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Adriana Acurio, M.D.

Pathology Department

Chicago Medical School

2012


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Blood Vessels PART II1. Vasculitis

2. Disorders of vascular hyperreactivity3. Vascular tumors


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VasculitisInflammation of the vessel wall with deleteriousconsequences on downstream tissues

Diverse disease group categorized by ETIOLOGY

and SIZE of vessel involvedThe most common etiologic mechanisms include:

1. Noninfectious (Immune-mediated inflammation)

2. Infectious (colonization by infectious pathogens)3. Physical/chemical injury (irradiation, mechanical

trauma, and toxins)

Distinction of etiology is important for

management


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Noninfectious VasculitisPathophysiologic mechanisms:

Immune complex deposition

1. Anti-neutrophil cytoplasmic antibodies2. Anti-endothelial cell antibodies


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Vessel Size Involvement


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Noninfectious Vasculitis

Immune Complex DepositionCirculating antigen-antibody complexes deposit invascular beds and cause an inflammatory response

Can be associated with:Autoimmune disorders Systemic Lupus Erythematosus

Drug hypersensitivities

PenicillinViral infections Hepatitis B virus


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Noninfectious Vasculitis:

Anti-Neutrophil Cytoplasmic AntibodiesANCAs are a diverse group of

autoantibodies directed againstneutrophils, monocyte lysosomes,and endothelial cells

They are classified based onintracellular distribution AND

target antigens:Perinuclear (p-ANCA):

Anti-myeloperoxidase (MPO-ANCA)

Cypolasmic (c-ANCA):

Anti-proteinase-3 (PR3-ANCA)


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ANCA titers are measured byELISA studies, type isdetermined by indirect

immunofluorescence Titers can reflect degree of

inflammatory activity andrecurrence (clinicalmanagement)

ANCAs directly activateneutrophils and stimulate

release of reactive oxygen speciesand proteolytic enzymes ~

endothelial cell dama e

Anti-Neutrophil Cytoplasmic Antibodies

Pathogenesis is poorlyunderstood ANCA production induced by

drugs or cross-reactivity

Predisposing inflammatory

stimuli upregulate MPO/PR3


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Noninfectious Vasculitis:

Anti-endothelial cell antibodiesIt is suspected that certain vasculitides are caused by

autoantibodies directed to endothelial cells in vessels

A prominent example is Kawsakis disease

For most vasculitidies, a specific causative agent has

not been defined. Therefore, site of involvement is avery important clue in diagnosis

P


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Capillaries

VenulesArterioles

Arteries Veins

Aorta

e um vesse vascu s

Immune complexmediated

(e.g., polyarten isnodosa)

Granulomas,no asthma(Wegener

granulomatosis)

Vasculitis withoutasthma or granulomas

(microscopicpolyangiitis)

Eosinophilia, asthma,and granulomas(Chrug-Strauss

syndrome)

Anti-endothelialcell antibodies

(e.g., Kawasakidisease)

Large vessel vasculitis

Paucit of immune com lexes often withANCA

_____________________ ,/ Small vesselvasculitis _______

Granulomatous disease(e.g., giant cell arterilis.

Takayasu arleritis)

Immune complex mediated

SLE IgA Cryoglobulin Other (e.g.,(e.g., SLE (e.g., Henoch- (e.g., cryoglobulin Goodpasturevasculitis) SchOnlein purpura) vasculitis) disease)

Kumar et al: Robbins & Cotran Pathologic Bass of Disease, 8th Edition.Copyright () 2009 by Saunders, an imprint of Elsevier, Inc. All rights reserved.

Vessel Size Involvement In VariousMOP

V a s c u l i t i d e sInvolvementIn-

Various

Vasa'Rides


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Giant-Cell (Temporal) ArteritisMost common form of vasculitis in the USAffects adults >50y, particularly elderly

Chronic, GRANULOMATOUS inflammation of:

Large vessels of the head (temporal, vertebral andophthalmic arteries)

Aorta

Ophthalmic arterial involvement can lead to

permanent blindness = medical emergencySensitive to treatment with corticosteroids and

anti-TNF in refractory cases (prompt diagnosis!)


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Giant-Cell (Temporal) Arteritis

Clinical FeaturesEtiology Uncertain, T cell response

against a vessel antigen,release of cytokines (TNF) andhumoral response mediated byanti-endotheilial antibodies

Morphologic Findings Granulomatous inflammation

of media

Intimal fibrosis Disruption of internal elastic

lamina


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Giant-Cell (Temporal) Arteritis

Clinical FeaturesSymptoms

Fever, fatigue, weight loss Headaches Facial pain Pain on palpation along the

course of the superficialtemporal artery

Ocular symptoms ranging fromdiplopia to complete vision lossare seen (ophthalmic artery

involvement, 50% of patients)Diagnosis Clinical findings Elevated ESR

Histologic confirmation


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Diagnosis: Clinical findings Elevated ESRTreatment:

Corticosteroids

Takayasu Arteritis

GRANULOMATOUS vasculitis ofmedium to large arteries, including the

Aorta

Aortic arch and great vessels (60%)

Distal aorta and branches (30%) Originally described in young females of

Japanese descent

Clinically and morphologically similar to

Giant-cell Aortitis, distinction = age: > 50 yo = Giant-cell aortitis

< 50 yo = Takayasu aortitis

Variable course, slow or rapid/

fulminant progression


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P


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Capillaries

VenulesArterioles

Arteries Veins

Aorta

e um vesse vascu s




granulomatosis)




syndrome)







Takayasu arleritis)





V a s c u l i t i d e sInvolvementIn-

Various

Vasa'Rides


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Polyarteritis Nodosa (PAN)Affects all ages, typically young adultsVariable clinical course, episodic with

long disease-free intervals

Clinical Findings:

Peripheral neuritis/ ischemia Hypertension (renal vessels)

Abdominal pain and melena (GI)

Renal failure (major cause of death)

Untreated it is fatal, often duringfulminant acute attackTreatment based on corticosteroids and

cyclophosphamide, 90% effective


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Polyarteritis Nodosa (PAN)

Acute stage: Transmuralinflammation (neutrophils,eosinophils, and mononuclear

cells) and fibrinoid necrosis andthrombosis

Chronic stage: fibrous thickening(scarring) of the vessel wall

Different stages can be seen in agiven patient

Weakening of arterial wall byinflammation leads to aneurysms,

impaired perfusion and ischemia


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Vascular thrombosis and

MI (trichrome stain)

Kawasaki Disease- Clinical Features

Clinical Findings: Conjunctival and oral erythema/ulcer

Edema of hands and feet witherythema of the palms and soles

Desquamative rash

Cervical lymphadenopathy Up to 20% of untreated patients

develop cardiovascular disease:

Aneurysm/rupture of coronary vessels

Thrombosis

Myocardial infarction, sudden death

Treatment with intravenous Igtherapy and aspirin, reducesrate of coronary artery diseaseto


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Capillaries

VenulesArterioles

Arteries Veins

Aorta

e um vesse vascu s




granulomatosis)




syndrome)







Takayasu arleritis)





V a s c u l i d i t e sInvolvementIn-

Various

Vasculidites


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Microscopic Polyangiitis

NECROTIZING vasculitis of capillaries, arterioles and venules Broad systemic involvement of skin, mucous membranes,

lungs, brain, heart, gastrointestinal tract, kidneys, and muscle

Necrotizing glomerulonephritis (90%) and pulmonary

capillaritis (60%) are common Pathogenesis:

Associated with MPO-ANCAs (p-ANCAs)

Immune complex deposition: Antibody response

to drug(e.g., penicillin), bacterial (e.g., streptococci),protein antigens

Manifestations are attributed to recruitment andactivation of neutrophils

Cyclophosphamide and steroids lead to

remission (renal and

brain involvement are difficult to treat)


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brain involvement are difficult to treat)


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Wegner Granulomatosis Clinical Features:

Males > females, usually in their 40s Chronic sinusitis Nasopharyngeal ulceration Persistent pneumonitis Renal disease (80%): hematuria, failure Rashes, muscle pains, articular involvement,

neuritis and fever

Responds to immunosuppressive

therapy, 80% of untreated patients diewithin 1 year


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Wegner GranulomatosisMorphologic Features:

Necrotizing granulomas arecharacteristic (central necrosis,fibroblastic proliferation, giant

cell reaction and mononuclearinfiltrate)

In the kidney, the inflammationaffects the glomeruli,

progressing formfocal/segmental to diffusecrescentic glomerulonephritis


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progression Arterial acute and chronic inflammation with luminalh b d d


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progression thrombosis can extend into contiguous veins and nervesresulting in fibrous scarring of all three structures


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Vasculitis Associated with Other

DiseasesImmunologic disease

Rheumatoid arthritis

SLE

Mixed cryoglobulinemia

Antiphospholipid antibody syndrome

Henoch-Schnlein purpura


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Infectious Vasculitis

Vessel wall inflammation due to colonization byinfectious pathogens (bacteria/fungi)

Subsequent immune complex deposition and

antibody cross-reactivity can occurCan lead to weakening of vessel wall and mycotic

aneurysms

Examples:

Bacterial pneumonia pulmonary hemorrhage

Bacterial meningitis - brain infarction

Aspergillus and Mucor - vasoinvasive fungal sp.


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Raynaud Phenomenon

Recurrent vasospasms of the fingers and toes inresponse to stress or cold

Primary Raynaud (Raynaud disease): Vasospasmwith no association with systemic illness

Secondary Raynaud phenomenon: Vasospasmassociated with other illness (autoimmune disease).Most common associations:Scleroderma (90%)

Mixed connective-tissue disease (85%)


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Raynaud Phenomenon

Patients often describe 3 phases of color change:

Intial white (vasoconstriction)

followed by blue (cyanosis)

red (rapid blood reflow)

Changes are reversible, must be distinguishedfrom irreversible causes of ischemia such as

vasculitis or thrombosisMost commonly affects fingers and toes but may

affect nose, ears and tongue


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Raynaud Phenomenon

Pathophysiology: UnknownStructural vessel wall abnormalities

and deficiencies in autonomiccontrol cause recurrent

vasoconstriction followed byimpared vasodilation of cutaneous

vessels in the prescence of stressfulstimuli

Epidemiology: Slightly moreprevalent in women in the 2ndor 3rd

decades


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Vascular Tumors

Benign Neoplasms, Developmental and Acquired Conditions

HemangiomaCapillary hemangiomaCavernous hemangioma

Lymphangioma

Simple (capillary) lymphangiomaCavernous lymphangioma (cystic hygroma)

Glomus tumor

Vascular ectasiasNevus flammeus

Spider telangiectasia (arterial spider)Hereditary hemorrhagic telangiectasis (Osler-Weber-Rendu disease)

Reactive vascular proliferationsBacillary angiomatosis


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Hemangioma

Tumors of blood-filled vessels, often present at birth

Most commonly seen in the head and neck, can alsopresent in internal organs such as liver

Their classification is based on histologic appearanceCapillary Hemangiomas: Strawberry Hemangiomas (newborn) Pyogenic Granulomas


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HemangiomaCavernous Hemangiomas:

Composed of larger vascular channels

Circumscribed, locally destructive, do not regress

In von Hippel-Lindau disease, they present in retina,central nervous system, pancreas, liver

Retinal cavernous hemangioma in patient with von Hippel-Lindau disease


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Bacillary Angiomatosis

Vascular proliferation secondary to Bartonella infectionaffecting immunosuppressed patients

Can involve the skin, bone, brain, and other organs. Twospecies have been implicated:

Bartonella henselae (cat-scratch disease)

Bartonella quintana ("trench fever transmitted by body lice)

Bacillary angiomatosis in patient with AIDS (silver stain highlighting bacilli)


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Vascular TumorsIntermediate-Grade Neoplasms

Kaposi sarcoma

HemangioendotheliomaMalignant Neoplasms

Angiosarcoma


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Angiosarcoma

Malignant vascular neoplasms composed of rapidlyproliferating, extensively infiltrating anaplastic cells

It is a rare malignancy showing association to special

settings:Hepatic angiosarcomas associated with exposure to vinyl

chloride monomer (VCM) in polyvinyl chloride (PVC)polymerization plants as well as arsenic-containing

insecticides and ThorotrastCutaneous angiosarcoma of breast after lumpectomy,

axillary lymph node dissection, and radiotherapy forprimary breast carcinoma


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Angiosarcoma


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