< Current issue
Dermatopathology: Practical & Conceptual January - March 1997
New Concept: Melanocytic Dysplasia, Dysplastic Nevus, and Dysplastic Nevus Syndrome: Myth! Part IV
Daniela Massi, M.D.
Timothy Nielsen, M.D.
A. Bernard Ackerman, M.D.
From Seminars in Diagnostic Pathology
1. Terms and Phrases in the Title and the Abstract of the Article in Seminars in Diagnostic Pathology Not Yet Defined in Comprehensible, Repeatable Fashion
2. Critique of Positions of Clark
Changed Little or Not at All Since 1978
3. Critique of Positions of Clark
Changed Radically Since 1978
From the British Medical Bulletin
A. Examples of Impenetrable Language
B. Examples of Unsupported Speculations and Dizzying Definitions
C. A Critique of Positions of Clark
Changed Radically Since 1978
Two Articles by Clark
Summary of our Position Concerning DN and DNS as Elicited by A Series of Questions About Them
C. A Critique of Positions of Clark
Changed Radically Since 1978
1) Change in the steps of tumor progression:
"Neoplastic systems come into being and are manifest through induction, development, and progression. These phenomena of tumor biology are characteristic of neoplasia and may be classified into six categories. The generic categories applicable to all neoplastic systems are indicated by bold face type in the following list. In melanocytic neoplasia, the specific terminology for some of the categories follows the generic category term.
1. Events at the beginning (inductive events) . . . 2. The precursor state. . . . 3. Primary cancer without competence for metastasis (intermediate lesions):
Malignant melanoma in situ and radial growth phase primary melanoma. . . .
4. Primary cancer with competence for metastasis:
Primary melanoma that has progressed to the vertical growth phase. . . .
5. Metastasis. . . . 6. Metastasis from metastasis."
In 1984, Clark and colleagues4 stated: "These generic steps of tumor progression are 1) a selective focal proliferation of structurally normal cells (a benign tumor); 2) an abnormal pattern of hyperplasia (aberrant differentiation); 3) an abnormal pattern of hyperplasia and random cytological atypia (aberrant differentiation and the appearance of cells with nuclear atypia); 4) primary cancer without competence for metastasis; 5) primary cancer with competence for metastasis and 6) metastatic cancer." The six stages in 1995 are different from those of 1984.
2) Change in the advisability of using the term melanoma in situ:
"Primary cancer without competence for metastasis (intermediate lesions): Malignant melanoma in situ and radial growth phase primary melanoma. . . . Melanoma in situ shows all tumor cells to be in the epidermal compartment, separated from the dermis by the basement membrane. Radial growth phase melanoma is characterized by tumor cells in the epidermis and papillary dermis similar in appearance to the cells of melanoma in situ."
In 1990, Clark14 wrote: "Until compelling evidence of this kind is generated, the term 'melanoma in situ' should be used with caution, if at all. . . . Without compelling evidence that melanoma in situ has most of the characteristics of invasive melanomas with potential for metastasis, it would seem quite unwise to recommend that such diagnosis be routinely rendered by pathologists. . . . The diagnosis of carcinoma in situ (melanoma in situ, malignancy in situ) is a contradiction in terms, the prototype of an oxymoron." Between 1966 and 1990, Clark used the term "melanoma in situ" in many of his publications, as he did in publications of his after 1990. Why he advised against the use of that diagnosis in 1990 only was never explained by him.
3) Change in the concept of "precursor state:
"However, in practice, the existence of the precursor state and its potential for progression to melanoma is based upon recognizable lesions. The most important of these lesions are common nevi, clinically atypical nevi, and dysplastic nevi."
Between 1978 and 1995, Clark and collaborators referred to "precursors" and "precursor lesions"; in 1995 they introduced the theory of the "precursor state." In the 1980s, Clark and co-workers consistently contrasted CAN and DN; in 1993, they used clinically atypical nevus as a synonym for DN, and, by 1995, they were referring, as they did here again, to three different types of melanocytic nevi, namely, CAN, DN, and atypical nevi.
Clark, et al.:
"A cutaneous phenotype manifested by freckles, sun sensitivity and solar degeneration of the dermis is also a predisposition to melanoma development; a precursor state without nevi. . . . The precursor state is an organ-wide alteration which predisposes the organ to the development of cancer. . . . Organ-wide, in the present context, refers to alteration of all epidermal and dermal structures, epithelial and mesenchymal. Thus, the alteration characterized by increased melanoma susceptibility may not be confined to a demonstrable lesion, such as some form of a melanocytic nevus."
The concept of a "precursor state without nevi" is new. Until now, Clark and cohorts had employed the term "precursor lesions" for the first "steps of melanocytic tumor progression," i.e., common acquired nevus-melanocytic dysplasia-radial growth phase of melanoma, as elaborated on in an article titled "A study of tumor progression: The precursor lesions of superficial spreading and nodular melanoma" that appeared in Human Pathology in 1984.
In a sense, everyone's skin could be viewed as being in a "precursor state" vis-à-vis possible development of melanoma.
4) Change in the concept of DNS:
"Dysplastic nevus syndrome was used to designate a familial melanoma family member who had clinically atypical nevi and dysplastic nevi. A member of a familial melanoma family who has clinically atypical nevi or dysplastic nevi or both is stated to be affected by the dysplastic nevus syndrome."
In 1980, Clark, Elder, and co-workers
wrote: "The clinical and histologic appearances of the DNS are similar whether the syndrome occurs in a familial melanoma kindred (B-K mole syndrome), in patients with sporadic melanoma (as reported here), or sporadically in patients without melanoma (unpublished observations). For these reasons, we now feel that the syndrome should be classified as DNS, sporadic type, or DNS, familial type. . . ."
Curiously, when asked in 1989 by Philip LeBoit, editor of Seminars in Dermatology, whether there was any position that, on the basis of his present knowledge he would now change, Clark answered: "Yes. I would have clearly distinguished between the dysplastic nevus syndrome, clinical, and melanocytic nevus with dysplasia of the type that may be seen in the dysplastic nevus syndrome, a histologic designation."15
In 1995, Clark
did not mention the presence of "common nevi" in patients with DNS. In 1984 they stated:
"A patient with the dysplastic nevus syndrome may have lesions with these five cardinal features (persistent lentiginous melanocytic hyperplasia, nuclear atypia, lamellar fibroplasia, concentric eosinophilic fibroplasia, and sparse lymphocytic infiltrates), and, at the same time, common acquired melanocytic nevi." Those "five cardinal features" constitute what Clark
regard as a DN in contrast to what they deem to be a CAN.
5) Change in the use of the term DNS:
"It would seem unwise to us to continue to use dysplastic nevus syndrome for the following reasons. First, the term implies a common pathway for cutaneous malignant melanoma and dysplastic nevi. . . . Secondly, some formal definitions of syndrome state that multiple tissue-organ systems must be involved. Thirdly, familial melanoma may occur without dysplastic nevi, and in this context there can be no relationship between the two lesions. For these reasons, we do not use the term dysplastic nevus syndrome."
Clark and co-workers introduced the term DNS in 198010 and never since then, despite the rhetoric, have they truly abandoned it.
6) Change in the use of the term DN:
"In contrast, the histologic term, dysplastic nevus is satisfactory and should be retained for it designates a pivotal lesion of biologic significance, when dysplasia is used as it is in other neoplastic systems."
In 1989, Clark stated:
"We do not presently make a histologic diagnosis of 'dysplastic nevus.' The diagnostic terminology is,'Compound (or junctional or dermal) nevus with melanocytic dysplasia of the type which may be seen in the dysplastic nevus syndrome'..." But Clark continued to use the term DN in every one of the numerous succeeding articles of his about "tumor progression," including the one under discussion here in the British Medical Bulletin, as well as in "sign out" of histopathologic sections.
7) Change in confidence about the assumption that melanocytic dysplasia follows upon a pre-existing CAN:
"Dysplasia may develop in a common nevus that has been present for some years. There is no question that classical dysplasia occurs in association with a classical histologic pattern of a common nevus. It is difficult to prove, however, that the common nevus preceded the dysplasia. If one assumes the common nevus-dysplastic nevus path to occur in temporal sequence, with a period of quiescence between the two lesions, it follows that the dysplasia is the result of causative mechanisms in addition to those responsible for the common nevus."
In 1984, Clark
wrote: "The common acquired melanocytic nevus is viewed as a focal proliferation of melanocytes, destined in most instances to follow a programmed pathway of differentiation that leads to disappearance of the nevus. If the pathway of differentiation is not followed, characteristic lesions result, and such lesions are regarded as formal histogenetic precursors of melanoma. Such a developmental flaw is termed aberrant differentiation, and the resultant precursor is designated melanocytic dysplasia."
Since 1989, Clark and co-workers seem to have acknowledged the legitimacy of the notion of a junctional type of DN. Is melanocytic dysplasia synonymous with a junctional DN, with the "shoulders" of a so-called CAN, with changes of incipient melanoma, or with a combination of these? Does it develop in a pre-existing junctional type of CAN, or only in a compound type of that purported nevus? What are the criteria, if any, for distinguishing histopathologically between melanocytic dysplasia and a junctional DN? No answers have been given to any of these queries.
8) Change in the perception of the role of UV light in formation of DN:
"Many epidemiologic studies of melanoma, addressing inductive factors, have been reported, but, thus far, light is the only exogenous inductive agent consistently identified as of significance. . . . There is no question, however, that nevi develop without any relationship to the direct effects of light. Melanocytic nevi occur in sites with little or no exposure to the direct effects of light."
In 1993, in an article that appeared in Seminars in Diagnostic Pathology, Clark
had emphasized the role of ultraviolet light in the induction of nevi when they wrote: "In the first of these steps, melanocytes may acquire mutations of DNA induced by UV light resulting in the formation of benign tumors (nevi). . . ."
9) Change in location of the gene purported to be responsible for the DN-melanoma syndrome:
"Although controversy about the matter still exists, linkage of cutaneous malignant melanoma without dysplastic nevi, as a phenotype, has been linked to 1p. Subsequent studies by Cannon-Albright et al. and Nancarrow et al. showed linkage of a familial melanoma locus (mlm) to chromosome region 9p139p22 near interferon-alpha (INFA) and d9s171. . . . Presently, it must be concluded that linkage studies show significant evidence of heterogeneity, with some showing linkage to 1p, others to 9p and others without demonstrable linkage."
admitted that their conclusions
based on linkage analysis about the location of the gene responsible for "dysplastic nevus-melanoma syndrome" have not been confirmed by others.
That is not surprising considering the fact that Clark and co-workers never presented consistent criteria for clinical and histologic diagnosis of DN, including in their publications that told of having located the gene responsible for the "dysplastic nevus-melanoma syndrome."
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