Glossary II 14



The manner in which nests come to be isolated by circumferential fibrous lamellae is difficult to define by simple observation of the static images of histologic sections. It is accepted that in some manner some of the nests of cells in dysplasias lose their continuity with the epidermis: they "drop off" into the dermis. Generally, there are few if any cells among the fibrous lamellae but, occasionally, individual dysplastic melanocytes are sometimes entrapped. In low grade dysplasias (e.g., mild to moderate atypias), the prominence of fibroplasia of this type is proportional to the degree of the cytologic atypia. This type of fibroplasia is not so uniformly a feature in high grade melanocytic dysplasias; it is inversely proportional to the degree of dysplasias in high grade lesions. From this perspective, the cells of many low grade dysplasias have a capacity to induce a specialized, confining stroma, whereas those of high grade dyplasia, in combination with markers also for low grade dysplasias, might have the capacity to release themselves from the confining fibrous lamellae during evolution to the higher grade. For some of the dermal nests of melanocytic dysplasias, the encircling fibrous tissue may be uniformly dense, rather than laminated.

Appositional fibroplasia, whether uniformly dense, or distinctly laminated, is common in dysplasias but is seldom encountered in the confines of a convincing vertical growth component. On this basis, nests of cells, confined by fibrous lamellae, might be characterized as sequestered or arrested in growth, and the lamellae, in toto, characterized as a marker for a reaction in a melanocytic dysplasia .

Multiple nests, regularly and widely (loosely) spaced in a widened papillary dermis, do not, in themselves, provide a marker for early variant vertical growth. For such nesting patterns to acquire the significance of a progressive vertical growth component, the stroma should have acquired the characteristic features of inflamed tumor stroma, and the tumor cells should have released themselves from any confining fibrous lamellae. For such dermal nests to replicate and, thereby, contribute new nests to the population in an expanding papillary dermis, the cells of the sequestered nests must alter the relationships between nests and stroma. In the alterations, a more pliable matrix would displace the fibrous barrier; the respective cells would have made a significant step in the transformation from dysplastic cells to melanoma cells: they would have made the transition from arrested to progressive vertical growth.

To characterize the alterations in the papillary dermis at level III as a hyperplasia of the papillary dermis is not entirely accurate. A similar stroma may be manifested in deep, recurrent melanomas that are far removed from level III, and may even be manifested in metastatic melanomas. In a variety of mesenchymal tissues, melanomas seem to possess a capacity to induce a stroma that is papillary dermis- like.

Growth factors: It has become fashionable to integrate the results of cell-marker studies into interpretations of histologic patterns (virtual images of a technical type). In turn, it is not a significant extension of fashion to fancifully translate the results of marker studies in experimental models into explanations for the histologic manifestations of disease. Growth factors may have a role in a variety of reactions; they may alter the histologic features of a neoplasm.

As an apparent source of growth factors, the epidermis is an important nidus. In all likelihood, most keratoacanthomas are a keratinocytic neoplasms in which common evolution is distorted in an accelerated manner in response to growth factors. In keratoacanthoma, a host immune response eventually would counteract, or turn off, the growth factors; the epithelium (in an aberrant and unprepared domain) then would revert to its more natural (albeit neoplastic) state). In the reversion, the lesion would be exposed to a hostile environment, and to a progressively hostile immune reaction and tumor stroma. The combinations would promote a process of regression but, in the act, some of the cells might acquire more definitive characteristics of a malignancy; portions might persist in the pattern of a common epidermoid carcinoma (i.e., carcinoma ex keratoacanthoma).

Growth factors may well be important as an explanation for the "maturation" observed in Spitz nevi. In most skin lesions, growth factors may be most active in the immediate vicinity of the epidermis. In Spitz lesions, nests of cells in the reticular dermis generally show the features of maturation (reduction in size of nests, and of the cells forming the nests): they are the farthest removed from the nidus generating the growth factors (i.e., the epidermis).

On the other hand, common nevus cells, when represented at the deep margin of the vertical growth component of common melanomas, often show some degree of atypia with slight enlargement of nuclei, and varying intensities of nuclear hyperchromatism. Such changes may be a response to growth factors generated in the vicinity of the vertical growth component; they may complicate decisions regarding the identification, and selection, of the proper gradient on the ocular micrometer for the assignment of a measurement of thickness (Breslow).

In desmoplastic and neurotropic melanoma, the cells of the neurotropic components tend to become epithelioid; they are plump and tend to cluster in the pattern of rigid fascicles. The transformation from a sarcomatous, desmoplastic pattern to that of a fasciculated, epithelioid pattern may be in response to growth factors generated by nerves that are included in the tumor (i.e., the nerve becomes a locus for the elaboration of growth factors) .

In a variety of conditions, growth factors are likely operative in the transformation of the epidermis into a locus which is hyperplastic, and excessively dedicated to terminal differentiation. This transformation is basic to the definition of lichen planus; in a modified form is an essential part of the epidermal pattern of superficial spreading melanoma.

In the modifications of the epidermis that ensue from the "release" of growth factors, the epidermal interstitium might be altered in a manner which facilitates the upward migration of neoplastic melanocytes (e.g., the fluidity of the interstitium is modified in a manner that favors a migration among keratinocytes of cells such as lymphocytes, histiocytes and even altered melanocytes. The phenomena of upward migration may relate to alterations of the mucinous interstitium of the epidermis, and to kinetics of the movement of cells once having entered the superficial unit of the epidermis. There are too many unknowns to defend the notion that the upward migration of melanocytes, in itself, clearly identifies the migrating cells as "melanoma" cells, particularly, if a requisite degree of cytologic atypia is not stipulated in the defense.

SSM in classic patterns, is characterized by a distinctive type of keratinocytic hyperplasia affecting the superficial unit of the epidermis (the population of cells that is committed to terminal differentiation). Cells in the superficial unit of the epidermis, if they are not individually eliminated in the process of apoptosis, are destined to replenish the keratin layer as effete, keratinized cells which are to be shed from its surface. In this manner, there is a progressive upward movement of cells to higher levels. Other populations of cells, if caught in this superficial unit, will participate in the upward migration; eventually, they may also be shed at the surface. This upward movement might, in part, explain the "upward migration" of neoplastic melanocytes in "melanoma" in situ, and in superficial spreading melanoma. In this manifestation, neoplastic melanocytes will have entered a domain which is committed to terminal differentiation and, sharing the destiny of terminally differentiated keratinocytes, will move in concert with neighbors to the surface.

Indeterminate melanocytic dysplasia: In the premalignant melanocytic dysplasias category, some lesions with only mild to moderate cellular atypia in lentiginous and junctional components; with some lentiginous spread in the epidermis away from any remnant of typical nevus; and with no significant host immune response, are not easily characterized as being of the same type as dysplasias with markers identifying respective patients as having an increased risk for the presence of other atypical nevi, or for the development of melanoma. These incomplete examples are best assigned to an indeterminate category (mild to moderate dysplasia of indeterminate type). In practice, many of these lesions are commonly associated with other lesions that are acceptable as markers for the dysplastic nevus syndrome. Some of the peculiar congenital nevi in infants, that are distributed in prominent lentiginous and junctional patterns; show cytologic atypia; and are relatively free of markers for host immune response, fall in this indeterminate category.

Interobserver consensus: For individual cases, the exploitation of patients, so freely vented in clinical trials, has until recently been ethically undesirable. In planning therapeutic trials, deviations among observers in the interpretation of histologic patterns must be arbitrarily accommodated.

In accommodating such deviations, consensus is often deemed of value. In the current practice of surgical pathology, diagnosis by consensus has become a fad. As a ploy, it is of little benefit, if the expressed majority opinion does not agree with the biologic behavior of a problematic lesion. The practice of pathology is not a democracy. Not all opinions, and interpretations are equal. The elaboration, and utilization, of democratic formulae provide no assurance that the pitfalls associated with the manipulation of virtual images have been avoided.

Junctional patterns: The significance of "junctional" patterns in nevi has not been adequately explained. In typical nevi, junctional components are often situated at the extremities of rete ridges. Junctional patterns may be expressive of abortive attempts at follicular neogenesis. In this proposal, the melanocytes of a hair bulb, and the respective papilla may modify follicular stroma in advance of the descent of the hair bulb into deeper regions. In melanocytic nevi, nests of melanocytes advance but the epithelium of the rete ridge is unable to follow.

Kinetics of the movement of nests of neoplastic cells in the emergence of vertical growth components: In the delivery of nests of dysplastic melanocytic cells into the dermis, the rate at which the transfer is made may exceed the capacity of the host immune response to sequester, and eventually destroy newly arrived dermal nests. If new nests are generated in relatively fixed loci from level I into  level II, then the delivery ("dropping off") of new nests in layers over older nests would result in distinctive columns in which nests of cells are stratified. In the columns of stratified nests, the oldest, and often, the least atypical cells will be deepest in the dermis, they will be situated near the interface between the papillary dermis, and the reticular dermis. The youngest, and most atypical cells will be found in the dermal nests near the dermal-epidermal interface. Three such columns, with as many as three nests of aytpical cells in each column, if regularly spaced and if associated with at least moderate atypia, and with markers for host immune response, satisfy the criteria for the recognition of variant vertical growth, if the nests are not all sequestered in concentrically laminated fibrous tissue. If they are all so sequestered, then the pattern might be characterized as arrested vertical growth; to designate such lesions as melanoma would be inappropriate. Such lesions qualify as borderline melanocytic neoplasia of indeterminate malignant potential (arrested vertical growth) .

In the conceptualization of variant vertical growth, the vector for the movement of cells is perpendicular to the basement membrane of the epidermis; the vector is directed from level I into level II. The nidus for the generation of successive generations of nests of cells would remain at the boundary of level I; the phenomena producing the organized patterns of nests of cells in the dermis would be dependent upon the persistence of generative nidi at the dermal­epidermal interface. A gradient of atypia from the dermal­epidermal interface to the deepest nest in the dermis could be cited as a measure of the age of the respective nests with the youngest nests the most atypical (as an alternative, the variations in degrees of atypia in the columns of cells in this process [variant vertical growth as defined in the concept of minimal deviation melanoma] may simply reflect the diminishing influence of growth factors as nests of cells, in their migrations, become remote in relationship to the nidi, and loci, at the dermal-epidermal interface) The other pattern of vertical growth would be dependent on phenomena in the dermis. The ability of cells in dermal nests to replicate in some manner and, in the process, to induce their own stroma, and blood supply (i.e, establish their own ecological niche) is characteristic of "typical" vertical growth. In this pattern, the cells at the dermal- epidermal interface would be free to continue their evolutionary diversions to progressively higher degrees of atypia (neoplasia). The cells in nests in the dermis would have acquired new properties which would permit them to survive, and multiply in the dermis, independent of both old and new phenomena in nests of cells at the dermal-epidermal interface. In this process, the generative nidi are the dermal nests themselves, and the vectors would be universally expansile in all directions from the dermal nidi. The resulting lesion would likely have the qualities of an expansile nodule, and the nests, within the nodule, would be closely spaced, often back to back.

In typical vertical growth, the variability in degrees of cytologic atypia, which often are so prominent in the columns of cells in variant vertical growth, are less likely to be a feature, particularly in thin lesions. Uniformity of cytologic features in vertical growth might be taken as evidence that the cells of the nodule initially are monoclonal. In typical vertical growth, the cytologic atypia of the epidermal component may deviate significantly from that of the vertical growth component in the dermis; the two phenomena are independent; but the component at the dermal- epidermal interface can also contribute new clones to the vertical growth com- ponent.

It should be noted that there is no predictable sequential relationship between variant, and typical, vertical growth. The two may be independent of each other from their inception; some melanomas enter typical vertical growth without an intermediate stage of variant vertical growth.

As indicated in the discussion of anatomic levels of the skin, extension of individual cells, and nests of neoplastic melanocytes from a vertical growth component into the reticular dermis, and among its preexisting collagen bundles (i.e., level IV invasion), qualifies as diffuse, or universal, vertical growth. In this pattern, the neoplastic cells would have become independent of a community of cells (variant, or typical, level III vertical growth) and would actively invade in diffuse patterns. Diffuse vertical growth is predisposed to vascular invasion. Any neoplastic cells in the circulation would comprise the fluid phase of diffuse vertical growth. For lesions that show no component of typical vertical growth, but extend in continuity from variant vertical growth in the papillary dermis to diffuse vertical growth in the reticular dermis, the distinctions between variant vertical growth, and diffuse vertical growth merely reflect relationships between tumor cells, and anatomic boundaries.

All of these phenomena can occur in the transition from dysplasia to melanoma, without the stipulation that the degree of atypia in the precursor lesion has attained the qualities of the common final pathway (high nuclear grade: grade III-IV). LMM commonly enters vertical growth without manifesting the features of the common final pathway. In some examples of LMM, the atypia may be only mild or moderate, in both the radial growth, and vertical growth, components (such lesions qualify as minimal deviation LMM; even more, they may validate the concept of minimal deviation melanoma) .

Lentiginous spread: If melanocytes proliferate in the basal layer of the epidermis, and diffusely spread in linear arrays among basal keratinocytes, the pattern is a manifestation of lentiginous spread. The distribution of respective melanocytes in lentiginous components defines the eventual limits of the epidermal domain over most melanocytic neoplasms.

In contrast, clustering of melanocytes in junctional patterns at the dermal-epidermal interface is the polar opposite of lentiginous spread. The derivation of the cells in junctional nests is uncertain, but a migration of cells out of a surfeit of cells in the lentiginous component into a specialized domain (i.e., junctional nests)is one possible explanation. Junctional nests thus might be viewed as a neoplastic accommodation for cells which have otherwise locally exhausted a limited epidermal domain (i.e., the lentiginous domain).

Alternately, cells in junctional nests might be characterized as having relinquished the epidermis as an ecological niche, but, in turn, as having not gained a new niche: they are indifferent cells in transition. They are cells which are destined either for residence in the dermis, or to contribute individual cells, or small nests of cells to the dermis.

The lentiginous component of a nevus has been characterized as a distorted recapitulation of the behavior of melanocytes as they populate the epidermis in developing skin. The junctional components have been characterized as an atavism in which cells revert to a more primitive phenotype; in such a reversion, the component cells lose their "right of domain” in the mature epidermis. In these virtual images, the cells in the junctional nests will have reverted to a primitive phenotype; one in which the primitive phenotype of neurocristic migrants is approached. They become phenotypically indifferent. If they migrate into the dermis and establish continuity with dermal nevus cells, they tend to relinquish melanocytic properties; in the act, they come to express the phenotype of dermal effector cells, with potentials for both fibrogenesis, and Schwann cell-like, properties.

Levels of invasion as a tool for defining distinctions between dysplasia patterns, and melanoma patterns: Levels of invasion, as defined in the characterization of "minimal deviation melanoma" of the dysplasia-melanoma sequence (3), provide the distinctions between dysplasia, and higher grades of neoplasia. In this approach, all level I & II lesions (modified Clark's criteria) qualify as dysplasias, and all lesions at level III, and deeper, qualify as melanomas; there are no melanomas at level I or II  (4).

Malignancy: The relativity of this designation is embodied in the concepts of  "cure," "survival," "progressive disease," "metastasis," and "fatality." If a "malignancy" is controlled by local excision, or other local therapy, a characterization of the lesion as "malignant" is a histologic accommodation. In fact, such a lesion, if evaluated solely by its histologic criteria, with no knowledge of the eventual outcome, would be better characterized as a "potentially life-threatening" neoplasm.

Gradations in the degree of malignancy of melanomas are dependent on many factors, not the least of which being the interrelationships between the age of a lesion, in its life history, as sequenced with time of excision. Many of the gradations in degree of malignancy, in part, are accommodated by attempts to histologically grade "malignant" neoplasms. Evaluations of features such as size, rapidity and destructiveness of growth, cytologic features, and vascular invasion, provide the impetus for the definition of histologic grades. Gradations in degree of malignancy are also accommodated by segmentation of neoplastic continua, and by then providing designations for the segments.

Size is a crude measure of the age of most neoplasms but, being a gross physical parameter, this attribute usually must be modified by histologic parameters, such as grade. In large part, melanomas have been managed as an exception, and size, alone (of the vertical growth component), has been touted as the prime parameter (it is implicit in this concession that the observer has the tools to appreciate a true........

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