Glossary IV 16

          

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vertical growth at level III. Pattern IV gives recognition to in-continuity spread of tumor from a vertical growth component into the reticular dermis, or even into the subcutis (with or without a remnant of a precursor) .

In some dysplasias, nests may be loosely, and regularly, spaced in the dermis; thereby, such lesions are three dimensional. For lesions of this type to qualify as dysplasia, the degree of atypia should be mild to moderate, the host immune response should be negligible, and the nests should be isolated by concentric fibrous lamellae. The pattern then qualifies as a dysplasia showing arrested level III growth (pattern III but of modified significance) .

Within the limits for the dysplasia category, as defined herein, a cytologic spectrum ranging from mild to severe atypia may be encountered without significant alterations in the definition of basic patterns (e.g., the definitions of patterns I & II remain constant). "Melanoma" in situ is an accommodation of pattern I in which a requisite degree of atypia adds specificity. From a different perspective, a similar distribution of nests of atypical cells, but manifested in both epidermal and dermal patterns, is basic to the definition of superficial spreading melanoma (SSM) at level II invasion (pattern II). In this accommodation of criteria for the diagnosis of SSM, there are three basic requisites:

1) a specific degree of cytologic atypia (moderately severe to severe in SSM),

2) patterns in which nests are distributed in the dermis (few in number and widely and randomly spaced), and

 3) an upper migration of atypical cells into the stratum malphigii (pagetoid pattern)

The upper migration of melanocytes in the epidermis is evidence of loss of both a domain in the basal layer, and cellular cohesion. As a consequence, the liberated cells enter the epidermal compartment of terminally differentiated keratinocytes; in the compartment, they migrate in compliance with its cellular kinetics. Upper migration of melanocytes may be seen in a variety of processes, including reactions; the phenomenon is not unique to neoplastic melanocytes, or to markedly atypical melanocytes.

Primary configuration: Common melanomas evolve from a population of cells in the epidermis. If on histologic examination of a lesion presumed to be a primary melanoma, lentiginous and junctional components are not represented in the epidermis over, or adjacent to, the vertical growth component, then such a lesion is characterized as lacking a primary configuration. For such a lesion, the possibility that the lesion is actually metastatic to the site cannot be ruled out. Some pigmented spindle cell melanomas and MDM of dermal type tend to be mostly dermal in distribution, and thus may fail this test for an identification of a “primary con- figuration."

Prognostic categories: The usual physical segments given recognition in prognostications by Breslow's criteria include four categories. In the concept of MDM, these prognostications are restricted to lesions showing patterns III or IV.

The categories include:

Category I: lesions (in vertical growth) with vertical dimensions ranging in size up to 0.75 mm are assigned to category 1.

Category II: lesions with vertical dimensions ranging in size from 0.76 to 1.5 mm are assigned to category II.

Category III: lesions with vertical dimensions ranging in size from 1.5 to 3.5-4 mm are assigned to category III.

Category IV: lesions with vertical dimensions measuring greater 4 mm are assigned to category IV.

In the concept of MDM, thin common melanomas (lesions in vertical growth) measuring 1 mm or less in vertical dimensions are assigned to a borderline category.

In the concept of melanocytic neoplasia of indeterminate malignant potential, both thin, common melanomas measuring less than 1 mm in vertical dimensions, and high grade dysplasias (dysplasias showing moderately severe to severe atypia) are accommodated. In addition, lesions showing pattern IlIa, in which all the nests of atypical cells are sequestered within coarse, concentric fibrous lamellae in a widened papillary dermis, can be cited as examples of arrested level III growth).

Pigmented schwannoma: this lesion is encountered in paravertebral locations. In it, cells with schwannian qualities are variously admixed with melanogenic cells. The patterns are variable. In some examples, uniform, closely spaced spindle cells form interlacing fascicles. Dendritic melanocytic cells are interspersed among the Schwann cell-like spindle cells. In other examples the cells are loosely spaced and form sheets and files in a clear matrix. This is an additional lesion that sometimes qualifies as a stigma of the lentigines-endocrine gland hyperplasia (Carney's) syndrome.

Radial growth: As envisioned by Clark, radial growth was descriptive of the clinical appearance of a significant, flat component, commonly manifested at the periphery of an even more significant nodular component (vertical growth). These images were expressions of gross dimensionalities and, in turn, could be correlated with histologic patterns. Histologically, radial growth is basically a “two dimensional” process, and vertical growth is three dimensional. Prior to Clark's definition of radial growth, the two dimensional component was usually dismissed as an intraepidermal extension of cells from a vertical growth component. Clark proposed that the radial growth component was, in fact, a remnant of a precursor lesion. In short, from his perspective most melanomas with universally expansile components would have had their origin in a clinically recognizable flat lesion.

The sequence in which components of melanocytic neoplastic continua have been defined, and documented, has led to conflicts in the structuring and restructuring of a nosology. With the initial guidelines, both radial growth and vertical growth were components of "melanoma." (e.g., radial growth was also melanoma). If the melanocytic dysplasias had been defined prior to the definition of radial and vertical growth components, current terminology might be significantly different; it might be less susceptible to the conflicts currently evoked by popular designations (and virtual images).

In the concept of minimal deviation melanoma, there are no melanomas at either level I or level II (i.e., all melanomas show patterns III or IV). In addition in this concept, it would be inappropriate to speak of a "radial growth component" in the absence of a "vertical growth component:" Radial growth is a remnant of a precursor; it assumes its identity only in the presence of a vertical growth component. Lesions, that are clinically "flat," and histologically are at level I or even Level II are assigned to the category of the dysplasias, regardless of the degree of atypia, or the upward migration of cells in the epidermis. Flat lesions at levels I & II (patterns I & II) with severe atypia are additionally characterized as having exhausted their phenotypic options as a dysplasia; in a common pathway of neoplastic transformations, accessible to several stages of the dysplastic phase, lesions having arrived at the level of severe dysplasia have followed one or another optional paths to a final extreme; dysplasias once having attained such qualities are representatives of a common final pathway.

Real images that conflict with observed clinical behavior:

Real images of histologic sections may be in conflict with clinical, and behavioral, data. The nature of real images may have been modified by natural, or unnatural, phenomena. Metastatic melanoma in the absence of a demonstrable primary lesion may lead to a thorough physical, and radiological, examination. If a non­tumoral area of altered cutaneous pigmentation is identified, the real images of a histologic preparation from this area may disclose only structural alterations in the epidermis and papillary dermis, increased vascularity, spotty inflammatory infiltrates, and melanin deposits. Such cutaneous alterations may be the only findings in the skin to account for the clinical paradox of metastases in the absence of a demonstrable primary melanoma (11). In the interpretation of such lesions, the evocation of virtual images may provide insights. In confronting this quandry, the evocation of virtual images, mirroring patterns of regression in a primary melanoma, provides both a probable delineation of the nature of the primary site, and insights into the antecedent phenomena, leading from specific to nonspecific patterns, and providing insights for tha interpretation of histologic patterns in the problem site.

The problem of regression in melanocytic lesions is not restricted to those examples in which all cellular markers have been eradicated. Lesions with only scattered nests of atypical cells in a widened, fibrotic papillary dermis, and even melanocytic dysplasias, in which a zone of regression interrupts characteristic histologic patterns, may present similar patterns, and problems, in regard to prognostic significance.

Responsibilities for clinical management of patients: It is the responsibility of pathologists to appreciate the vicarious nature of an interplay of real and virtual images, and to exercise cautions in the translation of the ensuing conceptualizations into language. At best, the selected linguistic symbols are only relative to reality. On the other hand, the vulnerability of pathologists, who attempt to formulate appropriate diagnoses, is embodied in his selection of linguistic symbols. In the final analysis, the documentation of clinical findings, and a correlation of those findings with the embroiled, and manipulated, real and virtual images, as recorded and emphasized in pathology reports, are among the responsibilities of clinicians. Discrepancies between the clinical and pathologic findings must be resolved by open discussions between clinicians and pathologists.

For high grade premalignant melanocytic dysplasias, including segments that in other schemes are classified as "melanoma" in situ, and melanoma at level II, if, by either histologic or clinical criteria, there are questions regarding adequacy of margins of excisions, a conservative re-excision is a safeguard for the patient, the clinician, and the pathologist. A malignant diagnosis for a benign, or borderline, neoplasm may lead to aggressive surgery, or even systemic therapy. If therapy is to be provided by a group, other than the one from which the original pathology interpretation was generated, it behooves the oncologists, who are planning therapy, to have the histologic material reviewed, and the diagnosis verified by local pathologists with whom the oncologists directly interact.

Segmentation of neoplastic continua: In the conceptualization of neoplasia, a borderland in the dysplasia­melanoma continua poses special problems: in this range, various labels have been assigned to indefinite categories. These labels, commonly employed for the evocation of virtual images, and for a correlation of virtual images with real images, fail to delineate the exact nature of the respective lesions. The currently popular labels include: 1) moderately severe and severe dysplasia (including a "common final pathway") (3), 2) "melanoma" in situ (4), 3) melanoma at level II (5), and 4) even thin "minimal deviation melanomas" (measuring less than 1 mm in vertical dimensions of a vertical growth component, and associated with markers for a preexisting premalignant melanocytic dysplasia) (6,7). Designations, such as lentigo maligna (including level II patterns as defined in the concept of minimal deviation melanoma), and thin lentigo maligna melanoma (thin level III or IV patterns), and both superficial spreading melanoma and acral lentiginous melanoma at either level II or thin level III are additional labels with ambiguities in regard to the nature of the respective lesions: the labels have relativity. Without regard for the selection and assignment of linguistic symbols, the basic patterns of borderline dysplasias can be characterized by the same virtual images that are used to characterize those of levels I & II invasion (as modified in the concept of minimal deviation melanoma) (3). Atypical cells may be intraepidermal ( in situ), or both intraepidermal and dermal (compound). If com- pound, the nests in the dermis must be few in number and widely spaced, if dysplasias are to be distinguished from patterns of early vertical growth ("minimal deviation melanoma" showing thin level III or IV invasion) (6,7). In this scheme, as developed in the concept of MDM, the chief variable in the full spectrum of dysplastic lesions is found in degrees of atypia, a technique dependent on the evocation of relevant virtual images. In the assessments, mild to moderate dysplasias constitute the low-grade dysplasias, and moderately severe and severe dysplasias are high grade lesions. Only the high-grade dysplasias need to be assigned to the dysplasia segment of the respective borderland of common melanocytic neoplasias.

Signet ring cell: as a cytologic variation, some melanomas contain peculiar cells with eccentric nuclei, and distinct cytoplasmic vacuoles. This variation is of significance as a possible source of error in the categorization of basic cell type.

Small round cell: cells that are "small" and "round" tend to have rather scanty cytoplasm, and uniform, round nuclei. Often this characterization carries with it the implication that nuclear chromatin is dense. Nevus cells are small and, in halo nevi, their chromatin often is dense. In the vertical growth components of thin common melanomas in the category of minimal cytologic deviation, the cells tend to be "small" but in many examples, the chromatic qualities of the nuclei are variable, though often delicate. Nucleoli tend to be conspicuous.

Some of the lesions currently characterized as "nevoid" melanomas are of round cell type with relatively bland nuclear characteristics. Other lesions, that, rightly or wrongly, are included in the "nevoid" category, are composed of plump spindle, or polygonal cells, and show nuclear grade II or III. Some of these lesions show typical , rather than variant vertical growth. Often, these lesions have been assigned to a Spitz category, even though the cytologic, and aggregate, features contradict such an interpretation. Many of the nodules in giant congenital nevi show bland nuclear qualities (i.e., nuclear grade I or II): they are variants of MDM of the dermal type. Some MDM of the dermal type are not peculiar to the setting of giant congenital nevi, but are composed of small distinctive cells. Such lesions may even manifest halo nevus-like phenomena in the vertical growth component. Occasionally, melanomas, with well developed ("thick") vertical growth components, are composed of small cells with scanty cytoplasm, round nuclei, heavy nuclear membranes, and prominent nucleoli; they show markers for host immune response. The patterns are disorganized and destructive. These lesions commonly have high mitotic rates, and should not be confused with minimal deviation lesions with lightly stained, uniform, small nuclei, and low mitotic rates. It would be inappropriate to include these variants in the category of "nevoid" melanoma.

None of the above small cell variants truly qualify as small cell, high grade (small blue cells) malignancies, but some melanomas arising in the dermal component of giant congenital nevi might be mistaken for a small blue cell (primitive neuroectodermal) malignancy, other than of the melanocytic category. In these melanomas of giant congenital nevi, cells have scanty cytoplasm; nuclei are intermediate in size; chromatin is irregularly condensed at the nuclear membrane level; and mitotic rates are high. Focally, in such lesions the stroma is myxoid. These tumors qualify as melanoblastoma of infancy; they are high grade malignancies . They occasionally show heteromorphism with scattered cells having the characteristics of rhabdomyoblasts. They, with other malignancies of small blue cells, such as neuroblastoma, embryonal rhabdomyosarcoma, and Wilm's tumor, belong in a group of primitive malignant tumors of infancy and childhood.

Spindle cell: In many examples of the typical melanomas, spindle cells often are locally clustered in nests among other nests that are composed of the polygonal cells. In areas, the two cell types may be intermixed in common nests. Spindle cells and dendritic cells are closely related.

Spindle cells take on special significance in some of the less common variants of melanoma, such as the acral lentiginous variant, or lentigo maligna melanoma. In the latter two examples, vertical growth components often are composed exclusively of spindle cells. By definition in these two variants, lentiginous patterns are preponderant in the radial growth components. An experienced observer probably would anticipate spindle cell qualities in the vertical growth component, if the radial component is preponderantly lentiginous. In addition, lentiginous patterns; spindle cells in vertical growth; and the properties of desmoplasia and neurotropism are closely interrelated. Finally, lentiginous components are often associated with nuclear grades I & II in the vertical growth component (e.g., lentigo maligna melanoma is often minimal deviation in type) .

The category of fascicular spindle cell melanomas is sufficiently distinctive to provide a basis for the classification a group of melanomas without attention to the clinical setting, or the character of the radial growth component.

Statistics: A prediction of the malignant potential of a melanoma has clinical, and therapeutic relevance. The appearance of metastases, following a diagnosis of a primary melanoma, and an assignment of the primary lesion to a prognostic category, is likely to be accepted as an affirmation of the utility of prognostic parameters. It is but a minor manipulation to go from the embroiled real and virtual images of a primary melanoma to an unquestioning acceptance of statistics in predicting the prognosis of a particular melanoma. If the focus of attention is the prediction of the likelihood for progressive disease (not disease-free survival), then for melanomas (lesions in vertical growth) in the range of 1.0 mm, and less, in vertical dimensions, it is very unlikely that any, or all of our parameters will accurately identify the specific lesions which will metastasize among a group of 100 comparable lesions. Our confidence in the utility of our virtual images, as related to prognostication, will be badly shaken. On the other hand, with a similar objective in the category of lesions in the range of 2 to 3.5 mm, the ability to identify lesions with the capability for metastasis will lend to our efforts at prognostication the quality of prescience. The validity of our respective virtual images will have been vindicated. If, in our prognostications, we attempt to extend our virtual images to uncommon forms of melanoma, then the utility of prognostic parameters will surely be called into question. The virtual images, which have utility for melanomas in the dysplasia­melanoma sequences (including minimal deviation melanoma of the halo nevus type), are not universally adaptable; they do not have equal application for the interpretation of pigmented spindle cell melanomas, minimal deviation melanomas of the Spitz type, and minimal deviation melanoma of the dermal type.

Technology and the art of pathology: The routine use of a battery of immuno- reactions, as an aid in the histologic interpretation of problematic lesions, is not the practice of the art of surgical pathology. Even in the technical arena, equivocal findings can be afforded diagnostic significance by the imposition of virtual images. In fact, the liberal application of technology in the interpretation of histologic preparations has greatly restricted the free expression of virtual images. To assume, that the nature of a problematic lesion is clearly defined by a battery of immunoperioxidase reactions, is to ignore the many cases in which the results of such studies are of no value, or are even confounding. The pathologist, who places too great a reliance on immunoreactions, will have reduced himself to a technologist. In addition, as one who is prejudiced by emphasizing real images of immunoreactions, and by limiting his access to virtual images, he will be handicapped. He will have unfavorably altered both his art and his technology.

Technical artefacts and their influence on real and virtual images: Physically distorted real images significantly compromise efforts to evoke pertinent virtual images. With the compromised real images of a technically unsatisfactory, histologic preparation, virtual images, often of an inappropriate character, are easily imposed. They may not mirror the real images, as they might have, had the histologic preparation been adequate. As an illustrative scenario, a problematic, technically distorted lesion may be a thin, but biologically significant, melanocytic neoplasm. The clinical impressions, which may have included both benign nevus and some variant of atypical nevus, or melanocytic dysplasia, would influence the character of the evoked virtual images. Finally, with ambiguous stimuli provided by attention to the clinical data, the defective real images may not provide adequate reinforcement, or refutation of the evoked virtual images. In these compromises, and impositions, a malignant lesion may be misdiagnosed as a benign process. For consultants, who must deal with technically inferior preparations, a disclaimer, with comments regarding the problems that compromise attempts to accurately interpret the material, is indicated.

Therapeutic commonness in the category of borderline neoplasia: In the common practice of assigning severe melanocytic dysplasias to the category of either "melanoma" in situ or superficial spreading melanoma at level II, the significance of vertical growth as a prime determinant of a potential capacity for metastasis, and as the proper marker for assigning a problematic lesion to the category of melanoma, is obscured. If the diagnosis of melanoma is restricted to lesions in vertical growth, and if all other related neoplasms are assigned to the category of dysplasias (as in the concept of MDM) (7), distinctions and implications are better defined. Even in this approach, some of the patterns in some thin lesions will be borderline in regard to satisfying the criteria for the recognition of early vertical growth (and the diagnosis of early melanoma). In practice, all such thin, problematic lesions are accessible to be manipulated by Breslow's criteria (8) and, in turn, the manipulations can be translated into therapeutic guidelines. Such a translation would carry with it, as a requisite, a recommendation for conservative re-excision of the primary site, and careful follow-up. For some of these borderline lesions, the integration of virtual and real images might have prompted a diagnosis of a dysplasia, but subsequent followup will have documented metastases. Some of these lesions on review may show focal areas of regression. For these deceptive lesions, an evaluation, at the time of the initial histologic interpretation, by Breslow's criteria would not have provided an indication for either wide local excision, or for regional lymph node dissection. Thus, even with the subsequent appearance of metastases, the patient would not be judged to have been harmed by any error in prognostication (i.e., an inaccurate prediction; the ill-effects of which would have been mollified by a quality of therapeutic commonness, and by appropriate recommendations) .

Thickness, labels, and prognostications: The accuracy of predictions, relative to the likely behavior of any given melanoma, is proportional to the vertical dimensions of the problematic lesion. There is relativity in the diagnosis of melanoma. The thicker the lesion in vertical growth, the more accurate will be any predictions based on prognostic parameters. For example, cutaneous melanoma may be characterized as either real or unpredictable. Real melanomas might be characterized as lesions in vertical growth with a predictable likelihood for metastasis. Practically, lesions greater than 1.5 mm in vertical dimensions (Breslow's criteria) (8) qualify as real melanomas. Below this limit, metastases are infrequent, and less predictable. Thin lesions, measuring less than 1.5 mm in vertical dimensions, and with vertical growth components, might be characterized as unpredictable melanomas. All thin superficial spreading melanomas (thin level III or IV), manifesting the features of the "common final pathway" (3), and measuring less than 1 mm in height qualify as borderline melanocytic neoplasia of indeterminate malignant potential. By current criteria, real melanomas are best managed by wider margins of excision than those with less impressive dimensions (e.g., a centimeter margin for each millimeter of vertical dimension by Breslow's criteria) .

Thin melanoma arising in atypical nevus (melanocytic dysplasia): The typical melanomas are sequentially related to precursor lesions, as manifested in the dysplastic nevus syndrome. For this group, and only in its borderland of thin lesions, is it useful to speak of a category of variant melanomas. The lesions in this borderland range from moderately severe dysplasias to thin melanomas, all measuring less than 1 mm in vertical dimensions. Included in the borderland are lesions that might otherwise be classified as melanocytic dysplasias (moderately severe, and severe, dysplasias), "melanoma" in situ, "melanoma" at level II, and "thin" melanoma at level III or IV. It is fruitless to promote arbitrary criteria for the definition of "melanoma" in this borderland and, in the process, to interdict the relevant criteria of others. The prognostic parameters simply do not accurately identify lesions with a significant potential for metastasis. Prognostically, a metastasis from a lesion in this.......

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