At least five groups of viruses are well known to affect the skin or the adjoining mucous surfaces: (1) the herpesvirus group, including herpes simplex types 1 and 2 and the varicella-zoster virus, which are DNA-containing organisms that multiply within the nucleus of the host cell; (2) the poxvirus group, including smallpox, milkers’ nodules, orf, and molluscum contagiosum, which are DNA-containing agents that multiply within the cytoplasm; (3) the papovavirus group, including the various types of verrucae, which contain DNA and replicate in the nucleus; (4) the picornavirus group, including coxsackievirus group A, causing hand-foot-and-mouth disease, which contain RNA rather than DNA in their nucleoids; and (5) retroviruses, including human immuno-deficiency virus (HIV), the cause of acquired immunodeficiency syndrome (AIDS). Primary HIV infection may be associated with both an exanthem and an enanthem, which are histologically nondescript lymphocytic infiltrates. The array of skin lesions associated with HIV is generally a consequence of eventual immunosuppression. Seborrheic dermatitis, psoriasis, xerosis, and pruritic papular eruptions may be seen in the early stages. As the infection advances and the CD4/CD8 ratio decreases, oral hairy leukoplakia, chronic herpes simplex, recurrent herpes zoster, Kaposi’s sarcoma, and other opportunistic infections, are also common (2). These associations have been recently reviewed (3). There is no unique histology of HIV infection in the skin. Primary exanthems of HIV show nonspecific lymphocytoid infiltrates with mild epidermal changes, primarily spongiosis (4). Seborrheic dermatitis in patients with AIDS may show nonspecific changes, including spotty keratinocytic necrosis, leukoexocytosis, and plasma cells in a superficial perivascular infiltrate (5). A “papular eruption” may exhibit nonspecific perivascular eosinophils with mild folliculitis, although epithelioid cell granulomas have also been reported (6). An “interface dermatitis” shows, as the name implies, vacuolar alteration of the basal cell layer, scattered necrotic keratinocytes, and a superficial perivascular lymphohistiocytic infiltrate. The vacuolar alteration and number of necrotic keratinocytes tend to be more pronounced than in drug eruptions. Biopsies of AIDS-related eruptions are often nonspecific.

The prototypic viral rash is the morbilliform rash of measles. Measles virus is a single stranded RNA virus that belongs to the family Paramyxoviridae. Measles is an epidemic disease with a worldwide distribution. Measles virus is transmitted via respiratory secretions, predominantly as aerosols but also by direct contact. The symptoms usually last for 10 days and resolve without consequence. However, there is an increased risk of more severe diseases, such as severe pneumonitis or encephalitis, in immunocompromised individuals.

A biopsy of the rash shows non-specific perivascular lymphocytic inflammation with epidermal spongiosis and mild vesiculation with scattered degenerated keratinocytes. Biopsies from AIDS patients with measles show necrosis of clusters of keratinocytes in the upper spinous layer and granular layer of the epidermis. Unlike in erythema multiforme the necrosis occurs in the basal layer keratinocytes. Multinucleated keratinocytes may or may not be prominent in the measles biopsy. Cytoplasmic swelling of the keratinocytes in the granular layer may be present even when multinucleated cells are sparse.

Virtually any drug may be associated with a morbilliform eruption; the nonspecific clinical and histologic changes make definitive implication of a specific agent difficult (8,9). The most common class of medications causing morbilliform eruptions is antibacterial antibiotics. The morbilliform rash consists of fine blanching papules, which appear suddenly, are symmetric, and often are brightly erythematous in Caucasian patients.

The typical morbilliform drug eruption displays a variable, often sparse, mainly perivascular infiltrate of lymphocytes and eosinophils. Eosinophils may be absent. In a recent study, 82% of 108 cases of drug eruptions (which had been identified in a single institution by pathologic diagnosis supported by chart review) exhibited an inflammatory infiltrate confined to the superficial dermis. Eighty percent exhibited a perivascular and interstitial pattern of dermal infiltrate. The infiltrate was composed of lymphocytes and eosinophils in approximately 29% of cases, lymphocytes and neutrophils in approximately 10% of cases, and lymphocytes, eosinophils, and neutrophils in approximately 21% of cases. Therefore, eosinophils were present in only 50% of cases. Approximately half (53%) of the cases exhibited epidermal–dermal interface (e.g., vacuolar) changes (10). There is a variable degree of urticarial edema (allergic urticarial eruption, see the following text). Distinction of morbilliform drug eruption from viral exanthem in the absence of eosinophils is generally not possible. More than occasional dyskeratotic epidermal cells should prompt consideration
of erythema multiforme and related conditions, for example, toxic epidermal necrolysis, Stevens–Johnson syndrome, or fixed drug eruption.

Urticaria is characterized by the presence of transient, recurrent wheals, which are raised, and erythematous areas of edema usually accompanied by itching. When large wheals occur, in which the edema extends to the subcutaneous tissue, the process is referred to as angioedema (11). Acute episodes of urticaria generally last only several hours. When episodes of urticaria last up to 24 hours and recur over a period of at least 6 weeks, the condition is considered chronic urticaria. Urticaria and angioedema may occur simultaneously, in which case the affliction tends to have a chronic course. In approximately 15% to 25% of patients with urticaria, an eliciting stimulus or underlying predisposing condition can be identified, including soluble antigens in foods,
drugs, insect venom, and contact allergens; physical stimuli such as pressure, vibration, solar radiation, cold temperature; occult infections and malignancies; and some hereditary syndromes. The reaction pattern of urticaria can also be seen in other conditions, notably bullous pemphigoid (7).

In acute urticaria one observes interstitial dermal edema, dilated venules with endothelial swelling, and a paucity of inflammatory cells. In chronic urticaria interstitial dermal edema and a perivascular and interstitial mixed-cell infiltrate with variable numbers of lymphocytes, eosinophils, and neutrophils are present. In angioedema the edema and infiltrate extend into the subcutaneous tissue. In hereditary angioedema there is subcutaneous and submucosal edema without infiltrating inflammatory cells.

Erysipelas is an acute superficial cellulitis of the skin caused by group A streptococci (12). It is characterized by the presence of a well-demarcated, slightly indurated, dusky red area with an advancing, palpable border. In some patients, erysipelas has a tendency
to recur periodically in the same areas. In the early antibiotic era, the incidence of erysipelas appeared to be on the decline and most cases occurred on the face. More recently, however, there appears to have been an increase in the incidence, and facial sites are now less common whereas erysipelas of the legs is predominant. Potential complications in patients with poor resistance or after inadequate therapy may include abscess formation, spreading necrosis of the soft tissue, infrequently necrotizing fasciitis, and septicemia. Erysipelas is usually produced by non-nephritogenic and non-rheumatogenic strains of streptococci.

The dermis shows marked edema and dilatation of the lymphatics and capillaries. There is a diffuse infiltrate, composed chiefly of neutrophils, that extends throughout the dermis and occasionally into the subcutaneous fat. It shows a loose arrangement around dilated blood and lymph vessels. This pattern may be descriptively termed “cellulitis” and is not diagnostic of erysipelas specifically. In erysipelas, streptococci may be found in the tissue and within lymphatics, in sections stained with the Giemsa or Gram stain.

Secondary syphilis (13), (14) is typically characterized by a generalized eruption, comprising brown–red macules and papules, papulosquamous lesions resembling guttate psoriasis, and, rarely, pustules.
Lesions may be follicular-based, annular, or serpiginous, particularly in recurrent attacks. Other skin signs include alopecia and condylomata lata, the latter comprising broad, raised, gray, confluent papular lesions arising in anogenital areas, pitted hyperkeratotic palmoplantar papules termed “syphilis cornee,” and, in rare severe cases, ulcerating lesions that define “lues maligna.” Some patients develop mucous patches composed of multiple shallow, painless ulcers.

The two fundamental pathologic changes in syphilis are: (1) swelling and proliferation of endothelial cells, and (2) a predominantly perivascular infiltrate composed of lymphoid cells and often plasma cells. In late secondary and tertiary syphilis, there are also granulomatous infiltrates of epithelioid histiocytes and giant cells. Biopsies generally reveal varying degrees of lichenoid inflammation and psoriasiform hyperplasia of the epidermis with variable spongiosis and basilar vacuolar alteration. Exocytosis of lymphocytes, spongiform pustulation, and parakeratosis also may be observed, with or without intracorneal neutrophilic abscesses. Scattered necrotic keratinocytes may be observed. The dermal changes include variable papillary dermal edema and a perivascular and/or periadnexal infiltrate that usually includes plasma cells and may be lymphocyte predominant, lymphohistiocytic, histiocytic predominant, or frankly granulomatous and that is of greatest intensity in the papillary dermis and extends as loose perivascular aggregates into the reticular dermis. Vascular changes such as endothelial swelling and mural edema accompany the angiocentric infiltrates in about half of the cases. A silver stain shows the presence of spirochetes in about a third of the cases, mainly within the epidermis and less commonly around the blood vessels of the superficial plexus. Immunohistochemistry, especially when combined with specialized microscopy, results in superior detection rates (15). Lesions of condylomata lata show all of the aforementioned changes observed in macular, papular, and papulosquamous lesions, but more florid epithelial hyperplasia and intraepithelial microabscess formation are observed. Silver or IHC stains show numerous treponemes. In addition to small, sarcoidal granulomata in papular lesions of early secondary syphilis, late secondary syphilis may show extensive lymphoplasmacellular and histiocytic infiltrates resembling nodular tertiary syphilis.

Pityriasis rosea is a self-limited dermatitis lasting from 4 to 7 weeks. It frequently starts with a larger herald patch followed by a disseminated eruption. The lesions, found chiefly on the trunk, neck, and proximal extremities, consist of round to oval salmon-colored patches following the lines of cleavage and showing peripherally attached, thin, cigarette-paper–like scales. Several typical and atypical clinical variants have been described including papular, vesicular, urticarial, purpuric, and recurrent forms. The cause of pityriasis rosea is still unknown, although a viral etiology such as human herpesvirus 7 (HHV-7) is suspected (18). Cell-mediated immunity may be involved in the pathogenesis due to the presence of activated helper-inducer T lymphocytes in the epidermal and dermal infiltrate in association with an increased number of Langerhans’ cells, and the expression of HLA-DR⁺ antigen on the surface of keratinocytes located around the area of lymphocytic exocytosis (19).

The patches of the disseminated eruption show a superficial perivascular infiltrate in the dermis that consists predominantly of lymphocytes, with occasional eosinophils and histiocytes. Lymphocytes extend into the epidermis (exocytosis), where there is
spongiosis, with intracellular edema, mild to moderate acanthosis, areas of decreased or absent granular layer, and focal parakeratosis with or without plasma cells. Intraepidermal spongiotic vesicles and a few necrotic keratinocytes are found in some cases. A common feature is the presence of extravasated erythrocytes in the papillary dermis, which sometimes extends into the overlying epidermis. Occasionally, multinucleated keratinocytes in the affected epidermis can be seen. Late lesions from the disseminated eruption are more likely to have a psoriasiform or lichen planus-like appearance and a relatively increased number of eosinophils in the inflammatory infiltrate.

Pityriasis lichenoides is an uncommon cutaneous eruption usually classified in two forms that differ in severity. The milder form, called pityriasis lichenoides chronica, is characterized by recurrent crops of brown–red papules 4 to 10 mm in size, mainly on the trunk and extremities, which are covered with a scale and generally involute within 3–6 weeks with postinflammatory pigmentary changes. The more severe form, called PLEVA or Mucha-Habermann disease, consists of a fairly extensive eruption, present mainly on the trunk and proximal extremities. It is characterized by erythematous papules that develop into papulonecrotic, occasionally hemorrhagic or vesiculopustular lesions that resolve within a few weeks, and can result in scarring (see also Section VB2). Febrile ulceronecrotic Mucha-Habermann disease (FUMHD) is a rare very severe variant that can be life-threatening (20).

In pityriasis lichenoides chronica, there is a superficial perivascular infiltrate composed of lymphocytes that extend into the epidermis, where there is vacuolar alteration of the basal layer, mild spongiosis, a few necrotic keratinocytes, and confluent parakeratosis. Melanophages and small numbers of extravasated erythrocytes are commonly seen in the papillary dermis. In PLEVA, the more severe form, the perivascular (predominantly lymphocytic) infiltrate is dense in the papillary dermis and extends into the reticular dermis in a wedge-shaped pattern. The infiltrate obscures the dermal–epidermal
junction with pronounced vacuolar alteration of the basal layer, marked exocytosis of lymphocytes and erythrocytes, and intercellular and intracellular edema leading to variable degree of epidermal necrosis. Ultimately, erosion or even ulceration may occur. The overlying cornified layer shows parakeratosis and a scaly crust with neutrophils in the more severe cases. Variable degrees of papillary dermal edema, endothelial swelling, and extravasated erythrocytes are seen in the majority of cases. Most of the cells in the inflammatory infiltrate are activated T lymphocytes. There is a predominance of CD8⁺ (cytotoxic-suppressor) over CD4⁺ (helper-inducer) T lymphocytes in the infiltrate, and there is expression of HLA-DR on the surrounding keratinocytes, suggesting a direct cytotoxic immune reaction in the pathogenesis of epidermal necrosis. Recent studies have suggested that PLEVA is a clonal T-cell disorder (21), although reports of patients with pityriasis lichenoides who have developed cutaneous lymphoma are rare. It is suggested that monoclonal expansion of T cells results most likely from a host immune response to an as yet unidentified antigen, perhaps a viral one (19).

Although several variants of pigmented purpuric dermatosis (PPD) have been described, they are all closely related and often cannot be reliably distinguished on clinical or histologic grounds (22). Clinically, the primary lesion consists of discrete puncta often limited to the lower extremities. Gradually, telangiectatic puncta appear as a result of capillary dilatation, and pigmentation as a result of hemosiderin deposits. In some cases, the findings may mimic those of stasis. Not infrequently, clinical signs of inflammation are present, such as erythema, papules, scaling, and lichenification. There are no systemic symptoms related to this disease process. The categorization of PPD as a form of cutaneous lymphoid dyscrasia has been suggested (23).

The basic process is a lymphocytic perivascular infiltrate limited to the papillary dermis. In some instances, the infiltrate may assume a band-like or lichenoid pattern, and may involve the reticular dermis in a perivascular distribution. Evidence of vascular damage may be present. The extent of vascular injury is usually mild and insufficient to justify the term “vasculitis”,
commonly consisting only of endothelial cell swelling and dermal hemorrhage. Extravasated red blood cells are usually found in the vicinity of the capillaries. In old lesions, the capillaries often show dilatation of their lumen and proliferation of their endothelium. Extravasated red blood cells may no longer be present, but one frequently finds hemosiderin, in varying amounts. The inflammatory infiltrate is less pronounced than in the early stage.

Postinflammatory hyperpigmentation may follow any dermatitis that affects the dermal–epidermal junction and results in release of melanin pigment from basal keratinocytes into the dermis. Lichenoid dermatoses such as lichen planus, vacuolar dermatoses such as discoid lupus, or apoptotic/cytotoxic dermatoses such as erythema multiforme or fixed drug
eruptions may all result in this reaction pattern. Lesions are sometimes biopsied to rule out melanoma. If features diagnostic of a specific underlying dermatosis are lacking in the biopsy, the descriptive diagnosis of postinflammatory hyperpigmentation may be all that can be made.

Sections show the phenomena of pigmentary incontinence. Melanin pigment deposited in the dermis is taken up by melanophages. These are large cells with abundant cytoplasm stuffed with pigment and with plump nuclei having open chromatin and sometimes a small nucleolus.

Urticaria pigmentosa (25) can be divided into four forms: (1) urticaria pigmentosa arising in infancy or early childhood without significant systemic lesions, (2) urticaria pigmentosa arising in adolescence or adult life without significant systemic lesions, (3) systemic mast cell disease, and (4) mast cell leukemia. Five types of cutaneous lesions are seen. The maculopapular type, the most common, consists usually of dozens or even hundreds of small brown lesions that urticate on stroking; a second type exhibits multiple brown nodules or plaques,
and, on stroking, shows urtication and occasionally blister formation. A third type, seen almost exclusively in infants, is characterized by a usually solitary, large cutaneous nodule, which on stroking often shows not only urtication but also large bullae. The fourth type, the diffuse erythrodermic type, always starts in early infancy and shows generalized brownish red, soft infiltration of the skin, with urtication on stroking. The fifth type of lesion, telangiectasia macularis eruptiva perstans (TMEP), which usually occurs in adults, consists of an extensive eruption of brownish red macules showing fine telangiectasias, with little or no urtication on stroking. Although mastocytosis is most typically a benign, self-limited disorder of childhood, up to 30% of adolescent and adult-onset disease represents cutaneous involvement by underlying systemic mastocytosis. CD25 immunoreactivity in a skin infiltrate may be a useful, though not specific, marker for systemic involvement (26).

In all five types of lesions, the histologic picture shows an infiltrate composed chiefly of mast cells, which are characterized by the presence of metachromatic granules in their cytoplasm. These granules can be visualized with a Giemsa or toluidine blue stain, or with the naphthol AS-D chloroacetate esterase reaction (Leder stain). The lesional cells are also positive with immunostains for KIT and mast cell tryptase (26). In the maculopapular type and in telangiectasia macularis eruptiva perstans, the mast cells are limited to the upper third of the dermis and are generally located around capillaries. In some mast cells, the nuclei may be round or oval, but in most, they are spindle shaped. The diagnosis may be missed unless special staining is employed. In cases with multiple nodules or plaques or with a solitary large nodule, the mast cells lie closely packed in tumor-like aggregates and the infiltrate may extend into the subcutaneous fat. In the diffuse, erythrodermic type, there is a dense, band-like infiltrate of mast cells in the upper dermis. Eosinophils may be present in small numbers in all types of urticaria pigmentosa with the exception of TMEP, in which eosinophils are generally absent because of the small numbers of mast cells within the lesions.

The eruption is characterized by pruritic, coin-shaped (nummular), erythematous, scaly, crusted plaques. The lesions tend to develop on the extensor surfaces of the extremities. Hypersensitivity to haptens such as metals may be involved in the pathogenesis of nummular dermatitis in some patients (29).

Nummular dermatitis is the prototype of acute and subacute spongiotic dermatitis. There is mild to moderate spongiosis, usually without vesiculation, and a superficial perivascular infiltrate composed of lymphocytes, histiocytes, and occasional eosinophils. The epidermis is moderately acanthotic and parakeratotic. The stratum corneum contains aggregates of coagulated plasma and scattered neutrophils, forming a crust. Mild papillary dermal edema and vascular dilatation may be present.

Eczematous dermatitis.

Meyerson’s nevus is a melanocytic nevus that is associated with an erythematous, eczematous halo that may symmetrically or eccentrically encircle the nevus (30). The lesion may be pruritic and scaly. Spontaneous resolution of the eczema over the course of weeks, without disappearance of the nevus, usually occurs. Meyerson’s nevi usually occur on the trunk and are more common in males. The simultaneous appearance of a Sutton’s (halo) nevus and Meyerson’s nevus has been reported after sunburn, as has the subsequent development of a Sutton’s nevus and vitiligo 6 months after removal of a Meyerson’s nevus, but this is not typical. Interferon-alpha therapy has been shown to induce Meyerson’s nevus (31).

The melanocytic nevus may be banal, congenital (32), or dysplastic (33), with superimposed
changes of an eczematous dermatitis characterized by epidermal acanthosis and spongiosis which encompass the nevus and the adjacent epidermis (the eczematous halo). Spongiotic intraepidermal vesicles and eosinophilic spongiosis may be present. The stratum corneum may show focal parakeratosis with collections of serum. The superficial dermal infiltrate is composed of lymphocytes, histiocytes, and eosinophils. The lymphocytes have been shown to be predominantly CD4+ (helper) T cells, in contrast to the CD8+ (suppressor) T cells that are found in halo nevi.

The prototype of acute spongiotic dermatitis is allergic contact dermatitis, for example as a reaction to poison ivy exposure. Usually between 24 and 72 hours after exposure to the antigen, the patient develops pruritic, edematous, erythematous papules and plaques and, in some cases, vesicles. Linear papules and vesicles are common in allergic contact dermatitis to poison ivy, reflecting the points of contact between the plant and the skin. Markers of genetic susceptibility to contact allergy are beginning to be identified (34).

Early lesions are an acute spongiotic dermatitis. If vesicles develop, they may contain clusters of Langerhans cells. Eosinophils may be present in the dermal infiltrate as well as within areas of spongiosis. In patients with continued exposure to the antigen, the biopsy may show a subacute or later a chronic spongiotic dermatitis, often lichen simplex chronicus due to rubbing. In a recent study, eosinophilic spongiosis and multinucleate dermal dendritic fibrohistiocytic cells, in the presence of acanthosis, lymphocytic infiltrate, dermal eosinophils, and hyperkeratosis, were considered to be particularly suggestive of allergic contact dermatitis compared to other spongiotic dermatoses (27).

Clinically, patients develop erythema and greasy scale on the scalp, paranasal areas, eyebrows, nasolabial folds, and central chest. Rarely, patients with seborrheic dermatitis develop generalized lesions. Patients with HIV infection often have severe, recalcitrant disease (2). In infants, the scalp (“cradle cap”), face, and diaper areas are often involved.

The histopathologic features are a combination of those observed in psoriasis and spongiotic dermatitis. Mild cases may exhibit only a slight subacute spongiotic dermatitis. The stratum corneum contains focal areas of parakeratosis, with a predilection for the follicular ostia, a finding known as “shoulder parakeratosis.” Occasional pyknotic neutrophils are present within parakeratotic foci. There is moderate acanthosis with regular elongation of the rete ridges, mild spongiosis, and focal exocytosis of lymphocytes. The dermis contains a sparse mononuclear cell infiltrate. In HIV-infected patients, the epidermis may contain dyskeratotic keratinocytes, and the dermal infiltrate may contain plasma cells.

Clinically, the term poikiloderma atrophicans vasculare is applied to lesions that, in the early stage, show erythema with slight, superficial scaling, a mottled pigmentation, and telangiectases. In the late stage the skin appears atrophic and the mottled pigmentation and the telangiectases are more pronounced. The condition may be seen in three different settings: (1) in association with certain genodermatoses; (2) as an early stage of mycosis fungoides (38); and (3) in association with dermatomyositis and, less commonly, lupus erythematosus.