Introduction 01


Malignant Melanoma

(A Historical Perspective)


Before the 1950’s,malignant melanoma was almost universally fatal. Precursors had not been defined, and most melanomas were diagnosed and treated late in their evolution: mostly, the diagnosis of an early melanoma was fortuitous. A review of histologic material from this period provides ready documentation of this uniform neglect: melanomas were large and bulky (1 cm or more in diameter), and metastases were common at the time of the initial presentation. Surgical procedures were radical: for melanomas of the extremities, hindquarter and forequarter amputations were routine.

In the late 1950's and the '60's, attempts to define early stages in the evolution of melanomas were embodied in the concepts of "atypical melanocytic hyperplasia, "melanoma in situ, "incipient melanoma,” and "superficial melanoma.” In addition, the concept of "precancerous melanosis" must be credited as both an appreciation for, and documentation of, a precursor of melanoma.

In the late 1960's, contributions by Clark and his co-workers provided insights into spectra of melanocytic neoplasia. In them, the relationships between melanoma cells and anatomic boundaries were utilized as a basis for the delineation of histologic micro-stages. Five levels, each related to specific anatomic boundaries or compartments, were defined but no single compartment, to which all the neoplastic cells were confined, was offered as providing a distinction, more or less, between melanoma and some, until then, undefined precursor. Later, level I was eliminated as a meaningful option; lesions that were confined to this level were not included in the category of "melanoma." One alternative was to characterize lesions at level I as "atypical melanocytic hyperplasia." Still later the concept of "melanoma in situ" was vigorously promoted (in a biased approach the concept of "atypical melanocytic hyperplasia was discredited"). The nature of the promotion provided an exposition of the susceptibility of language [as symbols of real and virtual images] to perverse manipulations) .

In later modifications, lesions at level II, with a requisite high degree of atypia, were assigned to the category of superficial spreading melanoma (SSM) at level II. Superficial spreading melanoma at level I was not an option. In contrast, actinically induced lesions at level I were characterized as lentigo maligna (LM). A degree of specificity thus was assigned to an "in situ” lesion in a setting of actinic damage. A specific precursor was given recognition and assigned a distinctive designation (i.e., identified as something other than "atypical melanocytic hyperplasia” or "melanoma in situ") The designation, precancerous melanosis, antedated that of lentigo maligna; it had equal utility as an identifier of patterns in a precursor lesion of a specific form of melanoma. In similar settings of actinic exposure, similar lesions at level II, with no restrictions on degree of atypia, were characterized as lentigo maligna melanoma (LMM) at level II (i.e., a specific precursor had evolved into a specific variant of melanoma).

In Clark's scheme in the definition of SSM and LMM, two components, radial growth and vertical growth, were defined; the former was identified as a remnant of a precursor lesion (most often characterized as the radial growth component even in the absence of vertical growth).

In Clark's scheme, for a lesion to be assigned to the "specific" category of SSM, a requisite degree of atypia was required in the remnant of the precursor. A requisite degree of cytologic atypia was not required in the definition of lentigo maligna melanoma.

With the definition of the "premalignant melanocytic dysplasias" as manifested in the dysplastic nevus syndrome (B-K mole syndrome or familial melanoma syndrome), the dysplasias were found to share many features with those of the radial growth components of fully evolved melanomas (including lentigo maligna melanoma and superficial spreading melanoma), and with those of both "atypical melanocytic hyperplasias" and "melanoma in situ." These common attributes notwithstanding, the terminology initially proposed by Clark and others remains the standard; one might have anticipated that the role of dysplasias in the evolution of common melanomas would have been accommodated by modifications in our terminology (e.g., the premalignant dysplasias of the dysplastic nevus syndrome at particular stages are indistinguishable from remnants of the precursor in lesions of SSM). The concept of premalignant melanocytic dysplasia has been criticized as etymologically incorrect; precriptionist would restrict the term, dysplasia, to congenital malformations. If genetically determined, then even melanocytic lesions would seem to qualify. A descriptionist might define dysplasia as “faulty growth.” If then qualified as premalignant and melanocytic, dysplasia has application to precursor lesions in the melanocytic category.

Superficial spreading melanoma (SSM) is associated with dysplasia-like patterns in the radial growth component but a requisite degree of atypia is required in its epidermal component. Whatever the limitations of the assigned linguistic symbols, superficial spreading melanoma is the common melanoma arising in the setting of the common premalignant melanocytic dysplasias (as manifested in the "dysplastic nevus syndrome)." SSM is melanoma arising in the background of a high grade dysplasia but is neoplastically linked in a sequence to lower grades of dysplasia. The designation, SSM, retains validity, even though currently the cytologic spectrum of the radial growth component (i.e., the remnant of the dysplastic precursor) tends to be broader than the restricted spectrum proposed by Clark. In characterizing a lesion as SSM, recognition is given to the fact that most dysplasias will have progressed to a high grade (i.e., nuclear grade) by the time the dermal component is sufficiently developed to be characterized as vertical growth (the special care in the wording of this definition should be appreciated; the definition does not require that the patterns of the radial growth component and those of the vertical growth components show cytologic parity) .

Lentigo maligna melanoma (LMM) remains the accepted designation for melanoma arising in an actinic lentiginous dysplasia (lentigo maligna). Acral lentiginous melanoma is an accepted designation for certain melanomas of the plantar and palmar surfaces. Similar lesions arise on the squamous mucosae and in the subungual sites. Patterns, basically similar to those of SSM but differing mainly in cytologic features, degrees of cytologic atypia, and patterns of epidermal response, may be encountered in both actinic and acral settings. On occasion, in both the actinic and acral settings, the patterns of SSM, as a regional variation in radial growth, are manifested in a background of patterns more in keeping with either lentigo maligna melanoma or acral lentiginous melanoma (i.e., both LMM and ALM - and their precursors - may focally manifest features of a common final pathway and come to resemble SSM) .

One approach to this overlap in patterns and syndromes would be to characterize SSM as an expression of a common final pathway which is accessible to a variety of premalignant dysplasias, including the actinic and the acral variants: this approach is embodied in the concept of minimal deviation melanoma. In the concept of minimal deviation melanoma (MDM), the designation, radial growth component, only has application to a lesion in vertical growth; in the absence of vertical growth, the pattern of a radial growth component, regardless of degree of atypia, is simply referred to as a dysplasia, and is qualified as to degree of atypia. In the concept of minimal deviation melanoma, attention is given to histologic variance in vertical growth.

Anatomic Levels:

In the definitions of degrees of dysplasia, and of microstages of melanomas, anatomic boundaries and domains have relevance for the interpretation of histologic patterns. In the elaboration of evolutionary stages of melanocytic neoplasia, boundaries and domains serve as markers. Even patterns of host immune response vary depending on the anatomic domains that have been affected by melanoma. Finally, relationships between melanocytic neoplasms and anatomic levels have relevance in the formulation of predictions of biologic potentials.

The anatomic domains and boundaries include:

Level I (an epithelial domain): The epidermal, or epithelial, domain is basically "two dimensional" with its boundary being the dermal-epidermal interface. Neoplasms situated above this boundary are "in situ" without attention to their degree of cytologic atypia, or to a histologic definition of "melanoma." For neoplasms in general, the designation gives recognition to processes that arise in an epithelial domain. Although such neoplasms tend to be confined for a period above the boundary between epithelium and stroma, they have a potential to evolve in stages. The stages are variably correlated with degrees of atypia; they are measured in part by the relationship between neoplastic cells and anatomic boundaries. This play with linguistic symbols is a more accurate rendering of "in situ" than the currently popular play promoting "melanoma" in situ. It defines the relationship between a population of neoplastic cells and a limited (primary) domain but does not, in itself, denote a degree or grade of neoplasia.

Level II: anatomically, level II is the papillary dermis with one boundary being the dermal-epidermal interface and the other being the interface between the papillary dermis and the reticular dermis. The connective tissue of this level is distinctive in regard to types of collagens, and to the distribution of the individual collagenous fibers (i.e., a delicate meshwork). It is rich in acid mucopolysaccharides, and has a distinctive component of delicate, arborizing elastic fibers which are PTAH negative. In its ability to peculiarly adapt to, and nurture, the epidermis, it is stroma in the strict sense of the definition. It, and its resident cells, including ecotatic lymphocytes and histiocytes, are responsive to functional and clonal changes in the native keratinocytes, and in the melanocytes of the epidermis.

In the evolution of melanocytic dysplasias, neoplastic melanocytes commonly migrate from level I to level II. In response to the neoplastic migrants, the stroma, and its ecotatic residents at level II, make only limited accommodations for the intrusion of a population of foreign cells: individual cells and individual nests of cells are accommodated but, by definition, the nests are few in number, and are randomly and widely spaced in the papillary dermis. They may be individually confined in a concentrically laminated fibrous matrix (arrested growth).

In characterizing the relationship between a population of neoplastic cells and anatomic levels, the deepest level to which the neoplastic cells have gained access should be the focus of the evaluation. Thus, in characterizing the dimensionality of a dysplasia at level II, only the component of cells within the papillary dermis are to be evaluated. At level II, the vertical dimensions of the papillary dermis (stroma), and the contours of the affected skin are little altered. The process, as evaluated by the patterns in the dermis, and exclusive of the component in the epidermis, basically retains a "two dimensional" character.

Level III: Level III is a modification of the definition of level II. At level III, recognition is given to spacial distortions of the papillary dermis as evidence of accommodations for expanding clones of neoplastic cells. The patterns in the papillary dermis, in regard to the distribution and aggregation of nests of foreign cells, acquires a three dimensional quality. A characterization of level III, as proposed in the concept of minimal deviation melanoma, has application in the definition of vertical growth; an amalgam of real and virtual images transmogrifies the plane of a histologic section into a three dimensional process. In turn in the concept of MDM, a three dimensional pattern is the requisite for the recognition of a vertical growth component. Finally, a vertical growth component constitutes the chief distinction between common melanomas and their precursors, the dysplasias.

There are no restrictions on the degree of the expansion of the papillary dermis at level III with the sole exception that the boundaries remain the same as those of level II (specifically, the volume of the papillary dermis is locally modified and augmented). The expansion of the papillary dermis may significantly deform the interfaces between both the papillary dermis and the epidermis, and the reticular dermis and the subcutis. The expanded stroma at level III qualifies as a community stroma; the stroma expands in concert with an expanding population of tumor cells. Neoplastic cells of this community may find their way into the lumens of stromal vessels, and then metastasize; they become transformed into universal migrants.

(Continued on NEXT PAGE:)



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