3. Critique of Positions of Clark et al. Changed Radically Since 1978

 
1) Elder et al: ". . . However, the gold standard for distinguishing banal and dysplastic nevi should be criteria that are linked with melanoma risk in case-control or cohort studies or are observed in lesions contiguous with and thus presumably precursor to established melanomas."
 
Critique: This sentence, like so many of those that pepper the publications of Clark et al. about "tumor progression," is impenetrable. To complicate matters further, since 1978, the same authors proposed many very different definitions of the term dysplasia in different articles and even in the same article. For example, in 1980, Clark and co-authors stated that their minimum criteria for diagnosis of DN was melanocytic nuclear atypia,10 yet 13 years later they contended that "the gold standard" for diagnosis of that nevus should be criteria that are linked to "melanoma risk . . . or . . . observed in lesions contiguous with and thus precursor to melanomas." There never can be a gold standard for diagnosis of DN, clinically or histopathologically, until that nevus is defined with precision morphologically. That has yet to be done. The same criticism applies to the equally specious notion of "banal nevus."
 
2) Elder et al.: "Most of the case control studies have been based on analysis of the clinical phenotype (clinically atypical nevi). Only one study has formally considered melanocytic (histological) dysplasia, although several have incorporated histological confirmation of the clinical diagnosis. No studies have assessed the particular contribution of cytological atypia to melanoma risk assessment. Further, some of these studies have established a relationship between risk and the number of atypical nevi, but the degree of clinical atypia has not been correlated with risk."
 
Critique: After having reviewed the entire literature about the subject of DN during the past nearly 20 years, Elder et al. can be heard, through the scramble of words, to have admitted at last that not a single study has reported definitive evidence of a direct correlation between histologic dysplasia/cytological atypia and increased risk of melanoma. They also acknowledged testimony of heightened risk for development of melanoma based on number of "atypical nevi," but not on "degree of clinical atypia." This represents a radical departure from what Clark, Elder, and others of their team had insisted for more than a decade.
 
3) Elder et al.: "Case control studies, by comparing prevalences in patients with melanoma (cases) with those in controls, have established that common nevi and clinically atypical nevi are associated with increased risk for melanoma in people who are not members of hereditary melanoma kindreds (Table 4) [our Fig. 7]. Clinically, atypical nevi are relatively common in the community, their incidence ranging from 5% to 20% (median, 13%; Table 5)" [our Fig. 8].
 
Critique: For many years, Clark and collaborators averred that "atypical nevi" were uncommon.2–4,10 Now they claim the reverse is true. Furthermore, the data presented in our Figs. 7–8 (original Tables 4–5) reflect lack of agreement about criteria for diagnosis of "common nevus" and "clinically atypical nevus," thereby accounting for different results reported on for prevalence of these nevi and for relative risk of melanoma.

View Figure  		Fig. 7  (orig. Table 4) The data presented here are meaningless, not only because the authors have different concepts of what constitutes "common nevi" and "atypical nevi," but because by 1995 (British Medical Bulletin, 1995) Clark and co-workers were making distinctions among "common nevi," "atypical nevi," and "dysplastic nevi."

View Figure  		Fig. 8  (orig. Table 5) The lack of uniform criteria for diagnosis of "atypical nevi" are mirrored in the discrepancy of the purported prevalence of them.
 
4) Elder et al.: "Taken together, these studies suggest that histological pattern features alone are quite prevalent in small nevi and cannot be associated as a sole finding with melanoma risk. Mild cytological atypia may also be prevalent in clinically banal nevi and should be interpreted with caution when observed as an isolated histological finding or with mild architectural changes in small lesions. Melanocytic (histological) dysplasia seems to be associated with melanoma risk, but it is not yet known whether this effect is independent of clinical atypia. The clinical cohort and case control studies confirm the melanoma risk association of clinical morphology, suggesting that clinical atypia should at present be considered the gold standard for assessment of risk based on analysis of nevi."
 
Critique: This statement, although obtuse, indicates a dramatic change in posture of Clark's group. Elder et al. confessed, reluctantly, that histopathologic features (both architectural and cytologic) commonly ascribed to DN are present also in small "banal" nevi. In short, according to them, "histologic dysplasia" is a feature of both CAN and DN, a hint that DN, rather than being the opposite of CAN, is actually a type of CAN. Because they came, at long last, to realize that "histologic dysplasia" fails to distinguish CAN from DN, Elder and co-workers were forced to retreat to a clinical definition of DN in order to preserve the very concept of it. That attempt surely will fail because the concept of DN (and DNS) was predicated on the illusion of melanocytic dysplasia, a term that continues to elude meaningful, repeatable definition by Clark, his co-workers, and pathologists in general.11
 
5) Elder et al.: "These findings are consistent with the hypothesis that tumor progression in nevi results in the accumulation of DNA damage, and in the progressive appearance of cytological atypia. . . . These data are consistent with the hypothesis that changes in cellular DNA induced by UV light are important in melanoma development and that some of these changes may occur in nevi, especially atypical or dysplastic nevi. The findings are also consistent with the nuclear abnormalities and disordered patterns of growth in atypical nevi."
 
Critique: This "hypothesis" fails to take into account the fact that the nevi under consideration here, i.e., DN, do not show cytologic atypia or any abnormalities of nuclei as judged through a conventional microscope. In short, the lines just quoted are sheer conjecture.
 
6) Elder et al.: "In the first of these steps, melan-ocytes may acquire mutations of DNA induced by UV light resulting in the formation of benign tumors (nevi). . . . The continuing action of UV light may drive an unstable tumor progression system, with increasing changes of clinical atypia and melanocytic dysplasia, followed in some lesions by attributes of the malignant phenotype such as invasion and tumorigenic proliferation."
 
Critique: Without ever having defined dysplasia, DN, or DNS in comprehensible fashion, the scientists proceed to create a fiction to explain them. In brief, instead of having established certifiable morphologic criteria for diagnosis of the nevi they call "dysplastic" and "common," these co-workers of nearly two decades duration resort to rampant speculation about "mutations of DNA induced by UV light" and "increasing changes of clinical atypia and melano-cytic dysplasia" driven by "an unstable tumor progression system." If only there were conclusive evidence for these inferences, a critical reader could begin to analyze it. Unfortunately, there is none.