Inflammation involving the REACTIVE SUPERFICIAL UNIT

For many inflammatory disorders of the skin, inflammatory infiltrates, and the effects of inflammation are relatively confined to the microanatomic structures of the epidermis and the adventitial dermis (i.e., a conceptualization in which the papillary dermis, the adnexal dermis, and the adventitia of vessels in the respective domains are grouped as a functional unit). Processes confined to the limited anatomic domain of the reactive superficial unit can then be characterized as inflammatory diseases of the reactive superficial unit. In the general category of inflammatory diseases of the skin, the reactive superficial unit is most commonly affected.

For most disorders affecting the reactive superficial unit, the phenomena include intraepidermal edema (spongiosis), varying degrees of hyperplasia of the basal unit of the epidermis (manifested in varying degrees of psoriasiform hyperplasia of the epidermis), and perivenular infiltrates of lymphoid cells in the upper 1/3 of the dermis. In combination, the resulting patterns are variably spongiotic and psoriasiform.

If the epidermal response includes a spotty, localized, watery expansion of the epidermal interstitial matrix, then we might presume that the epidermal histiocyte in combination with lymphocytes has altered the hydrophilia of the mucinous epidermal interstitium. Such an alteration, by expanding the epidermal interstitium, would offer the affected epidermal domain an opportunity for freer movement of antigenic material to the surface. The altered interstitium also would be open to migrating lymphocytes and histiocytes. The ingestion of antigenic material by migratory histiocytes, and the transport of such material to less sensitive sites, or even an alteration of the nature of the antigenic material would be facilitated. If the material, having been engulfed by histiocytes, is carried to a lymph node, the opportunity exists for an induction of an antigenic cascade.

In inflammatory diseases affecting both the papillary dermis and the epidermis, the nature of the insult determines what portions of cutaneous domains will be affected; in turn, depending on the nature of the antigen, the nature of the histologic response will be determined. The resulting histologic combinations, once having been characterized, provide the clues which will aid a pathologist in his efforts to assign morphologic patterns to specific categories of reactions (i.e., virtual images will have been grouped to form parcels, and the parcels then manipulated to form the categories).

Types of histiocytes and their role as site determinants: Dendritic histiocytes, including examples that are immunoreactive for either factor XIIIa, KP-1, or S-100 protein, are common in the dermis. Histiocytes, immunoreactive for either KP-1 or S-100 protein, are common in the epidermis. Dendritic histiocytes, immunoreactive for S-100 protein, are so common in the epidermis that they might be properly characterized as residents; these "Langerhans cells" are both S-100 protein and CD1a positive, and contain Birbeck granules. In some inflammatory diseases of the skin, Langerhans cells function as nidi for the fixation, and presentation of antigens. In turn, if the related immune response is cell mediated, a cell to antigen to cell response is required; the system is mediated at the level of T lymphocytes. In the epidermis, Langerhans cells appear as thin, pale, elongated nuclei with a thin rim of cytoplasm. Each cell resides in a lacuna in the stratum malpighii; dendritic processes extend out among keratinocytes. The domain defined by the extended dendrites provides a measure of the domain of a reactive subunit of the epidermis. The nucleus of a Langerhans cell often appears naked because its cytoplasm is so scanty. Dendritic histiocytes are pivotal in determining the nidi for interaction between antigen and lymphocytes; they are basic to inflammatory disorders affecting the reactive superficial unit.

Widening of the interstitial avenues of the epidermis generally represents an alteration in the fluidity of the epidermal interstitium. The widened spaces may be watery or mucinous; in association with the widened spaces, there will be an increase in the prominence of intercellular bridges (prickles). In some fashion, the expanded intercellular matrix (i.e., interstitium) becomes a milieu which facilitates the migration of lymphocytes and histiocytes into an altered (spongiotic) epidermis. The migrating cells collect about dendritic histiocytes among the keratinocytes. Presumably the inflammatory cells, in their migrations, are capable of disrupting, or of movement among, the inter-cellular bridges. In mild expansions of the epidermal interstitial domain, the changes are often focal; commonly an epidermal dendritic histiocyte with one or two satellite lymphocytes will be found, centrally located, in the area of edema. Intercellular edema of the epidermis qualifies as spongiosis. The areas of edema are generally situated between two neighboring rete ridges at the tip of a dermal papilla.

In some of the disorders in which neutrophils migrate into the epidermis, widening of interstitial avenues of the basal layer of the epidermis usually is apparent; it usually is limited to the epidermis over the tips of dermal papillae. In psoriasis, a disorder in which neutrophils often migrate into the epidermis, particularly over the tips of dermal papillae, histiocytes may be found in the basal unit of the epidermis but, in contrast to most of the other psoriasiform disorders, the histiocytes are not accompanied by significant numbers of T lymphocytes.

In some spongiotic or psoriasiform disorders, neutrophils are attracted into the epidermis. In the epidermis, they migrate to the granular layer. They eventually, in concert with keratininzing cells, find their way into the keratin layer to form "Munro microabscesses." Munro microabscesses are emphasized in the diagnosis of psoriasis, but are found in other psoriasiform disorders. They may be a feature of superficial fungus infection.

Neutrophils may accumulate in lytic defects in the superficial unit of the epidermis to form reticulated microabscesses (spongioform pustules). They may collect in lytic defects beneath the keratin layer (subcorneal pustules). In these peregrinations by neutrophils, the sites selected are often the thin plates of epidermis covering the tips of elongated, expanded dermal papillae, or areas of spongiosis in which epidermal avenues are open.

In more severe expressions of spongiosis, the expanding interstitium of the epidermis focally disrupts the cohesive forces between neighboring keratinocytes; a rounded defect with keratinocytes compressed at its periphery is the result. In the rounded defect, one or several dendritic histiocytes are closely associated with migratory histiocytes, and lymphocytes. The defect is a spongiotic vesicle. The cellular markers of a cell-mediated immune response are clearly displayed in the development of a spongiotic vesicle; the dendritic histiocyte, as the nidus, has a pivotal role.

Commonly, spongiotic and psoriasiform patterns are combined in a single lesion. This association is not surprising in view of the close association between cell-mediated immune reactions, and most psoriasiform and spongiotic disorders. In these spongiotic and psoriasiform disorders, the infiltrates extend from vessels into the papillary dermis; they extend along the vessels into the papilla; thence, they extend into the epidermis at the tips of dermal papillae. The common dermatitides of the skin, including contact dermatitides, the eczemas, and even many drug eruptions, are cell-mediated reactions expressed in spongiotic and psoriasiform patterns. On the other hand, it is unusual to find significant spongiosis in a lesion of psoriasis.

The spongiotic and psoriasiform disorders are commonly associated with markers for chronicity. In long standing lesions, both the basal units and the superficial units of the epidermis may be hyperplastic. In addition, the dermal infiltrates may be prominent, and the papillary dermis widened and fibrotic. Fibrosis of the papillary dermis may be expressed in laminated patterns. In these disorders, the inflammatory infiltrates in the dermis tend to be superficial, the prime locus for the interplay between antigen, dendritic histiocyte, and lymphocytes being the epidermis. Reactions in the epidermis influence the distribution and character of the infiltrates in the dermis.

The epidermal mucinous interstitium and neutrophils: Neutrophils are a variable feature of the epidermal response in the psoriasiform reactions, but are not confined to the dermal-epidermal interface. They migrate through the epidermis to its upper (outer) reaches. When identified in the latter domain, the resulting patterns are basic to a definition of the spongioform pustule of pustular psoriasis. Neutrophils are the reacting cell in subcorneal pustular dermatosis.

If the mucinous avenues are open near the surface of the skin, there may be provision for the passage of foreign materials from the skin surface down into the avenues. These materials may include direct irritants, antigens, and even toxins. In this regard, we might expect that, in psoriasiform disorders in which there is marked parakeratosis, the mucinous avenues are open to a level which facilitates passage of harmful materials into the mucinous interstitium. In turn, these materials may elicit an inflammatory response in which the preponderant cell is the neutrophil.

Cell Mediated Immunity, and Epidermal Reactions (two general categories): In the normal epidermis, the phenomena occurring in the basal epidermal unit, and those of the superficial epidermal unit are in equilibrium. A shift favoring the replication of keratinocytes of the basal epidermal unit would likely compromise the ability of the superficial unit to recruit cells for the process of terminal differentiation. It would impact unfavorably on the formation of an impervious keratin layer at the surface of the skin. A shift favoring the superficial unit would likely be associated with altered (subdued) rete patterns, and a contraction of the domain of the basal unit. The keratin layer would likely be expanded, and either compactly hyperkeratotic, or alternately both orthokeratotic and parakeratotic.

A cell mediated reaction in the epidermis commonly is manifested in either spongiotic patterns, spongiotic and psoriasiform patterns, or cell-rich lichenoid patterns. The first two categories of epidermal responses in cell mediated immune reactions includes disorders in which the epidermis is altered in a manner that might be spoken of as immunostimulation.

In the spongiotic variants, a localized portion of the epidermis shows widening of the spaces among keratinocytes. The area of epidermal edema may be limited to the expanse of epidermis over the tip of a rete ridge; it often is associated with a limited cap of parakeratotic debris. Within the limited expanse of altered epidermis, one or several elongated (dendritic) histiocytes will be represented, each isolated from its neighbor. In addition, one or several lymphocytes may be collected in close association with the histiocytes; they may be arranged in satellite-cell, or rosette-like patterns. In psoriasiform variants, the basal unit of the epidermis is distinctively hyperplastic with elongated rete ridges. The pattern of hyperplasia of the basal unit of the epidermis is so characteristic for psoriasis that, when a similar pattern is encountered in disorders other than psoriasis, the qualifier, psoriasiform, is deemed to be morphologically appropriate.

The second category of basic epidermal responses in the setting of cell mediated immunity is the result of the formation of lytic defects in the basal unit of the epidermis, often in association with a distinctive pattern of hyperplasia in the overlying superficial unit. This reaction, being prototypic of the changes in a lesion of lichen planus, is lichenoid.

Cellular immunity and site specificity: Most inflammatory processes of the skin are manifested morphologically in patterns of cellular immunity. The reacting cells are mostly T cells and histiocytes. The distribution of the infiltrates provides some indication of the sites in which antigens are fixed, or antigen-antibody complexes deposited. At this basic level, reaction patterns of the skin might be compared to the reaction patterns of experimental pathology. In experimental pathology, patterns of cell mediated immune reactions, that, on the basis of the distribution of inflammatory cells, qualify as either perivenular islands, interstitial (invasive or invasive-destructive) patterns, or granulomatous patterns, have been defined.

LEVEL 2