Adriana Acurio, M.D.

Pathology Department
Chicago Medical School
2012

Blood Vessels PART II

1. Vasculitis
2. Disorders of vascular hyperreactivity
3. Vascular tumors

Vasculitis

Inflammation of the vessel wall with deleterious

consequences on downstream tissues
Diverse disease group categorized by ETIOLOGY
and SIZE of vessel involved
The 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

Noninfectious Vasculitis
Pathophysiologic mechanisms:
Immune complex deposition
1. Anti-neutrophil cytoplasmic antibodies
2. Anti-endothelial cell antibodies

Vessel Size Involvement

Noninfectious Vasculitis
Immune Complex Deposition
Circulating antigen-antibody complexes deposit in
vascular beds and cause an inflammatory response
Can be associated with:
Autoimmune disorders
Systemic Lupus Erythematosus

Drug hypersensitivities
Penicillin

Viral infections
Hepatitis B virus

Noninfectious Vasculitis:
Anti-Neutrophil Cytoplasmic Antibodies
ANCAs are a diverse group of
autoantibodies directed against
neutrophils, monocyte lysosomes,
and endothelial cells
They are classified based on
intracellular distribution AND
target antigens:
Perinuclear (p-ANCA):
Anti-myeloperoxidase (MPO-ANCA)

Cypolasmic (c-ANCA):
Anti-proteinase-3 (PR3-ANCA)

Anti-Neutrophil Cytoplasmic Antibodies

ANCA titers are measured by
ELISA studies, type is
determined by indirect
immunofluorescence
Titers can reflect degree of
inflammatory activity and
recurrence (clinical
management)
Pathogenesis is poorly
ANCAs directly activate
understood
neutrophils and stimulate ANCA production induced by
release of reactive oxygen species drugs or cross-reactivity
Predisposing inflammatory
and proteolytic enzymes ~
stimuli upregulate MPO/PR3
endothelial cell damage

Noninfectious Vasculitis:
Anti-endothelial cell antibodies
It 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 a
very important clue in diagnosis

MO
InvolvementIn Various

Vessel Size Involvement In Various

Vasculitides

Vasa'Rides
Capillaries
Arterioles

Venules

Arteries

Veins

Aorta
Medium vessel vasculitis
Immune complex
mediated
(e.g., polyarten is
nodosa)
Large vessel vasculitis
Granulomatous disease
(e.g., giant cell arterilis.
Takayasu arleritis)

Anti-endothelial
cell antibodies
(e.g., Kawasaki
disease)

Vasculitis without
asthma or granulomas
(microscopic
polyangiitis)

Granulomas,
no asthma
(Wegener
granulomatosis)

Eosinophilia, asthma,
and granulomas
(Chrug-Strauss
syndrome)

Paucity of immune complexes (often with ANCA)

_____________________ ,/ Small vesselvasculitis _______

Immune complex mediated
SLE

IgA
Cryoglobulin
Other (e.g.,
(e.g., SLE
(e.g., Henoch(e.g., cryoglobulin Goodpasture
vasculitis) 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.

Giant-Cell (Temporal) Arteritis

Most common form of vasculitis in the US
Affects adults >50y, particularly elderly
Chronic, GRANULOMATOUS inflammation of:
Large vessels of the head (temporal, vertebral and
ophthalmic arteries)
Aorta

Ophthalmic arterial involvement can lead to

permanent blindness = medical emergency

Sensitive to treatment with corticosteroids and

anti-TNF in refractory cases (prompt diagnosis!)

Giant-Cell (Temporal) Arteritis

Clinical Features
Etiology
Uncertain, T cell response
against a vessel antigen,
release of cytokines (TNF) and
humoral response mediated by
anti-endotheilial antibodies
Morphologic Findings
Granulomatous inflammation
of media
Intimal fibrosis
Disruption of internal elastic
lamina

Giant-Cell (Temporal) Arteritis

Clinical Features
Symptoms
Fever, fatigue, weight loss
Headaches
Facial pain
Pain on palpation along the
course of the superficial
temporal artery
Ocular symptoms ranging from
diplopia to complete vision loss
are seen (ophthalmic artery
involvement, 50% of patients)
Diagnosis
Clinical findings
Elevated ESR
Histologic confirmation

Takayasu Arteritis
GRANULOMATOUS vasculitis of
medium 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:
Diagnosis:
> 50 yo = Giant-cell aortitis
Clinical findings
< 50 yo = Takayasu aortitis
Elevated ESR
Treatment:
Variable course, slow or rapid/
Corticosteroids
fulminant progression

Takayasu Arteritis
Clinical Findings:

Initial symptoms are nonspecific.

Progression leads to
Reduced blood pressure/pulses in arms
PULSELESS DISEASE
Ocular disturbances: visual defects,
retinal hemorrhages, and total blindness
Neurologic deficits
Pulmonary hypertension (Pulmonary
artery)
Narrowing of coronary ostia may lead to
myocardial infarction
Systemic hypertension (Renal arteries)

MO
InvolvementIn Various

Vessel Size Involvement In Various

Vasculitides

Vasa'Rides
Capillaries
Arterioles

Venules

Arteries

Veins

Aorta
Medium vessel vasculitis
Immune complex
mediated
(e.g., polyarten is
nodosa)
Large vessel vasculitis
Granulomatous disease
(e.g., giant cell arterilis.
Takayasu arleritis)

Anti-endothelial
cell antibodies
(e.g., Kawasaki
disease)

Vasculitis without
asthma or granulomas
(microscopic
polyangiitis)

Granulomas,
no asthma
(Wegener
granulomatosis)

Eosinophilia, asthma,
and granulomas
(Chrug-Strauss
syndrome)

Paucity of immune complexes (often with ANCA)

_____________________ ,/ Small vesselvasculitis _______

Immune complex mediated
SLE

IgA
Cryoglobulin
Other (e.g.,
(e.g., SLE
(e.g., Henoch(e.g., cryoglobulin Goodpasture
vasculitis) 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.

Polyarteritis Nodosa (PAN)

Segmental NECROTIZING transmural vasculitis of
small to medium-sized arteries
Involves visceral vessels (kidney, liver, heart and GI)
NOT pulmonary circulation
Pathogenesis is unknown; 3 categories are recognized:
Idiopathic
Cutaneous
HBV associated

Association with chronic HBV (30%), HBsAg-HbsAb

complex deposits in affected vessels

Polyarteritis Nodosa (PAN)

Affects all ages, typically young adults
Variable 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 during
fulminant acute attack

Treatment based on corticosteroids and

cyclophosphamide, 90% effective

Polyarteritis Nodosa (PAN)

Acute stage: Transmural
inflammation (neutrophils,
eosinophils, and mononuclear
cells) and fibrinoid necrosis and
thrombosis
Chronic stage: fibrous thickening
(scarring) of the vessel wall
Different stages can be seen in a
given patient
Weakening of arterial wall by
inflammation leads to aneurysms,
impaired perfusion and ischemia

Kawasaki Disease
Disease of early childhood (80% < 4yo) affecting large to
medium-sized (and small) arteries
Predilection for coronary arteries~
aneurysms/rupture/thrombosis ~ acute myocardial infarctions

Leading cause of acquired heart disease in children

Pathophysiology:
Formation of autoantibodies to endothelial and smooth
muscle cells leads to B-cell activation and cytokine release
T-cell mediates delayed-type hypersensitivity reaction
Infectious agents (most likely viral) are thought to trigger
the disease in genetically susceptible patients

Kawasaki Disease- Clinical Features

Clinical Findings:
Conjunctival and oral erythema/ulcer
Edema of hands and feet with
erythema 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 Ig

therapy and aspirin, reduces
rate of coronary artery disease
to <5%

Vascular thrombosis and

MI (trichrome stain)

MO
Involv ementIn Various

Vessel Size Involvement In Various

Vasculidites

Vasculidites
Capillaries
Arterioles

Venules

Arteries

Veins

Aorta
Medium vessel vasculitis
Immune complex
mediated
(e.g., polyarten is
nodosa)
Large vessel vasculitis
Granulomatous disease
(e.g., giant cell arterilis.
Takayasu arleritis)

Anti-endothelial
cell antibodies
(e.g., Kawasaki
disease)

Vasculitis without
asthma or granulomas
(microscopic
polyangiitis)

Granulomas,
no asthma
(Wegener
granulomatosis)

Eosinophilia, asthma,
and granulomas
(Chrug-Strauss
syndrome)

Paucity of immune complexes (often with ANCA)

_____________________ ,/ Small vesselvasculitis _______

Immune complex mediated
SLE

IgA
Cryoglobulin
Other (e.g.,
(e.g., SLE
(e.g., Henoch(e.g., cryoglobulin Goodpasture
vasculitis) 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.

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 and
activation of neutrophils

Cyclophosphamide and steroids lead to

remission (renal and

brain involvement are difficult to treat)

Microscopic Polyangiitis
Segmental fibrinoid
necrosis of tunica
media without
granulomatous
inflammation
Leukocytoclastic
vasculitis refers to the
destructive infiltration
and degranulation of
neutrophils
Same degree of activity
is seen in all lesions

Wegner Granulomatosis
NECROTIZING GRANULOMATOUS
vasculitis of small/medium-sized vessels
involving:
RESPIRATORY TRACT and KIDNEY
Clinically resembles PAN (distinction:
respiratory system)
Pathophysiology:
T cell-mediated hypersensitivity reaction (to
inhaled infectious, environmental agent?)
PR3-ANCAs are present in up to 95% of
cases, serve as marker of disease activity

Responds to immunosuppressive
therapy. 80% of untreated patients die
within 1 year

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 die
within 1 year

Wegner Granulomatosis
Morphologic Features:
Necrotizing granulomas are
characteristic (central necrosis,
fibroblastic proliferation, giant
cell reaction and mononuclear
infiltrate)
In the kidney, the inflammation
affects the glomeruli,
progressing form
focal/segmental to diffuse
crescentic glomerulonephritis

Thromboangiitis Obliterans
(Buerger Disease)
Vasculitis of medium and small arteries with predilection
for TIBIAL AND RADIAL ARTERIES
Most commonly seen in young cigarette smokers (<35 yo)
Pathogenesis:
Direct endothelial cell toxicity or immune response to
tobacco component
Patients are hypersensitive to tobacco extracts, and
impaired endothelium-dependent vasodilation when
challenged with acetylcholine

Thromboangiitis
Obliterans
(Buerger Disease)
Clinical Features:
Raynaud phenomenom
Caludication induced by exercise
Severe pain at rest due to neural
involvement
Unhealing ulcers of the toes, feet,
or fingers and gangrene
Vascular insufficiency and
gangrene
Smoking cessation reduces

progression

Arterial acute and chronic inflammation with luminal

thrombosis can extend into contiguous veins and nerves
resulting in fibrous scarring of all three structures

Vasculitis Associated with Other

Diseases
Immunologic disease
Rheumatoid arthritis
SLE
Mixed cryoglobulinemia
Antiphospholipid antibody syndrome
Henoch-Schnlein purpura

Infectious Vasculitis
Vessel wall inflammation due to colonization by
infectious pathogens (bacteria/fungi)
Subsequent immune complex deposition and
antibody cross-reactivity can occur
Can lead to weakening of vessel wall and mycotic
aneurysms
Examples:
Bacterial pneumonia pulmonary hemorrhage
Bacterial meningitis - brain infarction
Aspergillus and Mucor - vasoinvasive fungal sp.

Raynaud Phenomenon
Recurrent vasospasms of the fingers and toes in
response to stress or cold
Primary Raynaud (Raynaud disease): Vasospasm
with no association with systemic illness
Secondary Raynaud phenomenon: Vasospasm
associated with other illness (autoimmune disease).
Most common associations:
Scleroderma (90%)
Mixed connective-tissue disease (85%)

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 distinguished
from irreversible causes of ischemia such as
vasculitis or thrombosis
Most commonly affects fingers and toes but may
affect nose, ears and tongue

Raynaud Phenomenon
Pathophysiology: Unknown
Structural vessel wall abnormalities
and deficiencies in autonomic
control cause recurrent
vasoconstriction followed by
impared vasodilation of cutaneous
vessels in the prescence of stressful
stimuli

Epidemiology: Slightly more

prevalent in women in the 2nd or 3rd

decades

Vascular Tumors
Tumors

---

I.

I.

Vascular Tumors
Benign Neoplasms, Developmental and Acquired Conditions
Hemangioma
Capillary hemangioma
Cavernous hemangioma
Lymphangioma
Simple (capillary) lymphangioma
Cavernous lymphangioma (cystic hygroma)
Glomus tumor
Vascular ectasias
Nevus flammeus
Spider telangiectasia (arterial spider)
Hereditary hemorrhagic telangiectasis (Osler-Weber-Rendu disease)
Reactive vascular proliferations
Bacillary angiomatosis

Hemangioma
Tumors of blood-filled vessels, often present at birth
Most commonly seen in the head and neck, can also
present in internal organs such as liver
Their classification is based on histologic appearance
Capillary Hemangiomas:
Strawberry Hemangiomas (newborn)
Pyogenic Granulomas

Hemangioma
Cavernous 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

Lymphangiomas
The equivalent to hemangiomas in the lymphatic
system:
Capillary (simple) and Cavernous (Cystic hygromas)
Cystic Hygromas:
May present as huge tumors in the head/neck or axilla of newborns
Their unencapsulated growth patter makes them difficult to excise

Bacillary Angiomatosis
Vascular proliferation secondary to Bartonella infection
affecting immunosuppressed patients
Can involve the skin, bone, brain, and other organs. Two
species 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)

Vascular Tumors
Intermediate-Grade Neoplasms
Kaposi sarcoma
Hemangioendothelioma
Malignant Neoplasms
Angiosarcoma

Kaposi Sarcoma

Caused by human herpes-virus 8 (HHV-8) most

commonly affects AIDS patients (AIDS defining
illness, elderly and immunosuppressed
Viral infection leads to uncontrolled cellular
proliferation by disruption of Cyclin D and apoptotic
controls (via P53 inhibition)

Cutaneous lesions that progress from patches, plaques

to nodules

Angiosarcoma
Malignant vascular neoplasms composed of rapidly
proliferating, 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 Thorotrast
Cutaneous angiosarcoma of breast after lumpectomy,
axillary lymph node dissection, and radiotherapy for
primary breast carcinoma

Angiosarcoma

adrianaa99@gmail.com
773 257-2165