Common Variants 03



From a different perspective, superficial spreading  melanoma at level II is an expression of a common final pathway, variably encountered in the neoplastic progression leading from common precursors to the common melanomas. Having entered this pathway, the only option for further neoplastic progression is for the neoplasm to enter vertical growth. Superficial spreading melanoma at level II basically is a "segment" of a neoplastic continuum - the segment finds validation in a selection of an arbitrary set of criteria. SSM at level II is distinguishable from its more benign precursor stages, and from all subsequent stages in which nesting patterns in the dermal component acquire “three dimensions;” the distingushable feature is the formation of a plaque or nodule (patterns III & IV: a definition of "vertical growth" that is basic to the concept of minimal deviation melanoma [MDM]).

Superficial spreading melanoma is not a unique neoplasm; it issues from a common final pathway which, on occasion, is also accessible to neoplastic cells in the clinical and histologic setting of both lentigo maligna melanoma, and acral and mucosal lentiginous melanomas. Superficial spreading melanoma is melanoma vulgaris. By definition, its nuclear grade is high (i.e., grade III-IV). In the concept of MDM, thin lesions in vertical growth but measuring less than 1 mm in vertical dimensions are representative of a borderland of melanocytic neoplasia.

II. Lentigo maligna melanoma (LMM), as defined herein, is a lesion in vertical growth (i.e., pattern III or IV), and is the common melanoma of the sun-exposed skin of fair complected patients who are usually beyond the age of 40. By definition, a remnant of its precursor is represented at the margins of the vertical growth component in the patterns of a dysplasia (i.e., patterns I & II: radial growth). In fact, the precursor (lentigo maligna) is a special variant of a premalignant melanocytic dysplasia (patterns I & II) . Both it and other precursor lesions, such as those seen in the dysplastic nevus syndrome, can be evaluated by the same criteria, but often the histologic features of LM are sufficiently distinctive to allow an experienced observer to distinguish a precursor lesion of LM from a precursor lesion of the dysplastic nevus syndrome.

Clark and Mihm proposed the designation, lentigo maligna, for the precursor of lentigo maligna melanoma but, then, restricted the definition to lesions in which the neoplastic cells are confined to the epidermis (“in situ”). In practice, the designation, LM, should embrace dermal patterns (i.e., pattern II) in the same manner as the definition of melanocytic dysplasias in the dysplastic nevus syndrome (i.e., patterns I & II). The precursors of both SSM and LMM are basically two dimensional in regard to their dermal patterns. Scattered, randomly spaced nests in the upper portion of the dermis should be incorporated in the collection of accepted virtual images that have relavance in a definition of LM.

The epidermis in lesions of both LM and LMM often is remarkably unaffected (and shows the atrophy associated with aged skin). In contrast, the epidermis of superficial spreading melanoma at levels I & II is hyperplastic in a most distinctive manner. The hyperplasia affects the superficial unit (i.e., the unit comprised of keratinocytic cells showing terminal differentiation). The differences in the epidermal responses in these two variants suggest that either the epidermis of the elderly is unresponsive to growth factors produced by a clone of neoplastic cells, or that the cells of lentigo maligna do not as regularly produce growth factors as do those of superficial spreading melanomas.

The precursor lesion, whether manifested in pattern I, or pattern II [i.e., lentigo maligna (LM)], is expressed in a wide range of degrees of cytologic atypia. Some examples are deceptively bland. The restrictions on degree of atypia in the radial growth component, which are basic to the definition of SSM, are not imposed in the definition of LMM. Distinctive multinucleated giant cells in the lentiginous components and in junctional nests - often fascicular patterns - at the dermal-epidermal interface are a common feature. The designation, lentigo maligna, is not synonymous with "melanoma" in situ but, in common conceptualizations, the two designations often are equated. Certainly, a clinician is likely to afford greater significance to a diagnosis of LM than to that of a common premalignant melanocytic dysplasia showing a comparable degree of atypia. This caution may be justified; there may be a greater tendency for local recurrence in the category of lentigo maligna, and lentigo maligna melanoma than in the common premalignant dysplasias.

In low grade dysplasias in the setting of lentigo maligna, markers for host immune response often are scant. As is common with other lentiginous variants, the emergence of a vertical growth component is likely to be expressed in patterns of spindle cells and fascicles. In some examples, the degree of atypia, even in a vertical growth component, is mild. Such lesions, by cytologic criteria, are minimal deviation variants. Thin lesions in the setting of lentigo maligna melanoma are more likely than the common variant to be expressed in patterns of spindle cells and fascicles. In some examples, the degree of atypia, even in a vertical growth component, is mild; such lesions, by cytologic criteria, are minimal deviation variants. Thin lesions in the setting of lentigo maligna are more likely to be level IV lesions (pattern IV or diffuse vertical growth) than lesions of comparable vertical dimensions in the category of SSM. Arrested variant vertical growth is not a regular feature of an evolving, but early, LMM.

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 lentigo maligna melanoma. Diffuse vertical growth is variant (loosely spaced fascicles) vertical growth at level IV.

Cytologically, lentigo maligna melanoma showing minimal deviation (uniform pigmented spindle 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. In addition, it might be anticipated that an occasional example of atypical pigmented spindle cell nevus of Reed will evolve into a MDM of pigmented spindle cell type. In addition, some examples of LMM are composed of amelanotic plump spindle cells in loosely spaced fascicles; the cells and patterns might be mistaken for those of a Spitz “nevus.”

The lentiginous components of both LM and LMM are remarkably migratory. Their epidermal spread is fluid-like; the cut-off between dysplasia, and adjacent epidermis can be ill-defined. In addition, it may be 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. In such lesions, margins are difficult to define; recurrences of LM and LMM are common.

Lentigo maligna melanoma is actinic lentiginous melanoma in patterns III & IV (the setting is actinically damaged skin, and lentiginous qualities are prominent in radial growth). Lentigo maligna and thin lentigo maligna melanoma (i.e., less than 1 mm in vertical dimensions) are representative of borderline melanocytic neoplasia of indeterminate malignant potential (actinic variant). Nuclear grade often is only grade I or II. As such, thin LMM often is 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. The incidence of dysplasia in acral nevi is dependent on 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 nevi of Spitz type. In the high grade dysplasias, the patterns overlap with those seen in the radial growth components of acral lentiginous melanomas. 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 melanocytic 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 seems likely that the common acral "nevi" often are precursors in the same neoplastic system as high grade dysplasias and acral melanomas.

Acral melanomasin - lesions in vertical growth - are usually expressed in spindle cell and fascicular patterns. Vertical growth components commonly are physically significant at the time of 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 of cells are not as regularly a feature in 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 lentigo maligna melanoma. 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 parameters to provide therapeutic guidelines. Thin ALMs would qualify like the other thin melanomas, such as thin SSMs and thin LMMs, as borderline melanocytic neoplasia of indeterminate malignant potential (acral variant) .

Like lentigo maligna melanoma, acral lentiginous melanoma is distinguished by both clinical and histologic features. It is the common melanoma of palms, soles, subungual areas, and squamous (and even some glandular) mucosae. Its precursor (acral melanocytic dysplasia [ALD]) is less defined than that of LMM but is preponderantly lentiginous, and 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 acral lentiginous dysplasia (ALD), upper migration of neoplastic cells (e.g., a quality emphasized in the definition of the MANIAC phenomenon [an accommodation for those disciples of the doctrine of "melanoma" in situ who have encountered banal cytologic patterns in association with upward migration of melanocytes in some acral "nevi" and in recurrent nevi ["pseudomelanoma"]). The concept of MANIAC phenomenon is a balm. The phenomenon is common, and is not restricted to lesions manifesting higher grades of acral dysplasia. The cells, in their upward migrations, 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 expressed in pure spindle cell patterns, and, in addition, some of the vertical growth components may be remarkably bland cytologically (minimally deviant): thin acral lesions in vertical growth commonly show level IV invasion (diffuse vertical growth) .

If we accept the palms, soles, and subungual areas as modified squamous mucosae (they are devoid of pilosebaceous units), then acral lentiginous melanorna 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 melanocytic dysplasias and melanomas.

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 on occasion qualify as minimal deviation patterns). Acral melanocytic dysplasias showing moderately severe to severe atypia (i.e., high grade dysplasias) and thin acral lentiginous melanomas (less than 1 mm in vertical dimensions) are representative of a horderland 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 lentigo maligna melanomas and acral lentiginous melanomas. They are common on the trunk and the legs. In the radial growth components of such lesions, the patterns by definition, do not fully satisfy the criteria for the diagnosis of SSM. In this group, lesions, which are thin dysplasias - not otherwise classified - showing moderately severe to severe atypia, and thin melanomas (less than 1 mm in vertical dimensions) are also representative of a borderland of neoplasia.

V. Heteromorphic melanomas: Desmoplastic and neurotropic melanoma are peculiarly related to precursors in which markers for a preexisting 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 than 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 and are frequently, but not invariably, associated with lentiginous melanocytic dysplasias in the overlying epidermis. Thin melanomas in this category are rare, and poorly documented. The diagnosis is seldom made before an example is large, and biologically significant.

Desmoplasia: As an optional regional variation in some melanomas, but generally a relatively uniform pattern in lesions of significant bulk, individual tumor 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 junctional 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 (neurofibroma­like) patterns.

Lentiginous and junctional components, and actinic damage - all in association with desmoplasia in a dermal component - identify the respective lesion as a desmoplastic 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 CFP in the overlying epidermis). In SSM, nesting patterns in the epidermis are preponderant; perhaps, the phenomena favoring the expression of nesting patterns (i.e., rounded nests rather than fascicles) preclude the expression of the desmoplastic phenotype.

In thin lentigo maligna and acral lentiginous melanomas, borderline desmoplastic patterns are occasionally 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 sections of the 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 preexisting collagen bundles. 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; they may be overshadowed by a desmoplastic cornponent. 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; it may be deceptively bland. On the basis of bland cytologic features, some examples qualify as minimal deviation 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 for HMB-45.

Variations in patterns of fibroplasia are discussed in the glossary in the section on "fibroplasia."

Neurotropic melanoma: The quality of neurotropisrn 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 both 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 "desmoplasia" phenotype. Once acquired, expressions of neurotropism may be independent of expressions of desmoplasia. Neurotropism 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.

If nuclear grade is a valid parameter, it may have relevance to the capacity for a melanoma cell to enter the desmoplasia­neurotropism sequence. Melanomas that are prone to desmoplastic and neurotropic transformations are those that often enter vertical growth showing intermediate nuclear grades in the dermal component, and prominent lentiginous qualities in any associated epidermal component.

Neurotropism may be manifested in spindle cell nevi, such as Spitz nevus, combined nevus, or cellular blue nevus. Neurotropism may also encountered in the setting of glant congenital nevus.

VI. Nodular melanoma: The category of nodular melanorna commonly is manipulated as if it were biologically and histologically homogeneous. Some nodular melanomas in the clinical setting of lentigo maligna melanoma (actinically damaged skin of an elderly, fair-skinned patient) are composed of remarkably bland, pigmented spindle cells in fascicular patterns. Such lesions are better characterized as de novo lentigo maligna melanoma or as de novo minimal deviation pigmented spindle cell melanomas. In a similar vein, some forms of "nodular" melanoma are "de novo" counterparts of superficial spreading melanoma or acral lentiginous melanoma. The list is not exhausted with these examples: there are overlaps between the nodular and "nevoid" categories. In characterizing nodular melanomas as de novo variants, the observer is admitting an inability to identify a remnant of a precursor: no judgments regarding the nature of the lesion at an earlier stage of evolution is implied. Nodular melanomas are manipulatable by attention to depth of invasion and "thickness;" and to degrees of cytologic atypia, cell type, and clinical setting. The category of nodular melanoma is accessible for sub-classifications, and many of its components might be better assigned to some other category. The designation might be best restricted to lesions whose patterns in vertical growth are indistinguishable from those of the vertical growth component of fully evolved superficial spreading melanoma (i.e, high nuclear grade and large round or polygonal cells, often with pleomorphism). Other lesions showing lesser degrees of nuclear atypism, or other distinctive characteristics might be better assigned to other categories as de novo variants, including LMM variant, ALM variant, MDM variant, "nevoid" melanoma variant, etc. Even with this restricted definition, nodular melanoma may show mixtures of patterns in vertical growth, including polygonal and/or spindle cells, and typical and/or variant vertical growth patterns. In this approach, nodular melanoma is a high grade melanoma with no evidence of a significant radial growth component.


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