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If thin melanomas generally are “younger” than thick melanomas (there are some exceptions, and some melanomas [i.e., lesions in vertical growth] in all categories may persist as thin lesions for years), then diffuse vertical growth (pattern IV) is peculiarly common in many “young” spindle cell melanomas, including LMM.
Cytologically, LMM, showing minimal deviation (i.e., uniform cells with small, uniform nuclei) in vertical growth, are difficult to distinguish from solid components that may be encountered in some examples of pigmented spindle cell “nevus” of Reed. From these observations, it is obvious that at least some melanomas may enter vertical growth without acquiring the characteristics of the common final pathway. Even one example, if universally accepted, would validate the concept of MDM. If Helmut Kerl had been more receptive for, and less critical of, the concept of MDM, he might not have found himself a year later in the position of showing “the right stuff.”
The lentiginous components of both LM and LMM are remarkably migratory. In them, the epidermal spread is fluid-like, and the cut-off between dysplasia and adjacent uninvolved epidermis is histologically difficult to define; it often is difficult to make a distinction between the cells of the dysplasia at a margin, and the altered melanocytes of actinically damaged skin in the neighboring epidermis. Margins are difficult to define, and recurrences of LM and LMM are common.
LMM is actinic lentiginous melanoma in patterns III & IV (the setting is actinically damaged skin, and lentiginous qualities are prominent in radial growth). LM, and thin LMM are representative of borderline melanocytic neoplasia of indeterminate malignant potential (actinic variant). Nuclear grade often is only I or II. As such, thin LMM is usually a borderline, minimal deviation variant.
III. Acral lentiginous nevi and melanomas: The patterns in acral “nevi” have evoked controversy. A purely dermal, acral nevus is uncommon in daily histologic material; some examples show the pattern of a small congenital nevus. The incidence of dysplasia in acral nevi is dependent on the prejudices of the observers. Some observers have taken the position that the asymmetrical patterns in “acral nevi” are native to the site, and that dysplasias are uncommon. From another perspective, dysplasias (“acral nevi”) are common in acral locations, but usually are not associated with prominent lymphoid infiltrates. In practice, lentiginous and junctional, or compound patterns with mild to moderate atypia in the junctional component are common features of acral dysplasias (“nevi”). Spindle cell patterns are common in the junctional components, and some acral dysplasias also qualify as atypical spindle cell melanocytic neoplasms with “Spitz-like” qualities. In the high grade dysplasias, the patterns overlap wityh those seen in the radial growth components of ALM. In these high grade lesions, markers for host immune response, including lymphoid infiltrates, and dermal fibrosis, are prominent features. These overlaps in patterns offer support for the notion that acral lentiginous melanomas usually have their origin in acral lentiginous dysplasias (atypical “nevi” of acral type).
There is no reason to think that the acral neoplastic system differs significantly from that in other sites. In all other sites, low grade melanocytic dysplasias are more common than high grade dysplasias. On this basis, it seem likely that the common acral “nevi” are precursors (markers for remnants of an earlier phase) in the same neoplastic system as high grade dysplasias and acral melanomas.
Acral melanomas are usually expressed in spindle cell, and fascicular patterns in vertical growth. Vertical growth components commonly are large at the time of clinical and histologic diagnosis. They are expansile, but careful attention to patterns at the deep margins will usually show areas in which solid aggregates of cells extend into the reticular dermis among collagen bundles (level IV invasion). Loose infiltration by individual cells, and thin nests and fascicles of cells are not as regularly a feature of ALM at level IV as in SSM, or LMM at level IV. Bland cytologic patterns are not as common in the vertical growth components of acral melanomas as they are in LMM. When bland features are encountered in a lesion of ALM, such lesions would also be acceptable as a variant of MDM. Even if bland cytologic features are dominant, they do not interdict an evaluation of the lesions by the usual prognostic parameters to provide therapeutic guidelines. Thin ALM would qualify, like the other thin melanomas, such as thin SSM and thin LMM, as borderline neoplasia of indeterminate malignant potential.
ALM is the expected variant in palmar, plantar, subungual, and mucosal sites. Like LMM, it is distinguished by both clinical, and histologic features. It is the common melanoma of acral sites, and squamous (and even some glandular) mucosae. Its precursor (acral lentiginous dysplasia [ALD]) is less defined than that of LMM, but is preponderantly lentiginous. It is commonly associated with remnants of nevus cell patterns. The precursor of ALM is manifested in degrees of atypia (and dysplasia), and is associated with characteristic patterns of epidermal hyperplasia. In ALD, upward migration of neoplastic cells (e.g., a quality emphasized in the definition of the MANIAC phenomena [an accommodation for those disciples of the doctrine of “melanoma-in-situ” who have encountered banal cytologic features in associaton with upward migration of melanocytes in some acral “nevi,” and in recurrent nevi [“pseudo melanoma”]) is fairly common. The concept of MANIAC phenomena offers, as a balm, an excuse for the over-diagnosis of acral melanomas; the balm is not restricted just to lesions manifesting higher grades of acral dysplasia. In these upward migrations, the cells tend to maintain dendritic qualities, and to lie within open lacunae among keratinocytes.
The emergence of a vertical growth component in an acral dysplasia, as in LM, is often expreseed in pure spindle cell pattern; in addition, some of the vertical growth component may be remarkably bland cytologically (minimally deviant). Thin acral lesions, in vertical growth, commonly show level IV invasion (migrant vertical growth).
If we accept the palms, soles, and subungual areas as modified squamous mucosae (they are devoid of pilosebaceous units), then acral lentiginous melanoma is also mucosal lentiginous melanoma. Conjunctival melanomas, subungual melanomas, and other mucosal melanomas (and their antecedent dysplasias) are related histologically, and pathogenetically to plantar and palmar variants.
Melanomas in the acral category commonly deviate by showing only moderate to moderately severe cytologic atypia, and by often showing patterns of spindle cells and fascicles in vertical growth (i.e., variable combinations that often qualify as minimal deviation patterns). ALD, showing moderately severe to marked atypia, and thin ALM (less than 1 mm in vertical dimensions) are representative of a borderland of neoplasia (acral variant; nuclear grade I, II, & III).
IV. Unclassified variants: Melanomas with lentiginous qualities in radial growth are common in sites other than those defined for LMM and ALM. They are common on the trunk, and the legs. In the radial components of such lesions, the patterns, by definition, do not fully satisfy the criteria for the diagnosis of SSM. In this category of lesions, which are not otherwise classifiable, thin dysplasias, showing moderately severe to marked atypia, and thin melanomas (less than 1 mm in vertical dimensions) are also representative of a borderland of neoplasia.
V. Heteromorphic melanomas: When examples of desmoplastic and neurotropic melanoma are evaluated, the range of cytologic atypia is wide: some examples are minimally deviant cytologically. In addition, these two variants are peculiarly related to precursors in which markers for a pre-existing lentiginous dysplasia are common. Lesions expressing the qualities of the common final pathway rarely enter vertical growth in desmoplastic and neurotropic patterns. It is as if a degree of differentiation (i.e., a degree of atypia less then that of the common final pathway) is a requisite for melanocytic neoplasias to optionally enter vertical growth in desmoplastic and neurotropic patterns. Desmoplastic and neurotropic melanomas are seldom representative of the borderland of thin melanomas; they are frequently, but not invariably, associated with lentiginous melanocytic dysplasias in the overlying epidermis. The diagnosis is seldom made before an example is large and histologically significant.
Desmoplasia:
As an option in some melanomas, but generally as a diffuse pattern in lesions of considerable bulk, individual neoplastic cells are isolated in a dense fibrous matrix. The resulting patterns have sarcomatous qualities, and the lesions, in toto, are spoken of as desmoplastic melanomas. In cellular areas of such lesions, particularly areas near the deep margin, the cells may form interlacing fascicles (desmoplastic melanoma is usually a variant of fascicular, spindle cell melanoma). In many examples, a careful search will disclose one or more lentiginous and junctinal components in the epidermis over, or adjacent to, the desmoplastic component. In desmoplastic components, there is a tendency for the process to be more cellular in perifollicular sheaths. In foci in some lesions, there is a tendency for cells to be focally arranged in delicate, parallel fascicles to produce neuroid (neurofibroma-like) patterns.
Lentiginous and junctional components, and actinic damage, all in association with desmoplasia in a dermal component, identify the respective lesion as a variant of lentigo maligna melanoma. Less commonly, desmoplastic examples are found on protected skin, and some are found on acral skin, or squamous mucosae (desmoplastic acral lentiginous melanoma). It is uncommon to encounter the pattern of desmoplastic melanoma in the setting of superficial spreading melanoma (e.g., in association with patterns of the common final pathway in the overlying epidermis). In SSM, nesting patterns in the epidermis are preponderant; perhaps, the phenomena favoring the expression of nesting patterns preclude the expression of the desmoplastic phenotype.
In thin lentigo maligna, and acral lentiginous melanomas, borderline desmoplastic patterns occasionally are encountered in the papillary dermis, and superficially in the reticular dermis. In most examples, desmoplastic melanomas have significant bulk and extend through the reticular dermis into the subcutis.
Rarely, the precursor of “desmoplastic melanoma” is a small epithelioid malignant schwannoma. This relationship is established when the nature of a primary fasciculated tumor - one that is purely dermal with no epidermal components - is not appreciated on the initial biopsy specimen, and the lesion is incompletely excised. In such lesions, small nerves are hypercellular, and fascicles of small atypical spindle cells extend from the altered nerves to infiltrate the reticular dermis among pre-existing collagenbundles. Thus, some of these lesions, at their inception, are desmoplastic, peripheral, epithelioid malignant schwannomas rather than true, primary melanomas. In recurrences of such lesions, the fascicular components may be inconspicuous, and overshadowed by a desmoplastic component. By custom in this sequence, the desmoplastic component will likely be assigned to the melanoma category, but it must be admitted that the desmoplastic pattern is a common pathway, accessible to both neoplastic melanocytes and neoplastic nerve sheath cells.
Cytologic atypia in desmoplastic melanoma is variable in degree, and may be deceptively bland. On the basis of bland cytologic features, some examples qualify as minimal deviatin variants. With local recurrences, there is a tendency for dedifferentiation with increased prominence of cellular patterns, and with higher degrees of cytologic atypia (fascicular spindle cell patterns become prominent).
The cells of desmoplastic melanomas, usually, but not invariably, are immunoreactive for S-100 protein. In contrast, it is common for the tumor cells of such a lesion to be negative of HMB-45.
Variations in patterns of fibroplasia are discussed in the glossary in the section on “fibroplasia.”
Neutotropic melanoma:
The quality of neurotropism commonly has been dismissed as being nothing more than a variation of desmoplastic heteromorphism (i.e., the expression of disparate phenotypes in a single neoplasm). In practice, some heteromorphic variants are prominently fasciculated, and neurotropic from their inception. They may not manifest significant desmoplastic components. On the other hand, some desmoplastic melanomas may recur locally (and may do so repeatedly) without acquiring significant neurotropic components.
The ability to extensively infiltrate peripheral nerves may be something other than an expression of an incidental collision between desmoplastic melanoma and peripheral nerves. Phenotypic transformations probably predispose to neurotropism, and often seem to sequentially follow the expression of a “desmoplastic” phenotype. Once acquired, expressions of neurotropism may be independent of expressions of desmoplasia. Neutotropism may be an additional example of the ability of predisposed cells to find their niche, and to express an economy (see neoplastic economies and ecologic niche in the glossary). In expressing neurotropism, a melanoma will have revealed a new clone of cells with a new ecological niche, and new economies.
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