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).
A. Acanthosis. This sign of increased epidermal kinetics is illustrated in a photomicrograph of psoriasis. B. Parakeratosis, the retention of nuclei in the horny layer, is evident.
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).
The association of dyskeratosis and acantholysis is seen in this high-power view of Darier disease, which also demonstrates the intraepidermal cleft formation resulting from these phenomena.
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.
Table 6-1 Classification of Intraepidermal Blisters by Anatomic Level with Clinical Examples ||Download (.pdf)
Table 6-1 Classification of Intraepidermal Blisters by Anatomic Level with Clinical Examples
Subcorneal pustular dermatosis
Staphylococcal scalded-skin syndrome/bullous impetigo
Herpes virus infection
Familial benign pemphigus
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).
Spongiform vesicle resulting from edematous separation of keratinocytes (A). These are still partially attached to each other by desmosomes and have thus acquired a stellate appearance as is evident at higher magnification (B).
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. Single as well as clusters of acantholytic cells are seen. The round shapes result from the loss of intercellular connections. Cytologic smear preparation of pemphigus vulgaris.
Pemphigus vulgaris. An intraepidermal suprabasal cleft is visible that has resulted from suprabasal acantholysis. It contains acantholytic and inflammatory cells.
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).
Herpes simplex infection. The epidermis shows marked ballooning degeneration, cytolysis, and intraepidermal vesiculation. Acantholytic and multinucleated epidermal giant cells are a clue to herpetic infection.
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).
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).
Bullous pemphigoid. Subepidermal (junctional) cleft formation and a perivascular and interstitial lymphoeosinophilic infiltrate are characteristic (A). Eosinophilic spongiosis can also occur (B).
Table 6-2 Classification of Blisters at the Dermal–Epidermal Junction by Anatomic Level with Clinical Examples ||Download (.pdf)
Table 6-2 Classification of Blisters at the Dermal–Epidermal Junction by Anatomic Level with Clinical Examples
Junctional (at the lamina lucida)
Junctional epidermolysis bullosa
Dermolytic (below basal lamina)
Epidermolysis bullosa dystrophicans
Epidermolysis bullosa acquisita
Porphyria cutanea tarda
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
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.
The compartment of the papillary body consists of capillaries (C), fibroblasts (F), macrophages and dendritic cells (M), peripatetic lymphocytes (L) and mast cells (Mc), all embedded in a loose connective tissue of extracellular matrix, thin collagen fibers (Co), elastic fibers (E) that are mostly oriented perpendicularly to the skin surface, and branched reticulin fibers (R).
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.
Contact dermatitis. Intraepidermal spongiotic vesicles and pronounced intercellular edema are present in the epidermis. The dermis contains perivascular aggregates of lymphocytes and histiocytes admixed with occasional eosinophils.
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.
(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.
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.
(See Chapter 39.) Two types of reactions occur. In both there is interface dermatitis characterized by lymphocytes scattered along a vacuolated dermal–epidermal junction.
(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.
Lupus erythematosus. Hyperkeratosis, thinned epidermis devoid of rete ridges, and vacuolization of the basement membrane zone are present.
(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.
Lichen planus. There is hyperkeratosis, wedge-shaped hypergranulosis, basal cell vacuolization, and a lymphocytic infiltrate at the dermal–epidermal junction. This infiltrate “hugs” the basal cell layer and is associated with many cytoid bodies.
(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.
Dermatitis herpetiformis. Two papillae show microabscesses composed of neutrophils. Vacuolization and early cleft formation are evident in both papillae.