Pathology of Veins, Lymphatics, Vascular Tumors, & Vasculitis PDF

Pathology of the veins and lymphatics, vascular tumors, & vasculitis Dr. Aileen Azari-Yam M.D., Ph.D. 1 Objective Varicose veins Phlebothrombosis/Thrombophlebitis 2 Varicose Veins Varicose veins...

Pathology of the veins and lymphatics, vascular tumors, & vasculitis Dr. Aileen Azari-Yam M.D., Ph.D. 1 Objective Varicose veins Phlebothrombosis/Thrombophlebitis 2 Varicose Veins Varicose veins are abnormally dilated, tortuous veins produced by prolonged, increased intraluminal pressure with vessel dilation and incompetence of the venous valves. The superficial veins of the upper and lower leg are commonly involved because venous pressures in these sites can be markedly elevated (up to 10 times normal) by prolonged dependent posture. Up to 20% of men and a third of women develop lower extremity varicose veins. Obesity increases the risk 3 Varicose Veins, Clinical Features Incompetence of the venous valves leads to stasis, congestion, edema, pain, and thrombosis. Secondary tissue ischemia results from chronic venous congestion and poor vessel drainage leading to stasis dermatitis (also called “brawny induration” The brawny color comes from the hemolysis of extravasated red cells) and ulcerations; Poor wound healing and superimposed infections are common additional complications. Notably, embolism from these superficial veins is very rare, as opposed to the thromboembolism from thrombosed deep veins 4 Varicosities in two other sites Esophageal varices Liver cirrhosis >>> portal vein hypertension >>> opening of portosystemic shunts >>> increase blood flow into veins at the gastroesophageal junction (forming esophageal varices), rectum (forming hemorrhoids), and periumbilical veins of the abdominal wall (forming a caput medusa) Esophageal varices >>> rupture >>> massive (even fatal) upper GI hemorrhage. 5 Varicosities in two other sites Hemorrhoids Also result from primary varicose dilation of the venous plexus at the anorectal junction (e.g., through prolonged pelvic vascular congestion due to pregnancy or straining to defecate). Hemorrhoids are uncomfortable and may be a source of bleeding; they can also thrombose and are prone to painful ulceration. 6 Thrombophlebitis = Phlebothrombosis Venous thrombosis and inflammation Deep leg veins account for more than 90% of cases. Prolonged immobilization >>> Decreased blood flow >>> lower extremity deep venous thrombosis (DVT). Additional risk factors: congestive heart failure Pregnancy oral contraceptive use Malignancy Obesity Systemic hypercoagulability 7 Cancer hypercoagulability Cancer (esp. adenocarcinomas) >>> paraneoplastic syndrome with elaboration of procoagulant factors >>> hypercoagulability Migratory thrombophlebitis (Trousseau syndrome): venous thromboses appear in one location, disappear, and then occur in another site 8 Clinical aspects Thrombi in the legs tend to produce few, if any, reliable signs or symptoms. Indeed, local manifestations including vein dilation, edema, cyanosis, heat, erythema, or pain may be entirely absent, especially in bedridden patients. Homan sign: In some cases, pain can be elicited by pressure over affected veins, squeezing the calf muscles, or forced dorsiflexion of the foot Absence of these findings does not exclude DVT. 9 Pulmonary embolism, a serious clinical complication of DVT DVT >>> fragmentation or detachment of the venous thrombus >>> Pulmonary embolism In many cases, manifestation of thrombophlebitis is a pulmonary embolus. Depending on the size and number of emboli, the outcome can range from no symptoms to death. 10 VASCULAR TUMORS 11 Vascular neoplasms arise from: endothelium (e.g., hemangioma, lymphangioma, angiosarcoma) cells that support or surround blood vessels (e.g., glomus tumor) Primary tumors of large vessels (aorta, pulmonary artery, and vena cava) are mostly sarcomas. 12 Vascular neoplasms Benign tumors usually contain obvious vascular channels filled with blood cells (lymphatics will be filled with lymph), lined by a monolayer of normal-appearing ECs. Malignant tumors are more solidly cellular and more proliferative and exhibit cytologic atypia; they usually do not form well-organized vessels. The endothelial derivation of such neoplastic proliferations may require immunohistochemical markers such as CD31 or von Willebrand factor. 13 Benign Tumors, Hemangiomas Very common tumors composed of blood-filled vessels Constitute 7% of all benign tumors of infancy and childhood. Most are present from birth and initially increase in size, but many eventually regress spontaneously. Typically in the head, neck, and thoracic skin Types: Capillary hemangiomas Juvenile hemangiomas Pyogenic granulomas 14 Capillary hemangiomas the most common type occur in the skin, subcutaneous tissues, and mucous membranes of the oral cavities and lips, as well as in the liver, spleen, and kidneys Micro: thin-walled capillaries with scant stroma 15 Juvenile hemangiomas = strawberry-type hemangiomas extremely common: 1 in 200 newborns can be multiple. grow rapidly for a few months, but then fade by 1 to 3 years of age and completely regress by age 7 in most cases. 16 Cavernous hemangiomas Composed of large, dilated vascular channels. More infiltrative, frequently involve deep structures, and do not spontaneously regress Imaging studies cannot distinguish from their malignancy Micro: the mass is sharply delineated but unencapsulated, composed of large, cavernous blood-filled vascular spaces, separated by connective tissue stroma A component of von Hippel-Lindau disease, in which vascular lesions are found in the cerebellum, brain stem, retina, pancreas, and liver. 17 Hemangiomas (A) Hemangioma of the tongue. (B) Histology of juvenile capillary hemangioma. (C) Histology of cavernous hemangioma. (D) Pyogenic granuloma of the lip. 18 Pyogenic granulomas Capillary hemangiomas that present as rapidly growing red pedunculated lesions on the skin, gingiva, or oral mucosa. They bleed easily and are often ulcerated. A quarter of lesions develop after trauma, reaching a size of 1 to 2 cm within a few weeks. Curettage and cautery is usually curative. Pregnancy tumor (granuloma gravidarum) is a pyogenic granuloma that occurs infrequently (1% of patients) in the gingiva of pregnant women. may spontaneously regress (especially after pregnancy) or undergo fibrosis, but occasionally require surgical excision. 19 Other benign lesions Lymphangiomas Simple (capillary) lymphangiomas can be distinguished from capillary channels by lymphatic endothelial markers (e.g., VEGFR-3, LYVE-1, and others) or by the absence of erythrocytes Cavernous lymphangiomas (cystic hygromas) neck or axilla of children and rarely in the retroperitoneum neck lesions are common in Turner syndrome 20 Glomus Tumor (Glomangioma) Benign, exquisitely painful tumors arising from modified SMCs of the glomus bodies Glomus bodies: arteriovenous structures involved in thermoregulation. Although they may superficially resemble hemangiomas, glomangiomas arise from SMCs rather than ECs. Found in the distal portion of the digits, especially under the fingernails. Excision is curative. 21 Intermediate-Grade (Borderline) Tumors Cause: human herpesvirus 8 (HHV8) Most common in patients with AIDS Classification: Classic KS Multiple red-purple skin plaques or nodules, usually in the distal lower extremities; these progressively increase in size and number and spread proximally. Endemic African KS Transplant-associated KS AIDS-associated (epidemic) KS 22 KS pathogenesis HHV8 causes lytic and latent infections in Ecs A virally encoded G protein induces VEGF production, stimulating endothelial growth In addition, cytokines produced by inflammatory cells induces local proliferation In latently infected cells, HHV8 encoded proteins disrupt normal cellular proliferation controls (e.g., through synthesis of a viral homologue of cyclin D) and prevent apoptosis by inhibiting p53. 23 KS, morphology the cutaneous lesions progress through three stages: Patches are red-purple macules. Histology shows dilated irregular EC-lined vascular spaces with interspersed lymphocytes, plasma cells, and macrophages (sometimes containing hemosiderin). The lesions can be difficult to distinguish from granulation tissue. With time, lesions become larger, violaceous, raised plaques composed of dermal accumulations of dilated, jagged vascular channels lined and surrounded by plump spindle cells. Scattered between the vascular channels are extravasated erythrocytes, hemosiderin-laden macrophages, and other mononuclear inflammatory cells. 24 KS, morphology Nodular stage: composed of sheets of plump, proliferating spindle cells, mostly in the dermis or subcutaneous tissues, containing small vessels and slit-like spaces with red cells. Marked hemorrhage, hemosiderin pigment, and mononuclear inflammation are present mitotic figures are common round, pink, cytoplasmic globules representing degenerating erythrocytes within phagolysosomes. The nodular stage often precedes lymph node and visceral involvement. 25 KS, Clinical Features Most primary HHV8 infections are asymptomatic. Classic KS is—at least initially—largely restricted to the skin: surgical resection Radiation can be used for multiple lesions in a restricted area Chemotherapy for more disseminated disease 26 Kaposi sarcoma (A) Gross photograph illustrating coalescent red-purple macules and plaques of the skin. (B) Nodular stage with sheets of plump, proliferating spindle cells. 27 Hemangioendothelioma A spectrum of borderline vascular neoplasms Epithelioid hemangioendothelioma is a tumor of adults occurring around medium- and large-sized veins. Well-defined vascular channels are inconspicuous, and neoplastic cells are plump and often cuboidal (resembling epithelial cells). The clinical behavior is extremely variable; most are cured by excision, but up to 40% recur, 20% to 30% eventually metastasize, and 15% of patients will die of their tumor. 28 Angiosarcoma malignant endothelial neoplasms with histology varying from highly differentiated tumors that resemble hemangiomas to profoundly anaplastic lesions. Older adults, males and females, are more commonly affected occurs at any site, but most often involve skin, soft tissue, breast, and liver. 29 Angiosarcomas can arise in the setting of lymphedema, classically in the ipsilateral upper extremity several years after radical mastectomy for breast cancer (i.e., after lymph node resection and/or radiation); in such cases the tumor presumably arises from lymphatic vessels (lymphangiosarcoma). also induced by radiation and are rarely associated with prolonged insertion of foreign material (e.g., prosthetic devices). 30 Hepatic angiosarcomas associated with a variety of carcinogenic exposures including arsenic (e.g., in pesticides), Thorotrast (a radioactive contrast agent formerly used for radiologic imaging), and polyvinyl chloride. These agents have long latencies between initial exposure and tumor development. Angiosarcomas are locally invasive and can readily metastasize, with 5-year survival rates of approximately 30%. 31 Angiosarcomas, morphology Cutaneous angiosarcomas can begin as multiple, deceptively small and asymptomatic red papules or nodules. More advanced lesions are large, fleshy masses of red-tan to gray-white tissue with margins blurring imperceptibly into surrounding structures. Necrosis and hemorrhage are common. Microscopically, all degrees of differentiation can be seen, from plump, atypical ECs forming vascular channels to wildly undifferentiated tumors with no discernible blood vessels. The endothelial origin of these tumors can be demonstrated by IHC staining for CD31 or von Willebrand factor 32  Angiosarcoma (A) Angiosarcoma involving the right ventricle. (B) Moderately differentiated angiosarcoma with dense clumps of atypical cells lining distinct vascular lumens. (C) Immunohistochemical staining for the endothelial cell marker CD31 demonstrating the endothelial nature of the tumor cells. 33 Vasculitis 34  The two pathogenic mechanisms of vasculitis: Immune-mediated inflammation Immune complex deposition Antineutrophil cytoplasmic antibodies (ANCAs) Anti-EC antibodies Autoreactive T cells Direct invasion of vascular walls by infectious pathogens 35 Giant Cell (Temporal) Arteritis A chronic, granulomatous inflammation of large- to small-sized arteries that affects arteries in the head. The most common form of vasculitis among elderly adults in the US and Europe. The temporal arteries are not particularly vulnerable, but their name is attached to the disorder since they are the most readily Vertebral and ophthalmic arteries, as well as the aorta (giant cell aortitis), also can be involved. Because ophthalmic artery involvement can lead to sudden and permanent blindness, affected persons must be diagnosed and treated promptly. 36 Giant cell arteritis, Pathogenesis Result of a T cell–mediated immune response to an unknown vessel wall antigen. Proinflammatory cytokines (especially TNF) and anti-EC antibodies also contribute. The predilection for vessels of the head remains unexplained 37 Temporal arteritis, Clinical Features Rare before age 50 Symptoms may be only vague and constitutional—fever, fatigue, weight loss—or may involve facial pain or headache, most intense along the course of the superficial temporal artery, which can be painful to palpation. Ocular symptoms (associated with involvement of the ophthalmic artery) abruptly appear in about 50% of patients; these range from diplopia to complete vision loss. Diagnosis depends on biopsy and histologic confirmation. Can be extremely focal within an artery, adequate biopsy requires at least a 1-cm segment; even then, a negative biopsy result does not exclude the diagnosis. Corticosteroids or anti-TNF therapies are typically effective. 38  Giant cell (temporal) arteritis ) temporal artery showing giant cells at the degenerated internal elastic membrane in active arteritis ) Elastic tissue stain demonstrating focal destruction of internal elastic membrane (arrow) and intimal thickening (IT) characteristic of long-standing or healed arteritis. ) The temporal artery of a patient with classic giant cell arteritis shows a thickened, nodular, and tender segment of a vessel on the surface of head (arrow). 39 Takayasu arteritis a granulomatous vasculitis of medium and larger arteries characterized by ocular disturbances and marked weakening of the pulses in the upper extremities (hence the name pulseless disease). manifests with transmural fibrous thickening of the aorta—particularly the aortic arch and great vessels—with severe luminal narrowing of the major branch vessels shares many attributes with giant cell aortitis, including clinical features and histology; indeed, the distinction is typically made based on the age of the patient. Those over 50 years of age are designated as giant cell aortitis, while those under 50 are designated as Takayasu aortitis. has a global distribution. An autoimmune etiology is likely. 40 Morphology (Takayasu arteritis) Classically involves the aortic arch In a third of patients, it also affects the remainder of the aorta and its branches pulmonary artery involvement in half of cases coronary and renal arteries may be affected. irregular thickening of the vessel wall with intimal hyperplasia; When the aortic arch is involved, the great vessel lumens can be markedly narrowed or even obliterated >>> weakness of the peripheral pulses 41 Morphology, Takayasu arteritis Micro: the changes range from adventitial mononuclear infiltrates with perivascular cuffing of the vasa vasorum to intense mononuclear inflammation in the media. Granulomatous inflammation, replete with giant cells and patchy medial necrosis The histology is essentially indistinguishable from giant cell (temporal) arteritis. 42  Active Takayasu aortitis Destruction and fibrosis of the arterial media associated with mononuclear infiltrates and inflammatory giant cells 43 Clinical features, Takayasu arteritis Initial symptoms are usually nonspecific, including fatigue, weight loss, and fever. With progression, vascular symptoms appear and dominate the clinical picture, including reduced blood pressure weaker pulses in the upper extremities ocular disturbances, including visual defects, retinal hemorrhages, and total blindness neurologic deficits Involvement of the more distal aorta may lead to claudication of the legs Pulmonary artery involvement can cause pulmonary hypertension. 44 Clinical features, Takayasu arteritis Narrowing of the coronary ostia may lead to myocardial infarction Involvement of the renal arteries leads to systemic hypertension in roughly half of patients. The course of the disease is variable. In some patients there is rapid progression, while others enter a quiescent stage at 1 to 2 years, permitting long-term survival, albeit with visual or neurologic deficits. 45 Churg-Strauss Syndrome = allergic granulomatosis and angiitis a small-vessel necrotizing vasculitis Classically associated with: Asthma allergic rhinitis lung infiltrates peripheral eosinophilia extravascular necrotizing granulomas eosinophilic infiltration of vessels and tissues 46 Churg-Strauss Syndrome Cutaneous involvement (with palpable purpura), gastrointestinal bleeding, and renal disease (primarily as focal and segmental glomerulosclerosis) are the major associations. Cytotoxicity produced by the myocardial eosinophilic infiltrates often leads to cardiomyopathy; cardiac involvement is seen in 60% of patients and is a major cause of morbidity and death. Churg-Strauss syndrome is likely a consequence of hyperresponsiveness to some normally innocuous allergic stimulus. MPO-ANCAs are present in a minority of cases, suggesting that the disorder is pathogenically heterogeneous. The vascular lesions differ from those of PAN or microscopic polyangiitis by virtue of the presence of both granulomas and eosinophils. 47 Polyarteritis Nodosa (PAN) PAN is a systemic vasculitis of small- or medium-sized muscular arteries that typically affects renal and visceral vessels but spares the pulmonary circulation a third of patients have chronic hepatitis B >>> HBsAg-HbsAb complexes that deposit in affected vessels The cause remains unknown in the majority of cases. 48 PAN, morphology Segmental transmural necrotizing inflammation of small- to medium-sized arteries, often with superimposed aneurysms and/or thrombosis. Kidney, heart, liver, and GI vessels are involved in descending order Lesions usually involve only part of the vessel circumference with a predilection for branch points. Impaired perfusion of parenchyma distal to the lesions >>> ulcerations, infarcts, ischemic atrophy, or hemorrhage 49 PAN, morphology Transmural inflammation of the arterial wall with a mixed infiltrate of neutrophils, eosinophils, and mononuclear cells, frequently accompanied by fibrinoid necrosis and luminal thrombosis. Part of the vessel wall at the upper right (arrow) is uninvolved. 50 PAN, clinical features A disease of young adults but can occur in all age groups. The course is frequently remitting and episodic, with long symptom-free intervals. Typical presentation: Rapidly accelerating hypertension due to renal artery involvement Renal involvement is often a major cause of mortality. Abdominal pain and bloody stools Diffuse myalgias Peripheral neuritis, predominantly affecting motor nerves 51 Microscopic Polyangiitis = hypersensitivity vasculitis = leukocytoclastic vasculitis Microscopic polyangiitis is a necrotizing vasculitis that generally affects capillaries as well as small arterioles and venules. Unlike PAN, all lesions of microscopic polyangiitis tend to be of the same age in any given patient, suggesting a single episode of antibody or immune complex deposition. 52 Microscopic Polyangiitis The skin, mucous membranes, lungs, brain, heart, gastrointestinal tract, kidneys, and muscle all can be involved. Necrotizing glomerulonephritis (90% of patients) and pulmonary capillaritis are particularly common. Most cases are associated with MPO-ANCA. Recruitment and activation of neutrophils is responsible for manifestations. 53 Thromboangiitis Obliterans (Buerger Disease) Characterized by segmental, thrombosing, acute and chronic inflammation of medium- and small-sized arteries, especially the tibial and radial arteries, that often leads to vascular insufficiency, typically of the extremities. It occurs almost exclusively in heavy cigarette smokers, usually before the age of 35- idiosyncratic EC toxicity 54 Thromboangiitis Obliterans (Buerger Disease) Affected vessels of show acute and chronic inflammation, accompanied by luminal thrombosis. The thrombus can contain small microabscesses composed of neutrophils surrounded by granulomatous inflammation The thrombus may eventually organize and recanalize. The inflammatory process extends into contiguous veins and nerves (rare with other forms of vasculitis), and with time all three structures can be encased in fibrous tissue. 55  Thromboangiitis Obliterans (Buerger Disease) The lumen is occluded by a thrombus containing abscesses (arrow), and the vessel wall is infiltrated with leukocytes. 56 Infectious Vasculitis Cause: bacteria or fungi, and in particular Aspergillus and Mucor species. Vascular infections can weaken arterial walls >>> mycotic aneurysms Vascular infections >>> thrombosis and downstream infarction 57 58