Residency · Residency · Dermatology

Vasculitis on Biopsy: Small, Medium, and Large Vessel

Overview

Cutaneous vasculitis encompasses a spectrum of diseases characterized by inflammation and damage to blood vessel walls. Classification is based on the size of the predominantly affected vessel, following Chapel Hill Consensus Conference nomenclature. Skin biopsy is essential for diagnosis and classification and must include adequate depth to assess vessels of different calibers. Clinicopathologic correlation is critical, as the same histologic pattern can appear in multiple diseases.

Small Vessel Vasculitis

Leukocytoclastic Vasculitis (LCV)

Histopathology

LCV shows fibrinoid necrosis of postcapillary venule walls (eosinophilic fibrin deposition) with a neutrophilic infiltrate in and around vessel walls (transmural infiltration). Leukocytoclasis, the hallmark finding, refers to nuclear dust (karyorrhexis) from fragmented neutrophil nuclei. Endothelial swelling with luminal narrowing or occlusion, red blood cell extravasation (hemorrhage), and intraluminal thrombi may be present. These changes are best seen in fully developed lesions that are 18 to 24 hours old.

Clinical Presentation

LCV presents as palpable purpura: non-blanching, raised, violaceous papules and plaques predominantly on the lower extremities and other dependent areas. Lesions may vesiculate or ulcerate, tend to appear in crops, and individual lesions last 1 to 4 weeks.

Etiology

Approximately 50 percent of cases are idiopathic. Drug-induced causes include antibiotics, NSAIDs, allopurinol, hydralazine, and propylthiouracil. Infection-associated causes include hepatitis B and C, HIV, and streptococcal infection. Autoimmune etiologies include SLE, rheumatoid arthritis, and Sjogren syndrome. Malignancy-associated cases are most commonly linked to lymphoproliferative disorders.

Workup

The evaluation includes a complete history (medications, infections, symptoms of systemic disease), CBC, CMP, ESR/CRP, urinalysis (for renal involvement), hepatitis B and C serologies, ANA, complement levels (C3, C4, CH50), cryoglobulins, ANCA (if granulomatous features or systemic involvement are present), SPEP/UPEP if gammopathy is suspected, and skin biopsy for H&E and DIF (from an early lesion, ideally less than 24 to 48 hours old).

<image>Histopathology of leukocytoclastic vasculitis showing fibrinoid necrosis of small vessel walls, transmural neutrophilic infiltrate, leukocytoclasis (nuclear dust), and red blood cell extravasation</image>

IgA Vasculitis (Henoch-Schonlein Purpura)

IgA vasculitis is the most common systemic vasculitis in children, with a peak at 4 to 6 years, though it also occurs in adults with a worse prognosis. The classic tetrad includes palpable purpura (100 percent), arthralgia or arthritis (75 percent), abdominal pain or GI involvement (65 percent), and renal involvement (40 to 50 percent). It is often preceded by an upper respiratory infection, particularly streptococcal. On H&E, the LCV is indistinguishable from other forms. The pathognomonic finding on DIF is granular IgA deposition in vessel walls, along with C3 deposition. Management is supportive, as it is self-limited in most children over weeks to months. Urinalysis should be monitored for hematuria and proteinuria (IgA nephropathy). Corticosteroids are used for severe abdominal pain or nephritis. Adult IgA vasculitis follows a more aggressive course with a higher rate of renal insufficiency.

Urticarial Vasculitis

Urticarial vasculitis produces urticaria-like lesions that last more than 24 hours, leave bruising, and are painful rather than pruritic, distinguishing them from ordinary urticaria. Hypocomplementemic urticarial vasculitis syndrome (HUVS) is associated with anti-C1q antibodies, SLE, and systemic involvement (pulmonary, renal, ocular). Histologically, LCV is present but often with a less intense neutrophilic infiltrate. DIF shows C3, IgG, or IgM in vessel walls.

Cryoglobulinemic Vasculitis

Type I cryoglobulinemia involves monoclonal immunoglobulin (associated with lymphoproliferative disorders) and causes large vessel occlusion, livedo, and digital ischemia. Types II and III (mixed cryoglobulinemia) involve polyclonal IgG with monoclonal or polyclonal IgM and are strongly associated with hepatitis C. Palpable purpura, arthralgias, neuropathy, and glomerulonephritis are characteristic. Histologically, LCV is present with intraluminal hyaline thrombi (PAS-positive cryoglobulin precipitates) in dermal vessels. DIF shows IgM and C3 in vessel walls.

<image>Direct immunofluorescence patterns in cutaneous vasculitis: granular IgA in vessel walls (IgA vasculitis), intraluminal PAS-positive thrombi (cryoglobulinemic vasculitis), and pauci-immune pattern in ANCA-associated vasculitis</image>

ANCA-Associated Vasculitis

Granulomatosis with Polyangiitis (GPA, formerly Wegener)

GPA is characterized by c-ANCA (anti-PR3) positivity in approximately 90 percent of cases. The classic triad involves upper respiratory disease (sinusitis, nasal cartilage destruction, saddle nose deformity), lower respiratory disease (pulmonary nodules, cavities, hemorrhage), and renal disease (rapidly progressive glomerulonephritis). Cutaneous findings occur in 40 to 50 percent of patients and include palpable purpura, papules, nodules, ulcers, oral ulcers, and pyoderma gangrenosum-like lesions. Histopathology shows small vessel LCV with granulomatous inflammation featuring palisading granulomas with central basophilic ("blue") necrosis. DIF is pauci-immune (no or minimal immunoglobulin or complement deposition). Extravascular granulomas may be seen without vasculitis on skin biopsy.

Eosinophilic Granulomatosis with Polyangiitis (EGPA, formerly Churg-Strauss)

EGPA shows p-ANCA (anti-MPO) positivity in approximately 40 percent of cases. The triad includes asthma, eosinophilia (greater than 1,500 per microliter or greater than 10 percent), and vasculitis. Skin involvement occurs in 50 to 70 percent and includes palpable purpura, nodules, papules, and vesicles. Cardiac involvement is the leading cause of death. Histopathology shows small vessel vasculitis with prominent tissue eosinophilia and eosinophilic granulomas (palisading granulomas with an eosinophilic "red" core, contrasting with the "blue" necrosis of GPA). Extravascular granulomas may predominate on skin biopsy.

Microscopic Polyangiitis (MPA)

MPA shows p-ANCA (anti-MPO) positivity in approximately 60 percent of cases. It is a small vessel vasculitis affecting the kidneys (RPGN) and lungs (hemorrhage). Crucially, there is no granulomatous inflammation, which distinguishes MPA from GPA. The skin shows palpable purpura similar to LCV, and histology reveals pauci-immune small vessel vasculitis without granulomas.

Medium Vessel Vasculitis

Polyarteritis Nodosa (PAN)

PAN is a necrotizing arteritis of medium-sized muscular arteries without glomerulonephritis or small vessel vasculitis. It is ANCA-negative. Approximately 30 percent of classic PAN cases are associated with hepatitis B. Skin involvement includes livedo reticularis, subcutaneous nodules along arteries, ulcers, and digital gangrene. Systemic PAN involves the kidneys (renal artery aneurysms), GI tract (mesenteric ischemia), nerves (mononeuritis multiplex), and heart. Cutaneous PAN is a skin-limited variant with a favorable prognosis, presenting with livedo, nodules, and ulcers on the lower extremities.

Histopathologically, PAN shows fibrinoid necrosis of medium-sized arterial walls in the deep dermis and subcutis. A transmural mixed inflammatory infiltrate (neutrophils, lymphocytes, eosinophils) is present, and different stages of vessel injury may coexist. Intimal proliferation and luminal narrowing develop in chronic lesions. The biopsy must be deep enough to sample arteries in the subcutis; a punch biopsy may be insufficient, and incisional or excisional biopsy is recommended.

Kawasaki Disease

Kawasaki disease is a medium vessel vasculitis of childhood (peak 6 months to 5 years). The diagnosis requires fever for 5 or more days plus 4 of 5 criteria: bilateral conjunctival injection, oral mucositis, polymorphous rash, extremity changes (edema and desquamation), and cervical lymphadenopathy. Coronary artery aneurysms develop in 25 percent of untreated cases, making it the leading cause of acquired heart disease in children in developed countries. Treatment with IVIG plus aspirin within 10 days of fever onset reduces the aneurysm risk to less than 5 percent. Skin biopsy is rarely needed and shows non-specific perivascular inflammation.

<image>Clinical and histopathologic comparison of small vessel vasculitis (palpable purpura with LCV on biopsy) versus medium vessel vasculitis in polyarteritis nodosa (livedo reticularis and subcutaneous nodules with fibrinoid necrosis of muscular artery)</image>

Large Vessel Vasculitis

Giant Cell (Temporal) Arteritis

Giant cell arteritis is a granulomatous arteritis of large and medium arteries, primarily the temporal artery. It occurs in patients over 50 and is associated with polymyalgia rheumatica. Headache, jaw claudication, and visual loss (from ophthalmic artery involvement, a medical emergency) are the cardinal symptoms. Temporal artery biopsy shows granulomatous inflammation with giant cells centered on the internal elastic lamina, fragmentation of elastic fibers, and intimal hyperplasia. Skip lesions may necessitate a long biopsy specimen (2 to 3 cm) or bilateral biopsies. Treatment with immediate high-dose corticosteroids should not be delayed for biopsy results.

Takayasu Arteritis

Takayasu arteritis is a large vessel vasculitis involving the aorta and its branches, primarily in young women under 40. Known as "pulseless disease," it rarely involves the skin directly, though erythema nodosum-like lesions may occur.

Vasculopathy vs. True Vasculitis

Key Distinction

Vasculitis involves an inflammatory cell infiltrate with destruction of vessel walls. Vasculopathy involves vessel damage without significant inflammation, through thrombotic, embolic, or other non-inflammatory mechanisms.

Common Vasculopathies Mimicking Vasculitis

Livedoid vasculopathy is a segmental hyalinizing vasculopathy of dermal vessels producing atrophie blanche, with PAS-positive fibrin in vessel walls and minimal inflammation. Calciphylaxis shows medial calcification of small subcutaneous arteries with thrombosis, often in renal failure. Cholesterol embolization (atheroembolic disease) reveals biconvex clefts in arterioles representing dissolved cholesterol crystals. Antiphospholipid syndrome produces a thrombotic vasculopathy, not true vasculitis. Coumarin necrosis causes thrombosis without vessel wall inflammation.

Direct Immunofluorescence in Vasculitis

DIF patterns help classify the underlying etiology. IgA-predominant deposition indicates IgA vasculitis (Henoch-Schonlein). IgG/IgM/C3 deposition indicates immune complex-mediated LCV, cryoglobulinemic vasculitis, or lupus vasculitis. A pauci-immune pattern (negative or minimal deposition) indicates ANCA-associated vasculitis (GPA, EGPA, MPA). Fibrin alone is non-specific and can be seen in any vasculitis. DIF should be performed on an early lesion (less than 24 to 48 hours old), as immunoreactants degrade quickly.

Clinical Pearls

Always biopsy an early, fully developed lesion (18 to 24 hours old) for optimal histologic and DIF findings; old lesions may show only a lymphocytic perivascular infiltrate without diagnostic features. If palpable purpura is accompanied by abdominal pain, arthralgia, and hematuria in a child, IgA vasculitis is the leading diagnosis, and DIF showing granular IgA in vessel walls confirms it. ANCA-associated vasculitides show pauci-immune DIF -- the absence of immunoglobulin deposition in vessel walls combined with positive ANCA serology points to GPA, MPA, or EGPA. Suspected polyarteritis nodosa requires a deep biopsy (incisional or deep punch into subcutis) because medium-sized arteries lie at the dermal-subcutaneous junction, and a superficial shave biopsy will miss the diagnosis. Always check hepatitis B and C serologies in cutaneous vasculitis -- hepatitis B is associated with PAN, and hepatitis C is strongly associated with cryoglobulinemic vasculitis.

References

• Jennette JC, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11
• Sunderkotter C, et al. Nomenclature of cutaneous vasculitis: dermatologic addendum to the 2012 revised CHCC nomenclature. Arthritis Rheumatol. 2018;70(2):171-184
• Carlson JA, et al. Cutaneous vasculitis update: diagnostic criteria, classification, epidemiology, etiology, pathogenesis, evaluation and prognosis. Am J Dermatopathol. 2005;27(6):504-528
• Chen KR, Carlson JA. Clinical approach to cutaneous vasculitis. Am J Clin Dermatol. 2008;9(2):71-92
• Bolognia JL, et al. Dermatology. 4th Edition. Elsevier, 2018

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