Case 1 History
The patient is a 30-year-old male with a recent history of dry cough who presents with diffuse acute-onset, erythematous, oval-targetoid papules and plaques, particularly involving the upper and lower extremities.
Microscopic Findings
Sections show basal vacuolar change with scattered necrotic keratinocytes and sparse lymphocytic inflammation along the dermal–epidermal junction (DEJ) and occasional necrosis of basilar keratinocytes ( Fig. 1.1 ). The stratum corneum retains a normal basket-weave configuration. Necrosis is limited to single cells.
Diagnosis
Erythema Multiforme
Clinical Presentation
There are two categories of clinical presentation, namely erythema multiforme (EM), minor and major. EM minor presents as an acute self-limited eruption of thin papules and plaques that may assume a targetoid configuration. EM major, which encompasses the spectrum of toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome, is more dramatic, with diffuse or extensive skin and mucosal membrane involvement, blister formation, and sloughing. Whereas EM minor is often triggered by infection, such as herpes simplex labialis or Mycoplasma infection, EM major is often triggered by a medication, such as penicillin, phenytoin, or sulfa.
Histopathology
The histopathology of EM (both minor and major) shows a vacuolar pattern. In EM minor, vacuolar change is coupled with necrosis of scattered single keratinocytes, edema, and a variable lymphocytic infiltrate. In EM major, epidermal necrosis becomes confluent or zonal. Because the eruption is acute with a relatively abrupt onset, the stratum corneum prototypically maintains normal orthokeratotic morphology.
Differential Diagnosis
The differential diagnosis for EM includes acute graft-versus-host disease (GVHD), which can be distinguished by clinical history and in some cases by extension of the interface dermatitis along follicles or the presence of adnexal vacuolar change, and a fixed drug eruption, which exhibits a mixed infiltrate including granulocytes and melanophages ( Table 1.1 ).
| Erythema Multiforme | Acute Graft-Versus-Host Disease | Fixed Drug Eruption | |
|---|---|---|---|
| Pathophysiology | Viral antigen or drug metabolite binds to native protein, creating a complex that activates a cytotoxic immune response | Donor-derived CD8+ T lymphocytes react to host cell antigens | Drug binds to protein in the basal epidermis and creates a complex that activates a cytotoxic immune reaction |
| Time to onset | Variable | Usually >3 weeks after allogeneic stem cell transplantation | Typically hours after exposure to drug |
| Key histopathologic pattern | Acute vacuolar change with normal stratum corneum | Acute vacuolar change with adnexal involvement | Acute vacuolar change with melanophages |
| Infiltrate | Lymphocytes | Lymphocytes | Lymphocytes with admixed histiocytes, eosinophils, and neutrophils |
Acute Graft-Versus-Host Disease
Prominent follicular involvement by vacuolar change with single necrotic keratinocytes paired with adjacent lymphocytes (formerly known as satellite cell necrosis) suggests acute GVHD.
Clinical Presentation
Acute GVHD commonly presents within the first few weeks after allogeneic stem cell transplantation but can occur at any point in time after transplant and may be triggered by reductions in immunosuppression. The rash of GVHD is maculopapular and usually begins on acral surfaces and subsequently spreads. Blistering and involvement of mucosal surfaces may rarely occur. Systemic involvement is possible, with fever and injury to the digestive tract, manifesting as diarrhea. Rare cases have been described after solid organ transplantation. It is important to emphasize that the extent and severity of clinical disease do not always correlate with histopathologic features. The diagnosis of GVHD typically necessitates clinicopathologic correlation to exclude a drug reaction from the differential diagnosis.
Histopathology
GVHD shows a sparse infiltrate of lymphocytes aligned along the DEJ ( Fig. 1.2 ). There are accompanying vacuolar degeneration of basilar keratinocytes and scattered necrotic keratinocytes (see Fig. 1.2 ). Melanophages may be present. The degree of microscopic involvement is scored using the Lerner scale. Grade I consists of vacuolar change (exclusively) and can typically only be identified in retrospect. Grade 2 involvement consists of vacuolar change jointly with scattered necrotic keratinocytes (>2). Grade 3 involvement additionally shows perijunctional clefts caused by confluent vacuolar change, and grade 4 involvement consists of TEN-like epidermal necrosis. A distinctive feature of GVHD is extension of vacuolar change and basal keratinocyte necrosis along follicular epithelium.
Fixed Drug Eruption
In contrast to erythema multiforme, the inflammatory infiltrate in fixed drug eruption is typically mixed and includes lymphocytes, eosinophils, neutrophils, and melanophages.
Clinical Presentation
Round to oval circumscribed erythematous single or multiple patches or thin plaques present hours after exposure to a drug, such as a quinolone antibiotic or a nonsteroidal antiinflammatory drug. The term fixed refers to the involvement consistently occurring at the same location with each drug exposure. The rash diminishes after withdrawal from the drug and often leaves long-lasting postinflammatory pigmentary alteration.
Histopathology
The prototypical inflammatory pattern of a fixed drug reaction includes a superficial and deep infiltrate, acute vacuolar change with single necrotic keratinocytes and a mixed infiltrate that includes eosinophils, neutrophils, or both. Melanophages in the dermis are typical and represent an expected postinflammatory consequence of repeated bouts of inflammation at the same location ( Fig. 1.3 ).
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Erythema multiforme
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Vacuolar change with necrotic keratinocytes
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Basket-weave orthokeratosis
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Acute GVHD
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Vacuolar change with necrotic keratinocytes
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Adnexal vacuolar change
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Fixed drug eruption
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Vacuolar change with necrotic keratinocytes
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Mixed infiltrate with eosinophils, neutrophils, and melanophages
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Case 2 History
The patient is a 32-year-old female who presents with an erythematous, scaly rash over her bilateral cheeks, forehead, and dorsum of the nose. She reports that she has previously experienced joint pain in her wrists and fingers.
Microscopic Findings
Sections show lymphocytes scattered along the epidermis with associated vacuolar change of the basal layer of the epidermis. There is a perivascular and periadnexal infiltrate of lymphocytes and plasma cells involving the superficial and deep dermis ( Fig. 1.4 ). There is finely granular mucin deposition between dermal collagen. A colloidal iron stain highlights mucin.
Diagnosis
Systemic Lupus Erythematosus
Clinical Presentation
Systemic lupus erythematosus (SLE) is a chronic disease that can involve the skin, with a butterfly facial rash and scaly plaques between joints on the dorsal fingers and sun-exposed areas, as well as other organs, including the kidneys and joints. Photosensitivity is typical.
Histopathology
SLE shows vacuolar change along the basal layer of the epidermis, a variable perivascular dermal lymphocytic infiltrate, and mucin deposition.
Differential Diagnosis
The histopathologic findings of lupus erythematosus (LE) and dermatomyositis (DM) are nearly identical, but compared with LE, the findings in DM are often subtle and hypoinflammatory. Like LE, DM is characterized by vacuolar change and dermal mucinosis. Direct immunofluorescence (DIF) testing can sometimes inform the diagnosis, because bandlike reactivity for IgG and C3 can be found at the DEJ in involved and noninvolved skin in patients with SLE. This lupus band is typically not present in DM.
Dermatomyositis
Clinical Presentation
DM shows a rash in the periocular area that is heliotrope or violaceous in color. In addition, there may be involvement over the metacarpophalangeal joint (Gottron papules) and scaly patches on the shoulders with skin atrophy (representing a so-called shawl distribution). Symmetric proximal muscle weakness is also a clinical characteristic. It has been alleged that patients with DM are at increased risk for the development of internal malignancy and thus should undergo appropriate surveillance. Controlled studies have not clearly substantiated this risk, but vigilant surveillance has become a standard component of clinical care.
Histopathology
The epidermis is often (but not always) atrophic in DM. There is vacuolar change with a sparse lymphocytic infiltrate ( Fig. 1.5 ). In addition, variable dermal mucinosis may occur. CD123+ plasmacytoid dendritic cells are also increased in DM, but the density is less in comparison with LE. Often in DM, the CD123+ cells are in the epidermis.
