Nevoid Malignant Melanoma (A different perspective with emphasis on organoid patterns in vertical growth, and with secondary attention to monomorphic cytologic features)

Nevoid Melanomas: Nevoid lesions grotesquely recapitulate the patterns of normal tissue. For example, the designation, nevus, has clinical relevance, usually implying that a lesion is congenital, self-limited, and manifested in patterns that are distortions of those of normal tissue. For the interpretation of patterns in nevocytic nevus, a comparison with the development of tactile corpuscles has been offered as a model. Other observers have proposed that nevocytic nevi are a local surfeit of neurocristic effector cells; the surfeit is the expression of a failure of these cells to be locally incorporated in the population of normal cells in the early development of the skin. Nevocytic nevi have organoid qualities, a characterization that, in large part, gives recognition to zonal variations in patterns, with the patterns expressions of divergent phenotypes.

Some melanomas have been characterized as "nevoid.” In this extension of usage, recognition is given to patterns in vertical growth which might be confused with those of common nevi - the implication being that such a lesion might be mistaken for a common, or variant, nevus. Virtual images of common nevi provide the basis for the structuring of new virtual images in which organoid qualities, if encountered in a melanoma, are assigned significance. In large part, in structuring the virtual images to accommodate the “nevoid” features, a variant vertical growth-like pattern is the attribute that contributes an organoid quality but, in the published reports, not all examples have shown variant vertical growth-like patterns. The category is available as a default to which lesions with uncommon patterns may be assigned. The patterns of "nevoid” melanomas, as currently and broadly defined, can also be accommodated in the concept of minimal deviation melanoma. Both MDM of halo nevus type, and of dermal type are "nevoid” but have not been included in reports as variants of "nevoid” melanoma. If there is a malignant (metastasizing) counterpart of Spitz nevus, such a lesion, in its Spitz nevus-like features, is "nevoid,” but this variant has not been included in reports of "nevoid” melanoma. If all these variant (minimal deviation) melanomas were to be included as "nevoid” variants, the category would become nothing more than a selection of lesions from the broad category of MDM.

Some lesions currently classified as "nevoid” melanoma would also qualify as variants of nodular melanoma. A tumor, without a radial growth component but with a vertical growth component that is sufficiently developed to be characterized as that of a “nodular variant” of melanoma, is most likely beyond the borderland of thin melanocytic neoplasia. Melanomas measuring greater than 1 mm in vertical dimensions, that are not associated with a radial growth component, but are so bland in their cytologic features as likely to be mistaken for a benign nevus, might be characterized as "nevoid.” Some pigmented spindle cell melanomas are cytologically deceptive; they are not always associated with a radial growth component. Some of these pigmented spindle cell lesions are cytologically uniform with overall features that can be characterized as "nevoid" qualities. Such lesions usually would also qualify as MDM of pigmented spindle cell type.

In one study of "nevoid” melanomas, large- and small-celled variants were described. It was proposed that "large cell” variants are more aggressive than "small cell" variants. In turn, the reproductions of the large cell variant show solid nesting (i.e., typical vertical growth) patterns, and a preponderance of spindle, or dendritic, cells. Maturation is often emphasized in the diagnosis of "nevoid” melanoma but, in practice, this is not a defining quality. In so-called "large cell variants" of "nevoid” melanomas, maturation has not been a prominent quality. At best, the category of "nevoid” melanoma as currently defined is heterogeneous.

A lack of inflammation in "nevoid" melanomas might also be cited as a feature which promotes comparison with common nevi. From a different perspective, a lack of inflammation might be cited as a feature of a poor host immune response. It is commonly a feature of lesions at level IV. Thin melanomas at level IV are likely to show both "maturation" (i.e., stratified variations in cytologic features) and poor host immune response, thus also qualifying as "nevoid."

Any usefulness of the designation, "nevoid,” in the characterization of a melanoma would have to be found in the biased nature of virtual images of independent observers. Thus, the diagnosis will be favored by some, but of little utility to others. Some melanomas have been misdiagnosed as variants of benign nevus, prompting claims of malpractice. Such lesions usually have been thin; composed of pale cells with relatively bland nuclei (low to intermediate nuclear grade, and low mitotic rate); fascicular in vertical growth; and characterized by patterns of “maturation.” Such lesions might, or might not, be associated with a significant radial growth component. They show "nevoid" or "organoid" qualities, but have been rather nondescript cytologically: their cell type might be characterized as indeterminate.

Of all the categories embodying the virtual images of variant melanomas, that of "nevoid" melanoma is most susceptible to the vagaries of individual microscopy. If a review of histologic patterns in a melanoma evokes the virtual images of a nevus, the respective observer is entitled to characterize the lesion as a "nevoid” melanoma. If a single, specific lesion is to be characterized as "nevoid" melanoma, a list of basic requisites might include the following:

1. round, "nevoid” cells with bland cytologic features; atypia most pronounced at the dermal-epidermal interface; evidence of "maturation” at the deep margin

2. relatively little spread of lentiginous and junctional components in the epidermis away from the dermal component (a quality that would also qualify the lesion as "nodular” [i.e., no radial growth component])

3. prominent nesting and fascicular patterns in which nests and fascicles are loosely and regularly spaced (patterns of variant vertical growth as defined in the concept of MDM) .

The list might also include:

4. low nuclear grade

5. minimal markers for host immune response

6. extension of nests of cells into the reticular dermis among collagen bundles (as a consequence, the patterns may evoke virtual images of a peculiar congenital nevus)

7. ideally, the category should be homogeneous.

Utilizing the above criteria, the nevoid category is considerably refined, but is not entirely pure. The category would include both fascicular, round cell, variants showing typical vertical growth patterns; and nested, round cell, variants showing typical vertical growth patterns. In this manner, certain distinctive round cell melanomas are removed from the category of nodular melanoma. Fascicular, spindle cell variant vertical growth melanomas with organoid qualities would be excluded. Such lesions are given attention in the next section.

Variant vertical growth melanomas arising in, and closely associated with, a preexisting nevus usually evolve at the dermal-epidermal interface as a common, typical melanoma with radial growth components. If a melanoma enters vertical growth in progressive variant vertical growth patterns, the vertical growth component tends to blend with any remnant of a preexisting nevus; the resultant patterns will be organoid with apparent “maturation” from the superficial to the deep margins of the lesion. Such a lesion might be characterized as "nevoid” but, as "nevoid” melanoma has been defined above, the latter type would be excluded.

So-called small cell "Nevoid” melanomas are to be distinguished from small cell melanomas in which the basic patterns do not evoke the initial impression that the process is some variant of nevus. Many small cell melanomas show rather solid vertical growth patterns. In such examples, the aggregation of nests of cells produce patterns that do not evoke the virtual images of some variant of nevus; such lesions do not have organoid qualities.

Variant Malignant Melanoma (A Third Perspective)

Fascicular or nested, variant vertical growth melanomas: The current classification of melanoma places emphasis on anatomic site, environmental influences, and radial growth components (remnants of precursor lesions). In large part, the histologic features of the radial growth component (or the absence thereof) are influential. In the concept of MDM, emphasis is placed on the vertical growth component. Cytologic features and two alternate patterns, namely typical vertical growth and variant vertical growth, are significant.

In typical vertical growth, nests and fascicles of cells in the vertical growth component are closely, and regularly, spaced. The nests of cells are supported by a distinctive matrix; as the lesion enlarges, the nests and their stroma push aside or displace the connective of the reticular dermis (expansile growth). By the definition herein, a lesion showing typical vertical growth is at level III. For nests or fascicles to infiltrate the reticular dermis among collagen bundles would be a change in the character of the lesion, and evidence of a transition from level III to level IV invasion (i.e., diffuse vertical growth).

In variant vertical growth, nests and fascicles of cells in the vertical growth component are widely, and regularly, spaced; they are not tightly packed back to back. In the common, thin melanomas at level III, as encountered in the setting of premalignant dysplasias, a distinct pattern of variant vertical growth is relatively common; it usually is associated with prominent markers for host immune response. Most often the nests of cells are rounded. The tumor cells are rounded or polygonal. Although this pattern qualifies as variant vertical growth, the entrapment of nests of cell in laminated fibrous tissue additionally qualifies the pattern as arrested variant vertical growth (arrested level III invasion). Arrested variant vertical growth is peculiar to typical melanomas; it generally is a feature of thin lesions. If thin, this type of lesion is best included in the category of borderline melanocytic neoplasia. In neoplastic progression, a thin lesion showing arrested variant vertical growth at level III may transform into unqualified variant vertical growth at either level III or IV, or into typical vertical growth (by definition level III invasion as defined in the concept of MDM). Currently, with few exceptions, nesting patterns are not emphasized in the classification of melanomas.

A classification of melanoma that gives recognition to patterns of vertical growth would impact on the category of nodular melanoma, and even on some of the typical forms of melanoma such as acral lentiginous melanoma and lentigo maligna melanoma. In general, two major categories can be defined:

I. nested, round or polygonal cell melanomas

    A. variant vertical growth

    1. arrested variant vertical growth

    2. progressive variant vertical growth

    B. typical vertical growth

II. fascicular, spindle cell melanomas

    A. variant vertical growth

    B. typical vertical growth

Melanocytic neoplasia in the pattern of arrested variant vertical growth is usually a lesion measuring less than 1 mm in height (a melanocytic lesion in the physical borderland of neoplasia). It is distinguished by rounded nests of cells in a widened papillary dermis, and by confinement of each nest in concentrically oriented fibrous lamellae. A lesion showing this combination of features is unlikely to be associated with progressive disease, if completely excised. If a lesion showing this pattern measures less than 1 mm in height, it can be assigned to the category of borderline melanocytic neoplasia of indeterminate malignant potential.

Fascicular melanomas are characterized by:

1. relatively pure fascicular patterns

2. uniform degree of cytologic atypia (little in the way of                   nuclear pleomorphism)

3. spindle or polygonal cells

4. level IV invasion common, even in thin lesions

5. minimal markers for host immune response

6. in some examples, there is maturation

7. radial growth component may not be a significant feature

The fascicular spindle cell melanomas are divisible into a variant vertical growth category, and a typical vertical growth category. A variety of melanomas, including common and uncommon “types,” qualify as fascicular variant vertical growth spindle cell melanomas. The list includes some acral lentiginous melanomas, some lentigo maligna melanomas, some metastasizing Spitz nevus-like melanomas, and some pigmented spindle cell melanomas, There are occasional fascicular, variant vertical growth, round cell melanomas, but they are best assigned to the category of nevoid melanoma.

In lentiginous melanomas, including the acral variant and the actinic variant (lentigo maligna melanoma), fascicular patterns, and variant vertical growth are common. The cells commonly are spindle shaped. Fascicular melanomas in variant vertical growth commonly show level IV invasion, even in thin examples. In addition, such lesions may not be associated with significant markers for host immune response. Such lesions are histologically deceptive. They are organoid, or nevoid in character, and may even show some evidence of maturation (nests of cells, and the cells of the nests are smaller at the deep margin than at the dermal­epidermal interface. They have a rarely expressed propensity to express heteromorphism (i.e., desmoplasia and neuro- tropism). Most examples of LMM and ALM would also qualify as fascicular spindle cell melanomas.

Nodular melanoma with attention to the character of the vertical growth component: Some fascicular melanomas, that otherwise might be characterized as nodular, show level IV invasion, almost from their inception. Some nodular melanomas have been characterized as nevoid variants. Some "nodular" melanomas, with attention to cytologic details of vertical growth components, or to the characteristics of host immune response, could be assigned to an alternate category, such as halo nevus variant; dermal variant; or even Spitz variant. One simple approach to a refinement of the category would be to make a distinction between "nodular" melanomas showing typical vertical growth, and those with variant vertical growth. They could be subdivided as to cell type, including an indeterminate type, and characterized as showing either typical, or variant, vertical growth. The indeterminate category would exclude halo nevus-like, and Spitz nevus-like variants. In this approach, halo nevus-like variants, and Spitz nevus-like variants thus become "nevoid" types. Although a category of indeterminate cell type seems to be as ambiguous as the current nodular melanoma concept, there is, in this accommodation, an admission that the category functions as a default. If special features such as Spitz nevus-like cytology, distinctive, bland "epithelioid" cells of MDM of dermal type; pigmented spindle cells; or halo nevus-like phenomena are not identified in a melanoma, then the cell type might be characterized as nondescript, and lesions showing such features might be assigned to an indeterminate category. Superficial spreading melanoma would be exempt on the basis of distinctive radial growth patterns. Other lesions with, or without, radial growth, that are not characteristic examples of SSM, and do not have distinctive cytologic or immunologic markers, could then be assigned to a default category of melanoma of indeterminate cell type (i.e., nodular melanoma with the exclusion of MDM of the Spitz type, of the pigmented spindle cell type, and of the halo nevus type)

Fascicular, typical vertical growth, spindle cell melanomas with no radial growth components have in the past been either misdiagnosed as some variant of nevus   (i.e., Spitz type, or pigmented spindle cell type), or dismissed as a nodular variant of melanoma. Such melanomas may not be associated with well developed lentiginous and junctional components in the overlying epidermis:; this is particularly true of the pigmented spindle cell variants. They are commonly manifested in the pattern of an expansile nodule which displaces collagen bundles of the reticular dermis. Often the lesion has the configuration of a "keyhole" with a columnar extension into the deeper portion of the dermis, or the subcutis. On some sections this columnar component can be identified as a perifollicular extension. Fascicular, variant vertical growth, spindle cell melanomas may be fairly uniform in cytologic features, but generally there is nuclear atypia with dense nuclear membranes, prominent central nucleoli, and mitotic activity. Some examples appear to have been included in the literature as examples of "metastasizing Spitz nevus."

There is some utility in recognizing a category of fascicular, variant vertical growth melanomas of intermediate grade (a variant of MDM). If such a lesion is composed of round cells in fascicular patterns, it qualifies as a specific round cell variant that by the criteria defined herein is most qualified to be characterized as "nevoid" melanoma. If it has Spitz nevus-like qualities, it qualifies as fascicular melanoma of Spitz type. If it is composed of pigmented spindle cells, it qualifies as pigmented spindle cell, fascicular variant. If the cells are polygonal with no other distinguishing characteristics the lesion is a variant of indeterminate cell type. All these fascicular variant vertical growth melanomas are common in collections of malpractice cases.

Fascicular melanomas, not of the type (i.e., melanomas of indeterminate type) might be characterized as:

    1. fascicular and nested variant vertical growth melanoma (indeterminate cell type)

    2. fascicular and nested typical vertical growth melanoma (indeterminant cell type)

Such lesions are common in malpractice cases. In these contentious lesions, the cells often tend to be short, plump, polygonal cells. Often the cells are pigmented, but in some examples, the cells have pale, or clear, cytoplasm. Many of the lesions with typical vertical growth, that would qualify for this default category, are configured as an inverted wedge with the base abutting upon the epidermis. Closely interwoven fascicles of atypical cells form an expansile tumor that tends to displace the collagen bundles of the reticular dermis. Other examples with a similar overall configuration, and comparable cytologic features are characterized by loose spacing of fascicles of cells among collagen bundles of the reticular dermis (level IV variant [or diffuse] vertical growth). In many examples of both typical, and variant, vertical growth melanomas of indeterminate cell type, the atypical cells have round, or oval, nuclei; heavily stained nuclear membranes; and central nucleoli. Mitoses are a feature; their numerical representation provides a measure of grade of neoplasia. In both the variant vertical growth type, and the typical vertical growth type, lentiginous and junctional components often are minimal in the overlying epidermis.

Uncommon Variants of Melanoma

(Melanoma with high component of histiocytic giant cells):

Rarely, a melanoma contains a high component of multinucleated giant cells of histiocytic type. If such a lesion is encountered in bone in the absence of a history of a prior melanoma, it might be misinterpreted as a malignant giant cell tumor of bone.

Myxoid malignant melanoma: Myxoid melanoma is a rare variant. It is distinguished by distinctive cells, and stroma responses in the vertical growth component. The cells can be either "epithelioid" (rounded or polygonal), or spindle shaped; they have scanty cytoplasm and plump, irregular, densely chromatic nuclei. Often the cytoplasm is vacuolated. The cells cluster in small nests and ribbons, or are individually isolated in a myxoid matrix in the vertical growth component. They may be more closely clustered around vessels in the tumor. The matrix is purely myxoid and intensely basophilic. The myxoid changes can be found in primary lesions, recurrences, and metastases. For some examples, the lesion appears to be primary in soft tissue with no qualities of a primary configuration. This variant is poorly understood, and uncommon: it may be mistaken for a soft-tissue tumor. Myxoid melanoma is perhaps more common in the setting of the lentiginous melanomas than SSM. It may be manifested in the vertical growth of the mucosal melanomas, and present in botyroid patterns. These myxoid melanocytic malignancies, in the vagina or the oral cavity, may be mistaken for myxoid soft tissue sarcomas such as rhabdomyosarcoma, leiomyosarcoma, or liposarcoma. One reported example presented as a primary tumor of the ovary.

Signet ring cell melanoma: Rarely, a melanoma is composed of rounded cells with a signet ring cell configuration. In a metastasis, such a lesion may be misdiagnosed as metastatic adenocarcinoma.

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