Level IV: The reticular dermis contributes the domain at level IV; its boundaries are: 1) the interface between the papillary dermis and the reticular dermis, and 2) the interface between the reticular dermis and the subcutaneous fat.
The collagenous framework at level IV has its own distinctiveness in regard to types of collagen, and to the patterns in which coarsely bundled collagen fibers are arranged. Coarse elastic fibers, which are PTAH positive, are dispersed among the collagen bundles in interstitial spaces that are rich in acid mucopolysaccharides.
The reticular dermis does have some peculiar relationship with dermal melanocytes. Dermal melanocytes may be identified as incidental findings in the skin of the dark skinned races. Dermal melanocytoses, when identified, reside at level IV (in addition, tumors of dermal melanocytes, the blue nevi, are preponderantly lesions of the reticular dermis, although some examples have perifollicular cellular components). By proper criteria, reticular dermis is not stroma. It has no native role in the nurturing of epithelium and is not innately responsive to alterations in epithelial kinetics.
At level IV, there is a rich plexus of lymphatics, but the blood vessels are mostly conduits for the distribution of oxygenated blood to levels I & II (or III). In invasive, as opposed to expansile, migrations, individual cells, and nests and fascicles of cells insinuate among preexisting collagen bundles of the reticular dermis. For foreign cells to reside in the reticular dermis among preexisting collagen bundles, they must have acquired the property of invasive migration without attention to the needs of a community, and, in their migrations, individual nests must have acquired the capacity to induce their own stroma, independent of other nests of cells (i.e., a migrant’s stroma).
Level V: the boundary for level V is the interface between the reticular dermis and the subcutaneous fat; the respective domain is the soft tissue beneath the lower level of the dermis. This level generally has significance as a marker for deep invasion. In addition, a lesion at level V has access to a rich plexus of small and muscular vessels.
Anatomic Levels, Histologic Patterns, and Integrations of the Two:
Level I (epithelial domain) :
1. Lentiginous patterns: Each melanocyte of the normal epidermis has a rather fixed relationship with a localized collection of keratinocytes. In melanocytic hyperplasias, the numerical relationships between individual melanocytes, and a packet of functionally related keratinocytes may be altered. Lentiginous patterns are a marker for a population of migrating melanocytes which preferentially reside among basal keratinocytes. If melanocytes are hyperplastic, and closely spaced in the basal layer of the epidermis, and if the hyperplasia is spontaneous, the resulting lesion qualifies as a lentigo. If, in addition to an increase in the number of melanocytes per unit area of epidermal domain, there is cytologic atypia of the respective melanocytes, then the resulting lesion is both lentiginous and atypical. Commonly, there are other histologic associations for lesions of the latter type,
2. Junctional patterns: In lesions with prominent junctional components, the neoplastic cells may have acquired a cohesiveness that precludes a diffuse spread of cells in the basal layer away from their site of origin (i.e., significant lentiginous spread). If, in a locus of lentiginous melanocytic hyperplasia, some of the affected melanocytes cluster in nests or fascicles, then the resulting pattern is both lentiginous and junctional. If cells of such lesions are cytologically atypical then, like the atypical lentigines, there usually are other histologic associations. Histologic patterns, that can be accommodated within the limits imposed by the definition of level I, qualify as pattern I.
Level II and beyond (dermal domain) :
3. Compound and dermal patterns: Nests of melanocytic cells, residing solely in the dermis, qualify the respective lesion as a dermal variant. If a dermal component is combined with a lentiginous and junctional component, then the resulting lesion is compound. Atypia may also be manifested in this category. Histologic patterns that can be accommodated within the limits imposed by the definition of levels I - IV qualify as patterns I - IV respectively.
Migrations of Melanocytic Cells
(as related to both Anatomic Levels and Aggregate Patterns)
Continuity of patterns: In most nevi, common premalignant melanocytic dysplasias, and melanomas, cells initially proliferate in an epithelial domain. Some of these cells cluster to form nests or fascicles.
In current conceptualizations of the evolution of nevi, lentiginous and junctional components usually are assigned primacy; dermal components are assumed to be their derivatives. In some manner, some of the cells and nests relinquish their epithelial domain and come to lie in the dermis. One explanation for this migration is embodied in the concept of "dropping off." Surely, nests of nevus cells commonly "drop off" into the dermis, but not all of the cells in the dermal component of a compound nevus can be casually attributed to an epidermal origin. Compound nevi may have a dual origin (as proposed by Masson); their deep dermal component may not be a population of migrant cells from the epidermis. In fact, the presence of primary dermal nevus cells rnay be a stimulus for the growth and migration of nevus cells in, and from, the epidermis. In typical nevi, nests of cells, that "drop off" into the dermis, adapt to the patterns of preexisting nests in a manner that might be characterized as a "continuity of patterns;" the patterns blend. In the growth and maturation of nevi, several generations of nevocytic cells may be stratified in the dermis. In addition, at any selected level the patterns are comparable but at different levels the patterns vary. The transitions from one to the next level are not sharply defined. Continuity of patterns in nevi with epidermal and dermal components might be characterized as an expression of a basic sameness of cells, even in areas showing transitions in phenotype.
If a typical nevocytic nevus with compound patterns is selected as a model, boundaries in regions of transition from one zonal pattern to another (e.g., type A, B, & C patterns) will be found to be ill-defined. In typical nevi, some rounded nests of cells (type A patterns) will merge in areas with fascicles (type B patterns), and fascicles will merge with sheets of cells (type C patterns), all in a subtle fashion. The dermal component of a typical nevus may exert an organizing influence on nests of cells, which having "dropped off" into the dermis, come to lie in close proximity with nests of nevus cells already in the dermis. In this manner, enlargement of one or another of the dermal nests would likely establish "continuity" between two populations of cells. The evolution of "continuity of patterns" in a typical nevus would thus be effected.
"Dropping off" of entire nests of melanocytic cells may not be the only alternative as an explanation for the movement of melanocytic cells from an epidermal domain into the dermis. Eccentric protrusions into the dermis from junctional nests of cells, if followed by the formation of constrictions near the neck of the protrusions, would eventually separate from the mother nest. The newly separated protrusions would lead to the formation of daughter nests in the dermis. The remnants of the mother nests would retain their epidermal domain.
Alternately, some cells individually may "drop off" from the epidermis into the dermis: they may individually migrate out of a junctional nest, or the lentiginous component, into the dermis. In the evolution of lamellar fibrosis as manifested in premalignant melanocytic dysplasias, some of the dysplastic cells at the periphery of the confined nests become entrapped in the dermis among the lamellae: occasional isolated neoplastic cells are found amomg coarse lamellae in areas of lamellar fibrosis at the periphery of junctional nests in dysplasias. This process also may contribute to the formation of nests of cells in the dermis.
The lichenoid process (in general, a lytic process mediated at the level of immune reaction, and affecting a portion of an epithelial domain but having equal application to processes in which the target cell is a melanocytic cell rather than a keratinocyte), if part of a melanocytic dysplasia, is associated with the formation of a delicate fibromyxoid matrix at the dermal-epidermal interface (i.e., accretive fibrosis at the dermal-epidermal interface with focal incorporation of a limited portion of the damaged epidermal domain into the dermis). In such areas, junctional nests are not sharply defined at their interface with the dermis (i.e., basement membranes are incomplete). Individual neoplastic cells may become entrapped in this delicate fibrous tissue and may contribute to the dermal population. Lichenoid processes affecting the patterns of melanocytic neoplasia are basic to the phenomena encountered in the setting of halo nevus and halo nevus-like melanoma.
In the histologic examination of both typical nevi and low grade dysplasias (atypical nevi), efforts to identify junctional nests in the process of "dropping off" from the epidermis into the dermis are seldom rewarded. In melanocytic dysplasias, clefts are commonly observed at the interface between junctional nests and the overlying epidermis. These clefts appear to be artifacts but perhaps have significance as a marker for a potential space into which fibrocytes may extend and, by modifications of the matrix, effect a true separation between a junctional nest and the epidermis. Similar clefts are common in Spitz nevi: they have become one additional virtual image that is commonly cited as an aid in the diagnosis of Spitz “nevus.”
Rarely, in dysplastic nevi, clefts containing flattened dyskeratotic keratinocytes, which are loosely attached to their neighbors, define a potential line of cleavage between the domains of keratinocytes and junctional nests of melanocytes. With these patterns in mind, the detachment (dropping off) of junctional nests could involve a cellular process affecting interface keratinocytes that are adjacent to junctional nests. Such a process involving interface keratinocytes, if confirmed, would be akin to that of apoptosis. In it, connective tissue would extend from the papillary dermis into a defect in the junctional domain. In the process of inlaying fibrous tissue into the defect, remnants of the junctional nests would become entrapped in the dermal domain. As the end result, junctional nests, or portions thereof, would appear to have "dropped off" into the dermis (this approach is a modification of the proposed lichenoid phenomena) .
The so-called "pale acidophilic bodies" (Kamino bodies) of a Spitz “nevus” may be markers for the residua of a modified form of apoptosis in which the interface between a fascicle of tumor cells and the epidermis is modified. The modification may facilitate the "dropping off" of some of the affected fascicles.
Once "dropping off," in one form or another, has been accomplished, subsequent divisions of solitary, sequestered melanocytic cells, and their descendants, in the dermis, or of newly arrived portions of junctional nests in the dermis, whether as sequelae of lamellar fibrosis, or a modified lichenoid (apoptotic) reaction, would lead to the formation of additional nests of similar cells in the dermis (i.e., a second generation). For a premalignant melanocytic dysplasia, a lesion showing some or all of these variant patterns of "dropping off" would be one in transition to vertical growth (i.e., a borderline lesion in transition to melanoma).
In premalignant melanocytic dysplasias (and related atypical or dysplastic nevi), continuity of patterns is usually interrupted. The dysplastic cells, as in typical nevi, do form rounded nests or fascicles in an epithelial domain and some of the aggregates of cells "drop off" into the dermis. Those, newly arrived in the dermis, establish little or no continuity with any remnant of a preexisting nevus in the underlying dermis. In part, this loss of continuity is a result of the host immune response with condensations of fibrous tissue around the newly immigrated nests of dysplastic cells (e.g., lamellar or appositional fibroplasia: arrested growth). The lack of continuity in premalignant melanocytic dysplasias may also reflect a diminution in the number of optional phenotypes, as neoplasia progresses from nevus to dysplasia to melanoma (i.e., genotypical restrictions on the expression of phenotypes in neoplastic progressions). In these virtual images, dysplastic cells would be genotypically isolated in the dermis: they would have lost the sameness which, regardless of phenotype, characterizes typical nevus cells. The migrants, by their altered genotype, would have lost the capacity to establish continuity with any remnants of a nevus in the underlying dermis.
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