Cases 8-10 -

Vesicular Skin Diseases Reprinted with permission from: Dermatopathology: Practical & Conceptual | April - June 1998 | Volume 4, #2 | Pages 150-156. Published by Ardor Scribendi, Ltd. Kenneth S. Resnik, M.D.

LEARNING AND PRACTICING CLINICAL DERMATOLOGY THROUGH DERMATOHISTOPATHOLOGY Fundamental Lesions of the Skin Elevations: Part V — Vesicle and Bulla Kenneth S. Resnik, M.D. and A. Bernard Ackerman, M.D. Definition of Vesicle and Bulla In dermatology, any lesion that rises above the skin surface is called an elevation by us. Thus far in this series of essays designed to explain clinical lesions in terms of histopathologic findings, the elevations known as papule, nodule, tumor, plaque, and cord have been addressed. The subject of this piece is vesicle and bulla, i.e., non-cystic fluid-filled elevations that differ in size only. A blister less than 1.0 cm in greatest dimension is termed a vesicle and one 1.0 cm or larger in greatest dimension is designated a bulla. We retain the names vesicle and bulla, rather than referring to them simply as blisters, because those names have applicability clinically, e.g., miliaria crystallina and hand-foot-mouth disease present themselves always as vesicles and not bullae, and pemphigus vulgaris and epidermolysis bullosa simplex present themselves typically as bullae and not vesicles. Vesicles may evolve into bullae, as is the case often in conditions like allergic contact dermatitis, erythema multiforme, and bullous pemphigoid. Not all bullae, however, began as vesicles, e.g., those of pemphigus vulgaris, staphylococcal scalded skin syndrome, and epidermolysis bullosa. Case 8: This 50-year-old female presented herself to her dermatologist bearing an annular plaque with focal vesiculation on her posterior left thigh which was clinically considered to represent either erythema chronicum migrans or linear IgA dermatosis. Case 8 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 9: This 61-year-old female developed an indurated vesiculo-bullous plaque on the dorsum of her hand shortly after returning from a vacation in the Arizona desert. Clinical considerations for this lesion included allergic contact dermatitis, coccidiomycosis, herpes and bullous impetigo. At the time the punch-biopsy was received, tissue culture turned out to be positive for herpes simplex virus, bacterial culture excluded bullous impetigo, and deep fungal culture was pending. Case 9 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 10: An 18-year-old male presented himself to his dermatologist with a medical history of gluten-sensitive enteropathy and lesions on his knees, buttocks and elbows. A punch-biopsy was received with a clinical differential diagnosis of dermatitis herpetiformis versus folliculitis. Case 10 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Blistering skin diseases are referred to generically by microscopists as vesicular dermatitides (even though some of them, such as epidermolysis bullosa simplex and porphyria cutanea tarda are not truly dermatitides because they are devoid of inflammatory cells) and are recognized by the appearance of fluid filled spaces situated within or beneath the epidermis, and sometimes in both locations concurrently. As the terms denote, an intra-epidermal vesicular dermatitis is one in which serum accumulates within the epidermis and a subepidermal vesicular dermatitis is one in which serum collects beneath the epidermis. Intra-epidermal vesicular dermatitides may be classified according to the mechanism by which a vesicle forms (ballooning, spongiosis, or acantholysis) or the site at which a vesicle develops (intrabasalar, suprabasalar, intraspinous, or intragranular). A helpful adjunct to specific diagnosis of intraepidermal vesicular dermatitides is the composition of the infiltrate of inflammatory cells that accompanies them. Subepidermal vesicular dermatitides can be differentiated from one another by conventional microscopy on the basis of whether or not an infiltrate of inflammatory cells is present or not, and if present what those inflammatory cells are. Intra-epidermal vesicular dermatitides come into being consequent to intracellular edema (ballooning), intercellular edema (spongiosis), and loss of cohesion between keratinocytes (acantholysis), or as a result of a combination of these mechanisms. Intracellular edema, known also as ballooning, is identified by noting abundant pale cytoplasm of keratinocytes in the spinous zone. When ballooning is severe, keratinocytes rupture, resulting in reticular alteration which eventuates in vesiculation accompanied always by epidermal necrosis, e.g., in infections by herpesvirus and coxsackievirus. Intercellular edema, known also as spongiosis, is recognized by noting that spaces between keratinocytes are widened and intercellular bridges appear to be stretched across them. Prominent spongiosis is manifested as an intra-epidermal vesicle, e.g., in allergic contact dermatitis and nummular dermatitis. Loss of cohesion of keratinocytes, termed acantholysis, is recognized by observing keratinocytes that are separate from one another and are round. Acantholysis may lead to formation of an intraepidermal vesicle, e.g., in pemphigus vulgaris and Hailey-Hailey disease. When a vesicle consequent to ballooning and spongiosis becomes extraordinarily tense, it explodes, the result being formation of a subepidermal blister. No matter how pronounced acantholysis becomes, the blister remains intra-epidermal. If, however, a suprabasal blister, such as that of pemphigus vulgaris, becomes unroofed, the single layer of basal epithelium may come to be lost and an erosion then comes into being. Parenthetically, a cleft is a space that does not contain fluid and represents an artifact of preparation of tissue, e.g., a subepidermal cleft in lichen planus that seems to be a consequence of extensive vacuolar alteration. Clinically, a vesicle tends to be tense, whereas a bulla may be either tense or flaccid. For example, bullae in bullous pemphigoid at first are tense and those of pemphigus (foliaceus and vulgaris) from the outset are flaccid. Although trainees in dermatology are taught conventionally that blisters situated beneath the epidermis are tense and those positioned within the epidermis are flaccid, that often is not truly the case. Although the intra-epidermal blister of pemphigus vulgaris and Hailey-Hailey disease usually is flaccid, the intra-epidermal blister of dyshidrotic dermatitis and miliaria crystallina is tense. Likewise, a subepidermal blister may be flaccid, rather than tense, as is apparent in some expressions of erythema multiforme. Vesicles may arise directly from seemingly normal skin, e.g., in varicella, or develop on a papule, e.g., in response to the bite of an insect. Some vesicles eventuate in pustules, e.g., in dermatophytosis and in spongiotic vesicles that have become impetiginized, or into bullae, e.g., bullous impetigo and linear IgA bullous dermatosis. Bullae, like vesicles, may arise on what seems to be normal skin, e.g., suction blisters, or on urticarial plaques, e.g., bullous pemphigoid. Most vesicles are clear because they contain serum; some, however, are hemorrhagic because erythrocytes have been extravasated into their cavity, e.g., some examples of septic or leukocytoclastic vasculitis. When the roof of a blister is gray, it signifies that the epidermis is entirely necrotic. Because necrosis attracts neutrophils to it chemotactically, blisters with necrotic roofs often are transformed into vesiculo-pustules, as happens commonly in gonococcemia. Classification of Vesicles and Bullae We classify vesicles and bullae according to the location of accumulation of serum in the skin, i.e., within the epidermis or beneath it, or both together. The examples that follow are not set forth in an exhaustive list because they are meant to be representative of a concept, namely, that accumulation of serum in vesicles and bullae can be recognized readily by conventional microscopy and the mechanisms responsible for the accumulation can be understood, at least in part, by reflection on histopathologic findings. AN ATLAS OF VESICLES AND BULLAE Drawings by Larry Parsons, M.D. A CLASSIFICATION OF VESICLES I. INTRA-EPIDERMAL A. BALLOONING 1. Hand-foot-mouth disease Ballooning vesiculation accompanied by marked reticular alteration that, in time, may become subepidermal, marked subepidermal edema, and sparse infiltrate of lymphocytes 2. Infection by herpesvirus Ballooning vesiculation accompanied by marked reticular alteration with multinucleate ballooned keratinocytes and some acantholytic cells within the blister that, in time, may manifest itself as a subepidermal vesicle 3. Erythema multiforme Ballooning intra-epidermal vesiculation that, in time, may become subepidermal, necrotic keratinocytes, and sparse superficial perivascular infiltrate of lymphocytes that also is present along the dermo-epidermal junction 4. Fixed drug eruption Ballooning intra-epidermal vesiculation that, in time, may become subepidermal, necrotic keratinocytes, and superficial and deep perivascular mixed-cell infiltrate of lymphocytes, eosinophils, and neutrophils that also may obscure the dermo-epidermal junction B. SPONGIOTIC 1. Allergic contact dermatitis, dyshidrotic dermatitis Marked spongiotic vesiculation accompanied sometimes by subepidermal edema and a mixed-cell infiltrate that often contains eosinophils 2. Dermatophytosis Spongiotic vesiculation, mixed infiltrate of inflammatory cells, and hyphae in the cornified layer 3. Response to an insect bite. Spongiotic vesiculation that may eventually become subepidermal and situated above a wedge-shaped superficial and deep infiltrate of lymphocytes and eosinophils, many of the latter in the interstitium C. ACANTHOLYTIC 1. Infection by herpesvirus Intra-epidermal vesicle containing ballooned multinucleate and acantholytic keratinocytes 2. Blister beetle (Canthradin) dermatitis Acantholytic vesiculation without the nuclear and cytoplasmic changes typical of infection by herpesvirus II. SUBEPIDERMAL A. CELL POOR 1. Porphyria cutanea tarda Subepidermal blister beneath which dermal papillae usually are preserved and rims of homogeneous eosinophilic material are present around venules in the upper part of the dermis 2. Epidermolysis bullosa simplex Subepidermal vesicle with little, if any, infiltrate of inflammatory cells B. COMPOSITION OF INFILTRATE OF INFLAMMATORY CELLS 1. Neutrophils predominate a. Dermatitis herpetiformis Subepidermal vesicle replete with neutrophils and at the periphery of which neutrophils are lodged in subepidermal spaces b. Linear IgA bullous dermatosis Subepidermal vesicle replete with neutrophils at the periphery of which neutrophils are present in subepidermal spaces c. Bullous systemic lupus erythematosus Subepidermal vesicle replete with neutrophils and nuclear "dust" of neutrophils, a superficial and deep infiltrate of lymphocytes, and abundant mucin in the reticular dermis 2. Eosinophils predominate a. Bullous pemphigoid Subepidermal vesicle rich in eosinophils b. Herpes gestationis Subepidermal vesicle replete with eosinophils 3. Lymphocytes predominate a. Lichen planus Subepidermal vesicle associated with wedge-shaped hypergranulosis and a sparse infiltrate of lymphocytes 4. Mast cells predominate a. Urticaria pigmentosa Subepidermal vesicle beneath which is a dense diffuse infiltrate of mast cells and variable numbers of eosinophils III. INTRA- AND SUBEPIDERMAL CONCURRENTLY A. BALLOONING 1. Erythema multiforme Ballooning and subepidermal vesiculation, necrotic keratinocytes, and a superficial perivascular infiltrate of lymphocytes that also obscures the dermo-epidermal junction 2. Fixed drug eruption Ballooning and subepidermal vesiculation, necrotic keratinocytes, and superficial and deep perivascular mixed-cell infiltrate of lymphocytes, eosinophils, and neutrophils that also is present along the dermo-epidermal junction 3. Infection by herpesvirus Ballooning and subepidermal vesiculation, and multinucleate ballooned keratinocytes, some of which are acantholytic B. SPONGIOTIC 1. Response to an insect bite Spongiotic and subepidermal vesiculation situated above a wedge-shaped superficial and deep infiltrate of lymphocytes and eosinophils, the latter prominent interstitially A CLASSIFICATION OF BULLAE I. INTRA-EPIDERMAL A. BALLOONING 1. Infection by herpesvirus Same findings as in a vesicle of herpesvirus infection 2. Erythema multiforme Same findings as in a vesicle of erythema multiforme 3. Fixed drug eruption Same findings as in a vesicle of fixed drug eruption B. SPONGIOTIC 1. Allergic contact dermatitis and dyshidrotic dermatitis Same findings as in a vesicle of allergic contact dermatitis and dyshidrotic dermatitis C. ACANTHOLYTIC 1. Pemphigus foliaceus Acantholytic vesiculation within the upper part of the spinous layer and/or the granular layer of the epidermis 2. Pemphigus vulgaris Suprabasal acantholytic vesiculation accompanied by a sparse infiltrate of neutrophils and eosinophils 3. Hailey-Hailey disease Acantholytic vesiculation involving at least the lower half of a thickened epidermis 4. Infection by herpesvirus Same findings as in a vesicle of infection by herpesvirus II. SUBEPIDERMAL A. CELL POOR 1. Porphyria cutanea tarda Same findings as in a vesicle of porphyria cutanea tarda 2. Epidermolysis bullosa simplex Same findings as in a vesicle of epidermolysis bullosa simplex B. COMPOSITION OF INFILTRATE OF INFLAMMATORY CELLS 1. Neutrophils predominate a. Dermatitis herpetiformis Same findings as in a vesicle of dermatitis herpetiformis b. Linear IgA bullous dermatosis Same findings as in a vesicle of linear IgA bullous dermatosis c. Bullous systemic lupus erythematosus Same findings as in a vesicle of bullous systemic lupus erythematosus 2. Eosinophils predominate a. Bullous pemphigoid Same findings as in a vesicle of bullous pemphigoid b. Herpes gestationis Same findings as in a vesicle of herpes gestationis 3. Lymphocytes predominate a. Lichen planus Same findings as in a vesicle of lichen planus 4. Mast cells predominate a. Urticaria pigmentosa Same findings as in a vesicle of urticaria pigmentosa III. INTRA- AND SUBEPIDERMAL CONCURRENTLY A. BALLOONING 1. Erythema multiforme Same findings as in a vesicle of erythema multiforme 2. Fixed drug eruption Same findings as in a vesicle of fixed drug eruption 3. Infection by herpesvirus Same findings as in a vesicle of herpesvirus infection B. SPONGIOSIS 1. Response to an insect bite Same findings as in a vesicle induced by the bite of an insect In sum, vesicles and bullae are distinctive types of elevations, resulting as they do from accumulation of serum within or beneath the epidermis. Clinical features of vesicles and bullae can be explained on the basis of histopathologic findings. In the next issue of the journal, another type of elevation, namely, a pustule, will be elucidated in terms of its histopathologic findings.