Glossary III15

          

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vertical growth component, and the willingness to admit that a lesion with only two dimensions at its deepest level (and thus lacking a vertical growth component) might be better assigned to some category other than that of melanoma.

Malpractice: In a claim of malpractice, negligence generally is implied. A misdiagnosis is not in itself proof of negligence. The statutes are not uniform from state to state; in all cases, they are sufficiently vague to provide for the manipulation of imputations, records, statements, testimonies, and the emotions of the jurors. The responses to these variables are correlated to provide a judgment as to deviations from, or compliance with, a "standard of care." In practice, a verdict is a subjective evaluation of the performances of the contesting lawyers; the convincingness or arrogance of witnesses; the prejudices of the judge; and the emotionality, or rationality, of the jurors.

For defendants, encounters with the legal profession in malpractice suits are an exercise in futility. They generally are a humiliating experience in which members of one profession holds the peers of a different profession to a higher standard than that to which they hold themselves (or could even hope to attain). The prosecution of malpractice, with melanoma as the point of contention, is based on a presumption that natural phenomena (e.g., melanomas) are predictable, and are always manifested in easily diagnosable patterns. Success, in the prosecution of malpractice, often depends upon the manipulation of statistics with full knowledge that the results have no relevance to an individual's daily practice of pathology (or medicine)

The capricious nature of both the interpretations of histologic patterns, and of predictions of the behavior of individual lesions is revealed when, with follow-up, diagnosis and clinical behavior are discordant. Success, or failure, of these two exercises, particularly in the category of thin borderline lesions, mostly is a measure of the vicarious nature of neoplasia. In these endeavors, the odds are greatly against success, if the object is to select which thin lesion from a group will prove to be associated with progressive disease.

In our insistence on the liberal usage of the designation, melanoma, and on the inclusion of lesions with little or no potential for progressive disease in the respective category, we have created a milieu in which diagnoses (i.e., linguistic symbols) may be manipulated in support of imputations of malpractice. Witnesses, knowing full well that "truth," in itself, and under the strictest of conditions, is relative, are asked to swear "to tell the truth." Philosophies, rather than states of disease, and egos, rather than routines in practice, then become the basis for prosecution. Eventually, in pretrial depositions, and in the court room proceedings, linguistics in the form of forensics supplant images; they become the basis for a judgment.

In regard to neoplasia (and even in general), the prosecution, and the defense of malpractice claims are forensic manipulations of the individuality of virtual images. The legal shenanigans of malpractice proceedings provide a clear demonstration, that any judgment as to the validity of contentious segments of neoplastic continua, is to be found in the eyes of the beholder.

Maturation: Maturation is a feature of typical nevi; it is manifested in type A, B, & C patterns. In these intralesional transformations of a melanocytic nevus, the expression of one of the three patterns has a zonal character; itmay be influenced by the nature of the microenvironment in which the cells find themselves may influence phenotypic expression. Type A cells are found near the dermal-epidermal interface; type C cells are the deepest component.

Prominent variations in degrees of "maturation" in a vertical growth component of a melanoma may complicate decisions regarding a selection of the deepest nest of cells to be utilized in evalutions by Breslow's criteria. Nests of nevus-like cells at the deep margin of a vertical growth component, even those showing mild atypia mostly should be excluded; a nevus-like is the exception.

Melanoma:

1. arbitrary segmentations of a neoplast.ic continuum: Cutaneous malignant melanoma is a common, well documented neoplasm. In nature, it evolves as a continuum but, as a device for the manipulation of its patterns, the continuum must be segmented. As one option in the structuring of virtual images, both for the manipulation of real images, and the structuring of segments along a neoplastic continuum, a single cell (i.e., a universal precursor of all melanoma cells) might be characterized as a complete melanoma cell. Such a cell, with no restrictions as to an ecological niche, would, from its inception, possess the capacity to invade, and metastasize. In this approach, the relationship of descendants of this cell to anatomic boundaries would be purely physical, and would depend solely upon the size and age of the lesion, and on the chance encounters of newly generated daughter cells, as they impose upon anatomic boundaries. In this approach, with a single step from precursor cell to a complete melanoma cell, there is "one melanoma biologically and histologically" (this set of virtual images, and the set in which there are no malignant cells, only malignant tumors, if compared, present contradictions, but these conflicts have been ignored by some of the proponents of the concept of “one melanoma”).

In the concept of "melanoma" in situ, a population of neoplastic cells in the epidermis would be no different, in biologic characteristics, and potentials, than would a population of melanoma cells of a vertical growth component situated deep in the reticular dermis, or even melanoma cells metastatic to the brain. In this approach, identification of the segment to be properly embraced by the designation, "melanoma," would require nothing more than a recognition of the "malignant cells" beyond the native domain of their precursors (i.e., the basal layer of the epidermis). In addition, lesions with cytologic features comparable to those of "melanoma" in situ but lacking upward migration of neoplastic cells would be divorced not only from the defined segment, "melanoma" in situ, but even from the respective continuum. They would be assigned to the category of "common nevus." In this approach, one might anticipate a relationship between size - as estimated by utilizing Breslow's criteria - and levels of invasion (modified Clark's criteria). In this concept of "one melanoma," thin melanoma of a certain size might be expected to have a predictable relationship to anatomic boundaries, such that one might predict that all melanocytic neoplasms at a certain size, such as 0.55 mm, would also be level II lesions and that all such lesions measuring, say 0.1 mm, would be at level III. Clearly, such relationships do not hold; we should search for other explanations for the inconsistencies. A single, complete melanoma cell - as the precursor for all the subsequent generations of melanoma cells in a neoplasm that in its progressions has metastasized - does not provide a satisfactory explanation for the variable patterns that would be observed, if such a lesion could be followed, and sampled, at intervals - from its inception to metastasis.

To characterize certain variations of epithelial patterns as a "malignancy" (e.g., "melanoma") in situ is a presumption that can only be supported by fiat, and by political, rather than scientific, consensus: there are no sacrosanct decrees, biologic tests, or statistical analyses to confirm such an ordainment. The observation, that the cytologic features of some examples of "melanoma" in situ are comparable to those of cells in the vertical growth component(s) of most common melanomas, would seem to be the only justification for classifying a lesion at level I as a variant of melanoma. This observation is hardly sacerdotal. Paradoxically, for the concept's most ardent proponents, a specified degree of atypia is not a requisite for diagnosis. On the other hand, in practice both an appreciation of degrees of atypia, and a representation of either moderately severe, or severe atypia are required for a diagnosis of "melanoma" in situ. If the patterns are manipulated in any other manner, the definition loses specificity.

As an alternative to the concept of a single cornplete and primal melanoma cell, virtual images might be developed to define a complex neoplastic system with a precursor lesion, a borderline or indeterminate phase, and a tumoral (three dimensional) phase. A stage in which cells are members of a community, and/or a stage in which cells are active migrants, are options for the tumoral phase. For all of the defined segments, it would be proposed that ecotatic, and cytologic, distinctions, as manifested histologically, would be directly related to genetic peculiarities of the neoplastic cells; changes in, or additions of, ecotatic preferences, and the selection of new ecologic niches would be expressions of the acquisition of new, genetically imprinted attributes by the neoplastic cells. In short, the properties of neoplastic cells, at the stage in which the neoplasm has been histologically sampled, reflect a degree of differentiation; in early stages of neoplastic transformation, the ecological niche for neoplastic cells is little different from that of their normal precursor cells. With progression in neoplastic transformations, the cells would not be as restricted by anatomic sites, and boundaries. In a fully transformed cell, the restrictions would be few, and the cells would become active, universal migrants, independent of specific ecologic niches.

The vagaries of the most common form of cutaneous melanoma, and those of an even more common precursor, all of which are manifested in full efflorescence in the "dysplastic nevus­melanoma" ("familial melanoma") syndrome, are exemplary of the relationships between degrees of differentiation (steps in neoplastic progressions), and ecological niches.

In the neoplastic system, comprised of the common melanomas and their precursors, both the precursors, and the fully evolved melanomas (at both levels III & IV, but particularly at level III), share many cytologic features, immune responses, and certain dermal, and epidermal, domains. If, in defining the distinctions between melanoma and its precursors, emphasis is placed solely on degrees of cytologic atypia, the definition is likely to be extended to include "melanoma" in situ. In this approach, upward migration of neoplastic melanocytes often is observed as a concomitant of high degrees of cytologic aytpia (caveat: if the criteria for the diagnosis of "melanoma" in situ are not constrained by defined requisites for degrees of atypia, then the upper migration of melanocytes is too common a phenomenon to have import in the evaluation of stages of melanocytic neo- plasia) .

If, on the other hand, emphasis is placed primarily on patterns in which nests of atypical cells aggregate in the dermis (i.e., the identification of a vertical growth component), the diagnosis of "melanoma" in situ will, by definition, be eliminated as an option, but the "melanoma" category will be expanded to include examples in which:

1) the cytologic features deviate minimally from those of common nevi, and

2) the number of dermal nests approaches the point of indecisiveness (lesions embracing both of the latter two parameters represent the most common variant of minimal deviation melanoma).

In the scheme, in which nesting patterns in the dermis, and at least a moderate degree of atypia are the chief criteria for the diagnosis of melanoma, all lesions lacking the requisite patterns in the dermis would then be assigned to a category of precursor lesions. In certain schemes, precursor lesions of the defined type would be characterized as dysplasias (e.g., such lesions are characterized as dysplasias in the concept of minimal deviation melanoma, regardless of degree of atypia, and regardless of the anatomic relationship between epidermal neoplastic melano- cytes, and compartments of the epidermis [i.e., regardless of the presence or absence of a pagetoid {upward} migration of neoplastic cells]): only the presence of a vertical growth component establishes the diagnosis of melanoma, and excludes the diagnosis of dysplasia.

Melanocytic neoplasia of indeterminate malignant potential:

Histologic patterns are often ambiguous in providing distinctions between high grade melanocytic dysplasias, and thin common melanomas (lesions in vertical growth, but measuring less than 1 mm in vertical dimensions). In addition, distinctions, being arbitrary, are rarely rewarded by biologic proof of malignancy; most of these lesions are controlled by local excisions. Lesions, in these two categories, are accommodated in the concept of borderline melanocytic neoplasia of indeterminate malignant potential.

The designation, borderline melanocytic neoplasia, is a modification of the terminology currently used for the classification of problematic lesions in other organ systems. It is somewhat comparable to the designation that characterizes a set of cystic ovarian neoplasms (borderline ovarian neoplasia of low or uncertain malignant potential). In the latter concept, lesions of the ovaries of borderline type, even if implanted on peritoneal surfaces, remained borderline, if the peritoneal implants are not invasive in desmoplastic patterns. In practice, it is the uncertainness of predictions of malignant behavior (with the exception of examples of “intraepithelial carcinomas) , and not just a low malignant potential, that validates a borderline category for most of these ovarian lesions; the potential for progressive malignant growth is indeterminate.

The uncertainness of the malignant potential of the high grade melanocytic dysplasia (including “melanomas at level II") would justify their characterization as melanocytic neoplasia of indeterminate malignant potential (dysplasia category). In like fashion, thin common melanomas (lesions in vertical growth, and less than 1 mm in height) would qualify as melanocytic neoplasia of indeterminate malignant potential (melanoma category). An attempt to predict progressive disease (rather than 5 year survival) by the histologic examination of specific lesions in these two categories will rarely prove to be successful. Predictions of 5 year survivals currently are emphasized, but they find greatest utility as accommodations for the promotion of therapeutic trials. In turn, they have great utility, but questionable validity, in malpractice cases.

Micro-stages of neoplasia and virtual images: Definitions of micro-stages of neoplasia are dependent upon the structuring of relevant virtual images. The distinctions between high grade dysplasias, "melanoma" in situ, and thin melanomas at level II are learned responses with little biologic relevance. In large part, such distinctions are biased by the willingness of an observer to make a commitment to an arbitrary selection from among a collection of sets of criteria. Indisputable real images must be modified by virtual images to validate the chosen set of criteria, and the respective designations. A responsible observer, in selecting one of the sets, will have introduced the bias required for the definition and, thereby, the isolation of segments along what is, in nature, a neoplastic continuum.

In the concept of MDM, lesions with the basic features of common melanoma, but deviating in cytologic and aggregate patterns, were given special recognition with the anticipation that additional studies would define the biologic potential of the variant lesions. In these variant categories, the presumption was made that the special histologic features might also portend distinctions in biologic potentials. Consequently, a uniqueness was assigned to each category in regard to a special relationship with the usual prognostic parameters. It was recommended that thin lesions in the category of the common melanoma- premalignant dysplasia sequence are properly evaluated by the usual parameters. This was not a major concession since, by definition, these thin lesions are managed with expectations that the prognosis will be good. On the other hand, some variants of MDM were recognized as less amenable for evaluations by the usual parameters; MDM of the Spitz type is a good example.

Neoplastic economies (the needs of cells as those needs impact on histologic patterns): Economies are imposed on neoplastic cells during neoplastic progressions. The timing, or the sequence of steps, of neoplastic transformations cannot be predicted by the examination of histologic sections. A normal cell is limited by its phenotype (i.e., genomically based expressions) to do only what it is programmed to do. In neoplasia, the aberrations in the genome remove some of the normally imposed controls. A potential for multiple, graded aberrations, that are expressed in steps, are inherent in neoplastic cells. A neoplastic cell is sensitive to the level, in optional steps, to which neoplasia has progressed. In this approach, it would be inappropriate to presume that neoplastic cells, confined to the epidermis, have the same economies as those morphologically identical neoplastic cells in a metastatic locus in the brain. In high grade, large melanomas, the economies are characterized by extravagance, and independence; the tumor cells become truly imperious of the economy of its host.

The patterns in dysplasias and melanomas retain some of the features manifested in nevi. In dysplasias, the nesting patterns of neoplastic melanocytes at the dermal- epidermal interface anticipate a transfer of the nests, or portions thereof, into the dermal domain. In a manner comparable to the proposed fibroplasia that facilitates the "dropping off" of nests of nevus cells into the dermis, nests of dysplastic cells may induce a fibrous response that facilitates the eventual isolation of nests or portions of nests in a fibrous matrix in the dermis. Thereafter, the cells of the dermal nests are relatively independent of the phenomena of neoplastic progression in the epidermal domain.

Appositional fibroplasia (including lamellar fibrosis) at the interface of junctional nests and the dermis might be characterized as a host immune response, but could be, in part, an aberration of the delicate fibroplasia operative in the evolution of typical nevi (i.e., dropping off of nests of nevus cells). Perhaps it is a combined response involving fibrogenic properties of both the melanocytic cells in the nests, and the cells of the host immune response. In any case, the result is an expanded fibrous matrix in which nests of dysplastic cells often are isolated (sequestered) and widely and randomly spaced. If the sequestered nests are closely and regularly spaced in the papillary dermis, the patterns in aggregate qualify as arrested vertical growth.

Herein (and in the concept of MDM), the distinctions between dysplasias and melanomas are established by an evaluation of the density in which nests of cells are spaced in the dermis, and by the character of the host immune response. The patterns are an expression of the economy of a neoplasm at a given anatomic level, and in each step of neoplastic progression. In contrast to the patterns in the dysplasias, in melanomas, particularly those showing typical vertical growth, the ability of the neoplastic cells to induce, in concert with the lymphoid response, a dense, and often laminated, fibrous matrix is compromised. The cells in typical vertical growth have their own neoplastic economies. They typically aggregate in nests which are rounded, or fasciculated. The size of each nest tends to be fairly uniform but often, in examples showing variations in size of nests in the vertical growth component, there are correlations between the size of tumor cells forming a nest, and the size of the respective nests. In lesions showing variations in the size of individual nests, the larger nests usually are composed of larger cells.

In lesions showing a uniformity in the size of nests of cells, the uniformity might be evidence of a neoplastic economy: the nests can be no larger than the economies of both the stroma and the tumor cells will allow. At the limits for size of nests, the only alternatives would be for the nests to continue to increase in size at the risk of necrosis, or for the nest to release cells, either individually, or in the pattern of buds, off from the mother nests. In this manner, new nests would be derived from the dermal population of cells; the vertical growth component would have developed independence from the phenomena at the dermal-epidermal interface. The dermal component would no longer be dependent on the cellular kinetics in junctional nests at the dermal-epidermal interface.

Level III invasion is an economy. In it, neoplastic cells are dependent on their neighbors to maintain the integrity of the nests. Individual nests, of a lesion confined at “level III,” are dependent on a specialized stroma (community stroma). Not only are there different types of melanoma, the cells of the individual nests of melanomas most likely are functionally diverse. In all these suppositions, there is an onus to propose that the individual nests of cells are also communities in which cellular functions may be diversified, dependent on the location of cells in the nests. Those at the periphery may be concerned with maintaining an activated stroma. Those centrally located may be concerned with their own survival. If cells, by an unfavorable location in nests, are compromised metabolically, they may seek an exit from the nest and, thereby, initiate an expansion in the dermal population of nests of cells.

The economies of nests of spindle cells may differ from those of round, or polygonal, cells. Fasciculated melanomas which are composed preponderantly of spindle cells seem to have less need for a community stroma. In such lesions, variant vertical growth is a common manifestation. Also in fasciculated, spindle cell melanomas, fascicles may violate the boundary between levels III & IV early in their evolution  (e.g., thin fasciculated lesions commonly show level IV invasion). It would appear that nests of spindle cells are less dependent on a community stroma than are round or polygonal cells.

Melanomas showing only intermediate nuclear grade may be inherently more restricted in their ability to adapt to a new ecological niche than high grade lesions. On the other hand, they may retain more of the qualities which distinguish typical nevus cells (e.g., they occasionally are manifested in organoid or nevoid patterns). The cells of low and intermediate grade lesions may be more like common nevus cells in regard to stromal interactions and restrictions to particular economic niches. The neoplastic options expressed as desmoplasia and neurotropism may be genetic privileges available mostly to low and intermediate grade lesions, particularly lesions that have an association with lentiginous radial growth components, and with spindle cell patterns in vertical growth.

Neurocutaneous melanosis syndrome: a malformation, that by gross characteristics is not sharply defined as a tumor, qualifies as a dysplasia. Dysplasias can be either simply malformations, or evolving lesions that also qualify as premalignant. Premalignant lesions may be progressive with greater atypia at each neoplastic step, or may be retrogressive in which malignant potential is expressed in large part by the immaturity of the affected tissue, as evaluated by comparisons with the same tissue at various stages of prenatal development. The greater the degree of immaturity, the greater the potential for the dysplasia to behave in a malignant fashion. Neurocutaneous melanosis syndrome is a dysplasia expressed in degrees of immaturity, and in patterns that are representative of the developmental potential of neurocristic derivatives, including melanocytic, schwannian, and gangliocytic potentials. Some examples are both cutaneous and meningeal. Some are extensive, primitive dysplasias that extend in continuity from the surface of the central nervous system, through the mesenchyme, into the skin. In immature variants, the patterns are disorganized; melanocytic, schwannian, and immature gangliocytic components are represented. Melanomas may arise in any of the affected sites.

Neurocristic hamartoma: a congenital dysplasia derived from the aberrent development of neurocristic cells is a neurocristic hamartoma. In current usage, the designation often denotes a neurocristic dysplasia showing divergent dif- ferentiation, including melanocytic and schwannian components.

Falsification of real images: A potential for falsification of the nature of real images is inherent in the evocation, and imposition of virtual images. In the interpretation of problematic melanocytic lesions, virtual images of the common nevocytic nevus are easily evoked. They guide us in our search for comparable real images. In practice, a comparison of the real images of a problematical melanocytic lesion with the evoked virtual images of common (or even variant) nevocytic nevi will lead an observer to either confirm, or refute, the identity of the physical real images, and the evoked virtual images. In this process, if the evaluations are marred by a refractoriness to the nature of the real images, and If the virtual images of a benign nevocytic nevus then are rigidly and volitionally imposed, a biologically significant melanocytic lesion (melanoma) might be assigned to the category of the common nevocytic nevus. The interpretative process, in having failed to detect any discordance between real images of a deceptive melanoma and the false virtual images of a common nevus, would then equate the two.

Patterns of aggregation: Lentiginous and junctional patterns (pattern I) are basic to the definition of the common premalignant melanocytic dysplasias (also referred to as atypical nevi and dysplastic nevi). If lentiginous and junctional patterns are combined with scattered nests of atypical cells in the dermis, and if the dermal nests are few in number, and widely and randomly spaced, the combination qualifies as pattern II. Pattern IlI A gives recognition to variant vertical growth confined to level III with or without a remnant of a precursor (dysplasia). Pattern III B is distinguished from IlI A by typical rather than variant.......

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