more impact than
during adulthood, which is in contrast to epithelial skin cancer.
Number of moles and
atypical moles are indicators
for the risk of melanomas.
The number of melanocytic nevi (moles) on the body surface can be seen as
an indicator for the risk of developing melanoma, where the probability for
melanomas steadily increases with the number of moles on the skin4. In the
presence of atypical moles, the risk further increases. Atypical moles are moles
with either clinical atypical findings (e.g., size over 5 mm or irregular borders)
or microscopic abnormalities.
To take this risk into consideration, the impairments “atypical mole syndrome”
and dysplastic nevus syndrome have been included in EDGE. The atypical
mole syndrome is defined according to the following criteria:
■■ 50 to 100 or more nevi and
■■ at least one ≥ 8 mm diameter and
■■ at least one with atypical features
Depending on the number of atypical moles and a family history of melanomas,
there is a wide range of melanoma risk and therefore extra-mortality in this
impairment4, 5.
Table 1: Odds ratios of melanoma in relation to the number of common
and atypical nevi5
Numbers of atypical nevi
Numbers of common nevi
0
1
≥2
0–24
1.0*
5.9
5.5
25–49
1.8
6.5
2.0
50–99
2.4
5.6
12.0
≥ 100
2.6
6.2
53.5
*Odds ratios
Classification of melanoma in EDGE
EDGE ratings for melanoma
have been revised according
to the latest international
prognostic standards.
In 2009, a new internationally acknowledged staging classification for melanomas was instituted by the American Joint Committee on Cancer (AJCC)
after analysis of a large database of melanoma patients from 13 international
cancer centers including Australia and Europe3. The investigations of the
AJCC are the largest prognostic factor studies on melanoma patients
worldwide. The staging system is based on melanoma thickness in mm
and presence or absence of lesion ulceration as the two major prognostic
indicators. Additionally, T1 tumors without ulceration are categorized into T1a
or T1b according to mitotic rate. This was a change compared to the previous
classification, where Clark’s level of invasion had been used instead of mitotic
rate1. (Mitotic rate data may not always be reported, e.g., in older pathology
reports, therefore, in EDGE, Clark’s level can still be used in absence of mitotic
rate data for classifying T1 lesions). According to the AJCC staging analysis,
the location of melanomas (e.g. trunk, extremities, head) and growth patterns
(e.g. lentigo maligna, superficial spreading, nodular) need not be taken into
account for determining the prognostic staging group1.
Munich Re
Cutaneous Malignant Melanoma
Page 3/4
Table 2: Classification of T stages in AJCC 2009 melanoma staging3
Classification T
Thickness (mm)
Ulceration status/Mitoses
Tis
NA
NA
T1
≤ 1.00
a: Without ulceration and mitosis < 1/mm2
b: With ulceration or mitoses ≥ 1/mm2
T2
1.01–2.00
a: Without ulceration
b: With ulceration
T3
2.01–4.00
a: Without ulceration
b: With ulceration
T4
> 4.00
a: Without ulceration
b: With ulceration
Graph 2: Survival of melanoma patients related to staging published
by AJCC 20093
Survival rate proportion
1.0
0.9
0.8
0.7
0.6
T1a (n = 9,452)
T2a (n = 6,529) T3a (n = 3,127)
T4a (n = 1,064)
T1b (n = 2,389)
T2b (n = 1,517)
T3b (n = 2,164)
T4b (n = 1,397)
Source: Final version of 2009 AJCC
melanoma staging and classification3
0.5
0.4
0.3
0.2
0.1
0
0
2.5
5.0
7.5
10.0
12.5
15.0
17.5
20.0 Time (years)
Graph 3: Melanoma ten-year mortality rate in relation to tumor thickness2
10-year mortality rate ( percent)
100
80
60
40
Source: Prognostic factor analysis
of 17,600 melanoma patients: validation of
the American joint committee on cancer
melanoma staging system2
20
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Tumor thick­
ness (mm)
Looking at the prognosis of melanomas, it is worth noting that a very small
increase of thickness in melanomas makes a big difference in terms of survival.
Most of the prognostic impact takes place within the first four millimeters
where the ten-year mortality rate increases from 5 percent to 50 percent
(see Graph 3).
The new AJCC staging system has been implemented into the melanoma
section in EDGE. The Clark’s level can still be used instead of mitotic rate,
because there may be no information about mitosis in cases dating back some
years or depending on the reporting lab. Munich Re did an extensive extramortality analysis on the SEER (Surveillance Epidemiology and End Result)
database of the U.S. National Cancer Institute using the AJCC staging system
as the prognostic grid10.
Munich Re
Cutaneous Malignant Melanoma
Page 4/4
The most frequent T1a
melanomas have virtually
normal survival rates, but
then prognosis dramatically
­deteriorates with minimal
increase of the tumor depth.
On the basis of our analysis, the most frequent melanoma, stage 1A (T1aN0M0),
shows virtually normal survival rates and can be accepted as standard for life.
Progressively higher stages demonstrate increasing mortality with stage IIB
being insurable only at highly substandard rates. Fortunately, the vast majority
of newly diagnosed melanomas today fall into insurable categories and
again most of them into the favorable T1a group. Our results from the SEER
database are on all stages congruent with the published survival rates from the
AJCC studies1, 3. One result for Stage IB (T1bN0M0) as an example is given in
Graph 4.
Graph 4: Survival with derived excess mortality (patients vs. normal population)
Survival ( percent)
Excess death rate (per mille)
100
16
14
80
12
10
60
8
Melanoma Stage IB (T1bN0M0), N = 4526
Patients
Normal population
40
6
4
20
Source: Munich Re own calculations
based on U.S. SEER data base10
2
0
0
1
EDGE allows rapid and
reliable risk assessment
on the basis of only a few
prognostic criteria.
5
10
15
Years after diagnosis
1
5
10
15
Years after diagnosis
It is also evident from our results – as well as consistently shown by other
studies – that melanomas bear a significant long-term risk going beyond ten
years after diagnosis7, 8, 9. In a study at Duke University among 651 long-term
melanoma survivors, 25 percent developed recurrent disease after more than ten
years7. Also ultra-late recurrences after more than 15 years are not uncommon9.
Summary
Melanoma ratings are now based on the most recent AJCC staging system.
Extramortalities have been calculated based on the U.S. SEER database and have
been compared internationally. Results show that prognosis of melanoma rapidly
deteriorates with increasing tumor stage. Fortunately, these early diag­nosed
melanomas constitute the majority of all patients. In many cases, melanomas
bear a long-term risk which definitely goes beyond ten years after diagnosis.
Literature
Balch CM et al. Final version of the American joint
committee on cancer staging system for cutaneous
melanoma. Journal of ­clinical oncology 2001;
19: 3635–3648
2
Balch CM et al. Prognostic factor analysis of 17,600
melanoma patients: validation of the American joint
committee on cancer melanoma staging system.
Journal of C
­ linical Oncology 2001; 19: 3622–3634
3
Balch CM et al. Final version of 2009 AJCC
melanoma staging and classification. ­Journal of
Clinical Oncology 2009; 27: 1–8
4
Bauer J, Garbe C. Acquired melanocytic nevi as risk
factor for melanoma development. A compre­
hensive review of epidemi­ological data. Pigment
Cell Res 2003; 16: 297–306
5
Bataille et al. Risk of cutaneous melanoma in
relation to the number, types and sites of naevi: a
1
Dr. Jürgen Becher is a Senior
Medical Consultant for Munich
Re at the Centre of Competence
for Medical Risks Research,
Underwriting & Claims.
For more information, contact
Dr. Mark Skillan, Vice President
and Medical Director at Munich
American Reassurance Company.
He can be reached at
[email protected]
NOT IF, BUT HOW
case-control study. British Journal of Cancer 1996;
73: 1605–1611
Berrino et al. Survival for eight major ­cancers and
all cancers combined for ­European adults
diagnosed in 1995–99: results of the EUROCARE-4
study. Lancet Oncology 2007; 8: 773–783
7
Crowley NJ, Seigler HF. Late recurrence of malig­­
nant melanoma. Annals of Surgery 1990; 212: 173–
177
8
Gamel JW et al. The long term clinical course of
patients with cutaneous melanoma. Cancer 2002;
95: 1286–1293
9
Tsao H, Cosimi AB, Sober AJ. Ultra-late recurrence
(15 years or longer) of cutaneous melanoma. Cancer
1997; 79: 2361–2370
10
seer.cancer.gov/data/
11
seer.cancer.gov/faststats/
6
© 2013 Munich American Reassurance Company, Atlanta, Georgia