Vascular Pathology Quiz

Pathology of Veins and Lymphatics, Vascular Tumors, & Vasculitis

• The presentation covers the pathology of veins and lymphatics, vascular tumors, and vasculitis.
• The presenter is Dr. Aileen Azari-Yam M.D., Ph.D.

Objective

• Varicose veins
• Phlebothrombosis/Thrombophlebitis

Varicose Veins

• Varicose veins are dilated, tortuous veins caused by prolonged increased intraluminal pressure leading to vessel dilation and venous valve incompetence.
• Superficial veins of the upper and lower legs are commonly affected due to elevated venous pressure, potentially up to ten times normal, from prolonged standing.
• Up to 20% of men and a third of women develop lower extremity varicose veins.
• Obesity is a risk factor for varicose veins.

Varicose Veins, Clinical Features

• Incompetent venous valves cause stasis, congestion, edema, pain, and thrombosis.
• Chronic venous congestion creates tissue ischemia leading to stasis dermatitis (brawny induration).
• Hemolysis of red blood cells creates brawny coloration and ulcerations.
• Poor wound healing and infections are common complications.
• Thromboembolism from deep veins is more common than embolism from superficial veins.

Varicosities in Two Other Sites: Esophageal Varices

• Liver cirrhosis leads to portal hypertension.
• Portal hypertension leads to the opening of portosystemic shunts, increasing blood flow to veins at the gastroesophageal junction, rectum, and periumbilical veins (caput medusa).
• Esophageal varices may rupture and cause massive (potentially fatal) upper gastrointestinal (GI) hemorrhage.

Varicosities in Two Other Sites: Hemorrhoids

• Hemorrhoids result from primary dilation of the venous plexus at the anorectal junction, often due to prolonged pelvic vascular congestion, like pregnancy or straining during defecation.
• Hemorrhoids are painful, uncomfortable swellings prone to bleeding and thrombosis.
• Hemorrhoids are prone to ulceration.

Thrombophlebitis = Phlebothrombosis

• Venous thrombosis and inflammation.
• Deep leg veins account for over 90% of cases.
• Prolonged inactivity reduces blood flow leading to lower extremity deep venous thrombosis (DVT).
• Risk factors for DVT include congestive heart failure, pregnancy, oral contraceptive use, malignancy, obesity, and systemic hypercoagulability.
• Cancer, especially adenocarcinomas, can cause paraneoplastic syndromes and hypercoagulability.
• Migratory thrombophlebitis (Trousseau syndrome) involves migrating venous thromboses.

Clinical Aspects

• Thrombi in the legs often have few visible signs or symptoms, especially in bedridden individuals.
• Physical pain may be elicited by pressure over affected veins, squeezing calf muscles, or forced dorsiflexion of the foot.
• Absence of symptoms does not exclude DVT.

Pulmonary Embolism: A Serious Clinical Complication of DVT

• DVT fragments and detaches, causing a pulmonary embolism.
• Pulmonary embolism is a common manifestation of thrombophlebitis.
• The outcome of pulmonary embolism varies from asymptomatic to fatal, depending on the size and number of emboli.

Vascular Tumors

• Vascular neoplasms originate from endothelial cells or from cells supporting blood vessels (e.g., glomus tumor).
• Primary tumors of large vessels (aorta, pulmonary artery, vena cava) are frequently sarcomas.

Benign Tumors (Hemangiomas)

• Hemangiomas are very common tumors made of blood-filled vessels.
• 7% of benign tumors in infants and children are hemangiomas.
• Hemangiomas commonly regress, but frequently start at birth and increase in size.
• They often present in the head, neck, and thoracic skin.
• Types include capillary hemangiomas, juvenile hemangiomas, and pyogenic granulomas.

Capillary Hemangiomas

• The most frequent hemangioma type affecting the skin, subcutaneous tissues, oral mucosa and cavities, lips, liver, spleen, and kidneys.
• Composed of thin-walled capillaries with little supporting stroma.

Juvenile Hemangiomas (Strawberry-Type)

• Extremely common in newborns (1 in 200).
• Can be multiple hemangiomas.
• Grow rapidly, then fade, and typically disappear by age 7 for most patients.

Cavernous Hemangiomas

• Composed of large dilated vascular channels.
• More invasive, deep structures are frequently affected, and they don't typically disappear.
• Imaging studies may not differentiate them from malignancy.
• Composed of large cavernous blood-filled spaces separated by connective tissue stroma.
• A component of von Hippel-Lindau disease where lesions commonly affect the cerebellum, brain stem, retina, pancreas, and liver.

Pyogenic Granulomas

• Rapidly growing red, pedunculated lesions on the skin, gingival tissues, and oral mucosa.
• They frequently bleed easily and are often ulcerated.
• A quarter of the lesions emerge after trauma and reach 1-2cm in size within weeks.
• Curettage and cautery are typically curative.
• Pregnancy tumors (granuloma gravidarum) are a subtype occurring infrequently (1%) in pregnant women's gingival tissues.
• May regress spontaneously after pregnancy or undergo fibrosis, but may require surgical excision.

Other Benign Lesions (Lymphangiomas)

• Simple or capillary lymphangiomas are characterized by lymphatic endothelial markers (e.g., VEGFR-3, LYVE-1) and typically show absence of erythrocytes.
• Cavernous lymphangiomas (cystic hygromas) occur in the neck and axilla of children and rarely affect the retroperitoneum.
• Neck lesions are commonly linked to Turner syndrome.

Glomus Tumors (Glomangiomas)

• Benign, exquisitely painful tumors emerging from modified smooth muscle cells (SMCs) in glomus bodies.
• Glomus bodies are arteriovenous structures involved in thermoregulation.
• While superficially similar to hemangiomas, glomangiomas arise from SMCs rather than endothelial cells (ECs).
• Commonly found in the distal digits, especially on fingertips.
• Excision is a curative treatment.

Intermediate-Grade (Borderline) Tumors (Kaposi Sarcoma)

• Caused by human herpesvirus 8 (HHV8).
• Most common in individuals with AIDS.
• Classification includes classic KS, endemic African KS, transplant-associated KS, and AIDS-associated (epidemic) KS.
• Classic KS involves multiple red-purple plaques or nodules in the lower extremities, spreading proximally.

KS Pathogenesis

• HHV8 causes lytic and latent infections in endothelial cells (ECs).
• A virally encoded protein induces vascular endothelial growth factor (VEGF) production which stimulates endothelial growth.
• Cytokines produced by inflammatory cells trigger local proliferation.
• HHV8 encoded proteins disrupt normal cellular controls, like cycle controls (e.g., cyclin D homologues), and inhibit apoptosis by inhibiting p53.

KS Morphology

• Patches are red-purple macules with areas of dilated irregular EC-lined vascular spaces.
• Interspersed lymphocytes, plasma cells, and macrophages (sometimes with hemosiderin) are common.
• Lesions may be challenging to differentiate from granulation tissue.
• Lesions can become larger, violaceous, raised plaques with dilated vascular channels.
• Spindle cells surround the vascular channels; erythrocytes, hemosiderin-laden macrophages, and other mononuclear inflammatory cells are frequently found between vascular channels.
• Nodular stage shows sheets of plump proliferating spindle cells embedded in dermal and subcutaenous tissues.
• Small vessels and slit-like spaces with red blood cells, marked hemorrhage, hemosiderin pigments, and mononuclear inflammatory cells are prominent.
• Mittic figures are common, with cytoplasmic globules representing degenerating erythrocytes.
• The nodular stage typically precedes lymph node and visceral involvement.

KS Clinical Features

• Most primary HHV8 infections are asymptomatic.
• Classic KS starts as superficial skin lesions.
• Surgical resection is a frequent treatment option for multiple skin lesions.
• Radiation therapy may be used for multiple lesions.
• Chemotherapy may be used for disseminated diseases.

Hemangioendothelioma

• A spectrum of borderline vascular neoplasms that affects adults and involves blood vessels (veins).
• Epithelioid hemangioendothelioma in is a subtype that commonly involves medium and large sized veins.
• Well-defined vascular channels are often subtle and the neoplastic cells are frequently plump and often cuboidal resembling epithelial cells.
• Clinical behaviours vary; however, most are typically cured by surgical excision.

Angiosarcoma

• Malignant endothelial neoplasms whose histology ranges from highly differentiated tumors that mimic hemangiomas to profoundly anaplastic lesions.
• Commonly affects older adults (both men and women).
• Commonly affects skin, soft tissue, breasts, and liver.
• It can emerge in lymphedematous regions, especially after radical mastectomy and/or radiation therapy for breast cancer.

Hepatic Angiosarcomas

• Associated with many carcinogenic exposures, including arsenic (e.g., in pesticides), Thorotrast (a historic radioactive contrast agent), and polyvinyl chloride.
• Long latency exists between exposure and tumor development.
• Angiosarcoma is a locally invasive tumor type that readily metastasizes.
• 5-year survival rates for hepatic angiosarcoma approximate 30%.

Angiosarcoma, Morphology

• Cutaneous angiosarcomas may begin as multiple, deceivingly small, asymptomatic papules or nodules that appear as red.
• More advanced lesions manifest as large, fleshy masses ranging from red-tan to gray-white in colour with blurry margins into surrounding tissues.
• Necrosis and hemorrhage are common.
• Microscopically, the lesions display varied differentiation degrees from plump atypiacal endothelial cells (ECs) forming vascular channels, to tumors with no clear vascular patterns.
• Endothelial nature is detectable by IHC staining for CD31 and von Willebrand factor.

Vasculitis

• The presentation covers mechanisms and examples of diseases categorized together as vasculitis.

Pathogenic Mechanisms of Vasculitis

• Immune-mediated inflammation, resulting from immune complex deposition, antineutrophil cytoplasmic antibodies (ANCAs), anti-EC antibodies, and autoreactive T cells.
• Direct invasion of vascular walls by infectious pathogens.

Giant Cell (Temporal) Arteritis

• Chronic granulomatous inflammation of large-to-small arteries, often targeting those in the head.
• Commonly affects elderly adults in the US and Europe.
• Temporal arteries are frequently affected, along with vertebral and ophthalmic arteries, and the aorta (giant cell aortitis).
• Prompt diagnosis and treatment are crucial because ophthalmic artery involvement can lead to permanent blindness.

Giant Cell Arteritis, Pathogenesis

• Result of a T-cell-mediated immune response to an unknown vascular wall antigen.
• Proinflammatory cytokines (e.g., TNF) and anti-endothelial cell (EC) antibodies contribute.
• The precise reason for the predilection for vessels in the head remains unknown.

Temporal Arteritis, Clinical Features

• Rare before age 50.
• Symptoms may include non-specific symptoms such as fatigue, weight loss, fever, vague complaints of facial pain, and headaches, mostly intense along the superficial temporal artery.
  • Painful to palpation of the artery.
• Ocular symptoms (associated with ophthalmic artery involvement) are a concern, ranging from diplopia to complete vision loss.
• Diagnosis depends on biopsy.
• A 1cm segment for adequate biopsy is crucial despite being sometimes spotty and focalised within an artery.
• Negative biopsy results don't rule out the diagnosis fully.
• Corticosteroids or anti-TNF therapies are generally effective.

Takayasu Arteritis

• A granulomatous vasculitis of medium and large arteries.
• Characterized by ocular disturbances and weakened pulses in the upper extremities (also called pulseless disease).
• Transmural fibrous thickening is common, especially in significant vessels like the aorta and its branches.
• Features share similarities with giant cell aortitis; however, the distinction is frequently based on age. Patients over 50 are classified as having giant cell aortitis, while those under 50 are classified as Takayasu arteritis.
• Global distribution of the disease.
• The etiology is likely autoimmune.

Takayasu Arteritis, Morphology

• Typically affects the aortic arch, but involvement extends to other parts of the aorta and branches, frequently including the pulmonary artery, coronary, and renal arteries.
• Thickening of the vessel walls and intimal hyperplasia is characteristic.
• Involvement of the aortic arch often leads to narrowed or even obliterated great vessel lumens. This reduces peripheral pulse strength.

Takayasu Arteritis, Morphology (Microscopic)

• Microscopic changes vary from adventitial mononuclear cell infiltrates with perivascular cuffing of vasa vasorum
• to intense mononuclear inflammatory infiltrates
• including granulomas and giant cells throughout the arterial media.
• Patchy medial necrosis can also occur.
• Microscopic features tend to be similar to giant cell (temporal) arteritis.

Takayasu Arteritis, Clinical Features

• Initial symptoms are usually nonspecific such as weight loss, fever, and fatigue.
• Vascular symptoms like weaker pulses in upper extremities, visual disturbances, retinal hemorrhages, total blindness, and neurological deficits prevail later during the disease.

Clinical Features, Takayasu Arteritis (Continued)

• Involvement of the more distal aorta commonly leads to lower limb claudication.
• Pulmonary artery involvement may result in pulmonary hypertension.
• Narrowing of coronary ostia can result in myocardial infarction.
• Renal artery involvement frequently causes systemic hypertension.
• The disease course varies both in terms of rapid progression or quiescent stage that last 1-2 years, leading to long-term survival with neurological or visual deficits.

Churg-Strauss Syndrome

• Allergic granulomatosis and angiitis (or a small-vessel necrotizing vasculitis).
• Often associated with asthma, allergic rhinitis, lung infiltrates, peripheral eosinophilia, extravascular necrotizing granulomas, and eosinophilic infiltration of vessels and tissues.

Churg-Strauss Syndrome (Clinical Features)

• Cutaneous involvement (palpable purpura), gastrointestinal bleeding and renal disease (primarily focal and segmental glomerulosclerosis) are common.
• Myocardial eosinophilic infiltrates often cause cardiomyopathy, which is a significant cause of morbidity and mortality.
• The disease is thought to be triggered by hyperresponsiveness to a previously innocuous allergic stimulus.
• Many cases associate with myeloperoxidase-antineutrophil cytoplasmic antibodies (MPO-ANCAs).
• Microscopic examination typically shows both granulomas and eosinophils.

Polyarteritis Nodosa (PAN)

• Systemic vasculitis affecting small and medium sized muscular arteries.
• Typically involves renal and visceral vessels.
• The pulmonary circulation remains unaffected.
• A third of affected patients show chronic hepatitis B with the presence of HBsAg-HbsAb complexes in affected vessels.
• The etiology is not consistently known in a vast majority of cases.

PAN, Morphology

• Segmental transmural necrotizing inflammation of small and medium sized arteries.
• Often features superimposed aneurysms and/or thrombosis.
• The kidney, heart, liver, and gastrointestinal tract vessels tend to be affected in descending order.
• Lesions frequently involve only a variable portion of the vessel circumference with a predilection for branch points.
• Impaired perfusion of affected areas leads to ulcerations, infarcts, ischemic atrophy, or hemorrhage.

PAN, Morphology (Microscopic)

• Transmural inflammation shows a mixed infiltrate of neutrophils, eosinophils, and mononuclear cells.
• Fibrinoid necrosis and luminal thrombosis are frequent accompanying features.

Microscopic Polyangiitis

• Hypersensitivity vasculitis or leukocytoclastic vasculitis.
• Necrotizing vasculitis that frequently affects capillaries as well as small arterioles and venules.
• Lesions at various stages of development are equally prevalent for microscopic polyangiitis in a single patient.
• Typically associated with a single episode of antibody or immune complex deposition.

Microscopic Polyangiitis (Clinical Features)

• The skin, mucous membranes, lungs, brain, heart, gastrointestinal tract, kidneys, and muscles can be affected.
• Necrotizing glomerulonephritis and pulmonary capillaritis are common.
• Most cases show an association with myeloperoxidase-antineutrophil cytoplasmic antibodies (MPO-ANCAs). The neutrophils' recruitment and activation are responsible for the manifestations.

Thromboangiitis Obliterans (Buerger Disease)

• Characterized by segmental, thrombosing, acute and chronic inflammation of medium and small sized arteries.
• Mostly affects the tibial and radial arteries in the extremities.
• Exclusively seen in heavy cigarette smokers, typically before age 35, possibly due to idiosyncratic endothelial cell (EC) toxicity.

Thromboangiitis Obliterans (Buerger Disease), Morphology

• Affected vessels show acute and chronic inflammation with luminal thrombosis.
• Thrombi may feature microabscesses of neutrophils.
• Inflammatory process extends to nearby veins and nerves.
• In time, inflammation will encapsulate all three structures in a fibrous tissue.

Infectious Vasculitis

• Infectious agents like bacteria or fungi (e.g., Aspergillus and Mucor) may cause this condition.
• Vascular infections can result in the weakening of arterial walls leading to mycotic aneurysms.
• Thrombosis and downstream infarction can also occur following a vascular infection.