Pathology_Robbins

Pathology_Robbins. Hyperlipidemia—and, more specifically, hypercholesterolemia—is a major risk factor for development of atherosclerosis and is sufficient to induce lesions in the absence of other risk factors. The main cholesterol component associated with increased risk is low-density lipoprotein (LDL) cholesterol (“bad cholesterol”); LDL distributes cholesterol to peripheral tissues. By contrast, high-density lipoprotein (HDL) cholesterol (“good cholesterol”) mobilizes cholesterol from developing and existing vascular plaques and transports it to the liver for biliary excretion. Consequently, higher levels of HDL correlate with reduced risk. Recognition of these relationships has spurred the development of dietary and pharmacologic interventions that lower total serum cholesterol or LDL and/or raise serum HDL, as follows:


Pathology_Robbins

Pathology_Robbins. High dietary intake of cholesterol and saturated fats (e.g., present in egg yolks, animal fats, and butter) raises plasma cholesterol levels. Conversely, diets low in cholesterol and/or containing higher ratios of polyunsaturated fats, lower plasma cholesterol levels. Omega-3 fatty acids (abundant in fish oils) are beneficial, whereas (trans)-unsaturated fats produced by artificial hydrogenation of polyunsaturated oils (used in baked goods and margarine) adversely affect cholesterol profiles. Exercise and moderate consumption of ethanol raise HDL levels, whereas obesity and smoking lower them. Statins are a widely used class of drugs that lower circulating cholesterol levels by inhibiting hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in hepatic cholesterol biosynthesis (Chapter 7).


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Pathology_Robbins. Hypertension (see earlier discussion) is another major risk factor for development of atherosclerosis. On its own, hypertension can increase the risk for IHD by approximately 60% (see Fig. 10.8 ). Hypertension also is the major cause of left ventricular hypertrophy (LVH), which also can contribute to myocardial ischemia (see Fig. 10.8 Cigarette smoking is a well-established risk factor in men and probably accounts for the increasing incidence and severity of atherosclerosis in women. Prolonged (years) smoking of one or more packs of cigarettes per day doubles the rate of IHD-related mortality, while smoking cessation reduces the risk.


Pathology_Robbins

Pathology_Robbins. Diabetes mellitus is associated with raised circulating cholesterol levels and markedly increases the risk for atherosclerosis. Other factors being equal, the incidence of myocardial infarction is twice as high in diabetics as in non-diabetics. In addition, this disorder is associated with an increased risk for stroke and a 100-fold increase in atherosclerosis-induced gangrene of the lower extremities.


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Pathology_Robbins. Roughly 20% of cardiovascular events occur in the absence of identifiable risk factors. For example, in previously healthy women, more than 75% of cardiovascular events occur in those with LDL cholesterol levels below 130 mg/dL (a cutoff value considered to connote only borderline risk). Other factors that contribute to risk include the following: • Inflammation. Inflammatory cells are present during all stages of atheromatous plaque formation and are intimately linked with plaque progression and rupture (see the following discussion). There is some evidence that a systemic pro-inflammatory state is associated with the development of atherosclerosis and hence measures of systemic inflammation have been used in risk stratification. Of various systemic markers of inflammation, determination of C-reactive protein (CRP) has emerged as one of the simplest and most sensitive. CRP is an acute-phase reactant synthesized primarily by the liver in response to a variety of inflammatory


Pathology_Robbins

Pathology_Robbins. of C-reactive protein (CRP) has emerged as one of the simplest and most sensitive. CRP is an acute-phase reactant synthesized primarily by the liver in response to a variety of inflammatory cytokines. In some studies,


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Pathology_Robbins. CRP levels independently predict the risk for myocardial infarction, stroke, peripheral arterial disease, and sudden cardiac death, even among apparently healthy individuals Fig. 10.9 ). However, such studies are confounded by lack of precise definition of “healthy individuals” because clinically asymptomatic individuals may harbor http://ebooksmedicine.net C-Reactive protein (mg/L) 1.0–3.0<1.0 >3.0 Framingham estimate of 10-year risk (%)


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Pathology_Robbins. Fig. 10.9 PrognosticvalueofC-reactiveprotein(CRP)incoronaryarterydisease.Relativerisk(y-axis)reflectstheriskforacardiovascularevent(e.g.,myocardialinfarction).Thex-axisshowsthe10-yearriskforacardiovasculareventcalculatedfromthetraditionalriskfactorsidentifiedintheFraminghamStudy.Ineachriskgroup,CRPlevelsfurtherstratifythepatients.(Data from Ridker PM, et al: Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. NEnglJMed347:1557, 2002.) significant atherosclerotic lesions with associated inflammation. Thus elevated CRP levels may be a marker of underlying asymptomatic atherosclerosis. Furthermore, there is no direct evidence that lowering CRP diminishes cardiovascular risk or that CRP is involved in the formation of atheromas. It is of interest that CRP is reduced by smoking cessation, weight loss, and exercise, all of which could reduce the risk of atherosclerosis independently. Thus, whether elevated CRP is


Pathology_Robbins

Pathology_Robbins. of atheromas. It is of interest that CRP is reduced by smoking cessation, weight loss, and exercise, all of which could reduce the risk of atherosclerosis independently. Thus, whether elevated CRP is a marker of or a consequence of plaque inflammation remains to be resolved.


Pathology_Robbins

Pathology_Robbins. Hyperhomocysteinemia. Serum homocysteine levels correlate with coronary atherosclerosis, peripheral vascular disease, stroke, and venous thrombosis. Homocystinuria, due to rare inborn errors of metabolism, causes elevated circulating homocysteine (greater than 100 µmol/L) and is associated with early-onset vascular disease. Although low folate and vitamin B12 levels can increase homocysteine levels, supplemental vitamin ingestion does not affect the incidence of cardiovascular disease.


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Pathology_Robbins. Metabolic syndrome. Associated with central obesity (Chapter 8), this clinical entity is characterized by insulin resistance, hypertension, dyslipidemia (elevated triglycerides and depressed HDL), hypercoagulability, and a pro-inflammatory state, which may be triggered by cytokines released from adipocytes. The dyslipidemia, hyperglycemia, and hypertension are all cardiac risk factors, while the systemic hypercoagulabgramle and pro-inflammatory state may contribute to endothelial dysfunction and/or thrombosis. Lipoprotein(a) levels. Lipoprotein(a) is an LDL-like particle that contains apolipoprotein B-100 linked to apolipoprotein(a). Lipoprotein(a) levels are correlated with risk of coronary and cerebrovascular disease, independent of total cholesterol or LDL levels. Apolipoprotein(a) is homologous to plasminogen, suggesting a potential link between thrombogenesis and circulating molecules that can drive atherosclerosis.


Pathology_Robbins

Pathology_Robbins. Apolipoprotein(a) is homologous to plasminogen, suggesting a potential link between thrombogenesis and circulating molecules that can drive atherosclerosis. Elevated levels of procoagulants are potent predictors of risk for major cardiovascular events including myocardial infarction and stroke. Excessive activation of thrombin, which you may recall can initiate inflammation through cleavage of protease-activated receptors (PARs; Chapter 4) on leukocytes, endothelium, and other cells, may be particularly atherogenic.


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Pathology_Robbins. Clonal hematopoiesis. It is now recognized that a surprisingly high fraction of older individuals have clonal hematopoiesis (Chapter 12), defined by the presence of a major clone of cells in the bone marrow that have acquired somatic driver mutations in one or more well-characterized oncogenes or tumor suppressor genes. Despite the presence of these mutations, such patients typically have normal blood counts. Unexpectedly, epidemiologic studies have found that clonal hematopoiesis is strongly associated with an increased risk of death from cardiovascular disease, possibly because of alterations in the function of innate immune cells derived from mutated hematopoietic stem cells. Work is ongoing to further confirm this association and determine its mechanistic basis. Other factors associated with difficult-to-quantify risks include lack of exercise and living a competitive, stressful lifestyle (“type A personality”).


Pathology_Robbins

Pathology_Robbins. Other factors associated with difficult-to-quantify risks include lack of exercise and living a competitive, stressful lifestyle (“type A personality”). The currently held view of pathogenesis is embodied in the response-to-injury hypothesis. This model views atherosclerosis as a chronic inflammatory response of the arterial wall to endothelial injury. Lesion progression involves interaction of modified lipoproteins, monocytederived macrophages, T lymphocytes, and the cellular constituents of the arterial wall (Fig. 10.10 ). According to this model, atherosclerosis results from the following pathogenic events: EC injury—and resultant endothelial dysfunction— leading to increased permeability, leukocyte adhesion, and thrombosis Accumulation of lipoproteins (mainly oxidized LDL and cholesterol crystals) in the vessel wall Monocyte adhesion to the endothelium, migration into the intima, and differentiation into macrophages and foam cells


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Pathology_Robbins. Monocyte adhesion to the endothelium, migration into the intima, and differentiation into macrophages and foam cells Lipid accumulation within macrophages, which respond by releasing inflammatory cytokines SMC recruitment due to factors released from activated platelets, macrophages, and vascular wall cells Some details of these steps are presented next. EC injury is the cornerstone of the response to injury hypothesis. EC loss due to any kind of injury—induced experimentally by mechanical denudation, hemodynamic forces, immune complex deposition, irradiation, or chemicals—results in intimal thickening; in the presence of high-lipid diets, typical atheromas ensue. However, early http://ebooksmedicine.net 1. Chronic endothelial “injury”: Viruses Response to injury 2. Endothelial dysfunction (e.g., increased permeability, Platelet leukocyte adhesion), Monocyte monocyte adhesion, and migration 3. Macrophage activation,


Pathology_Robbins

Pathology_Robbins. Viruses Response to injury 2. Endothelial dysfunction (e.g., increased permeability, Platelet leukocyte adhesion), Monocyte monocyte adhesion, and migration 3. Macrophage activation, Smoothsmooth muscle recruitment, muscle cell accumulation of lipids in vessel wall 4. Macrophages and smooth muscle cells engulf lipid human atherosclerotic lesions begin at sites of intact, but dysfunctional, endothelium. These dysfunctional ECs exhibit increased permeability, enhanced leukocyte adhesion, and altered gene expression, all of which may contribute to the development of atherosclerosis. Suspected triggers of early atheromatous lesions include hypertension, hyperlipidemia, toxins from cigarette smoke, and homocysteinemia. Inflammatory cytokines (e.g., tumor necrosis factor [TNF]) also can stimulate proatherogenic patterns of EC gene expression. Nevertheless, the two most important causes of endothelial dysfunction are hemodynamic disturbances and hypercholesterolemia.


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Pathology_Robbins. The importance of hemodynamic factors in atherogenesis is illustrated by the observation that plaques tend to occur at ostia of exiting vessels, at branch points, and along the posterior wall of the abdominal aorta, where there is turbulent blood flow. In vitro studies further demonstrate that nonturbulent laminar flow leads to the induction of endothelial genes whose products protect against atherosclerosis. Such “atheroprotective” genes may explain the nonrandom localization of early atherosclerotic lesions.


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Pathology_Robbins. Lipids typically are transported in the bloodstream bound to specific apoproteins (forming lipoprotein complexes). Dyslipoproteinemias can result from mutations in genes that encode apoproteins or lipoprotein receptors, or from disorders that derange lipid metabolism, e.g., nephrotic syndrome, alcoholism, hypothyroidism, or diabetes mellitus. Common lipoprotein abnormalities in the general population (and indeed, present in many myocardial infarction survivors) include (1) increased LDL cholesterol levels, (2) decreased HDL cholesterol levels, and 3) increased levels of lipoprotein(a). Several lines of evidence implicate hypercholesterolemia in atherogenesis: The dominant lipids in atheromatous plaques are cholesterol and cholesterol esters.


Pathology_Robbins

Pathology_Robbins. Several lines of evidence implicate hypercholesterolemia in atherogenesis: The dominant lipids in atheromatous plaques are cholesterol and cholesterol esters. Genetic defects in lipoprotein uptake and metabolism that cause hyperlipoproteinemia are associated with accelerated atherosclerosis. Thus, homozygous familial hypercholesterolemia, caused by defective LDL receptors and inadequate hepatic LDL uptake, can lead to myocardial infarction by 20 years of age. Other genetic or acquired disorders (e.g., diabetes mellitus, hypothyroidism) that cause hypercholesterolemia lead to premature atherosclerosis. Epidemiologic analyses (e.g., the Framingham study) demonstrate a significant correlation between the levels of total plasma cholesterol or LDL and the severity of atherosclerosis. Lowering serum cholesterol by diet or drugs slows the rate of progression of atherosclerosis, causes regression of some plaques, and reduces the risk for cardiovascular events.


Pathology_Robbins

Pathology_Robbins. Lowering serum cholesterol by diet or drugs slows the rate of progression of atherosclerosis, causes regression of some plaques, and reduces the risk for cardiovascular events. The mechanisms by which dyslipidemia contributes to atherogenesis include the following: Chronic hyperlipidemia, particularly hypercholesterolemia, can directly impair EC function by increasing local oxygen free radical production; among other things, oxygen free radicals accelerate NO decay, damping its vasodilator activity.


Pathology_Robbins

Pathology_Robbins. With chronic hyperlipidemia, lipoproteins accumulate within the intima, where they are hypothesized to generate two pathogenic derivatives, oxidized LDL and cholesterol crystals. LDL is oxidized through the action of oxygen free radicals generated locally by macrophages or ECs and ingested by macrophages through the scavenger receptor, resulting in foam cell formation. Oxidized LDL stimulates the local release of growth factors, cytokines, and chemokines, increasing monocyte recruitment, and also is cytotoxic to ECs and SMCs. More recently, it has been shown that minute extracellular cholesterol crystals found in early atherosclerotic lesions serve as “danger” signals that can activate innate immune cells such as monocytes and macrophages to produce IL-1 and other pro-inflammatory mediators.


Pathology_Robbins

Pathology_Robbins. Inflammation contributes to the initiation, progression, and complications of atherosclerotic lesions. Normal vessels do not bind inflammatory cells. Early in atherogenesis, however, dysfunctional ECs express adhesion molecules that promote leukocyte adhesion, in particular, monocytes and T cells which migrate into the intima under the influence of locally produced chemokines. Monocytes differentiate into macrophages and avidly engulf lipoproteins, including oxidized LDL and small cholesterol crystals. Cholesterol crystals appear to be particularly important instigators of inflammation through activation of the inflammasome and subsequent release of IL-1 (Chapter 5). Activated macrophages also produce toxic oxygen species that drive LDL oxidation and elaborate growth factors that stimulate SMC proliferation.


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Pathology_Robbins. T lymphocytes recruited to the intima interact with the macrophages and also contribute to chronic inflammation. It is not clear whether the T cells are responding to specific antigens (e.g., bacterial or viral antigens, heat-shock proteins [see later], or modified arterial wall constituents and lipoproteins) or are nonspecifically activated by the local inflammatory milieu. Nevertheless, activated T cells in the growing intimal lesions elaborate inflammatory cytokines (e.g., IFN-γ), which stimulate macrophages, ECs, and SMCs. As a consequence of the chronic inflammatory state, activated leukocytes and vascular wall cells release growth factors that promote SMC proliferation and matrix synthesis. Intimal SMC proliferation and ECM deposition lead to conversion of the earliest lesion, a fatty streak, into a mature atheroma, thus contributing to the progressive growth of atherosclerotic lesions (see


Pathology_Robbins

Pathology_Robbins. Fig. 10.10 ). Several growth factors are implicated in SMC proliferation and matrix synthesis, including platelet-derived growth factor (released by locally adherent platelets, macrophages, ECs, and SMCs), fibroblast growth factor, and TGF-α. The recruited SMCs synthesize ECM (most notably collagen), which stabilizes atherosclerotic plaques. However, activated inflammatory cells in atheromas also can cause intimal SMC apoptosis and breakdown of matrix, leading to the development of unstable plaques (see later). MORPHOLOGYThedevelopmentofatherosclerosistendstofollowaseriesofmorphologicchangesdescribedbelow. Fatty Streaks. Fattystreaksbeginasminuteyellow,flatmaculesthatcoalesceintoelongatedlesions,1cmormoreinlength(


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Pathology_Robbins. Atherosclerotic plaques have three principal components:(1) cells,including SMCs,macrophages,and T cells; http://ebooksmedicine.net Fig. 10.11 Fattystreaks.(A)Aortawithfattystreaks(arrows), mainlyneartheostiaofbranchvessels.(B)Fattystreakinanexperimentalhypercholesterolemicrabbit,demonstratingintimal,macrophage-derivedfoamcells(arrows).(B,Courtesy of Myron I.Cybulsky,MD,University of Toronto,Toronto,Ontario,Canada.) Fig. 10.12 Atheroscleroticlesions.(A)Aortawithmildatherosclerosiscomposedoffibrousplaques,onedenotedbythearrow.(B)Aortawithseverediffusecomplicatedlesions,includinganulceratedplaque(open arrow), andalesionwithoverlyingthrombus(closed arrow).


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Pathology_Robbins. Fig. 10.13 Atheroscleroticplaque,coronaryartery.(A)Overallarchitecturedemonstratingfibrouscap(F) andacentralnecrotic(largelylipid)core(C); collagen(blue) isstainedwithMassontrichrome.Thelumen(L) ismoderatelynarrowedbythiseccentriclesion,whichleavespartofthevesselwallunaffected(arrow). (B)Moderate-powerviewoftheplaqueshowninA, stainedforelastin(black); theinternalandexternalelasticmembranesareattenuated,andthemediaofthearteryisthinnedunderthemostadvancedplaque(arrow). (C)High-powerviewofthejunctionofthefibrouscapandcore,showingscatteredinflammatorycells,calcification(arrowheads), andneovascularization(small arrows). http://ebooksmedicine.net (2) ECM, including collagen, elastic fibers, and proteoglycans; and (3) intracellular and extracellular lipid (see Fig.


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net (2) ECM, including collagen, elastic fibers, and proteoglycans; and (3) intracellular and extracellular lipid (see Fig. 10.13AandB ).Theproportionandconfigurationofeachcomponentvariesfromlesiontolesion.Mostcommonly,plaqueshaveasuperficialfibrouscapcomposedofSMCsandrelativelydensecollagen.Wherethecapmeetsthevesselwall(the“shoulder”)isamorecellularareacontainingmacrophages,Tcells,andSMCs.Deeptothefibrouscapisanecroticcore,containinglipid(primarilycholesterolandcholesterolesters),necroticdebris,lipid-ladenmacrophagesandSMCs(foam cells), fibrin,variablyorganizedthrombus,andotherplasmaproteins.Theextracellularcholesterolfrequentlytakestheformsofcrystallineaggregatesthatarewashedoutduringroutinetissueprocessing,leavingbehindempty“cholesterolclefts.”Theperipheryofthelesionsshowsneovascularization (proliferatingsmallbloodvessels)(see


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Pathology_Robbins. Fig.10.13C ).Themediadeeptotheplaquemaybeattenuatedandexhibitfibrosissecondarytosmoothmuscleatrophyandloss.Typicalatheromascontainrelativelyabundantlipid,butsomeso-calledfibrous plaques arecomposedalmostexclusivelyofSMCsandfibroustissue. Plaquesgenerallyprogressivelyenlargeovertimethroughcelldeathanddegeneration,synthesisanddegradationofECM(remodeling),andthrombusorganization.Atheromasalsooftenundergocalcification(see Fig.10.13C Atherosclerotic plaques are susceptible to several clinically important changes: Rupture, ulceration, or erosion of the luminal surface of atheromatous plaques exposes highly thrombogenic substances and induces thrombus formation. Thrombi may partially or completely occlude the lumen, leading to tissue ischemia (e.g., in the heart) (Chapter 11) ( Fig. 10.14 ). If the patient survives, thrombi become organized and incorporated into the growing plaque.


Pathology_Robbins

Pathology_Robbins. Fig. 10.14 ). If the patient survives, thrombi become organized and incorporated into the growing plaque. Hemorrhage into a plaque. Rupture of the overlying fibrous cap or of the thin-walled vessels in the areas of neovascularization can cause intra-plaque hemorrhage; the resulting hematoma may cause rapid plaque expansion or plaque rupture. Atheroembolism. Ruptured plaque can discharge debris into the blood, producing microemboli composed of plaque contents. Aneurysm formation. Atherosclerosis-induced pressure or ischemic atrophy of the underlying media, with loss of elastic tissue, causes structural weakening that can lead to aneurysmal dilation and rupture.


Pathology_Robbins

Pathology_Robbins. Large elastic arteries (e.g., aorta, carotid, and iliac arteries) and largeand medium-sized muscular arteries (e.g., coronary, renal, and popliteal arteries) are the vessels most commonly involved by atherosclerosis. Accordingly, atherosclerosis is most likely to present with signs and symptoms related to ischemia of the heart, brain, kidneys, and lower extremities. Myocardial infarction (heart attack), cerebral infarction (stroke), aortic aneurysm, and peripheral vascular disease (gangrene of extremities) are the major clinical consequences of atherosclerosis. The natural history, morphologic features, and main pathogenic events are schematized in


Pathology_Robbins

Pathology_Robbins. The natural history, morphologic features, and main pathogenic events are schematized in Figure 10.15 . The principal pathophysiologic outcome stemming from atherosclerotic lesions vary depending on the size of the affected vessel, the size and stability of the plaques, and the degree to which plaques disrupt the vessel wall. We next describe the features of atherosclerotic lesions that are typically responsible for the clinical manifestations. At early stages, remodeling of the media tends to preserve the luminal diameter by increasing the overall vessel circumference. Owing to limits on remodeling, however, eventually the expanding atheroma may impinge on blood flow. Although this most commonly happens as a consequence of acute plaque change ( described next), it can also occur gradually, with critical stenosis being the tipping point at which chronic occlusion limits flow so severely


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Pathology_Robbins. Fig. 10.14 Atheroscleroticplaquerupture.(A)Plaquerupturewithoutsuperimposedthrombus,inapatientwhodiedsuddenly.(B)Acutecoronarythrombosissuperimposedonanatheroscleroticplaquewithfocaldisruptionofthefibrouscap,triggeringfatalmyocardialinfarction.InbothAandB,anarrowpointstothesiteofplaquerupture.(B, Reproduced from Schoen FJ: Interventionalandsurgicalcardiovascularpathology:clinicalcorrelationsandbasicprinciples,Philadelphia, 1989, Saunders, p 61.) Usually young age Usually middle age to elderly At lesion-prone areas, and Cell death/degeneration accelerated by risk factors; Inflammation Endothelial dysfunction Plaque growth Monocyte adhesion/emigration Remodeling of plaque SMC migration to intima and wall ECM SMC proliferation Organization of thrombus ECM elaboration Calcification Fig. 10.15 Summaryofthenaturalhistory,morphologicfeatures,mainpathogenicevents,andclinicalcomplicationsofatherosclerosis.


Pathology_Robbins

Pathology_Robbins. Fig. 10.15 Summaryofthenaturalhistory,morphologicfeatures,mainpathogenicevents,andclinicalcomplicationsofatherosclerosis. that tissue demand exceeds supply. In the coronary artery (and other) circulations, this typically occurs when the vessel is approximately 70% occluded. At rest, affected patients have adequate cardiac perfusion; but with even modest exertion, demand exceeds supply, and chest pain develops because of cardiac ischemia (stable angina) (Chapter 11). The toll of chronic arterial hypoperfusion due to atherosclerosis in various vascular beds includes bowel ischemia, sudden cardiac death, chronic IHD, ischemic encephalopathy, and intermittent claudication (ischemic leg pain). Plaque erosion or rupture typically triggers thrombosis, leading to partial or complete vascular obstruction and often tissue infarction ( Fig. 10.15 ). Plaque changes fall into three general categories: Rupture/fissuring, exposing highly thrombogenic plaque constituents


Pathology_Robbins

Pathology_Robbins. Fig. 10.15 ). Plaque changes fall into three general categories: Rupture/fissuring, exposing highly thrombogenic plaque constituents Erosion/ulceration, exposing the thrombogenic subendothelial basement membrane to blood Hemorrhage into the atheroma, expanding its volume It is now recognized that plaques responsible for myocardial infarctions and other acute coronary syndromes often are asymptomatic before the acute event; symptoms are triggered by thrombosis on a lesion that previously did not produce significant luminal occlusion. The worrisome conclusion is that large numbers of asymptomatic individuals are at risk for a catastrophic coronary event. The causes of acute plaque change are complex and include both intrinsic factors (e.g., plaque structure and composition) and extrinsic factors (e.g., blood pressure). These factors combine to weaken the integrity of the plaque, making it unable to withstand vascular shear forces.


Pathology_Robbins

Pathology_Robbins. Certain types of plaques are believed to be at particularly high risk of rupturing. These include plaques that contain large numbers of foam cells and abundant extracellular lipid, plaques that have thin fibrous caps containing few SMCs, and plaques that contain clusters of inflammatory cells. Plaques at high risk for rupture are referred to as vulnerable plaques ( Fig. 10.16 ). The fibrous cap also undergoes continuous remodeling; its mechanical strength and stability are proportional to its collagen content, so the balance of collagen synthesis and degradation affects cap integrity. Collagen in atherosclerotic plaques is synthesized primarily by SMCs, and loss of SMCs understandably results in cap weakening. In general, plaque inflammation increases collagen degradation and reduces collagen synthesis, thereby destabilizing the mechanical integrity of the cap. Of interest, statins may have a beneficial effect not only by


Pathology_Robbins

Pathology_Robbins. Fig. 10.16 Vulnerableandstableatheroscleroticplaque.Stableplaqueshavedenselycollagenizedandthickenedfibrouscapswithminimalinflammationandnegligibleunderlyingatheromatouscores,whereasvulnerableplaqueshavethinfibrouscaps,largelipidcores,andincreasedinflammation.(Adapted from Libby P: Molecular bases of the acute coronary syndromes, Circulation91:2844, 1995.) http://ebooksmedicine.net reducing circulating cholesterol levels but also by stabilizing plaques through a reduction in plaque inflammation.


Pathology_Robbins

Pathology_Robbins. Factors extrinsic to plaques also are important. Thus, adrenergic stimulation (as with intense emotions) can increase systemic blood pressure or induce local vasoconstriction, thereby increasing the mechanical stress on a given plaque. Indeed, one explanation for the pronounced circadian periodicity in the onset of heart attacks (peak incidence between 6 AM and 12 noon) is the adrenergic surge associated with waking and rising—sufficient to cause blood pressure spikes and heightened platelet reactivity. Fortunately, not all plaque ruptures result in occlusive thromboses with catastrophic consequences. In fact, silent plaque disruption and ensuing superficial platelet aggregation and thrombosis probably occur frequently and repeatedly in those with atherosclerosis. Healing of these subclinical plaque disruptions—and their overlying thromboses—is an important mechanism of atheroma enlargement.


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Pathology_Robbins. B. True aneurysm (saccular) C. True aneurysm (fusiform) Aneurysms are congenital or acquired dilations of blood vessels or the heart (


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Pathology_Robbins. Fig. 10.17 ). “True” aneurysms involve all three layers of the artery (intima, media, and adventitia) or the attenuated wall of the heart; these include atherosclerotic and congenital vascular aneurysms, as well as ventricular aneurysms resulting from transmural myocardial infarctions. By comparison, a false aneurysm (pseudoaneurysm) results when a wall defect leads to the formation of an extravascular hematoma that communicates with the intravascular space (“pulsating hematoma”). Examples are ventricular ruptures contained by pericardial adhesions and leaks at the junction of a vascular graft with a natural artery. In arterial dissections, pressurized blood gains entry to the arterial wall through a surface defect and then pushes apart the underlying layers. Aneurysms and dissections are important causes of stasis and subsequent thrombosis; they also have a propensity to rupture—often with catastrophic results.


Pathology_Robbins

Pathology_Robbins. Fig. 10.17 ). Saccular aneurysms are discrete outpouchings ranging from 5 to 20 cm in diameter, often with a contained thrombus. Fusiform aneurysms are circumferential dilations up to 20 cm in diameter; these most commonly involve the aortic arch, the abdominal aorta, or the iliac arteries. Arteries are dynamic tissues that must withstand the constant mechanical stress of pulsatile blood flow. Aneurysms occur when alterations in SMCs or ECM compromise the structural integrity of the arterial media. Among the implicated factors in aneurysm formation are the following: • Inadequate or abnormal connective tissue synthesis. Several rare inherited diseases provide insight into the types of abnormalities that can lead to aneurysm formation. As discussed earlier, TGF-β regulates SMC proliferation and matrix synthesis. Thus, mutations in TGF-β receptors or downstream signaling pathways result in defective elastin and collagen synthesis; aneurysms in affected


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Pathology_Robbins. D. False aneurysm E. DissectionA. Normal vessel Fig. 10.17 Aneurysms.(A)Normalvessel.(B)Trueaneurysm,sacculartype.Thewallbulgesoutwardandmaybeattenuatedbutisotherwiseintact.(C)Trueaneurysm,fusiformtype.Thereiscircumferentialdilationofthevessel.(D)Falseaneurysm.Thewallisruptured,creatingacollectionofblood(hematoma)boundedexternallybyadherentextravasculartissues.(E)Dissection.Bloodhasenteredthewallofthevesselandseparated(dissected)thelayers. http://ebooksmedicine.net Fig. 10.18 Cysticmedialdegeneration.(A)Cross-sectionofaorticmediafromapatientwithMarfansyndrome,showingmarkedelastinfragmentationandareasdevoidofelastinthatresemblecysticspaces(asterisks). (B)Normalmediaforcomparison,showingtheregularlayeredpatternofelastictissue.Inboth (A)and(B),elastinisstainedblack.


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Pathology_Robbins. individuals often rupture, even when small. In Marfan syndrome (Chapter 7), defective synthesis of the scaffolding protein fibrillin leads to increased bioavailability of TGF-β in the aortic wall, with subsequent dilation due to dysregulated signaling and progressive loss of elastic tissue. Defective type III collagen synthesis leading to aneurysm formation is a hallmark of type IV Ehlers-Danlos syndrome (Chapter 7). Excessive connective tissue degradation. Increased matrix metalloprotease expression by macrophages in atherosclerotic plaque can contribute to aneurysm development by degrading arterial ECM in the arterial wall; similarly, decreased tissue inhibitors of metalloprotease expression can also tip the balance toward net ECM degradation. A genetic predisposition to aneurysm formation in the setting of inflammation may be related to polymorphisms in these factors.


Pathology_Robbins

Pathology_Robbins. Loss of SMCs or change in the SMC synthetic phenotype. Atherosclerotic thickening of the intima can cause ischemia of the inner media by increasing the diffusion distance from the lumen. Conversely, systemic hypertension can cause luminal narrowing of the aortic vasa vasorum, leading to ischemia of the outer media. Such ischemia results in SMC loss as well as aortic “degenerative changes,” which include fibrosis (replacing distensible elastic tissue), inadequate ECM synthesis, and accumulation of increasing amounts of amorphous proteoglycans. Histologically, these changes are collectively called cystic medial degeneration ( Fig. 10.18 ), although no true cysts are formed. Such changes are nonspecific; they can occur whenever ECM synthesis is defective, including in inherited disorders such as Marfan syndrome and acquired conditions such as scurvy. The two most important predisposing conditions for aortic aneurysms are atherosclerosis and hypertension.


Pathology_Robbins

Pathology_Robbins. Atherosclerosis is the dominant factor in abdominal aortic aneurysms, while hypertension is associated with ascending aortic aneurysms. Other conditions that weaken vessel walls and lead to aneurysms include trauma, vasculitis (see later), congenital defects, and infections, giving rise to so-called “mycotic aneurysms.” Mycotic aneurysms may result from (1) embolization of a septic embolus, usually as a complication of infective endocarditis; (2) extension of an adjacent suppurative process; or (3) direct infection of an arterial wall by circulating organisms. Tertiary syphilis is a rare cause of aortic aneurysms. A predilection of the spirochetes for the vasa vasorum of the ascending thoracic aorta—and the subsequent immune response to them—results in an obliterative endarteritis that compromises blood flow to the media; the ensuing ischemic injury leads to aneurysmal dilation that occasionally also can involve the aortic valve annulus.


Pathology_Robbins

Pathology_Robbins. Aneurysms occurring as a consequence of atherosclerosis form most commonly in the abdominal aorta and common iliac arteries, and may also involve the aortic arch and descending thoracic aorta. Abdominal aortic aneurysms (AAAs) occur more frequently in men and in smokers and rarely develop before 50 years of age. Atherosclerosis is a major cause of AAA, but other factors clearly contribute, since the incidence is less than 5% in men older than 60 years of age despite the almost universal presence of abdominal aortic atherosclerosis in this population.


Pathology_Robbins

Pathology_Robbins. In the majority of cases, AAA results from ECM degradation mediated by proteolytic enzymes released from inflammatory infiltrates in atherosclerotic lesions. Atherosclerotic plaques also compromise the diffusion of nutrients and wastes between the vascular lumen and the arterial wall, alternations that have deleterious effects on SMCs in the media. Due to this combination of effects, the media undergoes degeneration and necrosis, which results in arterial wall thinning. A familial predisposition to AAA, independent of genetic predilections to atherosclerosis or hypertension, appears to be a factor in some individuals. Of note, smokers who develop AAA tend to have more severe chronic obstructive pulmonary disease, particularly emphysema, suggesting that such patients are constitutionally predisposed to develop disorders associated with ECM degradation. http://ebooksmedicine.net Fig.


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Pathology_Robbins

Pathology_Robbins. Fig. 10.19 Abdominalaorticaneurysm.(A)Externalsiteofruptureofalargeaorticaneurysmisindicatedbythearrow. (B)Openedaorta,withthelocationoftherupturetractindicatedbyaprobe. Thewalloftheaneurysmisattenuated,andthelumenisfilledbyalarge,layeredthrombus. The clinical consequences of AAA include the following: Obstruction of a vessel branching off the aorta (e.g., the renal, iliac, vertebral, or mesenteric arteries), resulting in ischemia of the kidneys, legs, spinal cord, or gastrointestinal tract, respectively Embolism of atheromatous material (e.g., cholesterol crystals) or mural thrombus Impingement on adjacent structures (e.g., compression of a ureter or erosion of vertebrae by the expanding aneurysm) Rupture into the peritoneal cavity or retroperitoneal tissues, leading to massive, often fatal hemorrhage


Pathology_Robbins

Pathology_Robbins. Rupture into the peritoneal cavity or retroperitoneal tissues, leading to massive, often fatal hemorrhage The risk for rupture is related to the size of AAAs. Those 4 cm or less in diameter almost never burst, while those between 4 and 5 cm do so at a rate of 1% per year. The risk rises to 11% per year for AAAs 5 to 6 cm in diameter, and to 25% per year for aneurysms greater than 6 cm in diameter. Thus, aneurysms 5 cm in diameter or larger are managed surgically, either by open placement of tubular prosthetic grafts or with endoluminal insertion of stented grafts (expandable wire frames covered by a cloth sleeve). Timely intervention is critical, because the mortality rate for elective procedures is approximately 5%, whereas the rate for emergency surgery after rupture is roughly 50%.


Pathology_Robbins

Pathology_Robbins. A point worthy of emphasis is that because atherosclerosis is a systemic disease, a patient with AAA also is very likely to have atherosclerosis in other vascular beds and is at a significantly increased risk for ischemic heart disease and stroke. Thoracic aortic aneurysms most commonly are associated with hypertension, bicuspid aortic valves, and Marfan syndrome. Less commonly, disorders caused by mutations in the TGF-β signaling pathway are causative. These aneurysms manifest with the following signs and symptoms: Respiratory or feeding difficulties due to airway or esophageal compression, respectively, because of encroachment on mediastinal structures Persistent cough from irritation of the recurrent laryngeal nerves Pain caused by erosion of bone (i.e., ribs and vertebral bodies) Cardiac disease due to valvular insufficiency or narrowing of the coronary ostia; heart failure induced by aortic valvular incompetence


Pathology_Robbins

Pathology_Robbins. Cardiac disease due to valvular insufficiency or narrowing of the coronary ostia; heart failure induced by aortic valvular incompetence Aortic dissection occurs when blood splays apart the laminar planes of the media to form a blood-filled channel within the aortic wall ( Fig. 10.20 ). This development can be catastrophic if the dissecting blood ruptures through the adventitia and escapes into adjacent spaces. http://ebooksmedicine.net Fig. 10.20 Aorticdissection.(A)Anopenedaortawithaproximaldissectionoriginatingfromasmall,obliqueintimaltear(identified by the probe) associatedwithanintramuralhematoma.Notethattheintimaltearoccurredinaregionlargelyfreeofatheroscleroticplaque.Thedistaledgeoftheintramuralhematoma(black arrows) liesattheedgeofalargeareaofatherosclerosis(white arrow), whicharrestedthepropagationofthedissection.(B)Histologicpreparationshowingthedissectionandintramuralhematoma(asterisk). Aorticelasticlayersareblack, andbloodisred inthissection,stainedwithMovatstain.


Pathology_Robbins

Pathology_Robbins. Aortic dissection need not be associated with aortic dilation, and the older term dissecting aneurysm should be avoided. Aortic dissection occurs mainly in two age groups: (1) men 40 to 60 years of age with antecedent hypertension (more than 90% of cases); and (2) younger patients with connective tissue abnormalities that affect the aorta (e.g., Marfan syndrome). Dissections also can be iatrogenic (e.g., complicating arterial cannulation during diagnostic catheterization or cardiopulmonary bypass). Rarely, pregnancy is associated with aortic (or other vessel) dissection (roughly 10 to 20 cases per 1 million births). This typically occurs during or after the third trimester, and may be related to hormone-induced vascular remodeling and the hemodynamic stresses of the perinatal period. Dissection is unusual in the presence of substantial atherosclerosis or other causes of medial scarring, presumably because the medial fibrosis inhibits propagation of the dissecting hematoma (see


Pathology_Robbins

Pathology_Robbins. Fig. 10.20 Hypertension is the major risk factor for aortic dissection. Aortas in hypertensive patients show narrowing of the vasa vasorum associated with degenerative changes in ECM and variable loss of medial SMCs, suggesting that diminished flow through the vasa vasorum is contributory. Abrupt , transient increase in blood pressure, as may occur with cocaine abuse, is also known to cause aortic dissection. Most other dissections are related to heritable or acquired connective tissue disorders that give rise to abnormal aortic ECM, including Marfan syndrome, Ehlers-Danlos syndrome type IV, and defects in copper metabolism.


Pathology_Robbins

Pathology_Robbins. The trigger for the intimal tear and subsequent intramural hemorrhage is not known in most cases. Nevertheless, once the tear has occurred, blood under systemic pressure dissects through the media along laminar planes. Accordingly, aggressive pressure-reducing therapy may be effective in limiting an evolving dissection. In rare cases, disruption of the vasa vasorum can give rise to an intramural hematoma without an intimal tear. MORPHOLOGYInmostdissections,theintimaltearmarkingthepointoforiginisfoundintheascendingaortawithin10cmoftheaorticvalve(see Fig.10.20A ).Suchtearsusuallyaretransverseorobliqueinorientationand1to5cmlong,withsharp,jaggededges.Thedissectionplanecanextendretrogradetowardtheheartordistally,occasionallyasfarastheiliacandfemoralarteries,andusuallyliesbetweenthemiddleandouterthirdsofthemedia(see Fig.10.20B


Pathology_Robbins

Pathology_Robbins. The clinical manifestations of dissection depend primarily on the portion of the aorta affected; the most serious complications occur with dissections involving the proximal aorta and arch. Thus, aortic dissections generally are classified into two types ( Fig. 10.21 • Proximal lesions (type A dissections), involving the ascending aorta, with or without involvement of the descending aorta (DeBakey type I or II, respectively) http://ebooksmedicine.net Fig. 10.21 Classificationofdissections.TypeAdissections(proximal)involvetheascendingaorta,eitheraspartofamoreextensivedissection(DeBakeytypeI),orinisolation(DeBakeytypeII).TypeBdissections(distal,orDeBakeytypeIII)ariseafterthetakeoffofthegreatvessels.TypeAdissectionstypicallyhavethemostseriouscomplicationsandthegreatestassociatedmortality. • Distal lesions (type B dissections), usually beginning beyond the subclavian artery (DeBakey type III)


Pathology_Robbins

Pathology_Robbins. • Distal lesions (type B dissections), usually beginning beyond the subclavian artery (DeBakey type III) The classic clinical symptom of aortic dissection is the sudden onset of excruciating tearing or stabbing pain, usually beginning in the anterior chest, radiating to the back between the scapulae, and moving downward as the dissection progresses. The most common cause of death is rupture of the dissection into the pericardial, pleural, or peritoneal cavity. Retrograde dissection into the aortic root also can cause fatal disruption of the aortic valvular apparatus or compression of the coronary arteries. Common clinical presentations stemming from cardiac involvement include tamponade, aortic insufficiency, and myocardial infarction. Other complications are related to extension of the dissection to the great arteries of the neck and the renal, mesenteric, or iliac arteries, any of which may become obstructed. Similarly, compression of spinal arteries can cause transverse myelitis.


Pathology_Robbins

Pathology_Robbins. In type A dissections, rapid diagnosis and institution of intensive anti-hypertensive therapy coupled with surgical plication of the aortic intimal tear can save 65% to 85% of the patients. However, the mortality rate approaches 70% in patients who present with hemorrhage or symptoms related to distal ischemia, and the overall 10-year survival rate is only 40% to 60%. Most type B dissections can be managed conservatively; patients have a 75% survival rate whether they are treated with surgery or with anti-hypertensive medication only. Aneurysmsarecongenitaloracquireddilationsoftheheartorbloodvesselsthatinvolvetheentirewallthickness.Complicationsarerelatedtorupture,thrombosis,andembolization. Dissectionsoccurwhenbloodentersthewallofavesselandseparatesthevariouslayers.Complicationsariseasaresultofruptureorobstructionofvesselsbranchingofftheaorta.


Pathology_Robbins

Pathology_Robbins. AneurysmsanddissectionsresultfromstructuralweaknessofthevesselwallcausedbylossofSMCsorweakeningoftheECM,whichcanbeaconsequenceofischemia,geneticdefects,ordefectivematrixremodeling. Vasculitis is a general term for vessel wall inflammation. The two most common pathogenic mechanisms of vasculitis are immune-mediated inflammation and direct vascular invasion by infectious pathogens. Infections also can indirectly precipitate immune-mediated vasculitis (e.g., by generating immune complexes or triggering cross-reactivity). In any given patient, it is critical to distinguish between infectious and immunologic mechanisms because immunosuppressive therapy is appropriate for immune-mediated vasculitis but could exacerbate infectious vasculitis. Physical and chemical injury, including that due to radiation, mechanical trauma, and toxins, also can cause vasculitis.


Pathology_Robbins

Pathology_Robbins. Some 20 primary forms of vasculitis are recognized, and classification schemes attempt (with variable success) to group them according to vessel diameter, role of immune complexes, presence of specific autoantibodies, granuloma formation, organ specificity, and even population demographics ( Table 10.4 Fig. 10.22 The possible clinical manifestations are protean, but they largely depend on the specific vascular bed that is affected. Besides findings referable to the affected tissue(s), there are usually also signs and symptoms of systemic inflammation, such as fever, myalgia, arthralgias, and malaise. There is considerable clinical and pathologic overlap among these entities, as will be evident from the discussion of individual forms below. The main immunologic mechanisms underlying noninfectious vasculitis are as follows:


Pathology_Robbins

Pathology_Robbins. The main immunologic mechanisms underlying noninfectious vasculitis are as follows: This form of vasculitis is seen in immunologic disorders such as systemic lupus erythematosus (Chapter 5) that are associated with autoantibody production. The vascular lesions resemble those found in experimental immune http://ebooksmedicine.net *Thegranulomasofgiantcellarteritisarefoundwithinthevesselwallaspartoftheinflammationcomprisingthevasculitis,butneednotbepresenttorenderthediagnosis.Thegranulomasofgranulomatosiswithpolyangiitisarelarger,spanningbetweenvessels,andassociatedwithareasoftissuenecrosis.ANCA, Anti-neutrophilcytoplasmicantibodies.FromSeidmanMA,MitchellRN:Surgicalpathologyofsmall-andmedium-sizedvessels.InWinters,GL,ed.,Current concepts in cardiovascular pathology,Philadelphia,2012,Saunders.


Pathology_Robbins

Pathology_Robbins. AortaLarge vessel vasculitis Granulomatous disease (e.g., giant cell arteritis, Takayasu arteritis) SLE (e.g., SLE vasculitis) Paucity of immune complexes (often with ANCA) Vasculitis without asthma or granulomas (microscopic polyangiitis) Granulomas, no asthma (granulomatosis with polyangiitis) Eosinophilia, asthma, and granulomas (Churg-Strauss syndrome) Medium vessel vasculitis Immune complex mediated (e.g., polyarteritis nodosa) Anti-endothelial cell antibodies (e.g., Kawasaki disease) ArteriesVeinsArteriolesVenules Fig. 10.22 Vascularsitesinvolvedinthemorecommonvasculitidesandtheirpresumptiveetiology.Notetheconsiderableoverlapindistributions.ANCA,anti-neutrophilcytoplasmicantibody;IgA,immunoglobulinA;SLE,systemiclupuserythematosus.(Data from Jennette JC, Falk RJ: Nosology of primary vasculitis, CurrOpinRheumatol19:17, 2007.)


Pathology_Robbins

Pathology_Robbins. IgA Cryoglobulin Other (e.g., (e.g., Henoch-(e.g., cryoglobulin Goodpasture Schönlein purpura) vasculitis) disease) http://ebooksmedicine.net complex–mediated disorders, such as the Arthus phenomenon and serum sickness, and in some cases contain readily identifiable antibody and complement. Often, however, this type of vasculitis is a diagnostic challenge. Only rarely is the specific antigen responsible for immune complex formation known, and in most instances it is not clear whether the pathogenic antigen-antibody complexes are deposited into the vessel wall from the circulation or form in situ. In fact, in many suspected cases, even the antigen-antibody deposits are scarce, perhaps because the immune complexes have been degraded by the time of biopsy. Immune complex deposition is also implicated in the following vasculitides:


Pathology_Robbins

Pathology_Robbins. Immune complex deposition is also implicated in the following vasculitides: Drug hypersensitivity vasculitis. In some cases, drugs (e.g., penicillin) appear to act as haptens by binding to host proteins; other agents are themselves foreign proteins (e.g., streptokinase). In either case, antibodies directed against the drug-modified proteins or foreign molecules result in immune complex formation. The clinical manifestations can be mild and self-limiting, or severe and even fatal; skin lesions are most common. It is always important to consider drug hypersensitivity as a cause of vasculitis, since discontinuation of the offending agent usually leads to resolution.


Pathology_Robbins

Pathology_Robbins. Vasculitis secondary to infections. Antibodies to microbial constituents can form immune complexes that circulate and deposit in vascular lesions. For example, in up to 30% of patients with polyarteritis nodosa (discussed in greater detail later), the vasculitis can be ascribed to immune complexes composed of hepatitis B surface antigen (HBsAg) and anti-HBsAg antibody.


Pathology_Robbins

Pathology_Robbins. Many patients with vasculitis have circulating antibodies that react with neutrophil cytoplasmic antigens, so-called “anti-neutrophil cytoplasmic antibodies (ANCAs).” ANCAs are a heterogeneous group of autoantibodies directed against constituents (mainly enzymes) of neutrophil primary granules, monocyte lysosomes, and ECs. ANCAs are very useful diagnostic markers; their titers generally mirror clinical severity, and a rise in titers after periods of quiescence is predictive of disease recurrence. Although a number of ANCAs have been described, two are most important. These are classified according to their antigen specificity: Anti-proteinase-3 (PR3-ANCA), previously called c-ANCA. PR3 is a neutrophil azurophilic granule constituent that shares homology with numerous microbial peptides, possibly explaining the generation of PR3-ANCAs. PR3ANCAs are associated with granulomatosis with polyangiitis (see later).


Pathology_Robbins

Pathology_Robbins. Anti-myeloperoxidase (MPO-ANCA), previously called p-ANCA. MPO is a lysosomal granule constituent involved in oxygen free radical generation (Chapter 3). MPO-ANCAs are induced by several therapeutic agents, particularly propylthiouracil (used to treat hyperthyroidism). MPO-ANCAs are associated with microscopic polyangiitis and Churg-Strauss syndrome (see later). The close association between ANCA titers and disease activity suggests a pathogenic role for these antibodies. Of note, ANCAs can directly activate neutrophils, stimulating the release of reactive oxygen species and proteolytic enzymes; in vascular beds, this may lead to EC injury. While the antigenic targets of ANCA are primarily intracellular (and therefore not usually accessible to circulating antibodies), it is now clear that ANCA antigens (especially PR3) either are constitutively expressed at low levels on the plasma membrane or are translocated to the cell surface in activated and apoptotic leukocytes.


Pathology_Robbins

Pathology_Robbins. A plausible pathogenic sequence for the development of ANCA vasculitis involves the following: Drugs or cross-reactive microbial antigens induce ANCA formation; alternatively, leukocyte surface expression or release of PR3 and MPO (in the setting of infection) incites ANCA development in a susceptible individual. Subsequent inflammatory stimuli elicit the release of cytokines such as TNF that upregulate the surface expression of PR3 and MPO on neutrophils and other cell types. ANCAs bind to these cytokine-activated cells, causing further neutrophil activation. ANCA-activated neutrophils cause EC injury by releasing granule contents and elaborating reactive oxygen species.


Pathology_Robbins

Pathology_Robbins. ANCA-activated neutrophils cause EC injury by releasing granule contents and elaborating reactive oxygen species. The ANCA auto-antibodies are directed against cellular constituents and do not form circulating immune complexes, nor do the vascular lesions typically contain demonstrable antibody and complement; therefore ANCA-associated vasculitides often are described as “pauci-immune.” Of interest, ANCAs directed against proteins other than PR3 and MPO are sometimes seen in patients with non-vasculitic inflammatory disorders (e.g., inflammatory bowel disease, sclerosing cholangitis, and rheumatoid arthritis). Antibodies to ECs underlie certain vasculitides, such as Kawasaki disease (discussed later). Autoreactive T cells cause injury in some forms of vasculitides characterized by formation of granulomas.


Pathology_Robbins

Pathology_Robbins. Antibodies to ECs underlie certain vasculitides, such as Kawasaki disease (discussed later). Autoreactive T cells cause injury in some forms of vasculitides characterized by formation of granulomas. Presented next is a brief overview of several of the best-characterized vasculitides. Although each is presented as a distinct entity, it must be acknowledged that many cases of vasculitis lack a classic constellation finding or have overlapping features that may render classification difficult.


Pathology_Robbins

Pathology_Robbins. Giant cell (temporal) arteritis is a chronic inflammatory disorder, typically with granulomatous inflammation, that principally affects large-to small-sized arteries in the head. The temporal arteries are not more vulnerable than other arteries, but have leant their name to the disorder because the diagnosis is typically established by biopsy of these vessels. Vertebral and ophthalmic arteries, as well as the aorta (giant cell aortitis), are other common sites of involvement. Because ophthalmic artery vasculitis can lead to sudden and permanent blindness, affected individuals must be promptly diagnosed and treated promptly. It is the most common form of vasculitis among older adults in developed countries.


Pathology_Robbins

Pathology_Robbins. Giant cell arteritis likely occurs as a result of a T-cell– mediated immune response to an as-yet uncharacterized vessel wall antigen. Pro-inflammatory cytokines (especially TNF) and anti-EC antibodies also contribute. The characteristic granulomatous inflammation, an association with certain MHC class II haplotypes, and the excellent therapeutic response to steroids, all strongly support an immune etiology. The predilection for vessels of the head remains unexplained, although one hypothesis is that vessels in various parts of the body develop from distinct anlagen and may, therefore, express unique antigens. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Temporal arteritis is rare before 50 years of age. Signs and symptoms may be vague and constitutional (e.g., fever, fatigue, weight loss) or take the form of facial pain or headache, most intense along the course of the superficial temporal artery, which is 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 histology; however, because the vascular inflammation is patchy, a negative biopsy result does not exclude the diagnosis. Corticosteroid or anti-TNF therapies are effective treatments.


Pathology_Robbins


Pathology_Robbins

Pathology_Robbins. Takayasu arteritis is a granulomatous vasculitis of medium-and large-sized arteries characterized principally by ocular disturbances and marked weakening of the pulses in the upper extremities (hence the alternate name, pulseless disease). This disorder manifests with trans-mural scarring and thickening of the aorta—particularly the aortic arch and great vessels—with severe luminal narrowing of the major branch vessels ( Fig. 10.24 ). Aortic lesions share many of the clinical and histologic features of giant cell aortitis. Indeed, the distinction between the two entities is made largely on the basis of a patient’s age; in those older than 50 years of age are said to have giant cell aortitis, and lesions that occur in those younger than 50 years of age are designated Takayasu aortitis. Although historically associated with Japanese ethnicity and certain HLA haplotypes, Takayasu aortitis has a global distribution. An autoimmune etiology is likely.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYTakayasu arteritis classically affects the aortic arch and arch vessels; one third of cases also involve the remainder of the aorta and its branches. Occasionally,aorticrootinvolvementcausesdilationandaorticvalveinsufficiency.Pulmonaryarteriesareinvolvedin50%ofpatients,andrenalandcoronaryarteriesalsocanbeaffected.Thetakeoffsofthegreatvesselscanbemarkedlynarrowedandevenobliterated(see Fig. 10.24AandB ),explainingtheupper-extremityweaknessandfaintcarotidpulses.Thehistologicpicture(see Fig.10.24C )encompassesaspectrumrangingfromadventitialmononuclearinfiltratesandperivascularcuffingofthevasavasorum,tointensetransmuralmononuclearinflammation,togranulomatousinflammation,repletewithgiantcellsandpatchymedialnecrosis.Theinflammationisassociatedwithirregularthickeningofthevesselwall,intimalhyperplasia,andadventitialfibrosis.


Pathology_Robbins

Pathology_Robbins. Initial signs and symptoms usually are nonspecific, including fatigue, weight loss, and fever. With progression, vascular signs and symptoms appear and dominate the clinical picture. These include reduced upper-extremity blood pressure and pulse strength; neurologic deficits; and ocular disturbances, including visual field defects, retinal hemorrhages, and total blindness. Distal aorta disease can manifest as leg claudication, and pulmonary artery involvement can cause pulmonary hypertension. Narrowing of the coronary ostia can lead to myocardial infarction, and involvement of the renal arteries causes systemic hypertension in roughly one half of patients. The evolution of the disease is variable. Some cases rapidly progress, while others become quiescent after 1 to 2 years. In the latter scenario, long-term survival, albeit with visual or neurologic deficits, is possible.


Pathology_Robbins

Pathology_Robbins. Polyarteritis nodosa (PAN) is a systemic vasculitis of small-or medium-sized muscular arteries; it typically involves the renal and visceral vessels and spares the pulmonary circulation. There is no association with ANCAs, but one third of patients have chronic hepatitis B infection, which leads to the formation of immune complexes containing hepatitis B antigens that deposit in affected vessels. The cause is unknown in the remaining cases. MORPHOLOGYClassicPANisasegmental transmural necrotizing inflammation ofsmall-tomedium-sizedarteries,oftenwithsuperimposedthrombosis.Kidney,heart,liver,andgastrointestinaltractvesselsareaffectedindescendingorderoffrequency.Lesionsusuallyinvolveonlypartofthevesselcircumferenceandhaveapredilectionforbranchpoints.Impaired perfusion mayleadtoulcerations,infarcts,ischemicatrophy,orhemorrhagesinthedistributionofaffectedvessels.Theinflammatoryprocessalsoweakens the arterial wall, leadingtoaneurysmsandrupture.


Pathology_Robbins

Pathology_Robbins. Intheacutephase,thereistransmuralmixedinflammatoryinfiltratecomposedofneutrophilsandmononuclearcells,frequentlyaccompaniedbyfibrinoid necrosis andluminalthrombosis( Fig.10.25 ).Olderlesionsshowfibrousthickeningofthevesselwallextendingintotheadventitia.Characteristically,allstagesofactivity(fromearlytolate)coexistindifferentvesselsorevenwithinthesamevessel,suggestingongoingandrecurrentpathogenicinsults. http://ebooksmedicine.net Fig. 10.25 Polyarteritisnodosa,associatedwithsegmentalfibrinoidnecrosisandthromboticocclusionofasmallartery.Notethatpartofthevessel(upper-right, arrow) isuninvolved.(Courtesy of Sidney Murphree, MD, Department of Pathology,University of Texas Southwestern Medical School,Dallas,Texas.)


Pathology_Robbins

Pathology_Robbins. PAN is primarily a disease of young adults but can occur in all age groups. The clinical course typically is episodic, with long symptom-free intervals. The systemic findings—malaise, fever, and weight loss—are nonspecific, and the vascular involvement is widely scattered, so that the clinical manifestations can be varied and puzzling. A “classic” presentation involves involve some combination of rapidly accelerating hypertension due to renal artery involvement; abdominal pain and bloody stools caused by gastrointestinal lesions; diffuse muscular aches and pains; and peripheral neuritis, predominantly affecting motor nerves. Renal involvement often is prominent and is a major cause of death. Untreated, PAN typically is fatal; however, with immunosuppression, 5-year survival is close to 80%. Relapse occurs in up to 25% of the cases, more often in non–HBV-associated cases than those that follow HBV infection. The latter have a better long-term prognosis.


Pathology_Robbins

Pathology_Robbins. Kawasaki disease is an acute, febrile, usually self-limited illness of infancy and childhood associated with an arteritis of mainly largeto medium-sized vessels. Approximately 80% of patients are younger than 4 years of age. Its clinical significance stems from the involvement of coronary arteries. Coronary arteritis can result in aneurysms that rupture or thrombose, causing myocardial infarction. Originally described in Japan, the disease is now recognized in the United States and elsewhere. In genetically susceptible individuals, a variety of infectious agents (mostly viral) have been posited to trigger the disease. The vasculitis may result from a delayed-type hypersensitivity response directed against cross-reactive or newly uncovered vascular antigen(s). Subsequent cytokine production and polyclonal B cell activation result in auto-antibodies to ECs and SMCs that precipitate the vasculitis.


Pathology_Robbins

Pathology_Robbins. Kawasaki disease typically manifests with conjunctival and oral erythema and blistering, edema of the hands and feet, erythema of the palms and soles, a desquamative rash, and cervical lymph node enlargement (hence its other name, mucocutaneous lymph node syndrome). Approximately 20% of untreated patients develop cardiovascular sequelae, ranging from asymptomatic coronary arteritis, to coronary artery ectasia, to large coronary artery aneurysms (7 to 8 mm in diameter); the latter may be associated with rupture, thrombosis, myocardial infarction, and/or sudden death. Treatment consists of intravenous immunoglobulin infusions (which suppress inflammation through unclear mechanisms) and aspirin, which when given together markedly decrease the incidence of symptomatic coronary artery disease.


Pathology_Robbins

Pathology_Robbins. Microscopic polyangiitis is a necrotizing vasculitis that generally affects capillaries, as well as small arterioles and venules. It also is called hypersensitivity vasculitis or leukocytoclastic vasculitis. Unlike in PAN, all lesions of microscopic polyangiitis tend to be of the same age in any given patient. The skin, mucous membranes, lungs, brain, heart, gastrointestinal tract, kidneys, and muscle all can be involved; necrotizing glomerulonephritis (seen in 90% of patients) and pulmonary capillaritis are particularly common. Microscopic angiitis can be a feature of a number of immune disorders, such as Henoch-Schönlein purpura, essential mixed cryoglobulinemia, or the vasculitis associated with connective tissue disorders.


Pathology_Robbins

Pathology_Robbins. In some cases, antibody responses to antigens such as drugs (e.g., penicillin), microorganisms (e.g., streptococci), heterologous proteins, or tumor proteins have been implicated. These reactions can either lead to immune complex deposition or trigger secondary immune responses (e.g., the development of ANCAs) that are pathogenic. Indeed, most cases of microscopic polyangiitis are associated with MPO-ANCA. Recruitment and activation of neutrophils within affected vascular beds is probably responsible for the disease manifestations. Depending on the vascular bed involved, major features include hemoptysis, hematuria, proteinuria, abdominal pain or bleeding, muscle pain or weakness, and palpable cutaneous purpura. With the exception of patients with widespread renal or CNS involvement, immunosuppression and removal of the offending agent induce durable remissions. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Fig. 10.26 ANCA-associatedsmallvesselvasculitis.(A)Microscopicpolyangiitis(leukocytoclasticvasculitis)withfragmentedneutrophilsinthethickenedvesselwall.(BandC)Granulomatosiswithpolyangiitis.(B)Vasculitisofasmallarterywithadjacentgranulomatousinflammationincludinggiantcells(arrows). (C)Lungfromapatientwithgranulomatosiswithpolyangiitis,demonstratinglargenodularcavitatinglesions.(A, Courtesy of Scott Granter, MD, Brigham and Women’s Hospital, Boston, Massachusetts. C, Courtesy of Sidney Murphree, MD, Department of Pathology, University of Texas Southwestern Medical School, Dallas,Texas.)


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYMicroscopicpolyangiitisischaracterizedbysegmentalfibrinoidnecrosisofthemediawithfocaltransmuralnecrotizinglesions;granulomatousinflammationisabsent.Theselesionsresemblethoseofpolyarteritisnodosabutsparemedium-andlarge-sizedarteries,sothatmacroscopicinfarctsareuncommon.Insomeareas(typicallypostcapillaryvenules),onlyinfiltratingneutrophilsundergoingfragmentationareseen,givingrisetothetermleukocytoclastic vasculitis ( Fig.10.26A ).Althoughimmunoglobulinsandcomplementcomponentscanbedemonstratedinearlyskinlesions,mostlesionsare“pauci-immune”(i.e.,showlittleornoantibody). Previously called Wegener granulomatosis, granulomatosis with polyangiitis (GPA) is a necrotizing vasculitis characterized by a triad of the following: Necrotizing granulomas of the upper-respiratory tract (ear, nose, sinuses, throat) or the lower-respiratory tract (lung) or both


Pathology_Robbins

Pathology_Robbins. Necrotizing granulomas of the upper-respiratory tract (ear, nose, sinuses, throat) or the lower-respiratory tract (lung) or both Necrotizing or granulomatous vasculitis affecting smallto medium-sized vessels (e.g., capillaries, venules, arterioles, and arteries), most prominently the lungs and upper airways but other sites as well Focal necrotizing, often crescentic, glomerulonephritis “Limited” forms of disease can be restricted to the respiratory tract. Conversely, when widespread the disease may affect the eyes, skin, and other organs, most notably the heart; clinically, widespread GPA resembles PAN with the additional feature of respiratory involvement.


Pathology_Robbins

Pathology_Robbins. GPA is likely initiated as a cell-mediated hypersensitivity response to inhaled infectious or environmental antigens. PR3-ANCAs are present in almost 95% of cases and probably drive the tissue injury. The ANCA level also is a useful marker of disease activity, as antibody titers fall dramatically with effective immunosuppressive therapy and rise prior to disease relapse. MORPHOLOGYUpperrespiratorytractlesionsrangefromgranulomatous sinusitis to ulcerative lesions ofthenose,palate,orpharynx;lungfindingsalsovary,rangingfromdiffuseparenchymalinfiltratestogranulomatousnodules.Thereismultifocalnecrotizinggranulomatous vasculitis withasurroundingfibroblasticproliferation( Fig.10.26B ).Multiplegranulomatacancoalescetoproduceradiographicallyvisiblenoduleswithcentralcavitation( Fig.10.26BC ).Destructionofvesselscanleadtohemorrhageandhemoptysis.Lesionscanultimatelyundergoprogressivefibrosisandorganization.


Pathology_Robbins

Pathology_Robbins. Fig.10.26BC ).Destructionofvesselscanleadtohemorrhageandhemoptysis.Lesionscanultimatelyundergoprogressivefibrosisandorganization. Therenal lesions rangefrommild,focalglomerularnecrosisassociatedwiththrombosisofisolatedglomerularcapillaryloops(focal and segmental necrotizing glomerulonephritis) tomoreadvancedglomerularlesionswithdiffusenecrosisandparietalcellproliferationformingepithelialcrescents(crescen-tic glomerulonephritis) (Chapter14).


Pathology_Robbins

Pathology_Robbins. The typical patient is a middle aged man, although women and individuals of other ages can be affected. Classic presentations include bilateral pneumonitis with nodules and cavitary lesions (95%), chronic sinusitis (90%), mucosal ulcerations of the nasopharynx (75%), and renal disease (80%). Patients with mild renal involvement may demonstrate only hematuria and proteinuria, whereas more severe disease may portend rapidly progressive renal failure. Rash, myalgias, articular involvement, neuritis, and fever also may occur. If untreated, the mortality rate at 1 year is 80%. Treatment with steroids, cyclophosphamide, TNF inhibitors, and anti–B-cell antibodies (rituximab) has improved this picture considerably. Most patients with GPA now survive, but remain at high risk for relapses that may ultimately lead to renal failure. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Churg-Strauss syndrome (also called allergic granulomatosis and angiitis) is a small-vessel necrotizing vasculitis classically associated with asthma, allergic rhinitis, lung infiltrates, peripheral eosinophilia, extravascular necrotizing granulomas, and a striking infiltration of vessels and perivascular tissues by eosinophils. It is a rare disorder, affecting 1 in 1 million individuals. 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.


Pathology_Robbins

Pathology_Robbins. Churg-Strauss syndrome may stem from “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 granulomas and eosinophils.


Pathology_Robbins

Pathology_Robbins. Thromboangiitis obliterans (Buerger disease) is characterized by segmental, thrombosing, acute and chronic inflammation of mediumand small-sized arteries, principally the tibial and radial arteries, with occasional secondary extension into the veins and nerves of the extremities. Buerger disease occurs almost exclusively in heavy tobacco smokers and usually develops before 35 years of age. Direct EC toxicity caused by some component of tobacco is suspected; alternatively, a reactive compound in tobacco may modify vessel wall components and induce an immune response. Indeed, most patients with Buerger disease are hypersensitive to tobacco extracts. A genetic predilection is suggested by an increased prevalence in certain ethnic groups (Israeli, Indian subcontinent, Japanese) and an association with certain HLA haplotypes.


Pathology_Robbins

Pathology_Robbins. MORPHOLOGYInthromboangiitisobliterans,thereisasharply segmental acute and chronic transmural vasculitis of mediumand small-sized arteries, predominantlythoseoftheextremities.Intheearlystages,mixedinflammatoryinfiltratesareaccompaniedbyluminalthrombosis;smallmicroabscesses,occasionallyrimmedbygranulomatousinflammation,alsomaybepresent( Fig. 10.27 ).Theinflammationoftenextendsintocontiguousveinsandnerves(afeaturethatisrareinotherformsofvasculitis).Withtime,thrombicanorganizeandrecanalize,andeventuallythearteryandadjacentstructuresbecomeencasedinfibroustissue. Fig. 10.27 Thromboangiitisobliterans(Buergerdisease).Thelumenisoccludedbythrombuscontainingasterileabscess(arrow), andthevesselwallisinfiltratedwithleukocytes.


Pathology_Robbins

Pathology_Robbins. Fig. 10.27 Thromboangiitisobliterans(Buergerdisease).Thelumenisoccludedbythrombuscontainingasterileabscess(arrow), andthevesselwallisinfiltratedwithleukocytes. Early manifestations include cold-induced Raynaud phenomenon (see later), instep foot pain induced by exercise (instep claudication), and superficial nodular phlebitis (venousinflammation).ThevascularinsufficiencyofBuerger disease tends to be accompanied by severe pain—even at rest—undoubtedly from the neural involvement. Chronic extremity ulcerations may develop, progressing over time (occasionally precipitously) to frank gangrene. Smoking abstinence in the early stages of the disease often ameliorates further attacks; however, once established, the vascular lesions do not respond to smoking abstinence.


Pathology_Robbins

Pathology_Robbins. Vasculitis resembling hypersensitivity angiitis or classic PAN may be seen in association with many other diseases, including malignancies and immunologic disorders such as rheumatoid arthritis, systemic lupus erythematosus, anti-phospholipid antibody syndrome, and Henoch-Schönlein purpura. Rheumatoid vasculitis may occur in patients with severe, long-standing rheumatoid arthritis; it can cause a clinically significant aortitis but more typically affects small-and medium-sized arteries, leading to visceral infarction. Linking vasculitis to specific disorders may have important therapeutic implications. For example, although classic immune complex lupus vasculitis and antiphospholipid antibody syndrome share certain morphologic features, the former requires anti-inflammatory therapy while anticoagulation is indicated in the latter.


Pathology_Robbins

Pathology_Robbins. Localized arteritis may be caused by the direct invasion of arteries by infectious agents, usually bacteria or fungi, and in particular Aspergillus and Mucor spp. Vascular invasion may be part of a nearby local tissue infection (e.g., bacterial pneumonia or an adjacent abscesses), or—less commonly— may arise from hematogenous spread of bacteria or embolization from infective endocarditis. Vascular infections may weaken arterial walls and culminate in mycotic aneurysms described earlier, or may induce thrombosis and infarction. Thus, inflammation of vessels in bacterial meningitis can cause thrombosis and infarction, leading ultimately to extension of a subarachnoid infection into the brain parenchyma. http://ebooksmedicine.net Vasculitisisdefinedasinflammationofvesselwalls;itfrequentlyisassociatedwithsystemicmanifestations(includingfever,malaise,myalgias,andarthralgias)andorgandysfunctionthatdependsonthepatternofvascularinvolvement.


Pathology_Robbins

Pathology_Robbins. Vasculitiscanresultfrominfectionsbutmorecommonlyhasanimmunologicbasissuchasimmunecomplexdeposition,anti-neutrophilantibodies(ANCAs),oranti-ECantibodies. Fig.10.22 Table10.4 Several disorders are characterized by inappropriate or exaggerated vasoconstriction of blood vessels. Raynaud phenomenon results from vasoconstriction of arteries and arterioles in the extremities, particularly the fingers and toes, but also sometimes the nose, earlobes, or lips. The restricted blood flow induces paroxysmal pallor or cyanosis; involved digits characteristically show “red-white-andblue” color changes from most proximal to most distal, reflecting proximal vasodilation, central vasoconstriction, and more distal cyanosis, respectively. Raynaud phenomenon can be a primary entity or may be secondary to other disorders.


Pathology_Robbins

Pathology_Robbins. Primary Raynaud phenomenon (previously called Raynaud disease) is caused by exaggerated central and local vasomotor responses to cold or emotion; it affects 3% to 5% of the general population and has a predilection for young women. Structural changes in the arterial walls are absent except late in the course, when intimal thickening may appear. The course usually is benign, but in chronic cases, atrophy of the skin, subcutaneous tissues, and muscles may occur. Ulceration and ischemic gangrene are rare. Secondary Raynaud phenomenon refers to vascular insufficiency due to arterial disease caused by other entities including systemic lupus erythematosus, scleroderma, Buerger disease, or even atherosclerosis. Indeed, since Raynaud phenomenon may be the first manifestation of such conditions, every patient with Raynaud phenomenon should be evaluated for these secondary causes.


Pathology_Robbins

Pathology_Robbins. Vasospasm of cardiac arterial or arteriolar beds has been called cardiac Raynaud and in a subset of cases leads to Prinzmetal angina (angina due to vasospasm). If such spasm is of sufficient duration (20 to 30 minutes), myocardial infarction can result. Elevated levels of catechols also increase heart rate and myocardial contractility, exacerbating ischemia caused by the vasospasm. The outcome can be sudden cardiac death (caused by a fatal arrhythmia) or an ischemic dilated cardiomyopathy—so-called “Takotsubo cardiomyopathy” (also called “broken heart syndrome,” because of the association with emotional duress). Histologic findings in acute cases may include microscopic areas of necrosis characterized by myocyte hypercontraction (contraction band necrosis) (Chapter 11); in subacute and chronic cases, microscopic foci of granulation tissue and/or scar may be present.


Pathology_Robbins

Pathology_Robbins. Varicose veins and phlebothrombosis/thrombophlebitis account for at least 90% of cases of clinically relevant venous disease. Varicose veins are abnormally dilated tortuous veins produced by chronically increased intraluminal pressures and weakened vessel wall support. The superficial veins of the upper and lower leg typically are involved. Up to one fifth of men and one third of women develop lower-extremity varicose veins. Obesity increases the risk, and the higher incidence in women probably reflects the prolonged elevation in venous pressure caused by compression of the inferior vena cava by the gravid uterus during pregnancy. There is also a familial tendency toward premature varicosities.


Pathology_Robbins

Pathology_Robbins. Varicose dilation renders the venous valves incompetent and leads to lower-extremity stasis, congestion, edema, pain, and thrombosis. The most disabling sequelae include persistent edema in the extremity and secondary ischemic skin changes, including stasis dermatitis and ulcerations. The latter can become chronic varicose ulcers as a consequence of poor wound healing and superimposed infections. Of note, embolism from these superficial veins is very rare, in contrast with the relatively frequent emboli that arise from thrombosed deep veins (Chapter 4).


Pathology_Robbins

Pathology_Robbins. Venous dilations in two other sites merit special attention: • Esophageal varices. Liver cirrhosis (and less frequently, portal vein obstruction or hepatic vein thrombosis) causes portal venous hypertension (Chapter 16). This, in turn, leads to the opening of porto-systemic shunts and increased blood flow into veins at the (1) gastroesophageal junction (forming esophageal varices); (2) rectum (forming hemorrhoids); and (3) periumbilical veins of the abdominal wall (forming a caput medusae). Esophageal varices are most important since they are prone to ruptures that can lead to massive (even fatal) upper gastrointestinal hemorrhage. http://ebooksmedicine.net • Hemorrhoids are varicose dilations of the venous plexus at the anorectal junction that result from prolonged pelvic vascular congestion associated with pregnancy or straining to defecate. Hemorrhoids are a source of bleeding and are prone to thrombosis and painful ulceration.


Pathology_Robbins

Pathology_Robbins. Thrombosis of deep leg veins accounts for more than 90% of cases of thrombophlebitis and phlebothrombosis. These two terms are largely interchangeable designations for venous thrombosis accompanied by inflammation. Other sites where venous thrombi may form are the periprostatic venous plexus in males and the pelvic venous plexus in females, as well as the large veins in the skull and the dural sinuses (especially in the setting of infection or inflammation). Peritoneal infections, including peritonitis, appendicitis, salpingitis, and pelvic abscesses, as well as certain conditions associated with hypercoagulability (e.g., polycythemia vera) (Chapter 12) can lead to portal vein thrombosis.


Pathology_Robbins

Pathology_Robbins. In deep venous thrombosis (DVT) of the legs, prolonged immobilization resulting in venous stasis is the most important risk factor. This can occur with extended bed rest or even just sitting during long plane or automobile trips. The postoperative state is another independent risk factor for DVT, as are congestive heart failure, pregnancy, oral contraceptive use, malignancy, obesity, male sex, and age over 50 years. Inherited defects in coagulation factors (Chapter 4) often predispose affected individuals to development of thrombophlebitis. Venous thrombi also can result from elaboration of procoagulant factors from cancers (Chapter 6); the resulting hypercoagulable state can manifest as evanescent thromboses in different vascular beds at different times, so-called “migratory thrombophlebitis” or “Trousseau syndrome.”


Pathology_Robbins

Pathology_Robbins. Thrombi in legs tend to produce few, if any, reliable signs or symptoms. When present, local manifestations include distal edema, cyanosis, superficial vein dilation, heat, tenderness, redness, swelling, and pain. In some cases, pain is elicited by pressure over affected veins, squeezing the calf muscles, or forced dorsiflexion of the foot (Homan sign). However, many DVTs are asymptomatic, especially in bedridden patients, and the absence of findings does not exclude their presence. Pulmonary embolism is a common and serious clinical complication of DVT, resulting from fragmentation or detachment of the venous thrombus. In many cases, the first manifestation of thrombophlebitis is a pulmonary embolus. Depending on the size and number of emboli, the outcome can range from resolution with no symptoms to death.


Pathology_Robbins

Pathology_Robbins. The superior vena cava syndrome usually is caused by neoplasms that compress or invade the superior vena cava, such as bronchogenic carcinoma or mediastinal lymphoma. The resulting obstruction produces a characteristic clinical complex consisting of marked dilation of the veins of the head, neck, and arms associated with cyanosis. Pulmonary vessels also can be compressed, causing respiratory distress. The inferior vena cava syndrome can be caused by neoplasms that compress or invade the inferior vena cava or by a thrombus from the hepatic, renal, or lower-extremity veins that propagates cephalad. Certain neoplasms— particularly hepatocellular carcinoma and renal cell carcinoma—show a striking tendency to grow within veins, and these tumors may ultimately occlude the inferior vena cava. Obstruction of the inferior vena cava induces marked lower-extremity edema, distention of the superficial collateral veins of the lower abdomen, and— with renal vein involvement—marked proteinuria.


Pathology_Robbins

Pathology_Robbins. Primary disorders of lymphatic vessels are extremely uncommon. Much more commonly, lymphatic vessels are secondarily involved by inflammatory, infectious, or malignant processes. Lymphangitis refers to an acute inflammation caused by bacterial seeding of the lymphatic vessels (Chapter 3). Clinically, the inflamed lymphatics appear as red, painful subcutaneous streaks, usually associated with tender enlargement of draining lymph nodes (acute lymphadenitis). If bacteria are not contained within the lymph nodes, they can pass into the venous circulation and cause bacteremia or sepsis.


Pathology_Robbins

Pathology_Robbins. Primary lymphedema may occur as an isolated congenital defect (simple congenital lymphedema) or as the familial Milroy disease (heredofamilial congenital lymphedema), resulting from agenesis or hypoplasia of lymphatics. Secondary or obstructive lymphedema stems from the accumulation of interstitial fluid behind an obstructed, previously normal lymphatic; such obstruction can result from the following disorders or conditions: Tumors involving either the lymphatic channels or the regional lymph nodes Surgical procedures that sever lymphatic connections (e.g., axillary lymph nodes in radical mastectomy)


Pathology_Robbins

Pathology_Robbins. Tumors involving either the lymphatic channels or the regional lymph nodes Surgical procedures that sever lymphatic connections (e.g., axillary lymph nodes in radical mastectomy) Regardless of the cause, lymphedema increases the hydrostatic pressure in the lymphatics distal to the obstruction and causes edema. Chronic edema in turn may lead to deposition of ECM and fibrosis, producing brawny induration or a peau d’orange appearance of the overlying skin (as may occur in the skin overlying a breast carcinoma). Eventually, inadequate tissue perfusion may lead to skin ulceration. Rupture of dilated lymphatics, typically following obstruction by an infiltrating tumor mass, can lead to milky accumulations of lymph in various spaces designated chylous ascites (abdomen), chylothorax, and chylopericardium. Tumors of blood vessels and lymphatics include benign hemangiomas (extremely common), locally aggressive http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. Tumors of blood vessels and lymphatics include benign hemangiomas (extremely common), locally aggressive http://ebooksmedicine.net Table 10.5 Classification of Vascular Tumors and Tumor-Like Conditions neoplasms that metastasize infrequently, and rare, highly malignant angiosarcomas ( Table 10.5


Pathology_Robbins

Pathology_Robbins. Table 10.5 Classification of Vascular Tumors and Tumor-Like Conditions neoplasms that metastasize infrequently, and rare, highly malignant angiosarcomas ( Table 10.5 Vascular neoplasms arise either from endothelium (e.g., hemangioma, lymphangioma, angiosarcoma) or cells that support or surround blood vessels (e.g., glomus tumor). Primary tumors of large vessels (aorta, pulmonary artery, and vena cava) occur infrequently and are mostly sarcomas. Although a benign hemangioma cannot by confused with an anaplastic angiosarcoma, “gray-zone” lesions of uncertain malignancy are sometimes observed. Congenital or developmental malformations and non-neoplastic reactive vascular proliferations (e.g., bacillary angiomatosis) can also manifest as tumor-like lesions that may present diagnostic challenges. In general, benign and malignant vascular neoplasms are distinguished by the following features:


Pathology_Robbins

Pathology_Robbins. Benign tumors usually are composed of vascular channels filled with blood cells or lymph that are lined by a monolayer of normal-appearing ECs. Malignant tumors are more cellular, show cytologic atypia, are proliferative, and usually do not form well-organized vessels; confirmation of the endothelial derivation of such proliferations may require immunohistochemical detection of EC-specific markers. Ectasia is a generic term for any local dilation of a structure, while telangiectasia is used to describe a permanent dilation of preexisting small vessels (capillaries, venules, and arterioles, usually in the skin or mucous membranes) that forms a discrete red lesion. These lesions can be congenital or acquired and are not true neoplasms. • Nevus flammeus (a “birthmark”), the most common form of vascular ectasia, is a light pink to deep purple flat lesion on the head or neck composed of dilated vessels. Most ultimately regress spontaneously.


Pathology_Robbins

Pathology_Robbins. The so-called “port wine stain” is a special form of nevus flammeus. These lesions tend to grow during childhood, thicken the skin surface, and do not fade with time. Such lesions occurring in the distribution of the trigeminal nerve are associated with the Sturge-Weber syndrome (also called encephalotrigeminal angiomatosis). This uncommon congenital disorder is associated with facial port wine nevi, ipsilateral venous angiomas in the cortical leptomeninges, mental retardation, seizures, hemiplegia, and radiologic opacities of the skull. Thus, a large facial telangiectasia in a child with mental deficiencies may indicate the presence of additional vascular malformations.


Pathology_Robbins

Pathology_Robbins. Spider telangiectasias are non-neoplastic vascular lesions. These lesions manifest as radial, often pulsatile arrays of dilated subcutaneous arteries or arterioles (the “legs” of the spider) about a central core (the spider’s “body”) that blanch with pressure. Spider telangiectasias commonly occur on the face, neck, or upper chest and most frequently are associated with hyperestrogenic states (e.g., in pregnant women or patients with cirrhosis).


Pathology_Robbins

Pathology_Robbins. Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease) is an autosomal dominant disorder caused by mutations in genes that encode components of the TGF-β signaling pathway in ECs. The telangiectasias are malformations composed of dilated capillaries and veins that are present at birth. They are widely distributed over the skin and oral mucous membranes, as well as in the respiratory, gastrointestinal, and urinary tracts. The lesions can spontaneously rupture, causing serious epistaxis (nosebleed), gastrointestinal bleeding, or hematuria. Hemangiomas are very common tumors composed of blood-filled vessels These lesions 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 (


Pathology_Robbins

Pathology_Robbins. Fig. 10.28 ). While hemangiomas typically are localized lesions confined to the head and neck, they occasionally may be more extensive (angiomatosis) and can arise internally. Nearly one third of these internal lesions are found in the liver. Malignant transformation is rare. Several histologic and clinical variants have been described: Capillary hemangiomas are the most common type; these occur in the skin, subcutaneous tissues, and mucous membranes of the oral cavities and lips, as well as in the liver, spleen, and kidneys ( Fig. 10.28A). Histologically, they are composed of thin-walled capillaries with scant stroma ( Fig. 10.28B Juvenile hemangiomas (so-called “strawberry hemangiomas”) of the newborn skin are extremely common (1 in 200 births) and can be multiple. These grow rapidly for a few months but then fade by 1 to 3 years of age, with complete regression by 7 years of age in the vast majority of cases.


Pathology_Robbins

Pathology_Robbins. Pyogenic granulomas are capillary hemangiomas that manifest as rapidly growing red pedunculated lesions on the skin, gingival, or oral mucosa. Microscopically they resemble exuberant granulation tissue. They bleed http://ebooksmedicine.net Fig. 10.28 Hemangiomas.(A)Hemangiomaofthetongue.(B)Histologicappearanceinjuvenilecapillaryhemangioma.(C)Pyogenicgranulomaofthelip. (D)Histologicappearanceincavernoushemangioma.(A and D, Courtesy of John Sexton, MD, Beth Israel Hospital, Boston, Massachusetts. B, Courtesy of Christopher D.M. Fletcher, MD, Brigham and Women’s Hospital, Boston, Massachusetts. C, Courtesy of Thomas Rogers, MD, University of Texas Southwestern Medical School, Dallas, Texas.)


Pathology_Robbins

Pathology_Robbins. D.M. Fletcher, MD, Brigham and Women’s Hospital, Boston, Massachusetts. C, Courtesy of Thomas Rogers, MD, University of Texas Southwestern Medical School, Dallas, Texas.) Fig. 10.28C ). Roughly one fourth of the lesions develop after trauma, reaching a size of 1 to 2 cm within a few weeks. Curettage and cautery usually are curative. Pregnancy tumor (granuloma gravidarum) is a pyogenic granuloma that occurs infrequently in the gingiva of pregnant women. These lesions may spontaneously regress (especially after pregnancy) or undergo fibrosis, but occasionally require surgical excision. • Cavernous hemangiomas are composed of large, dilated vascular channels. Compared with capillary hemangiomas, cavernous hemangiomas are more infiltrative, frequently involve deep structures, and do not spontaneously regress. On histologic examination, the mass is sharply defined but unencapsulated and is composed of large blood-filled vascular spaces separated by connective tissue stroma (


Pathology_Robbins

Pathology_Robbins. Fig. 10.28D ). Intravascular thrombosis and dystrophic calcification are common. These lesions may be locally destructive, and surgical excision is required in some cases. More often the tumors are of little clinical significance, but they can be cosmetically troublesome and are vulnerable to traumatic ulceration and bleeding. Brain hemangiomas are problematic, because they may cause symptoms related to compression of adjacent tissue or may rupture. Cavernous hemangiomas constitute one component of von Hippel-Lindau disease (Chapter 23), in which vascular lesions are commonly found in the cerebellum, brain stem, retina, pancreas, and liver. In some cases cerebral cavernous hemangiomas are familial, caused by mutations in one of three tumor suppressor genes called CCM1, CCM2, or CCM3 Lymphangiomas are the benign lymphatic counterpart of hemangiomas.


Pathology_Robbins

Pathology_Robbins. Lymphangiomas are the benign lymphatic counterpart of hemangiomas. Simple (capillary) lymphangiomas are slightly elevated or sometimes pedunculated lesions up to 1 to 2 cm in diameter that occur predominantly in the head, neck, and axillary subcutaneous tissues. Histologically, lymphangiomas are composed of networks of endothelium-lined spaces that are distinguished from capillary channels only by the absence of blood cells.


Pathology_Robbins

Pathology_Robbins. Cavernous lymphangiomas (cystic hygromas) typically are found in the neck or axilla of children, and more rarely in the retroperitoneum. Cavernous lymphangiomas can be large (up to 15 cm), filling the axilla or producing gross deformities of the neck. These lesions are composed of massively dilated lymphatic spaces lined by ECs and separated by intervening connective tissue stroma containing lymphoid aggregates. The tumor margins are indistinct and unencapsulated, making definitive resection difficult. Of note, cavernous lymphangiomas of the neck are common in Turner syndrome. http://ebooksmedicine.net


Pathology_Robbins

Pathology_Robbins. http://ebooksmedicine.net Glomus tumors are benign, exquisitely painful tumors arising from specialized SMCs of glomus bodies, arteriovenous structures involved in thermoregulation. Distinction from cavernous hemangiomas is based on clinical features and immunohistochemical staining for smooth muscle markers. They most commonly are found in the distal portion of the digits, especially under the fingernails. Excision is curative. Bacillary angiomatosis is a vascular proliferation in immunocompromised hosts (e.g., patients with AIDS) caused by opportunistic gram-negative bacilli of the Bartonella family. The lesions can involve the skin, bone, brain, and other organs. Two species have been implicated: Bartonella henselae, whose principal reservoir is the domestic cat; this organism causes cat-scratch disease (a necrotizing granulomatous inflammation of lymph nodes) in immunocompetent hosts.


Pathology_Robbins

Pathology_Robbins. Bartonella henselae, whose principal reservoir is the domestic cat; this organism causes cat-scratch disease (a necrotizing granulomatous inflammation of lymph nodes) in immunocompetent hosts. Bartonella quintana, which is transmitted by human body lice; this microbe was the cause of “trench fever” in World War I. Skin lesions take the form of red papules and nodules, or rounded subcutaneous masses. Histologically, there is a proliferation of capillaries lined by prominent epithelioid ECs, which exhibit nuclear atypia and mitoses ( Fig. 10.29 ). Other features include infiltrating neutrophils, nuclear debris, and purplish granular collections of the causative bacteria. The bacteria induce host tissues to produce hypoxia-inducible factor-1α (HIF-1α), which drives VEGF production and vascular proliferation. The infections (and lesions) are cured by antibiotic treatment.


Pathology_Robbins

Pathology_Robbins. Kaposi sarcoma (KS) is a vascular neoplasm caused by Kaposi sarcoma herpesvirus (KSHV, also known as human herpesvirus-8, or HHV-8). Although it occurs in a number of contexts, it is most common in patients with AIDS; indeed, its presence is used as a criterion for the diagnosis. Four forms of KS, based on population demographics and risks, are recognized: Classic KS is a disorder of older men of Mediterranean, Middle Eastern, or Eastern European descent (especially Ashkenazi Jews); it is uncommon in the United States. It can be associated with malignancy or altered immunity but is not associated with HIV infection. Classic KS manifests as multiple red-purple skin plaques or nodules, usually on the distal lower extremities; these progressively increase in size and number and spread proximally. Although persistent, the tumors typically are asymptomatic and remain localized to the skin and subcutaneous tissue.