patoloji-ders-notlari

Title

Serdar Balcı

Pathology of VesselsNon-Atherosclerotic Vascular Diseases

Serdar BALCI, MD

PATHOLOGY OF VESSELS

Pathology of Vessels

• Narrowing, complete obstruction of vessel lumina
  • Progressively
    • Atherosclerosis
  • Acutely
    • Thrombosis or embolism
• Weakening of vessel walls
  • Dilation and/or rupture

Different vascular structures for different purposes

Robbins Basic Pathology

Layers of vessels

• Intima
  • Endothelial cell monolayer
  • Basal membrane
  • Internal elastic lamina
• Media
  • Smooth muscle cells and ECM
  • Loose connective tissue, nerve fibers, and smaller vessels of the adventitia
  • External elastic lamina
• Adventitia
  • Vasa vasorum

Arteries

• Large elastic arteries
  • Aorta, arch vessels, iliac and pulmonary arteries
  • Elastic fibers alternate with smooth muscle cells throughout the media
  • Expands during systole, recoils during diastole
  • Older age, the elasticity is lost
    • transmit high arterial pressures to distal organs
    • dilated and tortuous (ectatic) prone to rupture
• Medium-sized muscular arteries
  • Coronary and renal arteries
  • Elastin limited to the internal and external elastic lamina
  • Media is composed primarily of smooth muscle cells
    • Circularly or spirally arranged around the lumen
  • Regional blood flow is regulated
    • vasoconstriction vasodilation
    • Autonomic nervous system, local metabolic factors, acidosis

Small arteries (<2mm)

Arterioles (20-100 µm)

Connective tissue of organs

Media mostly composed of smooth muscle

Arterioles regulate blood flow resistance

Flow becomes steady rather than pulsatile

Capillaries

7-8µm, diameter of RBC

Lined by endothelial cells

Smooth muscle cell-like cells → pericytes

Rapid exchange of diffusible substances between blood and tissue

Diffusion of oxygen and nutrients is not efficient beyond 100 µm

Metabolically active tissues (heart) have the highest capillary density

Veins

• Postcapillary venules

  • Edema
  • Leukocyte migration

• Collecting venules

• Larger veins

• Compared to arteries

  • Veins larger diameters, larger lumina, and thinner walls, less distinct layers

• Prone to dilation, external compression, and penetration by tumors or inflammatory processes

• Veins have 2/3 of blood

  • Valves work against gravity

Lymphatics

Thin-walled, endothelium-lined channels

Excess fluid

Proteins

Mononuclear cells

Tumors and infections

Robbins Basic Pathology

Endothelium

• Continuous sheet of cells

• Nonthrombogenic blood-tissue interface

• Modulate inflammation

• Affect the growth of other cell types, smooth muscle cells

• Vasoreactivity

  • Relaxation → Nitric oxide
  • Contracting factors → Endothelin

• Interendothelial junctions

  • Open under hemodynamic stress (high blood pressure)
  • Vasoactive agents (histamine)

• Vacuolar transcytosis

• Passage of leukocytes during inflammation

• Fenestrations (holes) in liver and kidney endothelium for filtration

• Central nervous system impermeable blood–brain barrier

• Nonthrombogenic property

  • Laminar flow
  • Vascular endothelial growth factor
  • Firm adhesion to basement membrane

Endothelial activation

Bacterial products

Inflammatory cytokines

Hemodynamic stresses

Lipid products (atherosclerosis)

Advanced glycolysis products (diabetes)

Viruses

Complement

Metabolic insults (hypoxia)

Activated endothelial cells

• Shape changes
• Express adhesion molecules
• Produce cytokines, chemokines, growth factors, pro- and anticoagulant factors
• Rapid (within minutes)
  • Reversible, and independent of new protein synthesis
  • Endothelial contraction by histamines
• Days
  • Alterations in gene and protein expression

Endothelial dysfunction

Endothelium-dependent vasodilation

Hypercoagulable states

Increased oxygen free radical production

Initiate thrombosis

Promote atherosclerosis

Formation of the vascular lesions of hypertension and diabetes

Vascular Smooth Muscle Cells

Normal vascular repair

Atherosclerosis

Proliferate

Upregulate ECM collagen, elastin, and proteoglycan

Form growth factors and cytokines

Mediate vasoconstriction or vasodilation

• Pro-growth
  • Platelet-derived growth factor (PDGF)
  • Endothelin
  • Thrombin
  • Fibroblast growth factors
  • Inflammatory mediators
    • Interferon-γ (IFN-γ)
    • Interleukin-1 (IL-1)
• Quiescent state
  • Heparan sulfate
  • NO
  • Transforming growth factor-α (TGF-α)

Robbins Basic Pathology

NON-ATHEROSCLEROTIC VASCULAR DISEASES

CONGENITAL ANOMALIES

Berry aneurysms

Thin-walled arterial outpouchings in cerebral vessels

Branch points around the circle of Willis

Arterial media is congenitally attenuated

Spontaneously rupture

Fatal intracerebral hemorrhage

Arteriovenous fistulas

• Abnormal connections between arteries and veins
• No capillary bed
• Developmental defects
• Rupture of arterial aneurysms into adjacent veins
  • Penetrating injuries
  • Inflammatory necrosis of adjacent vessels
• Surgically → hemodialysis
• Extensive → cause high-output cardiac failure by shunting

Fibromuscular dysplasia

• Focal irregular thickening of the walls of medium-sized and large muscular arteries
• Medial and intimal hyperplasia and fibrosis
• Any age, frequently in young women
• Luminal stenosis
• Abnormal vessel spasm, reduces vascular flow
  • Renovascular hypertension
• Between focal segments → vascular outpouchings → rupture

DISORDERS OF BLOOD VESSEL HYPERREACTIVITY

Raynaud phenomenon

• Exaggerated vasoconstriction of arteries and arterioles
• In the extremities, fingers and toes
• Nose, earlobes, or lips
• Paroxysmal pallor or cyanosis
  • “red-white-and-blue” color changes from most proximal to most distal
  • Proximal vasodilation, central vasoconstriction, and more distal cyanosis

Primary Raynaud phenomenon

• Exaggerated central and local vasomotor responses to cold or emotion
• 3-5% of the general population, young women
• Structural changes in the arterial walls are absent
• In the late course intimal thickening may appear
• The course usually is benign
• In chronic cases
  • Atrophy of the skin, subcutaneous tissues, and muscles
  • Ulceration and ischemic gangrene are rare

Secondary Raynaud phenomenon

• Vascular insufficiency due to arterial disease
  • Systemic lupus erythematosus
  • Scleroderma
  • Buerger disease
  • Atherosclerosis

Myocardial Vessel Vasospasm

• Excessive constriction cause ischemia
• Persistent vasospasm lead to tissue infarction
• Endogenous
  • Epinephrine released by pheochromocytomas
• Exogenous
  • Cocaine or phenylephrine
• Elevated thyroid hormone increase the sensitivity of vessels to circulating catecholamines
• Autoantibodies and T cells in scleroderma cause vascular instability and vasospasm
• Extreme psychological stress

Vasospasm of cardiac arterial or arteriolar beds (cardiac Raynaud) 20-30 minutes → myocardial infarction

Elevated levels of catechols increase heart rate and myocardial contractility → increase ischemia caused by the vasospasm

Sudden cardiac death (fatal arrhythmia)

Ischemic dilated cardiomyopathy

VEINS AND LYMPHATICS

Varicose Veins of the Extremities

Abnormally dilated tortuous veins

Chronically increased intraluminal pressures

Weakened vessel wall support

Superficial veins of the upper and lower leg

20% of men and a third of women develop lower extremity varicose veins

Obesity, compression of the inferior vena cava during pregnancy

Familial tendency

• Venous valves incompetent
• Lower extremity stasis, congestion, edema, pain, and thrombosis
• Persistent edema in the extremity
• Secondary ischemic skin changes
  • Stasis dermatitis
  • Chronic varicose ulcers
    • Poor wound healing, infections
• Embolism from these superficial veins is very rare

Congestion in Portal Vein

• Esophageal varices
  • Liver cirrhosis
  • Portal vein obstruction
  • Hepatic vein thrombosis
• Rectum
  • Hemorrhoids
• Periumbilical veins
  • Caput medusae

Thrombophlebitis and Phlebothrombosis

Thrombosis and inflammation

Deep leg veins

Periprostatic venous plexus in males

Pelvic venous plexus in females

Large veins in the skull and the dural sinuses

Peritoneal infections

Hypercoagulability (polycythemia vera)

Deep venous thrombosis of the legs

• Prolonged immobilization
  • Extended bed rest
  • Long plane or automobile trips
  • Postoperative
• Congestive heart failure
• Pregnancy
• Oral contraceptive use
• Obesity
• Inherited defects in coagulation factors
• Procoagulant factors from malignant tumors
  • Migratory thrombophlebitis, Trousseau syndrome
• Local manifestations
  • Distal edema
  • Cyanosis
  • Superficial vein dilation
  • Heat
  • Tenderness
  • Redness
  • Swelling
  • Pain
• Homan sign
  • Pain squeezing the calf muscles, forced dorsiflexion of the foot
• Pulmonary embolism

Superior Vena Cava Syndromes

Neoplasms that compress or invade the superior vena cava

Bronchogenic carcinoma

Mediastinal lymphoma

Marked dilation of the veins of the head, neck, and arms

Cyanosis

Pulmonary vessels compressed → Respiratory distress

Inferior vena cava syndrome

Neoplasms that compress or invade the inferior vena cava

Thrombus from the hepatic, renal, or lower extremity veins

Hepatocellular carcinoma and renal cell carcinoma grow within veins

Marked lower extremity edema

Distention of the superficial collateral veins of the lower abdomen

Proteinuria

Lymphangitis

Acute inflammatory process by bacterial seeding

Red, painful subcutaneous streaks

Tender enlargement of draining lymph nodes (acute lymphadenitis)

Bacteremia or sepsis

Lymphedema

• Primary lymphedema
  • Isolated congenital defect (simple congenital lymphedema)
  • Familial Milroy disease (heredofamilial congenital lymphedema)
    • Agenesis or hypoplasia of lymphatics
• Secondary or obstructive lymphedema
  • Tumors involving either the lymphatic channels or the regional lymph nodes
  • Surgical procedures
    • Axillary lymph nodes in radical mastectomy
  • Postradiation fibrosis
  • Filariasis
  • Postinflammatory thrombosis and scarring
• Edema
• Chronic edema
  • Deposition of ECM and fibrosis
  • Brawny induration or a peau d’orange appearance of skin
  • Inadequate tissue perfusion
  • Skin ulceration
  • Rupture of dilated lymphatics
  • Milky accumulations of lymph in various spaces
    • Chylous ascites (abdomen), chylothorax, and chylopericardium

TUMORS OF VESSELS

Robbins Basic Pathology

Vascular Tumors

• Primary tumors of large vessels
  • Extremely rare and are mostly sarcomas
• Benign tumors
  • Obvious vascular channels filled with blood cells or lymph
  • Lined by a monolayer of normal-appearing endothelial cells
• Malignant tumors
  • More cellular
  • Cytologic atypia
  • Proliferative
  • No well-organized vessels
  • Immunohistochemical detection of endothelial cell–specific markers
    • CD31, von Willebrand factor

Vascular Ectasias

• Dilatation of vessels
  • Congenital or acquired
  • Not true neoplasms
• Nevus flammeus (a “birthmark”)
• Port wine stain in Sturge-Weber syndrome
• Spider telangiectasias in pregnancy, cirrhosis
• Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease)

Capillary hemangiomas

Most common type

Skin

Subcutaneous tissues

Mucous membranes of the oral cavities and lips

Liver, spleen, and kidneys

Thin-walled capillaries with scant stroma

Robbins Basic Pathology

Robbins Basic Pathology

Juvenile hemangiomasStrawberry hemangiomas

Newborn skin

Common (1 in 200 births)

Can be multiple

Grow rapidly for a few months but then fade by the age of 1 to 3 years, with complete regression by age 7

Pyogenic granulomas

Capillary hemangiomas

Rapidly growing red pedunculated lesions on the skin, gingival, or oral mucosa

Resemble exuberant granulation tissue

Bleed easily and are often ulcerated

Develop after trauma, reaching a size of 1 to 2 cm within a few weeks

Robbins Basic Pathology

Cavernous hemangiomas

Large, dilated vascular channels

More infiltrative, frequently involve deep structures

Do not spontaneously regress

Sharply defined, unencapsulated

Large, cavernous blood-filled vascular spaces, separated by connective tissue stroma

Intravascular thrombosis, dystrophic calcification

Robbins Basic Pathology

Lymphangiomas

• Simple (capillary) lymphangiomas
  • Head, neck, and axillary subcutaneous tissues
• Cavernous lymphangiomas (cystic hygromas)
  • Neck or axilla of children, rarely in the retroperitoneum
  • Can be large (up to 15 cm)
  • Common in Turner syndrome
  • Massively dilated lymphatic spaces lined by endothelial cells
  • Separated by intervening connective tissue stroma containing lymphoid aggregates
  • Tumor margins are indistinct and unencapsulated, definitive resection difficult

Glomus Tumors (Glomangiomas)

Benign, painful tumors

Specialized smooth muscle cells of glomus bodies

Arteriovenous structures involved in thermoregulation

Distal portion of the digits, especially under the fingernails

Excision is curative

Bacillary Angiomatosis

Vascular proliferation in immunocompromised hosts (AIDS)

Opportunistic gram-negative bacilli of the Bartonella family

Skin, bone, brain, and other organs

Skin lesions are red papules and nodules, or rounded subcutaneous masses

Proliferation of capillaries lined by prominent epithelioid endothelial cells

Nuclear atypia and mitoses

The bacteria induce host tissues to produce HIF-1α, VEGF production and vascular proliferation

Cured by antibiotic treatment

Bacillary angiomatosis.

Robbins Basic Pathology

Bacillary angiomatosis.

B: Histologic features are those of acute inflammation and capillary proliferation. Inset, Modified silver (Warthin-Starry) stain demonstrates clusters of tangled bacilli (black)

Robbins Basic Pathology

Kaposi Sarcoma

• HHV-8
• Classical form in elderly
• AIDS associated
• Transplantation associated
• KSHV (HHV8) is a γ-herpesvirus
  • sexually, non sexually transmitted
• Altered T cell immunity
• Lytic and latent infecitons in endothelial cells
• Viral G protein induces VEGF production
• Viral homologe of cyclin D causes proliferation
• Patched, plaque, nodular phases

Robbins Basic Pathology

Robbins Basic Pathology

Hemangioendotheliomas

Intermediate grade neoplasm

Sometimes resemble epithelial neoplasms morphologically

Excision is curative in a majority of the cases

40% of the tumors recur

20-30% metastasize

15% of patients die of their tumors

Angiosarcomas

Malignant endothelial neoplasms

Highly differentiated tumors resembling hemangiomas to wildly anaplastic lesions difficult to distinguish from carcinomas or melanomas

Older adults

No gender bias

Can occur at any site, most often skin, soft tissue, breast, and liver

• Hepatic angiosarcomas

  • Arsenical pesticides
  • Thorotrast
    • A radioactive contrast agent formerly used for radiologic imaging)
  • Polyvinyl chloride

• Arise in patients with lymphedema

  • Axillary lymph node resection for breast cancer
  • Lymphangiosarcoma

• Can be induced by radiation

• Long-term (years) foreign bodies (catheters)

• Skin

  • Begin as small, sharply demarcated, asymptomatic red nodules
  • Advanced lesions
    • Large, fleshy red-tan to gray-white masses
    • Necrosis and hemorrhage

• Aggressive tumors that invade locally and metastasize

• 5-year survival rates 30%

Robbins Basic Pathology

Moderately differentiated angiosarcoma with dense clumps of atypical cells lining distinct vascular lumina

Immunohistochemical staining of angiosarcoma for the endothelial cell marker CD31

Robbins Basic Pathology

Vascular Intervention

Thrombosis, intimal thickening and atherosclerosis is seen after stent or grafts

Robbins Basic Pathology