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de novo Melanoma: Most melanomas are associated with remnants of their precursor. In Clark’s scheme, these remnants, if associated with a vertical growth component, were to be characterized as a radial growth component. Melanomas which lack a radial growth component were to be assigned to the “nodular” category. Clearly, “nodular” melanoma is a waste basket category for a wide range of lesions. An alternative would be to classify lesions with no demonstrable “radial growth” component as de novo variants. The de novo lesions might then be additionally characterized as to site, predisposing factors (e.g., actinic damage), internal histologic patterns, and nuclear grade.
Dysplasia: The term, dysplasia, is descriptive of growth of abnormal tissue. Generally, the designation, dysplasia, denotes genetically determined, “ill” growth. In depicting the “ill” growth of cells, it gives recognition to abnormal growth of cells without necessarily carrying with it the implication of tumoral qualities (e.g., a hamartoma or choristoma is tumoral); it evokes the images of an “in-situ” process, and has application when characterizing an abnormal clone of cells which is confined to its native site (e.g., melanocytes confined to an epithelial domain).
Typical nevi may be lentiginous, junctional, or compound. Although some examples of common melanocytic nevi are tumoral, the basic process at the dermal-epidermal interface is a dysplasia.
The designation, dysplasia, has found broad usage. In one context, it gives recognition to an arbitrary segment of a neoplastic process (i.e., an arbitrary portion of a continuum). It gives recognition to a segment which has a potential to evolve in stages from lower to higher grades of neoplasia (i.e., a premalignancy). Dysplasias of this type are unpredictably related in a sequence with a malignancy; the melanocytic premalignant dysplasias and related atypical “nevi” are prototypic. In such schemes of neoplasia, the distinctions, such as they are, between premalignant dysplasias and respective malignancies are based on both morphologic and clinicopathologic features.
Lesions in the premalignant melanocytic dysplasia category (a category in which compound patterns at level II are acceptable) have little or no potential for metastasis; they are a potential threat to the well-being of the patient, if left undisturbed. Morphologically, they share cytological features with the cells of the respective malignancy; they commonly evoke similar stromal and cellular immune responses. They are representatives of a borderland in neoplasia in which morphologic, but not biologic, features are in common with some of the features of the respective malignancy. In this usage, premalignant melanocytic dysplasia is basically a two dimensional process in which cells and nests of cells proliferate in, or near, the dermal-epidermal interface. In such lesions, tumoral qualities, if manifested clinically, usually can be attributed to the presence of pre-existing population of nevus cells.
An appreciation for degrees of cytologic atypia is essential for a definition of degrees of dysplasia in the category of premalignant melanocytic dysplasias (and, for that matter, in all neoplasms in all organ systems in the practice of pathology). Paradoxically, for lesions in vertical growth, the diagnosis of melanoma is made by an evaluation of patterns of the vertical growth component, but the lesion is then assigned to a subcategory on the basis of patterns at the dermal-epidermal interface (i.e., radial growth component or any remnant of the precursor). The assignment of a grade of neoplasia, that is based on the character of the vertical growth component, might be more reasonable; in a sense, this is a major criterion in the concept of MDM.
Without attention to cell type, the designation, premalignant dysplasia, gives recognition both to cytologic atypia, and to abnormal patterns, including clustering of cells and distribution of nests of cells. The cells of a premalignant melanocytic dysplasia are themselves dysplastic at a precursory extremity of a neoplastic continuum. Neoplastic cells are the cells of a neoplasm. In general, the cells of a dysplasia are also neoplastic. Neoplastic cells usually are characterized as either benign or malignant. Benign neoplasms are composed of benign neoplastic cells, and malignant neoplasms are composed of malignant cells (these definitions are simplistic but are necessary in a community where simplistic, but contrary, positions are readily accepted by a large group of practicing pathologists). The relationships are such that their delineation seems excessive, but objections to the obvious have been promoted.
In practice, the distinctions among grades of neoplasia are relative; they are dependent on many attributes, not all of which are physical or histological. Some of the determinants are step-wise, evolutionary acquisitions. The physical and histological features are expressions of neoplastic transformations at the genome level. Not all of the genetic transformations find morphologic expression at the histologic level. Gentotypic transformations, in all the variations of neoplastic progressions, cannot be predicted by an examination of histologic and cytologic features. Thus, cytologic features are imprecise markers; they may be common to several stages of neoplastic transformations. Cell markers (transmission analysis), if they have any relevance, are an added dimension in the correlations between cytologic and histologic patterns, and biologic potentials.
Lesions which show only mild cytologic atypia in lentiginous and junctional components but are incomplete in regard to satisfying criteria for a fully evolved premalignant dysplasia, as might be seen in the setting of the dysplastic “nevus” syndrome, are common. They are mild dysplasias of indeterminate significance. In such lesions, the cells in the junctional nests are small. Markers for host immune response (e.g., lamellar fibrosis and perivenular lymphoid infiltrates) usually are inconspicuous or lacking. Occasionally, the atypia may be moderate, but the patterns are otherwise incomplete. Such lesions are best characterized as melanocytic dysplasias of incomplete type with the implication that they are not convincing markers for the type of lesions seen in the dysplastic “nevus” syndrome. In practice, when a lesion of this type is encountered, as one from a group of biopsy specimens and all of which are purported to be melanocytic dysplasias clinically, several of the other lesions will show the more characteristic pattern of premalignant dysplasia.
Whatever the genetic background, the physical expressions of premalignant melanocytic dysplasias usually present as “acquired” lesions; they are distinguished by varying degrees of cytologic atypia and markers for host immune response. The designation, premalignant, gives recognition to a commonness between a precursor lesion and its malignant counterpart. At best, the designations, premalignant and malignant, provide only an approximation of the potentials of a given lesion. For epithelial neoplasia (and in most respects, melanoma has epithelioid qualities), the distinctions between precursor and the respective malignancy can be appreciated by evaluations of the dimensionalities of the related, but different processes. Dimensions and relationships to anatomic boundaries are basic to definitions of the differences between precursor and malignancy. These two attributes have relevance in providing an appreciation for the relativity that is inherent in any definition of a malignancy.
In this approach to definitions of dysplasias and melanomas (as stipulated in the concept of MDM), there are no restrictions on degrees of atypia in the dysplasia category. In the melanoma category, with the criteria for conceptualization of MDM as a guide, the sine qua non for the histologic diagnosis of “melanoma” is a three dimensional component in the dermis with at least moderate cytologic atypia, and with markers for host immune response (i.e., vertical growth component). For small, thin lesions, the problem becomes one of defining the requisite number of nests in close spacings that satisfy the criteria for the earliest recognition of a three dimensional component (early vertical growth). In the concept of MDM, the histologic requisites of physical attributes on a single section were at least two strata of nests, and at least 2 or 3 nests in each strata for a total of 5 or 6 nests in local aggregation.
In practice, it is convenient to partition the category of the premalignant melanocytic dysplasias. The mild and moderate dysplasias qualify as low-grade dysplasias, and moderately severe to severe dysplasias qualify as high-grade dysplasias. In addition to nuclear grade or atypia, the presence of an “upward migration” of atypical cells into the epidermis provides a ready means for the partitioning of most lesions of the general category into one or the other to the two subgroups.
Ecologic niche, continuity of patterns, and induction of stroma:
In normal tissue, each cell is relatively confined to an ecologic niche. For normal epidermal and mesenchymal cells, the relationships are too obvious to require elaborations. For other cells, such as helper T cells and reticular cells (dendritic histiocytes), the relationships are less obvious and relate to the ability of transients to indentify their appropriate niches under stress.
The ability of “malignant” cells to survive and grow (i.e., establish a ecologic niche) is dependent on their succes in eliciting a tumor stroma in both primary and metastatic sites.
The distinctions between normal cells and malignant cells are progressive in non-obligatory steps. At certain levels along the steps of neoplastic progressions, the distinctions between premalignant neoplasia and malignancy are both histologically and biologically arbitrary. At certain anatomic levels in the skin (e.g., level I), some cells, which otherwise resemble malignant cells, by having demonstrated an ability to recognize, and reside solely within, the same ecological niche as their normal precursors, reveal themselves to be dysplastic cells, irrespective of their cytologic features. In this approach, cytologically malignant cells which are confined to a normal ecologic niche may not be committed to the same offenses as true malignant cells which have the ability to create their own, but new and different, ecological niche; cytologically malignant melanocytic cells, that are confined to level I (i.e., epidermis: a normal ecological niche for melanocytes), must be judged deficient in regard to having a capacity to violate the boundaries of their ecological niche. They must be judged deficient in those qualities which distinguish fully evolved malignant cells. They qualify as “dysplastic” cells.
For neoplastic melanocytic cells, the concept of an ecological niche may seem irrelevant, especially if the concept of “one melanoma” is promoted. From the perspective of a favored ecological niche, the appropriateness of the designation, “melanoma-in-situ,” would be called into question. From a slightly different perspective, even the appropriateness of the designation, “melanoma” at level II, might also be questioned. Both of these defined segments (i.e., virtual images which have been given significance by the assignment of a “loaded” designation) might be characterized as indeterminate neoplasias in regard to having acquired a capacity for malignant behavior. They might best be assigned to a borderline category of neoplasia and qualified as dysplasia variant. In this approach, there would be no melanomas at either level I or II (e.g., an approach as delineated in the concept of MDM).
Cytologically atypical melanocytic cells in the papillary dermis at level II (widely and randomly spaced nests in a papillary dermis that is not significantly widened) may also be characterized as having found their own, but a new, ecological niche. In this characterization, the atypical cells, individually and in nests, would be relatively confined in an immunologically hostile matrix. They would be likely to remain isolated in the immune mediated matrix, or even to undergo regression. In such lesions, the phenomena at the dermal-epidermal interface are not too different from the phenomena of “dropping-off” of nests of nevus cells into the dermis in the evolution of common nevi but, in contrast, the atypical cells elicit a hoat immune response, and the nests of newly immigrated atypical cells do not successfully and uniformly establish continuity with the nests of any remnant of a pre-existing nevus. Interruption of continulity of patterns is a characteristic of a common “atypical” nevus (i.e., a premalignant dysplasia in which a remnant of a pre-existing common nevus is represented).
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