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Lichenoid Dermatitis (TIER 2)
The cutaneous “lichens”(a designation that is now largely meaningless and obsolete) historically encompassed a wide range of clinical disorders with a real, or fanciful, resemblance to lichens (i.e., fungi and algae).
GENERAL DEFINITION
Clinically, the cutaneous “lichens” might be characterized as a select group in which the primary lesion is a small papule (1). In contrast, the
lichenoid reactions histologically embrace a heterogeneous group of disorders which, in numbers, greatly exceed the limits imposed by the clinical definition of the clinical “lichens” (2-4). The lichenoid reaction is a lytic process directed primarily against basal keratinocytes, including keratinocytes of the basal epidermal unit. Its
effects are manifested by lysis and coagulation of keratinocytes, lytic defects in the basal epidermal domain, and attrition of rete ridges at the dermal-epidermal interface (3). These changes may be associated with a cell-poor inflammatory reaction in which few lymphocytes violate the epidermal domain, or with a cell-rich
response in which migrating lymphocytes intermingle among keratinocytes bordering the zones of lysis (3). In the lichenoid category,
vesiculo-bullous reactions are rare. On the other hand, in the more general category of interface reactions, vesiculo-bullous reactions are common.
PATHOGENETIC SPECULATONS
Clinically, the “lichens” are papular; histologically, they generally are cell-rich. The cell-rich lichenoid reaction embraces the several clinical disorders; included in the category are lichen planus, lichen
striatus, and lichen nitidus. A variety of clinically dissimilar processes are expressed histologically in lichenoid patterns; the histologic definition of the lichenoid reaction embraces processes which are generally grouped in other categories. For processes such as erythema multiforme, pityriasis lichenoides, erythema dyschromicum perstans, and fixed drug eruptions, the histologic similarities suggest a commonness. This commonness is expressed in a basic reaction in which T lymphocytes are aggressor cells and keratinocytes are target cells.This reaction does not seem to be dependent on a specific antigen. For example, a variety of antigens apparently can predispose to a lichen planus-like reaction.
With lichen planus as the prototype of a cell-rich lichenoid reaction, cell marker studies indicate that T lymphocytes are preponderant (5, 6). Plasma cells,
as markers for derivatives of B lymphocytes, generally are not a feature; some examples of hypertrophic lichen planus are an exception. Plasma cells are a feature of lesions of secondary lues (a lesion with
lichenoid qualities), and may be a feature of mucous membrane lichen planus. In the histogenesis of a lesion of lichen planus, B cells have a role; colloid bodies are markers for the effects of cell-mediated
immunity, but such bodies are coated with immunoglobulins (7).
It is difficult to characterize an immune response as purely B- or T-cell in nature. Direct study of, and comparisons with, experimental models in which T cells are the prime mediators, such as graft vs host reaction
(8), points to the T lymphocyte as the prime aggressor in the histogenesis of most lichenoid reaction (9).
A transformed T lymphocyte of a T-cell dysplasia often has ultrastructural characteristics that are manifested by distinctive nuclear convolutions (10). With
light microscopy of a lesion in the same clinical category, these same nuclear characteristics can be appreciated. In lymphoid infiltrates in a variety of inflammatory processes, including lichen planus, lichen
striatus, linear inflammatory epithelial nevus, inflamed seborrheic keratosis, and lichenoid keratosis, basically similar cells (with similar nuclear characteristics) are common.
T lymphocytes have secretory functions, including the production of a lymphokine (MIF) which inhibits the migration of macrophages and a lymphokine which attracts eosinophils. As a consequence, histiocytes and
eosinophils are components of the infiltrates in some cell-mediated reactions. The granulomatous qualities of the infiltrates in lichen niditus might express the effects of lymphokines on macrophages; might be an
expression of a reaction to dying keratinocytes; or might provide evidence that the responsible antigen is relatively insoluble.
The Langerhans cells is a special dendritic histiocyte with special ecotaxic expressions, including a role in immune responses in the epidermal domain. It presents distinctive cell markers, including immunoreactivity
to antibodies directed to S-100 protein and CD1a. It is concerned with the presentation of antigen to T lymphocytes. In some cell-mediated reactions, the mast cell is an effector cell (11), but a significant role for the mast cell in lichenoid reactions has not been defined. In spongiotic disorders, the Langerhans cell is the nidus about
which fluid interstitium of the epidermis becomes watery. In lichenoid reactions, one or more Langerhans cells are to be found in the lytic defects in the basal unit of the epidermis.
The cell-poor category is also heterogeneous. Lupus erythematosus and dermatomyositis are examples. In early lesions of lupus erythematosus and in examples of subacute LE, the patterns at the dermal-epidermal
interface may be cell-rich.
In the cell-poor lichenoid category, the histologic patterns of lesions of lupus erythematosus provide one prototype (12). In this cell-poor category,
intermingling of aggressive T lymphocytes and target cells (basal keratinocytes) is rarely a prominent feature. Vacuoles on both sides of a thickened basement membrane and lysis of individual keratinocytes of the
basal layer are markers for a lichenoid reaction. The altered, hyalinized basement membrane contains deposits of IgG (a specific product of cells of B cell lineage) and components of complement (a reaction product).
It may function as an immune barrier to confine T lymphocytes to the dermal side of the basement membrane.
The “target” cell in cutaneous lichenoid reactions is the keratinocyte, although other epidermal cells, such as melanocytes, also may be affected. The effects on basal keratinocytes include vacuolization along
the basement membrane (as might be seen in erythema dyschromicum perstans); coagulation of keratinocytes and deposition of immunoglobulins on the surface of the dying keratinocytes (as might be seen in lesions of
lichen planus); and lysis of cells. The lytic process may affect the entire periphery of a rete ridge. The erosive process often alters the contour and length of affected rete ridges. The result is a pattern
in which rete ridges have pointed extremities (i.e., saw-toothing) as might be seen in a lesion of lichen planus. The effaced rete patterns of lupus erythematosus may not be evidence of a continuous lysis of cells
of the basal unit of the epidermis. It may be evidence of either atrophy, or of a phenotypic diversion of basal keratinocytes (the affected cells shift to the phenotype associated with terminal differentiation). It
may be evidence that epidermal kinetics of the basal unit are altered in the face of deposits of immunoglobulins at the dermal-epidermal interface.
The degenerative changes affecting keratinocytes in a lichenoid reaction have been characterized as apoptosis (13); they qualifie as pathologic
apoptosis. The latter term gives recognition to a sequence of cytoplasmic and nuclear changes leading to lysis, fragmentation, and coagulation of dying cells, particularly keratinocytes. In reference to
keratinocytes, the changes of apoptosis so closely correspond to those of a lichenoid reaction that the concept has found utility as an explanation for the changes, when in fact it simply may be a characterization
of the effects of a lichenoid reaction. In this approach to the concept of pathologic apoptosis, the designation, lichenoid reaction, also would have utility as a characterization of cellular changes in target cells
in other organ systems; as an example, the changes in viral hepatitis qualify as a “lichenoid” (i.e., cell-mediated) reaction in which the target cell is an hepatocyte. In practice, the distinctions between the
cellular changes in pathologic apoptosis and those of dyskeratosis are not clearly defined. They may be similar histologically. The concept of apoptosis gives recognition to a type of cellular disintegration which
is metabolically “programmed.” It has application to processes that work to maintain form in the daily pursuit of homeostasis (homeostatic apoptosis). The coagulated keratinocyte of apoptosis contains densely
aggregated cytoplasmic fibrils, and cytoplasmic organelles. The concept of apoptosis has application to both physiologic and pathologic processes. In the promotion of apoptosis as a pathologic process having
application in the understanding of phenomena in lichen planus and lichen planus-like disorders, proponents emphasize that the altered cells, or their fragments, are first phagocytyzed and then, in an endocytyzed
location, are moved into the dermis. The large fragments that come to lie within newly formed fibrous tissue persist for a variable period as the “colloid” or “Civatte” bodies of the lichenoid reaction. In a
discussion in the PICTORIALS, an alternate hypothesis for the “movement” of the larger products of dying cells will be presented.
Pigment incontinence and hyperpigmentation are common features of lichenoid reactions; the reaction often affects both keratinocytes and melanocytes. In some lichenoid drug reactions, a drug (e.g., atabrine) has a
peculiar affinity for melanized cells. In these cell-rich lichenoid reactions, the antigen, elicting a cell-mediated reaction, may be associated with, or incorporated in, melanin or
melanized products. Erythema dyschromicum perstans is a spotty, lichenoid reaction in which pigment incontinence and melanoderma are prominent features. The disorder is recognized clinically by the peculiar pigmentary changes (2). The melanoderma persists long after the lichenoid reaction has subsided. Again, by inference, melanized products may be antigenic.
For lichenoid reactions, a life history can be defined:
In a sequence, it is divisible into primary, established, and senescent phases. The senescent phase is cell-poor, but the markers for the effects of a cellular (established) phase persist. They are manifested by an
atrophic basal unit (effaced rete patterns), a widened, fibrotic papillary dermis, and altered vascularity (telangiectasia). At a clinical level, these features are poikilodermatous (13). If, during the established phase, melanogenesis is accelerated, the senescent phase is additionally characterized by pigmented histiocytes in the
altered papillary dermis (melanoderma) and by clinical hyperpigmentation. In combination, the clinical features qualify as a pigmented poikiloderma. Phototoxic reactions, berloque dermatitis, poikiloderma of
Civatte, and fixed drug reactions can be characterized in late stages as senescent lichenoid reactions with melanoderma (pigmented poikiloderma).
If the lichenoid reaction of lichen nitidus is an immune response, the antigen is apparently confined to the basal unit. The reaction often is accompanied by little or no disturbance in the superficial epidermal unit
(3), but
may be associated with lichen planus-like hypertrophy of cells of the superficial unit. A prominence of melanized products in the cytoplasm of both histiocytes and multinucleated giant cells is often a significant feature.
In many lesions of lichen striatus, a hyperplastic basal unit will show widened, mucoid, interstitial spaces (3). The follicular changes in the latter
disorder qualify, in certain stages, as follicular mucinosis (3). Even in lesions of the T cell dysplasias, follicular mucinosis, as a variant
component, is adequately documented. The evidence suggests that transformed T lymphocytes may, under certain conditions, enhance the secretory activities of target cells (keratinocytes) (15). The mucoid interstitium of follicular mucinosis expresses the influence of activated T lymphocytes on follicular epithelium. In an recent
idiosyncratic approach, all examples of follicular mucinosis would become a marker for a T cell lymphoma; this approach has little to recommend it.
The nevoid quality of lichen striatus has not been explained. The striate distribution of papules, resembling a linear nevus, may express a genetic chimera in which the lichenoid reaction marks the host’s response to
the chimerical clone. Perhaps, the linear qualities of inflammatory linear nevus similarly is an expression of a genetic chimera.
A cell-rich lichenoid reaction is basic to the host immune response in carcinomas of the skin, actinic keratoacanthomas, and clonal diseases such as actinic keratoses, porokeratoses, and Bowen’s disease. It, as an
expression of cell-mediated immunity, appears to play a role in diseases in other organ system in which the target cells are other than keratinocytes. In this approach, examples of target cells would include the
melanocytic cells of halo nevus and some melanomas. Even parenchymal cells of the viscera, with hepatocytes as an example in viral hepatitis, might cited as the target cells of “lichenoid” reaction. The cell-rich
lichenoid reaction is a marker for the effects of cell mediated immunity. In an established phase, it produces focal regression at the advancing margin of a dysplastic nevus, a melanoma, a carcinoma, or within a
clonal keratosis. Laminated fibrous tissue in an area of regression is the final product of the interplay between tumor cells and inflammatory cells (arrested or senescent phase). Similarly, the lichenoid reaction
is basic in the evolution of keratoacanthomas (16). The life history of the stroma in a keratoacanthoma can be divided into three phases. In the initial
phase of rapid growth, the stroma is refractory. Tumor cells invade the interstitium of the pre-existing connective tissue among connective tissue fibers (immunostimulatory phase of cell-mediated, or lichenoid,
reaction); the fibers become entrapped in the interstitium of the infiltrating epithelium. Lymphoid infiltrates are minimal. In the period of stable growth, the tumor cells encounter a reactive stroma of cellular
fibrous tissue with infiltrates of lymphocytes, histiocytes, and a variable component of plasma cells and eosinophils. Lichenoid patterns are focally prominent at this stage (established phase). The end stage is
characterized by focal, variable regression of the infiltrating tumor, and a desmoplastic, stromal response in which there are foreign body granulomas and keratinized debris (senescent phase). The cell-rich
lichenoid reaction relates to the phase of stabilized growth, and eventuates in the desmoplastic phase of tumor regression. The success or failure of the host immune response determines the evolution of actinic
keratoacanthoma, Success is often focal and incomplete.
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