The rate of increase in the numbers of primary sporadic basal cell carcinomas during follow up is associated with age at first presentation
Sudarshan Ramachandran1,
Anthony A. Fryer2,
Tracy Lovatt2,
Andrew Smith3,
John Lear3,
Peter W. Jones4 and
Richard C. Strange2,5
1 Department of Biochemistry, Good Hope Hospital, Sutton Coldfield, West Midlands, B75 7RR, UK,
2 Clinical Biochemistry Research Group, School of Medicine, Keele University, North Staffordshire Hospital, Staffordshire, UK,
3 Department of Dermatology, North Staffordshire Hospital, Stoke-on-Trent, Staffordshire, UK and
4 Department of Mathematics, Keele University, Staffordshire, UK
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Abstract
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Basal cell carcinoma (BCC) patients demonstrate marked variation in tumour numbers and site. Previous studies also show an association between age at first BCC presentation and development of BCC on the trunk. In this study we have investigated the association between age at first presentation and the rate of development of truncal and non-truncal tumours in 747 patients with BCC. We used negative binomial regression analysis to show that increasing age at first presentation was associated with an increased rate of BCC development (rate ratio 1.01/year, 95% CI 1.011.02, P < 0.001). In particular, development of tumours was greater in cases aged 60.069.9, 70.079.9 and 80.089.9 years than in those 40.049.9 years (P = 0.05, 0.01 and 0.039, respectively). While few cases aged over 70 years of age first present with a truncal BCC, the numbers of BCC/year were greater than in those with a head/neck BCC. The data suggest different genetic factors mediate the appearance of BCC in patients of different ages particularly those aged above and below 60 years.
Abbreviations: BCC, basal cell carcinoma
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Introduction
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Basal cell carcinomas (BCC) are the commonest cancers in Caucasians. They are generally slow-growing and rarely metastasise. Accordingly, they do not usually affect longevity (13). After presentation with their first BCC, patients can demonstrate striking phenotypic diversity during often lengthy follow up (4,5). For example, while many patients suffer only the lesion identified at their first presentation, others develop numerous further primary BCC over similar periods of follow up. Thus, in our case group we identified patients with up to 35 BCC (5,6). Importantly, this number includes only primary BCC with exclusion of any recurrences.
The mechanisms that determine BCC pathogenesis and in particular, this marked inter-patient variability in numbers of BCC/year are unclear although we suggested previously that the rate of appearance of tumours is mediated by the efficiency of immune surveillance in recognising existing micro-tumours. We proposed a scheme based on thresholds linked with the effectiveness of surveillance; falling below the first threshold is associated with a reduction that results in the appearance of relatively few BCC/year while the second threshold is associated with greater loss of surveillance and once crossed allows the appearance of numerous tumours/year (4,5). It is implicit that immune surveillance can recover and patients who demonstrated periods of BCC development may cease to produce lesions. A variety of factors cause changes in the effectiveness of surveillance. In particular, exposure to UV radiation can result in an immunosuppressive environment. Concurrent infections and/or stress can also impair local, cutaneous immunity in the presence of UV radiation. The model is based therefore, on the expectation that an interaction between host and environmental factors determines whether micro-tumours become clinically evident (4,5).
A further aspect of diversity in BCC patients is the site of their tumours; ~76% of BCC are found on the head/neck, ~16% of lesions on the trunk with the remainder being mainly found on the upper and lower limbs (79). Site, in particular the development of truncal BCC, is a further important phenotype in the context of numbers of BCC/year. Thus, first presentation with a truncal tumour is associated with significantly more subsequent BCC on this site compared with cases whose first tumour is on the head and neck; patients with their first BCC on the trunk developed, after first presentation, a mean of 0.13 truncal BCC/year of follow up while cases with an initial head and neck lesion developed 0.03 truncal BCC/year (7). In contrast, the accrual of non-truncal BCC was similar in patients with and without initial truncal lesions suggesting different mechanisms determine the development of truncal and non-truncal BCC and that development of truncal BCC should be considered separately from that of non-truncal tumours (7). Interestingly, the site of tumours is associated with age at first presentation. Thus, patients whose first BCC was on the trunk presented significantly earlier (mean 59.6 years) than those whose first tumour was on the head/neck (mean 64.9 years) (7). The molecular basis for these findings is unknown although they suggest that the three phenotypes, numbers of primary BCC/year of follow up, the site of lesions and age at first presentation, are interrelated and may be markers for different mechanisms determining BCC pathogenesis.
We now describe studies to determine if age at first presentation is linked with numbers of primary BCC/year of follow up. First, we determined in the total case group and in age-stratified patients, whether age at presentation was associated with the numbers of primary BCC/year of follow up. Secondly, we studied the effect of age at first presentation on numbers of primary truncal and non-truncal BCC/year in age-stratified patients.
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Materials and methods
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Patients
We studied 747 unrelated, Northern European Caucasians aged 2990 years at first presentation with one or more histologically proven BCC (4). They were recruited in the North Staffordshire Hospital with Ethics Committee approval and informed consent between 1991 and 1998. They represent ~20% of eligible patients. We excluded subjects with basal cell naevus syndrome, xeroderma pigmentosum or, those found at first presentation or during follow up to have a BCC and any other malignancy. Otherwise we tried to recruit all BCC patients. Those not recruited were missed in busy clinics. We confirmed that clinical characteristics (e.g. range of ages at diagnosis, proportion of males/females, BCC numbers and site, skin types) in the study group were typical indicating that the missed patients did not constitute a subgroup. Cases were examined by a dermatologist to determine numbers and site of new primary BCC at each presentation. BCC recurrences were not included in our statistical analyses. As arsenic is associated with development of truncal BCC, patients were asked about exposure. No such patients were identified. In a few cases, radiotherapy was used to treat BCC; no further lesions were found at these sites.
Statistical analysis
Stata release 6 (Stata Corporation, College Station, TX) was used to study the effect of patient age at first presentation on BCC numbers/year. BCC number (dependent count) comprised only primary BCC; recurrences were excluded from the analyses. The rate,
, at which primary BCC appear is assumed to depend on a linear function of covariates or predictors. The number of tumours after time t is
t. Either Poisson or negative binomial regression models are usually used to study this relationship. A Poisson model is used when the counts have means and variances that are approximately equal. However, most data of the type considered are overdispersed (10,11), hence a negative binomial regression is more suitable. Stata 6 software simultaneously tests for overdispersion (underdispersion is rare) during negative binomial regression. In negative binomial regression the rate ratio associated with a covariate is the ratio of the mean number of BCC produced in a fixed time when the covariate increases by 1 with all others in the model remaining unchanged. Thus, the rate ratio approximates to the mean number of BCC in one group (e.g. <60 years)/mean number of BCC in the complementary group (e.g. >60 years).
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Results
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Association of numbers of BCC/year with patient age at first presentation
We first used negative binomial regression (corrected for gender, normalized for follow up) to show, in 747 cases, that increasing age at first presentation was associated with increased numbers of primary BCC/year. Thus, risk of a further BCC increased by 1%/year (rate ratio 1.01/year, 95% CI 1.011.02, P < 0.001).
Comparison of numbers of BCC/year in patients stratified by age at first presentation
To determine if a particular age was associated with this change in the rate of increase in BCC numbers, we stratified patients by decades of age at first presentation (Table I
). Most cases (69.2%) were aged over 60 years with only 4.0% of the case group being <40 years at first presentation. Although the number of BCC/year is greater in male than female patients (4), proportions of males/females were not significantly different in these groups (trend test P = 0.47).
To compare the numbers of primary BCC/year, we used those aged 40.049.9 years at first presentation as reference category as there were only 30 subjects aged <39.9 years. Numbers of BCC/year in cases aged <39.9 years and 50.059.9 years were not significantly different to those in the reference category. In cases aged 60.069.9 years, and in those aged 70.079.9 and 80.089.9 years at first presentation, BCC numbers/year were significantly greater than in the reference category. To further clarify the age at which this increase in numbers of BCC/year occurred, we stratified the patients into 5 year bands and compared BCC numbers/year in these groups with that in the reference category (40.044.9 years; n = 27). We found that there was no significant difference in BCC numbers/year in patients who first presented in the age bands, <39.9 years (n = 30), 45.049.9 years (n = 46), 50.054.9 years (n = 48), 55.059.9 years (n = 79), and those in the reference category. In patients aged 60.064.9 years at first presentation (rate ratio 1.6, 95% CI 1.01.6, P = 0.05) and in age groups 65.069.9, 70.074.9, 75.079.9 and 80.089.9 years, the numbers of BCC/year were significantly greater than in the reference category (rate ratios 1.52.1, P values 0.0020.05).
The data show that, relative to younger patients, the number of BCC/year was greater in patients aged >60 years at first presentation. In a further analysis, we determined whether the numbers of BCC/year continued to increase in patients aged >60 years. We studied patients stratified by decades of age to maximize the numbers of patients in each group. Compared with those aged 50.059.9 years, we found that the numbers of BCC/year were significantly greater in those aged 60.069.9 years and, compared with those aged 60.069.9 years, BCC numbers/year were significantly greater in those aged 70.079.9 years. We found no significant difference in the numbers of BCC/year between patients aged 7079.9 years and those aged 80.089.9 years at first presentation (Table I
). The data suggest that the numbers of BCC/year demonstrated by patients progressively increase after 60 years of age with each decade up to ~80 years, after which no further increase is observed.
Association of BCC site with age-related rates of increase in tumour numbers
We next studied the association between the rate of increase in BCC numbers, age at first presentation and tumour site. In the 747 BCC cases, we identified 565 patients whose first BCC was on the trunk (70 patients) or on the head/neck (495 cases) (Table II
). Patients whose first tumour was on other sites or, in whom site of all tumours was not known were excluded. We used a negative binomial regression model (corrected for gender, normalized for follow up) to show that in both patients with an initial truncal and those with an initial head/neck tumour, increasing age at first presentation was significantly associated with increased numbers of primary BCC/year (rate ratio 1.06/year, 95% CI 1.041.09, P < 0.001 and rate ratio 1.01/year, 95% CI 1.0031.02, P = 0.004, respectively).
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Table II. Comparison of numbers of BCC/year in age-stratified patients with an initial tumour on the trunk or head/neck
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As expected (7), the 70 patients whose first tumour was on the trunk developed a greater number of BCC/year (rate ratio = 4.0, 95% CI 2.46.1, P = 0.001) than the 495 cases with an initial tumour on the head/neck (reference category). We next determined whether the greater number of BCC/year found in patients whose first BCC was on the trunk was evident in the age-stratified groups described above. Table II
shows comparisons of BCC numbers/year in age-stratified patients whose first BCC was on the trunk with that in the corresponding patients whose first lesion was on the head/neck. The proportion of patients with an initial tumour on the trunk declined with age (Table II
). Only one such case presented after 80 years of age and this age group was not studied further. In patients aged <39.9, 40.049.9 and 50.059.9 years, numbers of BCC/year in initial truncal BCC cases were not significantly different to those in cases whose first BCC was on the head/neck. However, in patients over 60 years at first presentation, numbers of BCC/year were greater in the truncal BCC group. Indeed, numbers of BCC/year were highest in cases who first presented between 70.0 and 79.9 years. The data show that the observed difference in numbers of BCC/year found in patients with initial truncal BCC compared with those with an initial lesion on the head/neck reflects differences in rates of tumour presentation in only patients aged >60 years at first presentation.
A further aspect of the truncal BCC phenotype is the finding that patients whose first tumour is on this site present with significantly more subsequent tumours/year on this site than do patients whose first lesion is on the head/neck (7). To determine whether this finding is determined by patient age at first presentation, we compared the numbers of non-truncal and truncal BCC/year in these two groups of patients stratified by decades of age (Table II
). Numbers of non truncal BCC/year were greater in patients whose first BCC was on the trunk than those whose first BCC was on the head/neck only in the cases aged 7079.9 years (Table II
). Before this age, the numbers of BCC/year was not significantly different in patients with an initial truncal or head/neck lesion. In contrast, numbers of truncal BCC/year were greater in patients whose first lesion was truncal and who presented at 40.049.9 years although this difference did not achieve statistical significance. Thereafter in the 5059.9 years and older groups, the numbers of truncal BCC was greater in the patients who first presented with a BCC on this site.
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Discussion
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BCC is largely a disease of the elderly although the age range at first presentation is wide. The mechanistic implications of this observation are unclear although previous studies have suggested differences in DNA-repair capacity and mutational spectra characterize the pathogenesis of early-onset (before 40 years) compared with later-onset BCC (1214). However, the proportion of patients aged <40 years at first presentation is small and such differences may not be relevant in the majority of patients who first present after 50 years. We have speculated that the development of BCC is linked with the effectiveness of immune surveillance, which is in turn determined by environmental and host factors including age. In this study we determined whether age at first presentation is associated with numbers of primary BCC/year of follow up. Tumour number is distinct from the issue of clinical aggressiveness of individual BCC, reflected in the rate and pattern of growth, difficulty of treatment and increased recurrence post-treatment. Indeed, previous studies have shown that this age is not linked with tumour aggressiveness. Thus, the proportion of BCC with aggressive growth characteristics and rates of recurrence within 5 years were not significantly different in younger (<50 years) and older patients (1517). We suggest that our analysis showing that age is associated with the number of BCC/year, reflects the effect of age on ability of immune surveillance to eliminate micro-tumours.
In the first analysis, we found that using patients aged between 40.0 and 49.9 years as the reference, increasing age at first presentation after 60 years, is linked with an increased number of BCC/year. Thus, stratifying patients into 10 or 5 year age groups showed that the numbers of BCC/year increased after 60 years.
Previous studies have indicated that the pathogenesis of truncal and head/neck BCC is different. For example, first presentation with a truncal BCC is linked with larger numbers of BCC/year and more subsequent tumours on this site than presentation with a head/neck tumour (79,18). Accordingly, in a second analysis, we compared the numbers of BCC/year in patients who first presented with a truncal with that in cases with an initial head/neck lesion. We found that the increased susceptibility of patients with an initial truncal BCC to a greater rate of increase in tumour numbers was also associated with age. Thus, while the numbers of BCC/year were not significantly different in the group comprising patients with an initial truncal from that with patients with an initial head/neck tumour up to 60 years of age, thereafter BCC numbers/year were significantly greater in the group with an initial truncal lesion. Further analysis showed that the association between BCC/year and age at presentation was different for truncal and non-truncal lesions. Thus, while the numbers of truncal BCC/year appeared to be greater in the initial truncal BCC group after the age of 40.049.9 years, the numbers of non-truncal BCC/year in patients with an initial truncal or initial head/neck BCC was not significantly different until after the age of 70 years. These findings provide further support for the view that the development of head/neck and truncal BCC involves different age-related mechanisms (7).
A further consideration is whether age at first presentation determines the numbers of BCC/year or whether this rate changes in an individual patient with increasing age. Only 69 patients (28 female, 41 male) had sufficiently long follow up (mean 11.9 years) to allow comparison of mean BCC/year between first presentation and age 60 years (excluding BCC at first presentation) with that in the same subjects after 60 years of age. Before 60 years (mean follow up 4.9 years), the mean number BCC/year of follow up was 0.13 while after 60 years (mean follow up 7.0 years), this rate had increased significantly (Wilcoxan signed rank test, P = 0.045) to 0.27. This finding indicates that BCC development is related to patient age and that age at first presentation may be a surrogate for this variable.
In conclusion, we suggest that studies on the mechanisms of BCC pathogenesis should include age at first presentation as a variable. We emphasize that our data are derived from English Caucasians who are likely to receive less UV than those resident in more southerly latitudes. Clearly, as UV is a key causative factor in BCC pathogenesis, our findings should be verified in cases from countries on a different latitude or, where there is greater chronic exposure to UV.
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Notes
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5 To whom correspondence should be addressed Email: paa00{at}keele.ac.uk 
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References
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Received April 12, 2002;
revised August 5, 2002;
accepted September 3, 2002.