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John W Kelly, Josephine M Yeatman, Cheryl Regalia, Grahame Mason and Entry Amanda P Henham
[Authors' response: The title of the article has been changed to incorporate the finding that dysplastic naevi constitute a strong risk factor for melanoma and a paragraph added to the introduction to set out the aims of the study more clearly.]
The clinical usefulness of using photography is also evaluated. Other interesting findings are the estimate of the number of melanomas that arise from pre-existing naevi (rather few), and the number of benign lesions that had to be excised to 'find' the number of melanomas (satisfyingly few). Could more be made of the idea of photographs preventing unnecessary excisions?
Scientific content and basis of the manuscript
- The major point is that the cohort was uncontrolled. There is some Discussion put aside to address this, suggesting that the incidence of melanoma was so much higher that the background incidence that a control group was unnecessary. However this is not entirely satisfactory because control groups can assist the reader in deciding several other factors, including whether or not the cohort was representative.
[Authors' response: The comment made in the discussion to defend the lack of a control group has been deleted.]
- Representativeness of the cohort is in fact an issue. To what extent are these patients typical of those in the general population to whom such results might be applied, in particular the recommendation of following them long term with photography? I imagine these patients were selected in some way from the rest of the private dermatological practice: how? Were they selected from those referred for skin cancer worries who had the defined number of DMN? Or from ALL referred patients? What proportion of the denominator does this represent? What was the importance of the fact that all patients had been followed for at least 12 months? Was this to 'wash-out' all the prevalent cancers? Since the cohort was collected over more than 8 years, to judge from the range of years quoted, and I imagine this to be a busy metropolitan dermatology practice, 278 patients may represent a very small proportion.
[Authors' response: To provide as much information as possible about the representativeness of the cohort a paragraph has been included in the Methods section to address the questions posed.]
- Entry definition: the justification for using people with 5 or more DMN might be expanded to satisfy those like myself who could not follow a logic here. I know that Mackie in her 1993 paper used a definition of 3 or more DMN, but this is not described, nor are all the other definitions used in the quoted studies described. In particular it might be worth speculating how different definitions might alter the numbers who need to be followed.
[Authors' response: A paragraph supporting the choice of people with 5 or more dysplastic naevi for entrance into the study have been included under the Methods section. This selection criterion is necessarily somewhat arbitrary and there is a paragraph of the discussion devoted to the entry criteria used in some studies that define syndromes associated with atypical or dysplastic naevi.]
- Clinical definition: How was this definition used to differentiate between DMN and melanomas, since these features are almost exactly the same as the clinical features of MM? Later in the Discussion there is mention of surface microscopy: if this was an important method of differentiating between melanoma and DMN it could be mentioned here.
[Authors' response: The clinical definition used is based on a previous study in which criteria for the diagnosis of dysplastic naevi were identified using photographs of pigmented lesions for which the histological diagnosis was known. This study was done by the lead author of this paper and explains how the criteria differ from those used to diagnose melanoma. It was not possible to include further discussion of this here without exceeding editorial requirements for length.]
- I was not happy with the argument explaining the thinner melanomas in those cohort with the State mean. I could argue that this IS simply the result of a bias introduced by increased surveillance, (plus another from the higher socio-economic group such as attend private dermatologists). It is unsatisfactory to simply state ". . . we believe that it is unlikely to provide a substantial explanation . . ."
[Authors' response: The unsatisfactory statement "We believe that it is unlikely to provide a substantial explanation" has been deleted.]
- Argument could be mounted against those about using the word 'dysplastic' from within this very paper! 'Dysplastic' implies that the cells of a lesion are moving through a less stable state towards malignant transformation. In other words the lesion ITSELF may become malignant. One of the most interesting points of this paper is that the vast majority of lesions arose de novo. For the same reason I did not like the implied comment (that even more melanomas might have been prevented) speculating about not knowing how many DMN might have become malignant.
[Authors' response: The nomenclature relating to dysplastic naevi is always controversial though we believe that dysplastic naevi are more important as risk markers than as precursors we would also say that a dysplastic naevus is more likely to transform to melanoma than benign naevus. The comment on page 8 about how many dysplastic naevi might have progressed to melanoma had they not been removed refers only to the dysplastic naevi that were identified as changing in comparison with baseline photographs in a way that was so suspicious that melanoma could not be ruled out on clinical grounds. These are therefore a special sub group of dysplastic naevi that would seemverymuchmore likely to have had a significant precursor role.]
Originality of thought
- The main finding has already been pioneered many times before. This study confirms it for Australia. The following of patients by photography has also been undertaken and evaluated before, for example by Mackie in 1993.
- The main originality of these data come from the 'other findings' referred to above as interesting.
Style, format, overall presentation
The paper is clear and very well-written.
Some text seems to be put in an unsatisfactory site:-
- discussion about the number of DMN used in the working definition of someone at risk might be better in the Methods.
[Authors' response: Discussion about the number of dysplastic naevi used in the working definition of someone at risk has been included in the Methods section.]
- Speculation about the effectiveness of self-examination, and discussion about the rate of finding of NMSC (if it is to be retained, see below), should be placed in the Discussion.
[Authors' response: Speculation about the effectiveness of self examination and discussion about the rate of finding of NMSC have been deleted.]
There are a few ambiguities:- The breakdown of the excision biopsies added to 210 rather than 213. This might be better presented as a small table.
[Authors' response: The correct figure for the breakdown of the excision biopsy on page 8 is 210 and not 213. We have incorporated these biopsy diagnoses in a table as suggested.]
- I think the data about accompanying NMSC is interesting enough to include, but not the attempt at analysing the overall rate in relation to that for the whole population, which is any case very weak scientifically.
[Authors' response: I have deleted the attempt at analysis of the rates of non melanoma skin cancer compared to that of the whole population.]
I found Figure 2 and 3 redundant: they might be better as Tables. In fact the data in Figure 2 might be better with additional cross tabulation to include the incidence of the melanomas, (how were they distributed across the DMN counts?).
[Authors' response: I have redrawn figures two and three as tables 1 and 2 as suggested with melanoma incidence figures for each subgroup.]
Reader interest
All studies of melanoma management are interesting to Australian clinicians, and I believe this to be no exception.
1. I assume this study was not prospective. If this is the case it should be stated. A control cohort with multiple DN who had no photography would have enabled precise determination of the effect of photographic intervention on patient outcome. I assume that no such control cohort exists, presumably because this was a retrospective study and all patients with multiple DN had baseline photography.
[Authors' response: The method for following this cohort was established prospectively and the analysis excluded melanomas that were detected at the initial visit. This has now been stated clearly in the Methods section. There was never any intention to include a control cohort.]
2. The clinical definition of dysplastic naevi (DN) includes the necessity of a macular component. While many histologically proven dysplastic naevi have a macular junctional component, some compound DN have junctional nests superimposed on their dermal component and therefore do not have any clinically macular areas. Nevertheless, the authors definition is standard and should not detract from the experimental design.
[Authors' response: I accept the criticism of the definition of dysplastic naevi though I believe that the definition that we used incorporates almost all dysplastic naevi and that dysplastic naevi without a macular component are uncommon. Our definition is clearly stated so that readers can assess the results in the light of the definition used.]
3. I am unsure why the authors believe that the melanoma described on the R chest [fourth paragraph of results] was de novo, since there was a 6 year history of a stable lesion prior to rapid growth. Even though no naevus was associated histologically it is more than possible that the nevus had been replaced with melanoma.
In addition, 8 of the new melanomas were in situ. These were considered to be all de novo. What is the pathological criteria used to distinguish de novo in situ melanoma (non lentigo maligna) from dysplastic junctional naevi with in situ melanoma changes. If this distinction is not clear then interpretation of de novo versus melanomas arising from preexisitng naevi is disputed.
[Authors' response: We accept that it is possible that the melanoma described on page 6 on the right chest had replaced a preexisting naevus. To allow for this possibility we used the word "likely". The studies referred to in references 22 and 24 would suggest that only a small percentage of preexisting naevi would be completely replaced by such an early melanoma.
The eight in situ melanomas were not only considered to be de novo because of the lack of histological evidence of a preexisting naevus but also because they appeared as new lesions on normal skin as demonstrated by the baseline photographs. Whilst dispute may arise in differentiating preexisting dysplastic naevus from melanoma this occurs only in exceptional lesions and did not arise in any of these in situ melanomas.]
4. The ratio of benign to melanoma excision in this high risk cohort was somewhat high at 10:1. I suspect that photography decreases specificity of diagnosis for melanoma. If the majority of lesions were biopsied because of changes from baseline photography, implications may be drawn for the use of photography as a screening strategy in the more general community. Since it was stated that an expert decision not to biopsy some of the changed lesions occurred within the cohort, it would be predicted that the benign to malignant excision ratio may be somewhat higher when used in a non-expert setting eg. general practitioners.
In this regard I am unclear of the basis of the statement that "baseline photographs therefore greatly reduce the number of excisions . . ." The only way to know this would be to have a control cohort with no photography (see comment 1 ).
[Authors' response: The second reviewer views the ratio of the benign lesions excisions (10 to 1) as high. The first reviewer feels that this is a low figure. Indeed in comparison with published standards for GPs and even for specialists this is a low ratio. We have stated, however, that this particular population was a group of high risk individuals with floridly atypical pigmented lesions. In such patients the index of suspicion for melanoma must remain high and the threshold for biopsyrelatively low to avoid missing melanomas. In the previously published cohort study of Marghoob et al (reference 11.) the biopsy rate in the cohort of patients with dysplastic naevi was 2.3 per patient (more than double that for the present study). By contrast the control population in Marghoob's study required only 0.2 biopsies per patient. We therefore believe that the ratio of 10 to 1 is a low ratio for this particular population.]
5. Mean rumour thickness is misleading in melanoma. Only median should be quoted.
[Authors' response: In response to the comment about mean and median tumour thickness we have reversed the order of mention of median and mean rumour thickness. We accept that median thickness is a better overall measure, however, the inclusion of the mean is relevant here because it shows that our cohort patients with dysplastic naevi did not develop the very thick tumours that are seen in the general population and that influence the mean.]
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