Leukocytoclastic vasculitis

Background

This disorder is also known as hypersensitivity vasculitis, allergic vasculitis, hypersensitivity vasculitis, and allergic angiitis. It is not a specific disease but rather a clinicopathologic entity affecting the small vessels of the skin. Clinically, there are erythematous macules and palpable purpura occurring on the lower legs. Advanced lesions may have hemorrhagic bullae with ulcerations and rarely annular lesions. Leukocytoclatic vasculitis is not a disease. Once the pathologist makes this diagnosis, the burden is upon the treating physician to determine an etiology.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/
Other Diagnostic Testing

Gross Appearance
and Clinical Variants

Histopathological Features
and Variants

Special Stains/
Immunohistochemistry/
Electron Microscopy

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

DISEASE ASSOCIATIONS CHARACTERIZATION

Chemicals Food additives, dyes, nicotine patches

Cancer Lymphomas, myelodysplasias, mycosis fungoides, hairy cell leukemia, rare visceral tumors

Drugs Pencillin, ampicillin, erythromycin, clindamycin, cephalosporin, sulfonamides, griseofulvin, furosemide, thiouracil, allopurinol, aspirin, iodine, GCSF, procainamide, quinidine, phenytoin, mefloquine

Infections E. coli, Streptococcus, influenza, hepatitis B, herpes simplex, CMV, parvovirus, HIV, malaria

Systemic disease Systemic lupus erythematosus, Behcet's disease, celiac disease, inflammatory bowel disease, cystic fibrosis, Sjogren's disease, subcorneal pustular dermatosis, sarcoidosis, pyoderma gangrenosum, Wiskott-Aldrich syndrome, alpha-1 antitrypsin deficiency, Henoch-Schonlein purpura

SPECIFIC ASSOCIATIONS

MULTIPLE MYELOMA

Successful management of cryoglobulinemia-induced leukocytoclastic vasculitis with thalidomide in a patient with multiple myeloma.

Cem Ar M, Soysal T, Hatemi G, Salihoglu A, Yazici H, Ulku B.

Department of Internal Medicine, Division of Haematology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.

Ann Hematol. 2005 May 19; [Epub ahead of print] Abstract quote

Leukocytoclastic vasculitis (LV) is a systemic inflammatory disorder involving mostly the small vessels. It is characterised by segmental angiocentric neutrophilic inflammation, endothelial cell damage and fibrinoid necrosis. LV is related to a variety of clinical disorders including cryoglobulinemia and, very rarely, multiple myeloma (MM), among many others.

The development of LV in patients with MM has been linked to cryoglobulinemia, infections, drugs and paraneoplasia. It has been speculated that myeloma patients with a poorer prognosis and progressive disease are more prone to develop LV. Thalidomide is a rediscovered old drug with anti-angiogenic, immunomodulatory and anti-inflammatory properties. It is highly effective in the treatment of MM and other clinical disorders such as leprosy, various cancers, graft-versus-host disease and autoimmune diseases.

We report here a female patient with Durie-Salmon stage IIA MM who initially presented with cryoglobulinemia and LV. LV in this patient was primarily considered to be the result of progressive cryoglobulinemia, which was closely associated with MM. She was successfully managed with thalidomide and dexamethasone.

WARFARIN

Warfarin-induced Leukocytoclastic vasculitis.

Yaghoubian B, Ngo B, Mak M, Ostrzega E, Tesoro J, Mitani GH.

Ambulatory Care Pharmacy, University of Southern California School of Pharmacy, Los Angeles, CA 90033, USA.

Cutis. 2005 Jun;75(6):329-38. Abstract quote

Skin reactions associated with oral coumarin-derived anticoagulants are an uncommon occurrence. Leukocytoclastic vasculitis (LV) is primarily a cutaneous small vessel vasculitis, though systemic involvement may be encountered.

We report 4 patients with late-onset LV probably due to warfarin. All 4 patients presented with skin eruptions that developed after receiving warfarin for several years. The results of skin lesion biopsies were available in 3 patients, confirming LV Cutaneous lesions resolved in all patients after warfarin was discontinued.

In 2 of the 4 patients, rechallenge with warfarin led to recurrence of the lesions. LV may be a late-onset adverse reaction associated with warfarin therapy.

PATHOGENESIS CHARACTERIZATION

GENERAL Immune complexes form and are deposited within the vessel walls leading to complement activation. There is chemotactic recruitment of neutrophils with additional injury to the vessel wall with fibrin deposition. TNF and IL-1 stimulate the endothelium to activate the intrinsic and extrinsic coagulation pathways, leading to occasional thrombosis.

PLATELETS

Platelet involvement in cutaneous small vessel vasculitis.

Meijer-Jorna LB, Mekkes JR, Van Der Wal AC.

Departments of Pathology and Dermatology, Academic, Medical Centre of the University of Amsterdam, Amsterdam, the Netherlands.
J Cutan Pathol 2002 Mar;29(3):176-80 Abstract quote
BACKGROUND: Secretory products of platelets serve important functions in inflammation and thrombosis. Participation of platelets in the tissue reaction associated with cutaneous small vessel vasculitis has not yet been evaluated, so we systematically investigated the presence of platelet aggregates in inflamed microvessels.

METHODS: Thirty-six biopsies containing vasculitis and 18 biopsies with perivascular or interface type dermatitis were reviewed and adjacent sections were immunohistochemically stained with anti-CD61 antibody recognizing GPIIbIIIa receptors on platelets and with anti-von Willebrand factor (anti-vWF) antibody.

RESULTS: Platelet aggregates were observed in 27 (75%) of the vasculitis biopsies and three (16.7%) of the perivascular dermatitis biopsies, of which two (11%) had traumatic vessel damage. In all vasculitis cases, platelet clumps were associated with diffuse immunostaining of the perivascular stroma with the initiator of platelet aggregation anti-vWF. In the non-vasculitis type of dermatitis anti-vWF staining remained strictly limited to the cytoplasm of endothelial cells in 10 cases, and in eight cases there was also slight diffuse perivascular staining, albeit less extensively than in vasculitis cases.

CONCLUSION: Formation of platelet aggregates appears to play a thus far unrecognized role in cutaneous small vasculitis. Secretory products of platelets will likely contribute to the inflammatory response and tissue damage in vasculitis. Moreover, platelet immunohistochemistry may be helpful in the diagnosis of microvascular damage in paraffin sections.

CLINICAL VARIANTS CHARACTERIZATION

Local disease Pustular vasculitis of the dorsal hands

HISTOPATHOLOGY CHARACTERIZATION

GENERAL
Most of the diagnostic changes occur about 18-24 hours after the initial appearance. There is infiltration of the small vessel arterioles and venules by neutrophils associated with fibrinoid necrosis.

Surrounding these vessels is nuclear dust, edema, and extravasated red blood cells. If there is an allergic hypersensitivity component, eosinophils may be present. If the vasculitis is intense, a hemorrhagic bullous eruption may occur and rarely cutaneous infarction

VARIANTS

Immunoglobulin A-associated lymphocytic vasculopathy: a clinicopathologic study of eight patients.

Crowson AN, Magro CM, Usmani A, McNutt NS.

Central Medical Laboratories, Winnipeg, Manitoba, Canada, Department of Dermatology, University of Oklahoma, OH, USA, Regional Medical Laboratories, St John's Medical Center, Tulsa, OK, USA, Department of Pathology, Division of Dermatopathology, Ohio State University, Columbus, OH, USA, and Department of Pathology, Division of Dermatopathology, Weill Medical College of Cornell University, New York, NY, USA.

J Cutan Pathol 2002 Nov;29(10):596-601 Abstract quote
INTRODUCTION: Cutaneous IgA-associated vasculitis can be a clue to Henoch-Schonlein purpura (HSP), which typically comprises renal and gastrointestinal tract disease and arthritis, whereby prominent and predominant IgA deposits within the cutaneous vasculature provoke a pustular leukocytoclastic vasculitis.

DESIGN: We describe eight patients with a novel expression of a cutaneous IgA vascular injury syndrome, namely a lymphoid vasculopathy which clinically and light microscopically resembled a pigmentary purpura (PP) in six, and correlate direct immunofluorescence (DIF) and clinical features to light microscopy.

RESULTS: Among associated diseases were prior viral infection, an HSP symptom complex, an undifferentiated connective tissue disease syndrome, lupus erythematosus profundus (LEP), Degos' disease and Berger's disease. Skin lesions comprised non-palpable petechial lesions involving lower extremities in all cases and also the upper extremities in two. A superficial perivascular lymphocytic infiltrate unaccompanied by vascular fibrin deposits was associated with prominent erythrocyte extravasation including into the epidermis. Mural and extravascular fibrin deposition was seen in one biopsy from a PP-like lesion and mural fibrinoid necrosis was seen in the cases of LEP and Degos' disease; in biopsies from these three cases, the presence of fibrin deposition warranted use of the appellation 'lymphocytic vasculitis'. In all patients, DIF showed prominent and predominant IgA deposits.

CONCLUSIONS: A non-necrotizing lymphocytic purpuric vascular reaction is one manifestation of vascular IgA deposition in the skin. A subpopulation of human lymphocytes bear surface Fc receptor and/or C3 receptors ('complement receptor lymphocytes') which can bind circulating immune complexes (ICs) or C3 generated via activation of the alternative complement cascade. Thus, circulating ICs are a potential pathogenic basis of this eruption, the histologic differential diagnosis of which is idiopathic PP and PP of drug or viral etiology.

SPECIAL STAINS/
IMMUNO-HISTOCHEMISTRY CHARACTERIZATION

DIRECT IMMUNOFLUORESCENCE If direct immunofluorescence is performed, IgM and C3 may be found in and around the vessel walls.

PROGNOSIS AND TREATMENT Dependent upon the underlying etiology of the vasculitis

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Commonly Used Terms

Fibrinoid necrosis-Hallmark of leukocytoclastic vasculitis with a ring of fibrin obliterating the vessel walls.

Nuclear dust -Fragments of inflammatory cells, mainly neutrophils, that are present around small blood vessels

Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation

Commonly Used Terms
This is a glossary of terms often found in a pathology report.

Diagnostic Process
Learn how a pathologist makes a diagnosis using a microscope

Surgical Pathology Report
Examine an actual biopsy report to understand what each section means

Special Stains
Understand the tools the pathologist utilizes to aid in the diagnosis

How Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurate

Got Path?
Recent teaching cases and lectures presented in conferences

Internet Links

Pathologists Who Make A Difference
Search for a Physician Specialist
Clinical Photo
Microscopic Photo

Last Updated July 29, 2005

Send mail to The Doctor's Doctor with questions or comments about this web site.
Read the Medical Disclaimer.

Copyright © The Doctor's Doctor

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/ Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

PATHOGENESIS	CHARACTERIZATION
GENERAL	Immune complexes form and are deposited within the vessel walls leading to complement activation. There is chemotactic recruitment of neutrophils with additional injury to the vessel wall with fibrin deposition. TNF and IL-1 stimulate the endothelium to activate the intrinsic and extrinsic coagulation pathways, leading to occasional thrombosis.
PLATELETS
Platelet involvement in cutaneous small vessel vasculitis. Meijer-Jorna LB, Mekkes JR, Van Der Wal AC. Departments of Pathology and Dermatology, Academic, Medical Centre of the University of Amsterdam, Amsterdam, the Netherlands.	J Cutan Pathol 2002 Mar;29(3):176-80 Abstract quote BACKGROUND: Secretory products of platelets serve important functions in inflammation and thrombosis. Participation of platelets in the tissue reaction associated with cutaneous small vessel vasculitis has not yet been evaluated, so we systematically investigated the presence of platelet aggregates in inflamed microvessels. METHODS: Thirty-six biopsies containing vasculitis and 18 biopsies with perivascular or interface type dermatitis were reviewed and adjacent sections were immunohistochemically stained with anti-CD61 antibody recognizing GPIIbIIIa receptors on platelets and with anti-von Willebrand factor (anti-vWF) antibody. RESULTS: Platelet aggregates were observed in 27 (75%) of the vasculitis biopsies and three (16.7%) of the perivascular dermatitis biopsies, of which two (11%) had traumatic vessel damage. In all vasculitis cases, platelet clumps were associated with diffuse immunostaining of the perivascular stroma with the initiator of platelet aggregation anti-vWF. In the non-vasculitis type of dermatitis anti-vWF staining remained strictly limited to the cytoplasm of endothelial cells in 10 cases, and in eight cases there was also slight diffuse perivascular staining, albeit less extensively than in vasculitis cases. CONCLUSION: Formation of platelet aggregates appears to play a thus far unrecognized role in cutaneous small vasculitis. Secretory products of platelets will likely contribute to the inflammatory response and tissue damage in vasculitis. Moreover, platelet immunohistochemistry may be helpful in the diagnosis of microvascular damage in paraffin sections.

CLINICAL VARIANTS	CHARACTERIZATION
Local disease	Pustular vasculitis of the dorsal hands

HISTOPATHOLOGY	CHARACTERIZATION
GENERAL	Most of the diagnostic changes occur about 18-24 hours after the initial appearance. There is infiltration of the small vessel arterioles and venules by neutrophils associated with fibrinoid necrosis. Surrounding these vessels is nuclear dust, edema, and extravasated red blood cells. If there is an allergic hypersensitivity component, eosinophils may be present. If the vasculitis is intense, a hemorrhagic bullous eruption may occur and rarely cutaneous infarction
VARIANTS
Immunoglobulin A-associated lymphocytic vasculopathy: a clinicopathologic study of eight patients. Crowson AN, Magro CM, Usmani A, McNutt NS. Central Medical Laboratories, Winnipeg, Manitoba, Canada, Department of Dermatology, University of Oklahoma, OH, USA, Regional Medical Laboratories, St John's Medical Center, Tulsa, OK, USA, Department of Pathology, Division of Dermatopathology, Ohio State University, Columbus, OH, USA, and Department of Pathology, Division of Dermatopathology, Weill Medical College of Cornell University, New York, NY, USA.	J Cutan Pathol 2002 Nov;29(10):596-601 Abstract quote INTRODUCTION: Cutaneous IgA-associated vasculitis can be a clue to Henoch-Schonlein purpura (HSP), which typically comprises renal and gastrointestinal tract disease and arthritis, whereby prominent and predominant IgA deposits within the cutaneous vasculature provoke a pustular leukocytoclastic vasculitis. DESIGN: We describe eight patients with a novel expression of a cutaneous IgA vascular injury syndrome, namely a lymphoid vasculopathy which clinically and light microscopically resembled a pigmentary purpura (PP) in six, and correlate direct immunofluorescence (DIF) and clinical features to light microscopy. RESULTS: Among associated diseases were prior viral infection, an HSP symptom complex, an undifferentiated connective tissue disease syndrome, lupus erythematosus profundus (LEP), Degos' disease and Berger's disease. Skin lesions comprised non-palpable petechial lesions involving lower extremities in all cases and also the upper extremities in two. A superficial perivascular lymphocytic infiltrate unaccompanied by vascular fibrin deposits was associated with prominent erythrocyte extravasation including into the epidermis. Mural and extravascular fibrin deposition was seen in one biopsy from a PP-like lesion and mural fibrinoid necrosis was seen in the cases of LEP and Degos' disease; in biopsies from these three cases, the presence of fibrin deposition warranted use of the appellation 'lymphocytic vasculitis'. In all patients, DIF showed prominent and predominant IgA deposits. CONCLUSIONS: A non-necrotizing lymphocytic purpuric vascular reaction is one manifestation of vascular IgA deposition in the skin. A subpopulation of human lymphocytes bear surface Fc receptor and/or C3 receptors ('complement receptor lymphocytes') which can bind circulating immune complexes (ICs) or C3 generated via activation of the alternative complement cascade. Thus, circulating ICs are a potential pathogenic basis of this eruption, the histologic differential diagnosis of which is idiopathic PP and PP of drug or viral etiology.

SPECIAL STAINS/ IMMUNO-HISTOCHEMISTRY	CHARACTERIZATION
DIRECT IMMUNOFLUORESCENCE	If direct immunofluorescence is performed, IgM and C3 may be found in and around the vessel walls.