Caveats, Pitfalls, Pratfalls, and Prejudices in the Interpretation of Melanocytic Lesions: the Manipulation of Virtual Images
(a Glossary, in Alphabetical Order)
Ancillary concepts, features, and phenomena that are involved in, or relate to, neoplastic progressions include the following:
Acidophilic body: Acidophilic bodies (sometimes characterized as "pale" acidophilic bodies, or "Kamino" bodies) are approximately the size of neighboring keratinocytes. They may be encountered in junctional nests among melanocytic cells, generally near the attachment of junctional nests to the epidermis, or in the epidermis over areas of junctional activity. They may even be found in dermal nests of tumor cells, that are near the dermal-epidermal interface. They somewhat resemble "colloid bodies" of a lichenoid reaction but usually are less symmetrical in outline, and do not show a central zone of pallor (i.e., a central defect as a marker of the site in which a nucleus has undergone lysis).
Acidophilic bodies are common in the setting of spindle cell nevus of Spitz type. They are also fairly common in the pigmented spindle cell nevus of Reed. Similar, but less numerous and smaller, bodies may even be identified in common premalignant dysplasias. They may also be encountered in the epidermal component of melanomas; when identified in the latter setting, they have no diagnostic utility. Being common in spindle cell nevi of Spitz type, they generally become a part of the complement of virtual images which are evoked in evaluating the real images of a suspected Spitz nevus.
Anaplasia: This term has various connotations, one of which gives recognition to collections of primitive, uniform, small round cells that, in aggregate, resemble the undifferentiated cells of an embryo.
Anaplasia of the small round cell type (small blue cell type) might be characterized as “retrodifferentiation” (an expression of neoplasia in which grade is measured by comparisons with patterns found in normal adult, fetal, and embryonal tissue): in undifferentiated, round cell neoplasms, such as primitive neuroectodermal tumors, the embryologically most primitive components are assigned the highest grade of neoplasia; they then assume prime importance in prognostications.
In the skin, melanoblastoma of infancy is an example of a high grade, "small blue" cell neoplasm. It arises in the setting of a giant congenital nevus, and is distinguished from MDM-like lesions (atypical nodular hyperplasias) of giant congenital nevi by size, nuclear atypia, mitotic rate, and malignant potential. It belongs in a category with other blastomas of infancy, and other peripheral small round cell tumors, such as Ewing's tumo; and peripheral primitive neuroectodermal tumor; and cutaneous small cell undifferentiated carcinoma (Merkel cell tumor) .
The concept of anaplasia also has application for the interpretation of patterns in some high grade malignant neoplasms. In this variation, cells are large (e.g., large cell anaplasia), markedly atypical, and lack distinguishing characteristics (even those of embryonic tissue). Large cell anaplasia generally is a feature of high grade, dedifferentiated tumors.
In regard to melanomas, the designation, anaplasia, has greatest utility in the characterization of large cell, amelanotic lesions (i.e., lesions in which the absence of identifiable cytoplasmic melanin complicates the interpretation of a problematic lesion on routine histologic sections). Such tumors, in metastatic sites, are commonly interpreted as something other than melanoma. They may be interpreted as undifferentiated carcinoma, lymphoma, or even sarcoma.
Ancient change: Ancient change has specific connotations in the setting of schwannoma, and cellular blue nevus. It gives recognition to cytologic pleo- morphism, lysis of groups of cells, and characteristic vascular changes. The lysis of groups of cells may be associated with the release of enzymes that alter the walls of neighboring vessels. The process may be akin to that of apoptosis in physiologic, and pathologic depletion of cells. The process should not be confused with patterns of neoplastic progression, in which bland nuclear qualities may lead an observer to believe that the changes are regressive rather than progressive. It would be a mistake to equate the patterns of regressive changes in cellular blue nevus with the progressive neoplastic changes in the vertical growth component of MDM of the dermal type. Generally, mitotic activity is not a feature of the "ancient changes" in cellular blue nevus (see section on "lymphoid infiltrates").
Angiogenesis (angioplasia): The capillaries of the papillary dermis are a component of level II. A vascular plexus is also prominent at the interface between level IV and V.
Angiogenesis (angioplasia) is a common accompaniment of stromal reactions of the skin; it is a significant feature of melanocytic neoplasias at levels II and III. The presence of genetically altered melanocytes, in either the epidermis or the dermis, usually is associated with an augmentation of the vascular plexus of the upper portion of the dermis.
A tumor that has attained level III has acquired the capacity to induce its own stroma (the expanded matrix has the characteristics of a hyperplasia [and fibrosis] of the papillary dermis), and the vessels to support it (i.e., angioplasia).
In variant level III invasion (widely and regularly spaced nests of tumor cells), limitations on the richness of the vascular plexus may influence the distance at which nests of tumor cells are spaced, relative to one another. On the other hand, in typical level III invasion (closely spaced nests of tumor cells), the ability to the tumor to induce its own stroma with an independent, rich plexus of vessels may allow for a closer, more intimate spacing of nests of tumor cells.
The angiogenesis that is associated with cellular immune responses, and that associated with the induction of tumor stroma probably are different, but the two usually are part and parcel.
Ectasia of thin-walled vessels is a common feature in the reticular dermis beneath a vertical growth component. These dilated vessels should be carefully examined for evidence of vascular invasion.
Atypical hyperplasia: Hyperplasia is a general designation that gives recognition to an numerical increase in a specific component. It has application to cells, cellular components, and to stromal components. Atypical is a qualifier that signifies that a cell, or a pattern is "not of the type." In general pathology, the qualifier, atypical, is commonly used to characterize cytologic features. To qualify a cell as atypical indicates that the cytologic features are of a type often seen in neoplasia, particularly malignancies. Some regenerative changes may share cytologic features with malignant cells, and qualify as atypical. If atypia is interpreted as being of regenerative type, then it should be qualified as such (i.e., regenerative atypia) If, locally, there is an increased number of cells, and if those cells are cytologically atypical, then the resulting patterns qualify as atypical hyperplasia. This is acceptable usage of these terms.
Cellular host immune response: A cellular lymphoid infiltrate in a neoplasm generally is a marker for a cell mediated immune response.
Lymphoid infiltrates (cellular immune responses) are not a feature of uncomplicated typical nevi; they are the hallmark of halo nevi. In premalignant melanocytic dysplasias, the intensity of a cellular immune response is generally proportional to the degree of the dysplasia (degree of cytologic atypia). Cellular immune responses are a prominent feature of many melanomas at level III, but tend to be an inconspicuous feature of vertical growth components at level IV.
In high grade dysplasias, in some level III melanomas, and in halo nevi, the lymphoid infiltrates tend to be band-like at the interface between the papillary dermis (or tumor stroma in the case of level III melanomas) and the reticular dermis. Infiltrates of lymphocytes may also extend into nests, and intermingle among tumor cells (tumor infiltrating lymphocytes) The latter patterns are merely a modification of the so-called lichenoid reaction with the stipulation that the target cells are melano- cytes, rather than keratinocytes (the relationships also qualify as halo nevus-like phenomena) .
In intimate association with neoplastic cells, lymphocytes and histiocytes, of a cell mediated reaction, mediate the lysis and destruction of the neoplastic cells. As a result, neoplastic cells in affected nests are more loosely spaced, and are often separated by irregular, small clefts. (These clefts, like those in the epithelial domain of inverted follicular keratosis, may be favored site for the accretive inlay of fibrous tissue; an inlay of fibrous tissue in these defects may partition the nests and eventuate in an incorporation of the fragmented portions in dermal mesenchyme; as a consequence, the entrapped nests may appear to have "dropped off" into the dermis) .
The epidermal components of dysplasias, and the radial growth components of melanomas commonly are associated with infiltrates of lymphoid cells in true "lichenoid" patterns. The resulting lytic defects in the epidermal domain contain cellular debris (colloid bodies), lymphocytes and histiocytes. They are the result of the lysis of both normal keratinocytes, and neoplastic melanocytes. In some dysplasias, the lichenoid reaction may, on a given section, mask the nature of the underlying lesion; they may lead to a diagnosis of an inflammatory process (i.e., established, or senescent, lichenoid reacion). In a similar fashion, it may obliterate a melanoma in the primary site (see section on regression) .
Admixtures of tumor cells, and tumor infiltrating lymphocytes, when identified in melanomas, have been cited in some prognostic statistical analyses as a significant (favorable) variable.
Some melanomas, such as the organoid, or nevoid, variants, tend to be manifested in fascicular patterns, show atypia in uniform patterns, and extend into the reticular dermis in patterns of variant level IV invasion; these lesions rarely show significant patterns of host immune response. All these features are deviations from patterns in more common forms of melanomas; they make for deceptive real images. Such lesions, if mistakenly assigned to the category of benign nevus, may lead to later claims of malpractice.
Controversies: The enthusiasm for controversy, as introduced into pathology conferences in the 1970's, has somewhat abated. Controversies became a tool to be manipulated for selfaggrandizement, and for the promotion of a following. The popularity of controversies reveals the susceptibility of practicing dermatopathologists to the force of personalities. Controversies are mostly a play upon linguistic symbols, rather than a significant manipulation of real and virtual images.
De novo melanoma: Most melanomas are associated with remnants of their precursor. In Clark's scheme, these remnants were characterized as radial growth; melanoma lacking 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 an epithelial neoplasm, 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. Melanocytes are a component of most cutaneous epithelia. Typical nevi may be lentiginous, junctional, or compound.
The designation, dysplasia, has found broad usuage. In one content, it gives recognition to a an arbitrary segment of a neoplastic process (continuum) that 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, to malignancies; the melanocytic premalignant dysplasias, and related atypical nevi are prototypic of premalignant dysplasias. In such neoplastic schemes, the distinctions, such as they are, between dysplasias, and respective malignancies are based on both morphologic, and clinicopathologic features. Lesions in the dysplasia category have little, or no, potential for metastasis; in themselves, they are rarely a threat to the well-being of the patient. Morphologically, they share cytological features with cells of the respective malignancy, and 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, if tumoral qualities are manifested clinically, they usually are histologically attributable to a preexisting population of nevus cells.
An appreciation for degrees of cytologic atypia is essential to 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, in the evaluation of 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 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 to cytologic atypia; and to abnormal patterns, including clustering of cells, and distribution of nests of cells. The cells of a dysplasia are themselves “dysplastic” at a precursory extremity of a neoplastic continuum. Neoplastic cells are the cells of a neoplasm. In general, dysplastic cells 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 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 stepwise, evolutionary acquisitions. The physical and histologic features are expressions of neoplastic transformations at the genome level. Not all of the genetic transformations find morphologic expression at the histologic level. Genotypic 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 for several stages of neoplastic transformations. Cell markers (“transmission analysis”), if they have any pertinence, 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 dysplasia, as might be seen in the setting of the dysplastic nevus syndrome, are common. They are dysplasias of indeterminate type. 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 otherwise incomplete. Such lesions are best characterized as melanocytic dysplasias of indeterminate 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, 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 by 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 potential of a given lesion. These two attributes have relevance in an appreciation of the relativity that is inherent in any definition of a malignancy. For epithelial neoplasia (and in most respects, melanoma has epithelioid qualities), the distinction 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.
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 minimal deviation melanoma 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 spacing 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 dysplasia qualify as high-grade dysplasias. In addition to nuclear grade, or atypia, the presence of an "upward migration" of the atypical cells into the epidermis provides a ready means for the partitioning of most of the lesions of the general category into one or the other of the two subgroups.
Ecological niche, continuity of patterns, and induction of stroma: In normal tissue, each cell is relatively confined to an ecological niche. For normal epidermal, and mesenchymal, cells, the relationships are too obvious to require elaboration. For other cells, such as helper T cells, and reticular cells (dendritic histiocytes), the relationships are less obvious; they relate to the ability of transients to identify their appropriate niches under stress.
The ability of "malignant" cells to survive, and grow (i.e., establish a ecological niche) is dependent on their success 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 ecological niche may not be committed to the same offenses as true malignant cells that have the ability to create their own 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 the capacity to violate the boundaries of their ecological niche. They must be judged deficient in those qualities which distinguish fully evolved malignant cells. They then become "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 that have been given significance by the assignment of a "loaded" designation) might be characterized as intermediate neoplasias, in regard to having acquired a capacity for malignant behavior. They might be best assigned to a borderline category of neoplasia, and then 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 a immunologically hostile matrix. They would be likely to remain isolated in the immune mediated matrix, or to even 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 typical nevi but, in contrast, the atypical cells elicit a host 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 preexisting nevus. Interruption of continuity of patterns is a characteristic of an "atypical nevus" (e.g., a premalignant dysplasia in which a remnant of a preexisting typical nevus is represented) .
The ecological niche for cells at level III is a tumor stroma which resembles an expanded papillary dermis (i.e., pattern III). Host immune response is often best developed at the advancing margin of a nodule formed of nests of tumor cells (vertical growth component). In this niche, the cells of the nodule are confined by a condensed, circumferential immune response: they collect in a community, and the respective stroma is community stroma (the community itself may in some examples be hostile to lymphocytes). They would have adapted to form a community in which all the neoplastic cells are dependent on each other, and on a "community" stroma, and its blood supply.
The ecological niche for cells at level IV is locally, and universally, unrestricted. The cells are not dependent on the stroma of a community; they are migrants in the fibrous framework of the preexisting reticular dermis, and subcutis. In addition, they possess the potential to colonize distant organs by their capacity to induce a "migrant" or "universal" stroma in distant sites.
For some observers, cells, that by their cytologic characteristics are "malignant," and by their affinities, one for the other, have clustered to form isolated nests (without attention to anatomic level), are likely to be assigned to the category of a "malignancy." They are then assumed to be imperious to the needs of normal, and even certain neoplastic, cells to find, and reside in, a niche (this assumption is basic to the philosophy of those who tout the validity of the concept of "melanoma in situ" and "one melanoma"). From this perspective (i.e., the perspective of proponents of "one melanoma"), neoplasia is thus reduced to the level of individual cells (i.e., from this perspective there are malignant cells as well as malignant neoplasms) .
Epithelioid qualities: The definition of the qualifier, epithelioid, has been extended from a characterization of patterns in which non-epithelial cells are clustered to also embrace distinctive cytologic features, regardless of the patterns in which the distinctive cells are distributed. An "epithelioid" cell is plump with cytoplasmic acidophilia. It has a round, eccentric nucleus with variable prominence of nucleoli. Usually, the cells, so designated, are round or polygonal, but the designation also has application for spindle cells (e.g., the cells of many primary epithelioid malignant schwannomas are spindle shaped) .
In desmoplastic and neurotropic melanomas, fascicular components focally may be prominent. The resulting patterns are epithelioid, but the cells usually are spindle shaped. In the latter usage of the qualifier, epithelioid, attention is given to both the protoplasmic nature, and to the close approximation, of the cells forming the fascicles.
Fibroplasia: In this section, attention is given to relationships between nests of either dysplastic cells or melanoma cells, and their stroma.
In melanomas, the nests formed by clusters of cells have epithelioid qualities. In the nests, cells cluster in a clear, fluid matrix; in turn the nests and their matrix are supported by a fibrous, or fibromyxoid, stroma. One variant of stroma, as seen at level III, might be characterized as induced, or community, stroma (it is delicate and the fibers are randomly disposed). Community stroma is an accommodation by stroma for a population of neoplastic cells in the dermis, and is basic to the definition of level III growth ("invasion," vertical growth, and "melanoma").
Another variant, that might be characterized as reactive stroma (in it, laminated fibers are concentrically arranged around nest of tumor cells) is peculiar to premalignant melanocytic dysplasias. In appositional growth, brightly acidophilic fibrous lamellae condense at the periphery of many of the junctional nests, as they push into the papillary dermis from their attachment at the extremities of rete ridges. Flattened cells, often seen at the periphery of junctional nests, may have acquired the capacity to contribute to the formation of a laminated fibrous matrix.
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