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Nodular Type and Older Age as the Most Significant Associations of Thick Melanoma in Victoria, Australia
Alexander J. Chamberlain, MBBS;
Lin Fritschi, MBBS, PhD;
Graham G. Giles, PhD, MSc;
John P. Dowling, MBBS;
John W. Kelly, MDBS
Arch Dermatol. 2002;138:609-614.
ABSTRACT
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Objectives To explore the clinical associations of thick melanoma and to compare
the clinicopathological variables of nodular and superficial spreading types.
Design Cross-sectional study of all invasive primary melanomas recorded by
the Victorian Cancer Registry for 1998 and those reviewed by the Victorian
Melanoma Service between October 1, 1994, and April 31, 1999.
Setting Population-based cancer registry and public hospital–based multidisciplinary
melanoma clinic.
Patients This study included 1422 patients recorded by the Victorian Cancer Registry
and 674 patients who had attended the Victorian Melanoma Service; unclassifiable
tumor types were excluded, leaving 1144 and 645 patients, respectively, eligible
for analysis.
Main Outcome Measures Melanomas were categorized by thickness into thin ( 1 mm), intermediate
(>1-3 mm), and thick (>3 mm) and compared according to patient age, sex, and
tumor type and site. Superficial spreading and nodular types were also compared
in this manner. Use of the Victorian Melanoma Service database enabled a more
comprehensive analysis of historical and phenotypic characteristics.
Results Thick melanoma was predominantly nodular, occurring in older men, mostly
on the head and neck and associated with fewer nevi. Nodular melanoma was
thicker and found mostly on the lower limbs or head and neck; it had a greater
association with a history of solar keratoses than did superficial spreading
melanoma.
Conclusion Nodular type and older age are the most significant associations of
thick melanoma.
INTRODUCTION
AUSTRALIA HAS the highest incidence of melanoma in the world,1 and this incidence continues to increase.2 The lifetime risk of developing a melanoma for an
Australian is estimated to be 1 in 30 before age 75 years.3
On a global scale, the rate of increase in the incidence of melanoma is greater
than that of any other malignancy in white populations.4
The most accurate measure of prognosis with respect to primary cutaneous melanoma
is Breslow thickness. Currently, tumors with a thickness less than 1 mm are
generally cured with surgery, whereas 5-year survival for those thicker than
4 mm is approximately 50%.5
During the past few decades, large increases in the incidence of melanoma
have been reported in various countries, including Australia.4
Most of this increase in incidence has been in thin lesions.1, 3-4,6-9
The substantial decline in median tumor thickness during this period has been
attributed to large-scale efforts to improve early detection. Despite these
trends, the incidence of thick melanoma is stable or increasing in Australia,1, 6 the United States,8
and parts of Europe.10-13
These thick lesions are responsible for driving melanoma mortality rates,
which have been steadily increasing for many decades in Australia but now
seem to be stabilizing in men and declining in women.14
The key measure of success of secondary prevention programs will be a sustained
decline in melanoma mortality rates for both sexes. The burden of thick lesions
must be reduced if this is to be achieved. Several studies in Australia and
elsewhere have shown that thick lesions are more often nodular15-18
and suggest that it is predominantly older men who have these advanced tumors.15-19
There is some evidence16-19
suggesting that the head and neck is a relatively more common site for thick
melanoma.
However, these studies of thick melanoma are limited in their examination
of phenotypic associations. Therefore, the first objective of our study was
to examine a broad range of phenotypic factors associated with thick melanoma
to identify potential risk groups. Our study aimed to confirm the results
of previous studies in this area and to examine additional risk factors, such
as the association between melanoma thickness and dysplastic nevus and total
nevus numbers along with numbers of solar keratoses (SKs) and history of sunburns
or nonmelanoma skin cancer (NMSC). We hoped to identify goals for screening
strategies and public education programs aimed at early detection.
Our second objective was to examine the tumor type most associated with
thick melanoma, namely, nodular melanoma (NM), and to compare this with the
most common tumor type, superficial spreading melanoma (SSM), to identify
any associations with the phenotypic factors.
Our study was based on 2 databases. The Victorian Melanoma Service (VMS)
database incorporates detailed phenotypic data and is supported by a review
of all histopathologic findings by a single expert dermatopathologist (J.P.D.).
The VMS is a subset of cases held by the population-based Victorian Cancer
Registry (VCR). Our study examines both of these Victorian sets of data.
PATIENTS AND METHODS
PATIENTS AND DATA COLLECTION
We based our study on 2 groups of patients with invasive primary melanoma—those
derived from the VCR, a state-based cancer registry, and those from the VMS,
a state-based multidisciplinary consultative treatment service established
in 1994 to coordinate management of cutaneous melanoma. Victoria is the second
most populous state in Australia, occupying the southeastern corner of the
continent (latitude, 34°-39° south; population, 4.37 million at the
1996 census).
The computerized records of 674 patients attending the VMS at Alfred
Hospital between October 12, 1994, and March 31, 1999, were examined. Twenty-nine
patients with unclassifiable tumor type were excluded, leaving 645 (337 men
and 308 women) eligible for the analysis. We estimate that 6% to 10% of the
VCR patients were also included in the VMS dataset, but case matching was
not possible because of confidentiality requirements.
The VMS data collection process is as follows. Historical aspects, recorded
by an oncology nurse by means of a standardized questionnaire, include previous
NMSC, previous SKs, number of blistering sunburns (0, 1-5, or >5), skin phototype
(I, II, III, or IV-VI), eye color (blue, green, light brown, or brown), and
hair color (blond, red, light brown, brown, or black). All patients are examined
by a dermatology registrar and a dermatologist (J.W.K.). Total numbers of
melanocytic nevi are grouped (<20, 20-50, >50-100, >100-200, >200) and
dysplastic nevi are counted exactly, whereas freckles and solar lentigines
are recorded as few, moderate, or many. Histopathologic findings for all cases
are reviewed by a single expert dermatopathologist (J.P.D.).
A total of 1422 cases of invasive cutaneous melanoma recorded by the
VCR for 1998 were also examined. We excluded 278 patients for which no tumor
type was recorded on the pathology report, leaving 1144 (581 men and 563 women)
eligible for the analysis. Details held by the VCR were limited to date of
birth, date of diagnosis, sex, site, tumor type, thickness, and level.
The VCR, a population-based registry established in 1982, was made possible
because of amendments to the Victorian Cancer Act (1958) that made notification
of all cancers mandatory for all hospitals and pathology laboratories. Pathology
reporting is in the form of full-text copies of the pathologists' reports.
Currently, approximately 250 hospitals and 50 pathology laboratories report
cancer to the registry. Incoming notifications are matched against the register
to determine whether the case has been reported by another source. Demographic
details and International Classification of Diseases, Ninth
Revision,20 and International
Classification of Diseases–Oncology21
codes for tumor site and histologic features, respectively, are entered into
the system and then examined for internal consistency and completeness. Further
notifications or inconsistent data are resolved by follow-up with notifying
agencies or by reference to the VCR's consultant pathologist.
For the purpose of the analyses, tumor thickness was categorized into
3 groups—thin (1 mm), intermediate (>1-3 mm), and thick (>3 mm).
These categories were chosen to make best use of the available data considering
that melanoma thickness has been shown to represent a steady continuum of
risk with no natural break points.
Tumor type was classified as SSM, NM, or lentigo maligna melanoma according
to the classification systems of Clark et al22
and McGovern et al.23 Nodular melanoma is characterized
by dermal invasion wherever there is intraepidermal growth, that is, vertical
growth without evidence of an associated radial growth phase. If the intraepidermal
component extends beyond the width of 3 rete ridges beyond the invasive component
in any section, the melanoma is classified as having a radial growth phase.
Superficial spreading melanoma is the archetypal radial growth phase melanoma
and is characterized by a pagetoid distribution of malignant melanocytes.
Lentigo maligna melanoma is characterized by the proliferation of atypical
melanocytes along the dermoepidermal junction and down appendages in association
with atrophy and solar elastosis. A final group, designated "other," referred
to a variety of less common types of melanoma, including acral lentiginous,
desmoplastic, spitzoid, and spindle cell melanoma, which were grouped because
of low numbers. Within the VCR data set, this also included balloon cell and
nevoid melanoma. Categories for age were 30 years and younger, 31 to 50 years,
51 to 70 years, and older than 70 years. Tumor site was recorded as anterior
trunk, back, head and neck, and upper or lower limb.
STATISTICAL METHODS
The association of thickness category with age group, sex, and tumor
type and site was tested using the  2 statistic. Mean tumor
thicknesses for age group, sex, and tumor type and site were calculated, and
differences between groups were tested using t tests
and analysis of variance. Logistic regression was used to examine the risk
of having a thick melanoma (>3 mm) compared with having a thin melanoma (1
mm) by the variables age group, sex, and tumor type and site. Similar analyses
were performed for tumor type (NM vs SSM) with the variables age group, sex,
thickness category, and site. Statistical analyses were performed using a
software program (SPSS, release 9.0.1; SPSS Inc, Chicago, Ill).
RESULTS
CHARACTERISTICS OF THICK MELANOMA
Victorian Cancer Registry
The sex ratios (masculinity) for thin, intermediate, and thick melanomas
were 0.93:1, 1.15:1, and 1.72:1, respectively. Thick melanomas were predominantly
NM and were found on older persons, particularly on the head and neck (Table 1).
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Table 1. Association of Melanoma Thickness Categories With Patient
Sex and Age and Tumor Type and Site in 1144 Patients Recorded by the Victorian
Cancer Registry in 1998*
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The significant variables in the univariate analyses were entered into
a multivariate analysis, with thick vs thin lesions as the outcome variable.
Superficial spreading melanoma and upper limb were the reference groups for
type and site, respectively. After adjusting for other variables, NM (odds
ratio [OR], 67.05; 95% confidence interval [CI], 32.56-138.07) and the rarer
variants of melanoma (OR, 7.21; 95% CI, 2.74-18.98) were more likely to be
thick. Older persons (OR, 1.06; 95% CI, 1.04-1.08) were more likely to have
thick lesions than were younger persons. Men (OR, 1.63; 95% CI, 0.91-2.89)
were somewhat more likely than women to have thick lesions, but this did not
reach statistical significance. When other factors were accounted for, there
were no significant differences in tumor site between thick and thin lesions.
Victorian Melanoma Service
In the univariate analyses of the VMS data, similar results as those
from the VCR were seen with respect to thick melanomas. Of 645 patients analyzed,
194 men (30%) and 207 women (32%) had thin melanomas, 93 men (14%) and 78
women (12%) had intermediate-thickness melanomas, and 50 men (8%) and 23 women
(4%) had thick melanomas. Thick lesions were more likely to occur in men (2.17:1),
to be of nodular type (67%), to be found in older people (67% were >50 years),
and to occur on the head and neck (where 22% were >3 mm and 13% were 1
mm) or anterior trunk (where 15% were >3 mm and 7% were 1 mm). When all
factors were considered in the multivariate analysis, patient sex, age, and
tumor type and site remained significant. As shown with the VCR data, the
OR for NM (OR, 125.41; 95% CI, 43.82-358.92) was large and that for age (OR,
1.05; 95% CI, 1.02-1.08) was small. The association with male sex was significant
(OR, 5.81; 95% CI, 2.18-15.43). Melanomas on the anterior trunk (OR, 13.79;
95% CI, 2.01-94.82) and lower limb (OR, 8.62; 95% CI, 1.58-46.89) were more
likely to be thick than those on other sites, although the confidence intervals
were wide.
The historical details and phenotypic characteristics recorded for each
VMS case were also examined according to the thickness categories. Total nevus
number was the only variable to show a significant association with tumor
thickness, with thicker lesions being associated with lower nevus counts (Table 2). Variables that did not show an
association with thick melanoma included history of NMSC, history of SKs,
history of blistering sunburns, number of dysplastic nevi, number of freckles,
number of lentigines, skin phototype, hair color, and eye color.
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Table 2. Association of Melanoma Thickness Categories With Total Numbers
of Melanocytic Nevi, Victorian Melanoma Service, 1994-1999*
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COMPARISONS BETWEEN NM AND SSM
Victorian Cancer Registry
The sex (masculinity) ratios for SSM and NM were 0.92:1 and 1.19:1,
respectively. Nodular melanoma showed a slight male preponderance that did
not reach statistical significance (P = .08). Most
NMs were thicker than 3 mm and occurred in older persons. Nodular melanoma
showed a predilection for lower limb and head and neck sites (Table 3).
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Table 3. Association of Melanoma Type With Sex, Thickness, Age, and
Tumor Site in Victoria for 1998*
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A multivariate analysis was performed with NM vs SSM type as the outcome
variable. Thin lesions and upper limb were the reference groups for thickness
and site, respectively. After adjusting for other variables, lesions thicker
than 3 mm were highly likely to be NM (OR, 57.78; 95% CI, 30.47-109.54). Lesions
of intermediate thickness were also more likely to be NM (OR, 16.15; 95% CI,
9.39-27.78) than SSM. With respect to tumor site, lesions on the lower limb
(OR, 2.44; 95% CI, 1.32-4.51) or head and neck (OR, 2.42; 95% CI, 1.23-4.77)
were more likely to be NM. Age was no longer significantly associated with
NM after adjusting for other variables.
Victorian Melanoma Service
Of the 581 patients analyzed, the distribution by type and sex was as
follows: 241 men (41%) and 216 women (37%) had SSM and 68 men (12%) and 56
women (10%) had NM. Sex (masculinity) ratios for SSM and NM were 1.12:1 and
1.21:1, respectively. The univariate analyses of the VMS data demonstrated
that NM was more likely than SSM to be thick (39% vs 4% were >3 mm; P<.001) and to be found on older persons (19% vs 10%
were >70 years and 41% vs 26% were 50 to 70 years; P<.001).
There were no significant differences in sex or tumor site. In the multivariate
analysis, thickness and older age remained significant.
When the historical and phenotypic details were examined for each tumor
type, the only significant association was a history of SKs, which was more
likely with NM (41% vs 29%; P = .008). There was
no statistical difference in the proportion of those who reported multiple
primary melanomas, which was approximately 10% for both types (NM, 8.6%; SSM,
9.7%).
COMMENT
The VCR data indicate that thick melanoma is predominantly nodular (56%)
and mainly affects older persons (87% were >50 years). Men are affected more
than women (2:1), and the head and neck is the most common site (35%). When
all factors are considered together, nodular type and older age are the only
significant predictors of thickness. Furthermore, nodular type proved to be
the single most important determinant of thick melanoma. The VMS findings
were similar to those of the VCR, although male sex remained a significant
variable in multivariate analysis. The VMS analysis produced a novel finding
in the association between thick melanoma and lower numbers of melanocytic
nevi.
The key difference between NM and SSM was thickness, and this was apparent
for both sets of data. Nodular melanoma showed a predilection for the head
and neck and the lower limb in the statewide data alone, whereas the VMS data
demonstrated that older age was a differentiating feature. In addition, NM
showed an association with SKs, although there was no difference with respect
to history of NMSC.
The significance of nodular type and older age has been demonstrated
in several studies15-18,24
examining thick melanoma. Hersey et al16 found
that 62% of melanomas thicker than 3 mm were nodular and that 75% were in
patients older than 50 years. A Swedish study15
demonstrated that nodular type is the most significant determinant of thick
melanoma.
There is some evidence for a site predilection for thick melanomas.
Several studies16-18
concur that the head and neck is a more common site for thick lesions, and
our data support this finding. Both data sets showed a predilection of thick
lesions for the head and neck, but this did not remain significant in the
multivariate analyses. Hanrahan et al24 made
the same observation that tumor site was not related to thickness when tumor
type was taken into account. Nodular melanoma, however, was associated with
head and neck location in the multivariate analysis of the VCR data.
Similarly, there does not seem to be a consensus regarding sex. Although
thick melanoma seems to occur more often in men, this has not been observed
in every study. Hersey et al16 showed that
more than two thirds of melanomas thicker than 3 mm occurred in men, and this
trend has been supported elsewhere to lesser degrees.15, 18
On the other hand, the New York Melanoma Cooperative Group found no difference
in thickness between women and men in a study of more than 700 cases.17
Multiple factors seem to contribute to the development of thick melanoma,
including factors intrinsic to NM and those intrinsic to the elderly. There
is now evidence25 to suggest that NM grows
more rapidly, possessing greater biological "aggressivity" than other tumor
types. It is established that NM has a poorer prognosis than SSM, but in a
large study of prognostic factors,26 this was
attributed to thickness alone. A few groups27-28
have shown a poorer prognosis for nodular growth pattern independent of tumor
thickness.
Our data suggest that thick melanoma and NM occur more often on sites
that are easily visible. There is evidence that thick lesions are no more
likely than thin lesions to be found on sites that are difficult to observe.15 This is in conflict with the conclusion of Hanrahan
et al24 that a predilection for "hard-to-see"
sites is one of the key explanations why older persons develop thick melanomas.
This particular study24 has also shown that
persons 50 years and older are only marginally less likely (0.86:1) to recognize
the changes of melanoma than are younger persons, which suggests that most
possess the skills required to detect these tumors. Although the elderly have
more benign pigmented lesions such as seborrheic keratoses, they tend to have
fewer melanocytic nevi29 to obscure the detection
of melanoma.
We showed an association between thick melanoma and fewer nevi, and
this may be related to a greater average age of patients with thick lesions.
Perhaps it is also related to the observation that NMs, which comprise most
of the thick lesions, are less nevus associated than SSMs. Evidence suggests
that this applies to clinical counts of total nevi30-31
and the histologic association of a preexisting nevus.31-32
It is also possible that persons with large numbers of nevi are more aware
of their risk of melanoma and detect their melanomas earlier or receive closer
medical surveillance.
Ambivalence on behalf of the elderly regarding their health and poorer
medical care may also contribute to the problem of advanced melanoma. In some
studies,26-27,33
age has been found to be an independent poor prognostic indicator, although
this is only weak and considered by other researchers34
to be largely related to tumor thickness.
Allowing for the interplay between these factors, it follows that NMs
are more difficult to diagnose at an early stage. Although the "ABCD" system
of melanoma diagnosis has promoted the early diagnosis of flat lesions with
radial growth, NMs often fail to fulfill these diagnostic criteria.35 Nodular melanomas are clinically distinct from melanomas
with radial growth in that they are usually of smaller diameter, more symmetrical
in shape, more uniform in color, and frequently amelanotic. At the same time,
the diagnostic features of early NM are yet to be clearly defined. Hanrahan
et al24 found that changes in sensation and
bleeding were reported more often by patients with NM vs SSM, whereas a change
in color was reported significantly less frequently.
In our comparison of NM and SSM, the one consistent difference was tumor
thickness. The site predilection for the head and neck and the lower limb
demonstrated in the VCR data for NM was not borne out in the VMS data. Conversely,
the association of NM with older age was seen only in the VMS data. We were
unable to show any major difference with respect to historical and phenotypic
variables, except for the association between a history of SKs and NM. Although
age and sex may be partly responsible as confounding variables, this association
with the subtype NM (albeit weak) has not been reported previously, to our
knowledge.
Solar keratoses can be considered a marker of cumulative sun exposure,
and case-control studies36-37
have shown that they are a significant risk factor for melanoma. The association
between numbers of SKs and melanoma was no different between histologic subtypes
in one recent Australian study,37 although
NM has been linked to a greater degree of solar elastosis than SSM.38 The relationship between melanoma and sun exposure
is complex and difficult to study. Although the incidence of NMSC (particularly
squamous cell carcinoma) corresponds well with cumulative sun exposure, epidemiologic
evidence39 indicates that melanoma risk corresponds
more with intermittent sun exposure and severe sunburns. A Canadian study40 of 719 invasive melanomas (only 7% of which were
lentigo maligna melanoma) suggests that the density of melanoma on (continuously)
sun-exposed sites is higher than that on sun-protected (ie, intermittently
exposed) sites in persons older than 50 years, but the converse is true for
those younger than 50 years. These associations of NM with SKs and older age
(VMS data) provide clues that cumulative UV exposure may be more important
in the causation of NM than of SSM.
There has been some debate about the histogenesis of NM. It has been
argued that all melanomas have a common original growth pattern and that the
various clinical subtypes represent differences in the timing of onset of
vertical growth as well as site-related differences.38, 41-42
We, along with others,43 have identified early
NMs (<1-mm thick and Clark level 2). If there is a common initial phase
shared by NM and radial growth phase melanomas (SSM, lentigo maligna melanoma,
and acral lentiginous melanoma) then it would seem to occur so early in their
evolution as to be unlikely to be clinically identifiable. Arguments about
the histogenesis of NM do not alter the need to improve the early detection
of this clinical subtype.
There were limitations to our study. First, although a single expert
dermatopathologist reviewed all of the histopathologic findings for the VMS,
those recorded by the VCR were derived from a variety of pathology services
from around the state rather than a common pathologist. Although a proportion
of these pathologists are likely to have expertise in the histopathologic
diagnosis of melanoma, we acknowledge that some general pathologists may not
classify tumor type in the same rigorous manner as a specialist melanoma dermatopathologist,
leading to the potential for bias. The fact that our results for tumor type
in the thick category (VMS and VCR) are not dissimilar to those from another
large Australian series16 that examined thick
melanoma supports their validity. Second, the VCR data are population based,
whereas the VMS data may be subject to referral bias. Finally, the VMS is
a tertiary referral service that deals with thicker lesions and those requiring
more advanced surgery, and this was reflected in the mean thicknesses for
each tumor type. For these reasons we chose to include analyses from both
sources.
How then do we improve the secondary prevention of thick melanoma? Older
persons clearly represent the high-risk group, in particular, but not exclusively,
men. Further work is required to establish the best methods of early detection.
The early features of NM need to be investigated, and this is the subject
of current research at the VMS. The features of this subtype need to be promoted
to the population older than 50 years and to general practitioners. Increased
suspicion and a lower threshold for biopsy would also seem appropriate for
head and neck lesions that are new or changing. If it becomes apparent that
these melanomas truly evade early diagnosis, we may not see much more of an
improvement in mortality rates for melanoma. Until this is clarified, this
issue remains the most important challenge in the secondary prevention of
deaths from melanoma.
AUTHOR INFORMATION
Accepted for publication September 13, 2001.
This study was supported by a scientific research grant from the Australian
Dermatology Research & Education Foundation, Sydney and a Schering-Plough
research award (Dr Chamberlain) for trainees of the Australasian College of
Dermatologists.
This study was presented at the Fifth International Conference on Melanoma,
Venice, Italy, February 28, 2001.
We thank Jane Berry, RN, and Merran Tyler, RN, who were responsible
for interviews and data entry for the VMS, and Kathryn Whitfield and the staff
at the VCR for their assistance.
Corresponding author and reprints: Alexander J. Chamberlain, MBBS,
Department of Dermatology, Churchill Hospital, Oxford Radcliffe NHS Trust,
Old Road, Headington, Oxford OX3 7LJ, England.
From the Victorian Melanoma Service (Drs Chamberlain, Dowling, and
Kelly), the Department of Epidemiology and Preventive Medicine, Monash University
(Dr Fritschi), and the Department of Anatomical Pathology, Alfred Hospital
(Dr Dowling), Prahran, Victoria, Australia; and the Cancer Epidemiology Centre,
Anti-Cancer Council of Victoria, Carlton, Victoria (Dr Giles). Dr Chamberlain
is currently with the Department of Dermatology, Churchill Hospital, Oxford
Radcliffe NHS Trust, Oxford, England, and Dr Fritschi is currently with the
Department of Public Health, University of Western Australia, Nedlands.
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