Case 1 History
A 43-year-old female presents with a 2-day history of 1- to 3-mm palpable purpura distributed symmetrically under the sock line on her bilateral lower legs. She also reports intermittent low-grade fever over the past few weeks.
Microscopic Findings
Sections show a mixed perivascular infiltrate with many neutrophils and admixed leukocytoclastic debris ( Fig. 6.1 ). There is deposition of coarsely eosinophilic fibrin in vessel walls, and intradermal extravasated red blood cells (purpura) are also noted.
Diagnosis
Cutaneous Leukocytoclastic Vasculitis
Clinical Presentation
Leukocytoclastic vasculitis (LCV) is a descriptive histopathologic diagnostic term that has been adopted as a clinical diagnosis . The trigger that incited a bout of LCV typically cannot be inferred from histopathologic sections. The prototypical clinical presentation consists of erythematous to violaceous palpable purpuric macules and papules, most often on the lower extremity, as in this case. Involvement above the waist is uncommon in ambulatory patients. Coalescing purpuric papules may create plaques of involvement, and secondary ulceration may occur as a consequence of vascular occlusion. Associated symptoms include itching, burning, and pain. Resolution occurs within a few weeks unless a new bout ensues. Minor joint pain, fever, and malaise may also be present and may predate the cutaneous rash.
Histopathology
LCV is defined by a distinct constellation of microscopic findings. There is a distinctly vasocentric infiltrate that includes many neutrophils, but it may also include lymphocytes and eosinophils. Leukocytoclasis is universally present but can occasionally be challenging to identify in biopsies from areas of very early (or very late) involvement. Fibrin deposition produces small eosinophilic rings that encircle affected vessels. At scanning magnification, the perivascular changes may appear smudgy because of the presence of admixed leukocytoclastic debris. Extravasated erythrocytes are also present and correspond to the clinical finding of purpura.
The composition of inflammatory infiltrate varies over time. Biopsies showing very early involvement may simply exhibit perivascular neutrophils and erythrocytes with scant leukocytoclasis. Biopsies of fully developed papules exhibit the spectrum of features discussed in the preceding paragraph. A biopsy of late or waning involvement may be nondiagnostic because fibrin deposition and neutrophils may become inconspicuous while larger numbers of lymphocytes accrue in the perivascular infiltrate.
Differential Diagnosis
LCV can be triggered by a wide variety of stimuli, including medications and connective tissue diseases. Infective (septic) vasculitis can also affect small vessels ( Table 6.1 ).
| Idiopathic | Infectious Vasculitis | Medication-Induced Vasculitis | IgA Vasculitis | |
|---|---|---|---|---|
| Pathophysiology | Triggered by a reaction to immune complexes | Bacterial, fungal, viral | Allopurinol, penicillins, sulfonamides, thiazides, propylthiouracil, TNF-α blockers, immunotherapy | Recent streptococcal infection may be a triggering cause |
| Clinical features | Palpable purpura on lower extremities | Variable | Palpable purpura on lower extremities | Retiform purpura on buttocks and lower extremities |
| Histopathology | LCV | Hypoinflammatory small vessel vasculitis with thrombi | LCV; admixed eosinophils in some cases | LCV with IgA deposition by immunofluorescence |
Infectious Vasculitis
Bacteria, fungi, and viruses can all trigger small vessel vasculitis. Special staining (either histochemical or immunohistochemical) can be used to attempt to confirm the causative infectious agent.
Clinical Presentation
The clinical presentation of infectious vasculitis is highly varied. Clinical involvement maybe maculopapular and purpuric. Associated pustules can sometimes be found. Accompanying systemic symptoms or findings may provide additional insight regarding the precise infectious cause.
Histopathology
The microscopic pattern of infectious vasculitis typically differs from that of LCV. The perivascular neutrophilic infiltrate is often sparse, and fibrin deposition may be minimal. Associated small vessel thrombosis may occur ( Fig. 6.2 ). Particularly problematic in the assessment of bacterial septic vasculitis is the fact that it is challenging, if not impossible, to demonstrates microbes in tissue using Gram staining. This is particularly true of vasculitis associated with enteric microbes, suchas Escherichia coli . Rarely, Gram stains may highlight bacilli or cocci within endothelial cells or small vessel thrombi.
Deep fungal infection with associated cutaneous involvement represents a life-threatening disorder that requires aggressive antimicrobial therapy if there is to be any hope of cure. Fungi do not typically trigger septic or infectious vasculitis in the same fashion as bacteria. Rather, fungal infections with associated involvement of small vessels are referred to as angioinvasive . In conventional histopathologic sections, a vasculitis-like configuration with perivascular inflammation and purpura can be seen. Fungal microbes are often only visible after completing histochemistry using Gomori methenamine silver or periodic acid-Schiff staining. In special stains, pathogenic fungi are typically identified within the dermis, and extension into occluded vessels may also be seen.
Viral vasculitis may be secondary in nature. Contiguous with a primary focus of infection by herpes simplex virus or varicella zoster virus, there may be an intense inflammatory reaction that involves small blood vessels in an LCV-like configuration. Secondary herpesviral vasculitis can typically be readily distinguished from conventional LCV by means of the clinical context. Cytomegalovirus infection can also be rarely identified as a primary infection involving endothelial cells in immunocompromised patients. There may be associated perivascular inflammation that creates a vasculitis-like configuration in tissue samples.
Medication-Induced Vasculitis
Clinical Presentation
The development of vasculitis as a medication reaction is preceded (by definition) by administration of an offending drug. The exact time course varies, but typically the agent has been delivered a few days or a few weeks before the onset of the vasculitic outbreak. Causative drugs include immunotherapeutic agents, tumor necrosis factor-α blocking agents, antibiotics, thiazides, and propylthiouracil. A detailed clinical and drug history, careful evaluation of other possible causes, and improvement after discontinuation of the drug are factors used to determine whether a particular agent represents the cause of vasculitis.
Histopathology
Idiopathic LCV and medication-induced LCV may be histopathologically identical. Biopsies of either condition may include eosinophils ( Fig. 6.3 ). Because the microscopic findings are not distinctive, careful clinical correlation is required.
