Chapter 6. Basic Pathologic Reactions of the Skin

The skin is composed of different tissue compartments that interconnect anatomically and interact functionally. It is difficult to envisage epidermal function without signals from the dermis or passenger leukocytes traveling to and from the skin. On the other hand, epidermis, dermis, and subcutaneous tissue are heterogeneous in nature and an analysis of pathologic processes involving the skin should therefore consider both this heterogeneity and the interactions of the individual cutaneous compartments; only then will it be understood why a few basic reactions lead to a multiplicity of reaction patterns within this tissue.

Pathophysiologically, the skin can be subdivided into three reactive units that extend beyond anatomic boundaries (Fig. 6-1); they overlap and can be divided into different subunits that respond to pathologic stimuli according to their inherent reaction capacities in a coordinated pattern.

The superficial reactive unit comprises the subunits epidermis, the junction zone, the subjacent loose, delicate connective tissue of the papillary body and its capillary network, and the superficial vascular plexus (see Fig. 6-1, SRU). The reticular layer of the dermis represents a second reactive unit and is composed of coarse connective tissue and the deeper dermal vascular plexus (see Fig. 6-1, DRU). The third reactive unit, the subcutaneous tissue, is also anatomically and functionally heterogeneous; septal and lobular compartments may be involved either alone or together (see Fig. 6-1, S). Hair follicles and glands are a separate (fourth) reactive unit embedded in these three basic units.

Epidermis

(See Fig. 6-1, E)

Keratinocytes, which have the capacity to synthesize keratin protein, represent the bulk of the epidermis. The epidermis, an ectodermal epithelium, also harbors a number of other cell populations such as melanocytes, Langerhans cells, Merkel cells, and cellular migrants (see Chapter 7). The basal cells of the epidermis undergo proliferation cycles that provide for the renewal of the epidermis and, as they move toward the surface of the skin, undergo a differentiation process that results in surface keratinization. Thus, the epidermis is a dynamic tissue in which cells are constantly in nonsynchronized replication and differentiation; this precisely coordinated physiological balance between progressive keratinization as cells approach the epidermal surface to eventually undergo programed cell death and be sloughed, and their continuous replenishment by dividing basal cells is in contrast to the relatively static minority populations of Langerhans cells, melanocytes, and Merkel cells. However, at the same time, these dynamic keratinocytes are interconnected through cohesive molecular interactions that guarantee the continuity, stability, and integrity of the epithelium. Stability for this directional cellular flow is provided by the basal membrane complex (see Chapter 53), which anchors the epidermis to the dermis, and the stratum corneum, which encases the epidermis on the outside. It is here that individual cell differentiation ceases as the keratinizing cells are firmly interconnected by an intercellular cement-like substance forming a permeability barrier (see Chapter 47). These forces of cohesion are finally lost at the surface of the epidermis where the individual cornified cells are sloughed (desquamated). Therefore, pathologic changes within the epidermis may relate to the replicative kinetics of epidermal cells, their differentiation, alterations in cohesive forces, or a combination of these factors (see Chapter 46). These primary factors may also influence the stability and migratory characteristics of Langerhans cell, melanocytes, and migrant lymphocytes, accounting for the complexity of certain reaction patterns that arise from primary pathological defects in the epidermal layer. For example, unless a Langerhans cell expresses the chemokine receptor CCR6, it cannot migrate from the dermis to the epidermis, and without expression of the CCR7 receptor, migration to the lymph node is not possible. Because cytokines that regulate the expression of such receptors are synthesized and secreted by keratinocytes within the immediate microenvironment of Langerhans cells, impairment of keratinocyte homeostasis may have far-reaching functional implications that are reflected in the complexity of the resultant reaction patterns.

Disturbances of Epidermal Cell Kinetics

The mitotic rate of germinative basal cells, the desquamation rate of corneocytes, and the generation time of epidermal cells determine the homeostasis of the epidermis (see Chapter 46). Under physiologic conditions, there is a balance among proliferation, differentiation, and desquamation. Enhanced cell proliferation accompanied by an enlargement of the germinative cell pool and increased mitotic rates lead to an increase of the epidermal cell population and thus to a thickening of the epidermis (acanthosis) (Fig. 6-2A). A shift in the ratio of resting to proliferating cell as is the case in psoriasis (see Chapter 18) will lead to both an increase in the turnover of the entire epidermis and to a considerable increase of the volume of germinative cells that have to be accommodated at the dermal–epidermal junction. This, in turn, results in a widening and elongation of the rete ridges, which is accompanied by a compensatory elongation of the connectivetissue papillae, resulting in an expansion of the dermal–epidermal interface and, consequently, in an increased surface area for dermal–epidermal interactions (see Fig. 6-2).

In contrast to acanthosis is epidermal atrophy. Although there are many causes, one primary etiology is a decrease in epidermal proliferative capacity, as may be seen with physiological aging or after the prolonged use of potent topical or systemic steroids. With atrophy, the epidermal rete ridges are initially lost, followed by progressive thinning of the epidermal layer. Depending on the underlying causes and how they affect the keratinocyte differentiation program, there may also be hyperkeratosis or parakeratosis (thickening of the stratum corneum or retention of nuclei into the stratum corneum, respectively). It is likely that many forms of acanthosis and atrophy have primary effects of the homeostasis and function of keratinocyte stem cells, critically important slow-cycling minority populations of epidermal cells that are normally sequestered in the bulge areas of hair follicles and at tips of epidermal rete ridges.

Disturbances of Epidermal Cell Differentiation

A simple example of disturbed epidermal differentiation is parakeratosis, in which faulty and accelerated cornification leads to a retention of pyknotic nuclei of epidermal cells at the epidermal surface that is normally formed by anucleate cell remnants that form a “basket-weave” architectural pattern (see Fig. 6-2B). A parakeratotic stratum corneum is not a continuous sheet of cornified cells but a loose structure with gaps between cells; these gaps lead to a loss of the barrier function of the epidermis.

Parakeratosis can be the result of incomplete differentiation in postmitotic germinative cells due to factors that influence the timing and complex integrity of the differentiation program whereby keratin pairs of relatively low molecular weight are progressively assembled as cells approach the epidermal surface. Alternatively, parakeratosis can also be the result of reduced transit time, which does not permit epidermal cells to complete the entire differentiation process, as for example in psoriasis. However, “parakeratosis” of cellophane-stripped epidermis becomes microscopically visible as early as 1 hour after trauma; here, parakeratosis does not represent disturbed differentiation; rather, it results from direct cellular injury to a viable epidermis deprived of its protective horny layer. Therefore, the morphologic term parakeratosis may signify a programed disturbance of differentiation and maturation, alterations in cell replication kinetics, or direct cellular injury.

Dyskeratosis represents altered, often premature or abnormal, keratinization, of individual keratinocytes but it also refers to the morphologic presentation of apoptosis of keratinocytes. Dyskeratotic cells have an eosinophilic cytoplasm and a pyknotic nucleus and are packed with keratin filaments arranged in perinuclear aggregates. Such a cell will tend to round up and lose its attachments to the surrounding cells. Therefore, dyskeratosis is often associated with acantholysis (see Section “Disturbances of Epidermal Cohesion”) but not vice versa (Fig. 6-3).

In some diseases, dyskeratosis is the expression of a genetically programed disturbance of keratinization as is the case in Darier disease (see Chapter 51). Dyskeratosis may occur in actinic keratosis and squamous cell carcinoma. Dyskeratosis may also be caused by direct physical and chemical injuries. In the sunburn reaction, eosinophilic, apoptotic cells—so-called sunburn cells—are found within the epidermis within the first 24 hours after irradiation with ultraviolet B (UVB) (see Chapter 90), and similar cells may occur after high-dose systemic cytotoxic treatment. Individual cell death within the epidermis is a regular phenomenon in graft versus host reactions of the skin (see Chapter 28) and in erythema multiforme (see Chapter 39). It is important to remember that although both premature or abnormal keratinization and apoptosis may produce an end product referred to as “dyskeratosis,” the early events and mechanisms responsible are different. Whereas cells early in the process of abnormal keratinization often have increased eosinophilic keratin aggregates within their cytoplasm with viable-appearing nuclei, apoptotic cells during early evolutionary stages have shrunken, pyknotic, and sometimes fragmented nuclei in the setting of normal-appearing cytoplasm.

Disturbances of Epidermal Cohesion

Epidermal cohesion is the result of a dynamic equilibrium of forming and dissociating intercellular contacts. Specific intercellular attachment devices (desmosomes) and the related intercellular molecular interactions are responsible for intercellular cohesion. However, epidermal cohesion must permit epidermal cell motion. Desmosomes dissociate and reform at new sites of intercellular contact as cells migrate through the epidermis and keratinocytes mature toward the epidermal surface. Intercellular cohesive forces are strong enough to guarantee the continuity of the epidermis as an uninterrupted epithelium but, on the other hand, are adaptable enough to permit locomotion, permeability of the intercellular space, and intercellular interactions.

The most common result of disturbed epidermal cohesion is the intraepidermal vesicle, a small cavity filled with fluid. A classification of intraepidermal blistering by anatomic level is shown in Table 6-1.

Three basic morphologic patterns of intraepidermal vesicle formation are classically recognized. Spongiosis is an example of the secondary loss of cohesion between epidermal cells due to the influx of tissue fluid into the epidermis. Serous exudate may extend from the dermis into the intercellular compartment of the epidermis; as it expands, epidermal cells remain in contact with each other only at the sites of desmosomes, acquiring a stellate appearance and giving the epidermis a sponge-like morphology (spongiosis). As the intercellular edema increases, individual cells rupture and lyse, and microcavities (spongiotic vesicles) result (Fig. 6-4). Confluence of such microcavities leads to larger blisters. Epidermal cells may also be separated by leukocytes that disturb intraepidermal coherence; thus, the migration of leukocytes into the epidermis and spongiotic edema are often a combined phenomenon, best illustrated by acute allergic contact dermatitis. The accumulation of polymorphonuclear leukocytes within the epidermis, the resulting separation of epidermal cells, and their subsequent destruction by neutrophil-derived enzymes, eventually lead to the formation of a spongiform pustule, one of the histopathologic hallmarks of psoriasis (see Chapter 18).

Acantholysis is a primary loss of cohesion of epidermal cells. This is initially characterized by a widening and separation of the interdesmosomal regions of the cell membranes of keratinocytes, followed by splitting and a disappearance of desmosomes (see Chapter 53). The cells are intact but are no longer attached; they revert to their smallest possible surface and round up (Figs. 6-3 and 6-5). Intercellular gaps and slits result, and the influx of fluid from the dermis leads to a cavity, which may form in a suprabasal (Fig. 6-6), midepidermal, or even subcorneal location. Acantholytic cells can easily be demonstrated in cytologic smears (see Fig. 6-5) and in some conditions have diagnostic significance.

Acantholysis occurs in a number of different pathologic processes that do not have a common etiology and pathogenesis. Acantholysis may be a primary event leading to intraepidermal cavitation (primary acantholysis) or a secondary phenomenon in which epidermal cells are shed from the walls of established intraepidermal blisters (secondary acantholysis). Primary acantholysis is a pathogenetically relevant event in diseases of the pemphigus group (see Chapter 54), in which it results from the interaction of autoantibodies and antigenic determinants on the keratinocyte membranes and related desmosomal adhesive proteins, and in the staphylococcal scalded-skin syndrome, where it is caused by a staphylococcal exotoxin (epidermolysin) (see Chapter 177). In familial benign pemphigus, it results from the combination of a genetically determined defect of the keratinocyte cell membrane and exogenous factors (see Chapter 51). A similar phenomenon, albeit more confined to the suprabasal epidermis, occurs in Darier disease, where it is combined with dyskeratosis in the upper epidermal layers (see Fig. 6-3) and a compensatory proliferation of basal cells into the papillary body (see Chapter 51). When acantholysis results from viral infection, it is usually combined with other cellular phenomena such as ballooning, giant cells, and cytolysis (Fig. 6-7; see Chapters 193 and 194).

Indeed, a loss of epidermal cohesion can also result from a primary dissolution of cells (i.e., cytolysis). In the epidermolytic forms of epidermolysis bullosa, genetically defective and thus structurally compromised basal cells rupture as a result of trauma so that the cleft forms through the basal cell layer independently from preexisting anatomic boundaries (see Chapter 62). Cytolytic phenomena in the stratum granulosum are characteristic for epidermolytic hyperkeratosis, bullous congenital ichthyosiform erythroderma, ichthyosis hystrix, and some forms of hereditary palmoplantar keratoderma (see Chapters 49 and 50).

Dermal–Epidermal Junction

(See Fig. 6-1, J)

Epidermis and dermis are structurally interlocked by means of the epidermal rete ridges and the corresponding dermal papillae, and foot-like submicroscopic cytoplasmic microprocesses of basal cells that extend into corresponding indentations of the dermis. Dermal–epidermal attachment is enforced by hemidesmosomes that anchor basal cells onto the basal lamina; this, in turn, is attached to the dermis by means of anchoring filaments and microfibrils (see Chapter 53). These structural relationships correlate with complex molecular interactions that serve to bind the epidermis, basement membrane, and superficial dermis in a manner that promotes resistance to potentially life-threatening epidermal detachment. The basal lamina is not a rigid or impermeable structure because leukocytes, Langerhans cells, or other migratory cells pass through it without causing a permanent breach in the junction. After being destroyed by pathologic processes, the basal lamina is reconstituted; this represents an important phenomenon in wound healing and other reparative processes. Functionally, the basal lamina is part of a unit that, by light microscopy, appears as the periodic acid-Schiff–positive “basement membrane” and, in fact, represents the entire junction zone. This consists of the lamina lucida, spanned by microfilaments, and subjacent anchoring fibrils, small collagen fibers, and extracellular matrix (see Chapter 53). The junction zone is a functional complex that is primarily affected in a number of pathologic processes.

Disturbances of Dermal–Epidermal Cohesion

The destruction of the junction zone or its components usually manifests as disturbance of dermal–epidermal cohesion and leads to blister formation. These blisters appear to be subepidermal by light microscopy (Fig. 6-8), but in reality may be localized at different levels and result from pathogenetically heterogeneous processes. A classification of blisters at the junction by anatomic level is given in Table 6-2. Subepidermal blister formation occurs in forms of epidermolysis bullosa (see Chapter 62) or can be the result of a complex inflammatory process that involves the entire junction zone, as is the case in lupus erythematosus, erythema multiforme, or lichen planus; therefore, it may be a phenomenon occurring in a group of etiologically and pathogenetically heterogeneous conditions. In bullous pemphigoid (see Fig. 6-8), cleft formation runs through the lamina lucida of the basal membrane and is caused by autoantibodies directed against specific antigens on the cytomembrane of basal cells (junctional blistering) (see Fig. 6-8A; see Chapter 56). The presence of eosinophil granules that contain major basic protein that is toxic to keratinocytes also causes keratinocyte injury and may present as eosinophilic apongiosis (Fig. 6-8B). Junctional blistering also occurs in the junctional forms of epidermolysis bullosa, but here it is due to the hereditary impairment or absence of molecules important for dermal–epidermal cohesion (see Chapter 62; see Table 6-2).

In subepidermal blistering, the target of the pathologic process is below the basal lamina (dermolytic blistering) (see Table 6-2). Reduced anchoring filaments and increased collagenase production result in dermolytic dermal–epidermal separation in recessive epidermolysis bullosa (see Chapter 62); circulating autoantibodies directed against type VII collagen in anchoring fibrils are the cause of dermolytic blistering in acquired epidermolysis bullosa (see Chapter 60). Other immunologically mediated inflammatory mechanisms result in dermolytic blistering in dermatitis herpetiformis (see Chapter 61), and physical and chemical changes in the junction zone and papillary body are the cause for a dermolytic cleft formation after trauma in porphyria cutanea tarda (see Chapter 132).

Molecular and Cellular Mechanisms for Reaction Patterns Affecting the Superficial Reactive Unit

Although Virchow envisioned what is today known as the superficial reactive unit as a simple layer of cells involved in producing environmentally protective surface keratin, we now realize that this layer is a potent producer of regulatory and stimulatory molecules that, when perturbed, choreograph architectural and cytologic changes that produce the reaction patterns that we equate with specific clinical disorders. Upon immunological stimulation via cytokines with attendant activation of signal transduction pathways, for example, the keratinocyte often acquires an “activated” phenotype whereby the nucleus enlarges, the nucleolus becomes more prominent, and the cell may actually appear atypical. Hyperproliferation frequently accompanies keratinocyte activation, and biosynthetic alterations also may develop, resulting in production of additional factors, such as keratinocyte-derived cytokines, that further fuel the activated phenotype. In such instances, epidermal thickening and increased mitotic activity is evidenced by conventional histology, and Ki-67 staining will disclose evidence of suprabasal cell cycling. It is likely that such activated and hyperproliferative states involve stimulation at the level of the epidermal and follicular stem cell compartments, as is also seen in wound healing responses. In such circumstances, normally quiescent stem cells that are normally sequestered at the tips of epidermal rete ridges and in the bulge regions of hair follicles begin to proliferate and differentiate, further driving the acanthotic epidermal thickening. Alterations in epidermal kinetics are frequently also evidenced by faulty differentiation. Premature differentiation may trigger defective cell adhesion, and hence cells may seem abnormally keratinized (dyskeratotic) as well as separated (acantholytic). Other factors that may perturb adhesion may provide exquisite correlation between the molecular composition of the superficial reactive unit and the morphology of the reaction patterns themselves, as is the case in various forms of pemphigus, where the level of keratinocyte dyshesion and acantholytic blister formation follows precisely the concentration gradients of the targeted adhesive proteins (desmogleins 1 and 3) that assist in binding keratinocytes at the level of the desmosome.

The patterns of cellular inflammation that affect the superficial reactive unit also are dictated at a molecular level. Circulating leukocytes, often T cells, bind the endothelium of postcapillary venules of the superficial vascular plexus upon cytokine-induced endothelial activation (see also dermal reaction patterns in Section “Molecular and Cellular Mechanisms for Reaction Patterns Affecting the Dermis”). This results in expression of endothelial–leukocyte adhesion molecules at the endothelial surface that slows circulating leukocytes to a roll, followed by more secure directed binding and transvascular diapedesis. Cells so extravasated may remain in the perivascular space or migrate upward toward the nearby epidermal layer as a consequence of chemokinetic and chemotactic gradients. Depending on their immunologic mission, the responding leukocytes may either produce cytotoxic injury at the dermal–epidermal interface, or migrate through the basement membrane into the epidermis in the company of transudate that contributes to the intercellular edema that forms the pattern of spongiosis. Thus, depending on the nature of the provocative stimulus as well as the complex downstream molecular events that are set into motion, specific reaction patterns result that, upon recognition, provide key diagnostic information.

Pathologic Reactions of the Entire Superficial Reactive Unit

(See Fig. 6-1, SRU)

Most pathologic reactions of the superficial skin involve the subunits of the superficial reactive unit jointly and thus include the papillary body of the dermis with the superficial microvascular plexus. This is a highly reactive tissue compartment consisting of capillaries, pre- and postcapillary vessels (see Chapter 162), mast cells, fibroblasts, macrophages, dendritic cells, and peripatetic lymphocytes all embedded in a loose connective tissue and extracellular matrix (Fig. 6-9). The prominence of involvement of one of the components over the others may lead to the development of different clinical pictures. A few examples of such interactions are detailed below.

Allergic Contact Dermatitis

(See Chapter 13.) In allergic contact dermatitis, there is an inflammatory reaction of the papillary body and superficial microvascular plexus and spongiosis of the epidermis (see Fig. 6-4) with signs of cellular injury and parakeratosis. Lymphocytes infiltrate the epidermis early in the process and aggregate around Langerhans cells, and this is followed by spongiotic vesiculation (Fig. 6-10). Parakeratosis develops as a consequence of epidermal injury and proliferative responses, and the inflammation in the papillary body and around the superficial venular plexus stimulates mitotic processes within the epidermis, which, in turn, result in acanthosis and epidermal hyperplasia in chronic lesions.

The reaction pattern that involves the superficial vascular plexus of vessels is one of a superficial perivascular lymphocytic infiltrate, often with admixed eosinophils and histiocytes. As noted above, many of these lymphocytes also migrate into the epidermal layer to produce a pattern referred to as exocytosis. The superficial perivascular pattern of inflammation is one of a number of inflammatory patterns that may be of assistance at low magnification in generating an initial differential diagnostic algorithm for various types of dermatitis. Pathophysiologically, very early forms of allergic contact dermatitis (e.g., within 24 hours) will exclusively involve perivascular lymphocytes, their influx preceded by mast cell degranulation that releases factors promoting adhesive interactions with superficial dermal endothelium. The epidermal changes follow soon thereafter.

Psoriasis

(See Chapter 18.) The initial lesion of psoriatic lesions appears to be the perivascular accumulation of lymphocytes and monocytoid elements within the papillary body and superficial venules and focal migration of leukocytes (often neutrophils, although T cells are integral to pathogenesis as well) into the epidermis. Acanthosis caused by increased epidermal proliferation, elongation of rete ridges sometimes accompanied by an undulant epidermal surface (papillomatosis), and edema of the elongated dermal papillae together with vasodilatation of the capillary loops and a progressive perivascular inflammatory infiltrate develop almost simultaneously (see Fig. 6-2); the disturbed differentiation of the epidermal cells results in parakeratosis, and small aggregates of neutrophils infiltrating the epithelium from tortuous capillaries (squirting capillaries) result in spongiform pustules and, in the parakeratotic stratum corneum, to Munro microabscesses. The stimulus for increased epidermal proliferation follows signals released from T cells that are attracted to the epidermis by the expression of adhesion molecules at the keratinocyte surface and are maintained by cytokines released by keratinocytes (see Chapter 18). Therefore, the composite picture characteristic of psoriasis results from a combined pathology of the papillary body with participation of superficial venules, the epidermis, and circulating cells.

Psoriasis is an instructive example of the limited specificity of histopathologic reaction patterns within the skin because psoriasiform histologic features occur in a number of diseases unrelated to psoriasis.

Interface Dermatitis

Inflammation along the dermal–epidermal junction associated with vacuolation or destruction of the epidermal basal cell layer characterizes interface dermatitis. This common type of reaction may lead to papules or plaques in some skin diseases and bullae in others.

Erythema Multiforme

(See Chapter 39.) Two types of reactions occur. In both there is interface dermatitis characterized by lymphocytes scattered along a vacuolated dermal–epidermal junction.

Lupus Erythematosus

(See Chapter 155.) Inflammation, edema, and a lymphocytic infiltrate in the papillary body and superficial venular plexus, as well as in the deeper layers of the dermis, are hallmarks of lupus erythematosus. The main target is the dermal–epidermal junction, where scattered lymphocytes appear and immune complex deposition leads to broadening of the PAS-positive basement membrane zone, accompanied by hydropic degeneration and destruction of basal cells and progressive atrophy (Fig. 6-11). Cytoid bodies in the form of anucleate keratin aggregates that may undergo amyloid transformation result from apoptosis of individual epidermal cells that are infiltrated and coated by immunoglobulins. The changes in the junctional zone reflect on epidermal differentiation resulting in thickening of stratum corneum (orthokeratosis) and parakeratosis. Lupus erythematosus readily illustrates the heterogeneity, as well as the lack of specificity, of cutaneous reaction patterns: histologically, it is possible to distinguish between acute and chronic lesions but not between cutaneous and systemic lupus erythematosus. In certain chronic, persisting lesions, the changes in the junctional zone initially associated with atrophy secondarily result in hyperplasia, hyperkeratosis, and an increased interdigitation between epidermis and connective tissue, whereas in acute cases, the destruction of the basal cell layer may lead to subepidermal blistering.

Lichen Planus

(See Chapter 26.) This disease also exhibits a primarily junctional reaction pattern with accumulation of a dense lymphocytic infiltrate in the subepidermal tissue and cytoid bodies at the junction (Fig. 6-12). Lymphocytes encroach on the epidermis, destroying the basal cells, but they do not infiltrate the suprabasal layers and blister formation only rarely ensues. These alterations are accompanied by changes of epidermal differentiation—there is a widening of the stratum granulosum (hypergranulosis) and hyperkeratosis. Identical changes can be seen in the epidermal type of graft-versus-host disease (see Chapter 28). Current thinking imputes a delayed hypersensitivity reaction to a keratinocyte antigen, the nature of which is unclear. The association of CD8+ lymphocytes in apposition to and even surrounding apoptotic keratinocytes (so-called satellitosis) supports this view. The expression of Fas/FasL is also in favor of a role for apoptosis in the pathogenesis of these lesions.

Dermatitis Herpetiformis

(See Chapter 61.) This condition is usually included among the classic bullous dermatoses; however, it illustrates that the preponderance of one or several pathologic reaction patterns may obscure the true pathogenesis of the condition. The deposition of immunoglobulin A and complement on fibrillar and nonfibrillar sites within the tips of the dermal papillae, and the activation of the alternative pathway of the complement cascade, lead to an influx of leukocytes (primarily neutrophils), which form small abscesses at the tips of the dermal papillae, as well as inflammation and edema (Fig. 6-13). This explains why the primary clinical lesion in dermatitis herpetiformis is urticarial or papular in nature, because only in the case of massive neutrophil infiltration will there be tissue destruction and cleft formation below the lamina densa that results in clinically visible vesiculation.

(See Fig. 6-1, DRU)

The dermis represents a strong fibroelastic tissue with a network of collagen and elastic fibers embedded in an extracellular matrix with a high water-binding capacity (see Chapter 63). In contrast to the tightly interwoven fibrous components of this reticular layer of the dermis (Fig. 6-14), the previously described fibrous texture of the papillary body and the perifollicular and perivascular compartments is loose (see Fig. 6-9), and the orientation of the collagen bundles here follows the structures they surround.

The dermis contains a superficial and deep vascular network. In the upper dermis, the superficial plexus supplies individual vascular districts consisting of several dermal papillae. Superficial and deep networks are connected so intimately that the entire dermal vascular system represents a single three-dimensional unit (see Chapter 162). On the other hand, there are profound functional differences between superficial and deep dermal vascular networks, which explain the differences of homing patterns of inflammatory cells to these sites.

As for the superficial microvascular system, two reaction patterns occur: (1) acute inflammatory processes in which the epidermis and junctional zone are often involved together with the vascular system, and (2) more chronic processes that often remain confined to the perivascular compartment. In this context, it should be noted that the cytologic composition (“acute vs. chronic inflammation”) of an inflammatory infiltrate within the skin does not always mirror the temporal characteristics of an inflammatory process. Thus, polymorphonuclear leukocytic infiltrates are not always synonymous with an acute process; conversely, chronic processes are not always represented by a lymphohistiocytic infiltrate.

Inflammation confined to the superficial connective tissue–vascular unit is characterized by endothelial activation, vascular dilatation, increased permeability, edema, a reduction of intravascular blood flow, an accumulation of red blood cells in the capillary loops, and cellular infiltration of the perivascular tissue. Depending on the degree of inflammation, the macroscopic corollary of the histologic changes represents erythematous, urticarial, and infiltrative (papular) lesions. The release of mediators from immunoglobulin E-laden mast cells in type I immune reactions, such as immune forms of urticaria, is histologically manifested primarily as vasodilatation, edema of the papillary body, and a rather sparse infiltrate of leukocytes (neutrophils) and histiocytic elements around the superficial venules (Fig. 6-15). These lesions usually resolve relatively rapidly without any residual pathology. However, more massive reactions lead to a dense perivascular infiltrate (Fig. 6-16A), and this may represent a transition to those processes where edema is less pronounced and where dense lymphocytic infiltrates surround the vessels in a sleeve-like fashion, as is the case in cutaneous drug eruptions (see Figs. 6-16A and 6-16B). More dramatic alterations occur when the vascular system itself is the target of the inflammatory process, resulting in a destruction of at least some of the vessel components, as is the case in necrotizing vasculitis. These exudative changes result in clinical palpable purpura (Fig. 6-17; see Chapter 163).

Chronic inflammatory reactions of the superficial microvascular plexus usually reveal lymphocytic infiltrates in close association with the vascular walls and are clinically manifested as erythema. In purpura simplex (see Chapter 168), damage to the vessel wall is much less evident than in necrotizing vasculitis, but the integrity of the vessels is also impaired, as is evidenced by hemorrhage into the tissue. Lymphocytes and, as a secondary reaction, histiocytic elements partly laden with phagocytosed material including iron, constitute the inflammatory infiltrate.

The reaction patterns described for the vascular system of the papillary body and the superficial venular plexus also occur in the deep dermis, but there are morphologic and functional differences because here larger vessels are involved. Lymphocytic infiltrates surrounding the vessels in a sleeve-like fashion lead to clinical signs only when they are substantial, and then they represent the histopathologic substrate for papular or nodular lesions. This is the case with drug eruptions (see Chapter 41; see Fig. 6-16B) and it is also true for deep-seated infiltrates in lupus erythematosus. In the case of necrotizing vasculitis of the medium-sized and larger vessels, there is usually a much more pronounced inflammatory infiltrate, clinically appearing as papular and nodular lesions, and secondary changes due to the interruption of the vascular flow are more pronounced: necrosis, blistering, and ulceration result as is the case in cutaneous panarteritis nodosa of the macroscopic type (see Chapter 164). In contrast to the macroscopic variant, microscopic polyarteritis nodosa affects vessels of varying sizes including venules and arterioles, involves lungs and kidneys, and is positive for perinuclear neutrophil antibodies. Granulomatous vasculitis also leads to nodular lesions, whereas the hyalinizing vascular changes and vascular occlusion in livedoid vasculitis result in ischemic necrosis (see Chapter 163).

Lymphocytic Infiltrates

Although lymphocytic infiltrates occur in the majority of inflammatory dermatoses, there are a number of pathologic processes in which such infiltrates are the most prominent features and thus determine the histologic picture. Lymphocytic infiltrates are formed in inflammatory or proliferative conditions and in the latter may represent a benign or malignant process. They may differ in their cytologic appearance and distribution, may be confined to the periadventitial compartments of the vascular system (superficial and deep perivascular dermatitis), or may occur diffusely throughout the collagenous tissue (diffuse dermatitis). They may be confined almost exclusively to the papillary dermis (interface dermatitis) and spare the subepidermal compartment or may exhibit pronounced epidermotropism. They may be independent of vessels, sparse (interstitial dermatitis) or nodular (nodular dermatitis). Because lymphocytes are a heterogeneous population of cells, the analysis of such infiltrates should take into account not only the cytomorphology and distribution pattern but histochemical properties and immunologic markers as well. The analysis of round cell infiltrates by monoclonal antibodies (immunophenotyping) and determination of their clonality are important aspects of dermatopathology (see Chapter 146).

Among the many possible reaction patterns characterized by lymphocytic infiltrates, several typical patterns can be distinguished.

• Superficial perivascular infiltrates are often accompanied by secondary reactions of the epidermis. Lymphoid cells surround the vascular channels in a sleeve-like fashion but often extend diffusely to the epidermis, which may reveal focal parakeratosis in these areas. Clinically, these changes are often characterized as palpable figurate erythemas such as erythema annulare centrifugum, but polymorphic light eruption, drug eruptions (see Fig. 6-16A), or insect bites can produce a similar histopathologic picture.
• Lymphocytic cuffing of venules without involvement of the papillary body and the epidermis may occur in figurate erythemas and in drug eruptions (see Fig. 6-16B). The infiltrates of chronic lymphocytic leukemia show a similar distribution pattern but are usually more pronounced.
• Perivascular lymphocytic infiltrates with a mucinous infiltration of the nonperivascular connective tissue may be found in lymphocytic infiltration of Jessner–Kanof, reticular erythematous mucinosis or in lupus erythematosus (Fig. 6-18) and dermatomyositis (see Chapters 155 and 156).
• Nodular lymphocytic infiltrates, which extend throughout the dermis exhibiting focal accumulations of histiocytic cells and thus acquiring the appearance of lymphoid follicles, are typical of lymphocytoma cutis (see Chapter 146). Phagocytosed polychrome bodies in histiocytic cells (tingible body macrophages), mitoses in the center of the lymphoid follicles, and an admixture of eosinophils are characteristic features, as is the fact that the papillary body is usually spared so that a conspicuous grenz zone is found between the infiltrate and the epidermis.
• Nonfollicular lymphocytic infiltrates sparing the superficial reactive unit may also occur in benign lymphoid hyperplasias, but in these cases, the differentiation from malignant lymphoma is very difficult. Polymorphic infiltrates showing histiocytes, plasma cells, and occasional eosinophils are usually benign, whereas most malignant non-Hodgkin lymphomas exhibit a more monomorphous cytologic picture.
• Nodular accumulations of lymphocytes with an admixture of plasma cells and eosinophils accompanied by vascular hyperplasia are characteristic of angiolymphoid hyperplasia (Fig. 6-19), in which blood vessel walls are thickened and the endothelial cells proliferate and become swollen, and enlarged.
• Atypical lymphocytic infiltrates involving both the superficial and deeper dermis, and cytologically characterized by pronounced pleomorphism of the cellular infiltrate, are characteristic of lymphomatoid papulosis, one of the spectrum of CD30+ lymphoproliferative disorders (see Chapter 145). This condition exemplifies the problems that arise when the histopathology of a lesion is used alone to determine whether a process is benign or malignant. Without knowledge of the clinical features and the course of disease, a definite diagnosis is extremely difficult.

Polymorphonuclear Leukocytic Infiltrates

Although neutrophils are the classic inflammatory cells of acute bacterial infections, there are diseases in which neutrophils dominate the histopathology, even in the absence of a bacterial cause. In pyoderma gangrenosum, massive neutrophilic infiltration of the dermis leads to sterile abscesses, breakdown of the tissue, and ulceration (see Chapter 33). In dermatitis herpetiformis, neutrophils accumulate in the tips of dermal papillae and form papillary abscesses (see Fig. 6-13) that precede the dermolytic blister formation described in Section “Disturbances of Dermal–Epidermal Cohesion” (see also Chapter 61). In erythema elevatum diutinum, neutrophils are the predominant cells centering around superficial and middermal vessels, which exhibit fibrinoid homogenization of their walls (toxic hyalin) and signs of vasculitis (see Chapter 163). The neutrophil is also the predominant cell in the early stages of the more common necrotizing vasculitis (see Fig. 6-17). Neutrophils also represent the majority of the often massive inflammatory infiltrate in acute febrile neutrophilic dermatosis, which is accompanied by pronounced subepidermal edema (see Chapter 32).

Granulomatous Reactions

Skin is an ideal tissue for granuloma formation in which histiocytes play a key role. Although these cells are involved at one time or another in practically all inflammatory processes, it is only the proliferation and focal aggregation of histiocytic cells that may be termed a granuloma. When such cells are closely clustered they resemble epithelial tissue, hence the designation epithelioid cells. Development of giant cells, storage of phagocytosed material, and the admixture of inflammatory cells, such as lymphocytes, plasma cells, and eosinophils, may render the histologic picture of a granulomatous reaction more complex. To these have to be added vascular changes and alterations in the fibrous structure of the connective tissue. Granulomas almost always lead to destruction of preexisting tissue, particularly elastic fibers, and in such instances result in atrophy, fibrosis, or scarring. Tissue damage or destruction manifests either as necrobiosis or fibrinoid or caseous necrosis, or it may result from liquefaction and abscess formation or from replacement of preexisting tissue by fibrohistiocytic infiltrate and fibrosis.

Sarcoidal granulomas (see Chapter 152) are typically characterized by naked nodules consisting of epithelioid cells, occasional Langerhans giant cells, and only a small number of lymphocytes (Fig. 6-20). Silica, zirconium, and beryllium granulomas and a number of foreign-body granulomas may have such histopathologic features.

Granulomatous reactions of the skin comprise a large spectrum of histopathologic features. Palisading granulomas surround necrobiotic areas of the connective tissue with histiocytes in radial alignment (Fig. 6-21). Granuloma annulare, necrobiosis lipoidica, rheumatoid nodules, and the juxtaarticular nodules of syphilis belong to this group. These reactions may have significance as signs of systemic disease. For example, when there are prominent neutrophils in the necrobiotic area of granuloma annulare or necrobiosis, one may suspect an associated inflammatory bowel disease. Endocrinopathies can also be associated with these disorders, diabetes mellitus is a classic example associated with necrobiosis lipoidica. Of course, rheumatoid nodules can be associated with rheumatoid arthritis but can also occur as a result of trauma in some cutaneous locations. Drugs may also cause these reactions.

Infectious granulomas with a sarcoidal appearance may occur in tuberculosis, syphilis, leishmaniasis, leprosy, or fungal infections. Necrosis can also develop within the granuloma proper, as is the case for fibrinoid necrosis in sarcoidosis, caseation in tuberculosis, or the necrosis developing in mycotic granulomas. Many of the infectious granulomas are associated with epidermal hyperplasia, often exhibiting intraepidermal abscesses in which the causative organism can be found, often in a multinucleate giant cell. In the dermis there is a mixture of cells, including histiocytes, epithelioid cells, eosinophils, neutrophils, and lymphocytes.

It is often difficult to classify granulomatous reactions within the skin by histopathology alone, for even completely different etiologic conditions such as immunopathies and some forms of vasculitis are associated with the development of granulomas.

A specific form of granulomatous reaction results when the cellular infiltrate consists almost exclusively of the key granuloma cell, the histiocyte. One property of this cell is its capacity to store phagocytosed material. In xanthomatous reaction patterns, histiocytes take up and store fat and are thus transformed into foam cells. They are distributed either diffusely, as is the case in diffuse normolipemic xanthomatosis, or as an aggregate infiltrate mimicking a tumor, as in the xanthomas occurring in the hyperlipoproteinemias and xanthelasma (see Chapter 135).

Fibrous Dermis and Extracellular Matrix

(See Fig. 6-1, DRU)

Sclerosing processes of the skin involve mainly the connective tissue of the dermis (see Figs. 6-1, DRU, and 6-14) but usually reflect dynamic changes of structure and function that involve practically all compartments of this organ. The hallmark of scleroderma (see Chapter 157) is the homogenization, thickening, and dense packing of the collagen bundles, a narrowing of the interfascicular clefts within the reticular dermis, and the disappearance of the boundary between this portion of the dermis and the papillary body. There is also a diminution of the small papillary and subpapillary vessels, which appear narrowed, and, in the early stages, a perivascular lymphocytic infiltrate and edema. The impressive thickening of the dermis not only results from an increase of its fibrous components, but is also caused by the fibrosis of the superficial layers of the subcutaneous fat that follows lymphocytic infiltration and a histiocytic reaction.

Sclerodermoid changes may be found in the toxic oil syndrome and l-tryptophan disease, eosinophilic fasciitis (see Chapter 36), and mixed connective tissue disease; they also occur in pachydermoperiostosis, where an increase of fibroblasts and ground substance accompany the sclerotic changes, and in porphyria cutanea tarda, which shows typical hyalinization of the papillary vessels. In lichen sclerosus, there is a massive edema of the papillary body and a dense lymphocytic infiltrate that initially hugs the epidermis and later separates the edematous papillary body from the reticular dermis (see Chapter 65). As sclerosis sets in, there is also a disappearance of elastic tissue from the papillary body; the concomitant involvement of the epidermis includes hydropic degeneration of basal cells, atrophy, and, at the same time, hyperkeratosis. Changes in the junctional zone in this condition may occasionally lead to a separation of the epidermis from the dermis and thus to blister formation.

Faulty synthesis or cross-linking of collagen results in a number of well-defined diseases or syndromes but leads to relatively few characteristic histopathologic changes. In the different types of the Ehlers–Danlos syndrome (see Chapter 137), the faulty collagen cannot be recognized histopathologically, and only the relative increase of elastic tissue may indicate that something abnormal has occurred in the dermis. In generalized elastolysis, a fragmentation of elastic fibers is the histopathologic substrate of the clinical appearance of cutis laxa, and the fragmentation and curled and clumped appearance of elastic fibers are similarly diagnostic in pseudoxanthoma elasticum (see Chapter 137). On the other hand, in actinic elastosis, the histologic correlate of dermatoheliosis, all components of the superficial connective tissue are involved (see Chapter 109). Except for a narrow grenz zone below the epidermis, the papillary body, and the superficial layers of the reticular dermis are filled with clumped and curled fibers that progressively become homogenized and basophilic. They are stained by dyes that have an affinity for elastic tissue and thus histochemically behave similar to elastic fibers.

Such profound changes of dermal architecture become clinically apparent: the taut and firm connective tissue in scleroderma reflects the sclerotic texture and homogenization of the collagen bundles seen histologically; the loose folds of cutis laxa are a result of the fragmentation of elastic fibers; the cobblestone-like papules in pseudoxanthoma elasticum correspond to the focal aggregation of the pathologically altered elastic material; and the coarseness of skin lines and surface profile in dermatoheliosis are the clinical manifestations of the focal aggregation of elastotic material.

The reaction patterns that affect the dermis take the forms of cellular infiltrations as well as acellular patterns that primarily are based in the extracellular matrix. However, these two general categories are difficult to separate, as there is constant interplay between the cellular and acellular components of the dermis. As discussed above, the vascular plexuses in the dermis are the primary conduits for influx of cellular elements, and leukocyte–endothelial adhesion molecule expression play a critical role in regulating leukocyte entry and the reaction patterns that result. The adhesive molecules themselves assist in regulating the relative strength and kinetics of the influx of various cell types, and hence some stimuli may provoke an adhesion cascade that favors entry of neutrophils or eosinophils, whereas others may result in infiltration of primarily mononuclear cells. Moreover, once inflammatory cells have extravasated into the dermal interstitium, their migratory fate and secondary morphological alterations are also in large part determined by molecular cues in their new microenvironment. Hence, an encounter with insect bite venom may provoke interstitial accumulation of histiocytes and eosinophils, and perhaps poorly formed granulomas, whereas an immune response in the setting of Lyme disease may provoke intensely perivascular localization of lymphocytes conjuring up the appearance of a “coat-sleeve.” Mediators released by cellular infiltrates may have a profound effect on the extracellular matrix as well, resulting in additional dermal reaction patterns. For example, fibrogenic mediators such as TGFβ, may have a variety of effects on dermal homeostasis, including fibroblast transformation in the direction of myofibroblasts, with attendant collagen synthesis as might be seen as a normal response to wounding, but in this setting resulting in the diffuse dermal thickening that correlates with the reaction pattern typical of morphea scleroderma.

(See Fig. 6-1, S)

Inflammatory processes in the subcutaneous adipose tissue take a slightly different course than in the connective tissue of the dermis because of the specific anatomy of the subcutis (see Chapters 7 and 70). Inflammation of subcutaneous fat reflects either an inflammatory process of the adipose tissue proper or the fat lobules (see Fig. 6-1, L) or a process arising in the septa (see Fig. 6-1, Sep); it can involve small venules and capillaries or arise from the larger muscular vessels. The histopathologic manifestations may vary accordingly. Small-vessel pathology is usually manifested locally, involving the neighboring fat lobules, whereas the destruction or occlusion of a larger vessel influences the entire tissue segment. Destruction of fat, be it of a traumatic or inflammatory nature, leads to the release of fatty acids that by themselves are strong inflammatory stimuli, attracting neutrophils and scavenger histiocytes and macrophages; phagocytosis of destroyed fat usually results in lipogranuloma formation.

Septal processes that follow inflammatory changes of the trabecular vessels are usually accompanied by edema, infiltration of inflammatory cells, and a histiocytic reaction. This is the classic appearance in erythema nodosum (Fig. 6-22; see Chapter 70). Recurring septal inflammation may lead to a broadening of the interlobular septa, fibrosis, the accumulation of histiocytes and giant cells, and may result in vascular proliferation. By contrast, in nodular vasculitis (Fig. 6-23), large-vessel vasculitis in the septal area is accompanied by necrosis of the fat, followed by histiocytic reactions, epithelioid cell granulomas within the fat lobules, and a fibrotic reaction sclerosing the entire subcutaneous fat. On the other hand, lobular panniculitis results from the necrosis of fat lobules as the primary event, as is the case in idiopathic nodular panniculitis (see Chapter 70), followed by an accumulation of neutrophils and leukocytoclasia. The lipid material derived from necrotic adipocytes contains free and esterified cholesterol, neutral fats, soaps, and free fatty acids, which, in turn, exert an inflammatory stimulus. Histiocytic cells migrate into the inflamed fat, and phagocytosis leads to foam cell formation. Epithelioid granulomas with giant cells may also result, and all types of fibrosis may develop. Therefore, fat necrosis is the primary, and inflammation the secondary, event in this type of panniculitis.

The inherent capacity of the adipose tissue to respond to pathologic stimuli also holds true for disease conditions that affect the subcutaneous tissue only secondarily or result from exogenous factors. Traumatic panniculitis leads to necrosis of fat lobules and a reactive inflammatory and granulomatous tissue response. After the injection of oils or silicone, large cystic cavities may be formed, whereas after the injection of pentazocine, for instance, fibrosis and sclerosis dominate the histopathologic picture. Oily substances may remain within the adipose tissue for long periods without causing a significant tissue reaction; oil cysts evolve that are surrounded by multiple layers of residual connective tissue, so that the tissue acquires a “Swiss cheese” appearance. Animal or vegetable oils often lead to tuberculoid or lipophagic granulomas with massive histiocytic reactions, foam cells, and secondary fibrosis.

Panniculitis also occurs as a result of infectious agents (cocci, mycobacteria, and other bacterial and fungal organisms) or a specific disease process. In sarcoidosis, fat is gradually replaced by epithelioid cell nodules and, in lymphoma, by specific lymphomatous infiltrates. In lupus panniculitis, a dense lymphocytic infiltrate of the septal and lobular tissue determines the histopathologic picture, as does involvement of vessels manifesting as vasculitis. However, destruction of fat, liquefaction, and lipogranuloma may be so pronounced that the vascular component can hardly be recognized, and the histopathologic picture may resemble idiopathic nodular panniculitis.

We are in the infancy of understanding the molecular underpinnings of various reaction patterns in the subcutis. This is in part because our understanding of the normal physiology of subcutaneous fat has only recently moved past the historical notion of energy storage. We now know that the subcutis is a potent source of stem cells that have remarkable differentiation plasticity and thus implications for use in regenerative medicine. The fat lobule itself is much more that an energy storage site; it also generates a variety of proinflammatory and thrombogenic cytokines that, as is the case with epidermally derived cytokines, are likely to play a key role in regulating the various reaction patterns to which fat is heir. Moreover, given its location deep to the dermal–epidermal environmental interface, the subcutaneous fat has the spatial attributes to serve as a barometer for systemic molecular cues that may herald generalized disease. Finally, perturbation in the fat producing specific reaction patterns in association with aberrant cytokine production may themselves contribute to systemic health and disease, as is currently speculated with regard to proinflammatory mediators produced in the subcutis that may contribute to the evolution of some forms of cardiovascular disease.

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