Diseases of small and medium-sized blood vessels

Caliber-persistent artery (Dieulafoy’s disease)

The term caliber-persistent artery describes an arterial branch that lacks a normal arterial branching pattern and thus produces an oversized vessel in an unusual location . This condition most commonly involves the gastric mucosa, but has been reported in several other locations including small bowel, colon, gallbladder, esophagus, lip, and eyelid. Erosion of the vessel into the lumen of the stomach or bowel may lead to fatal hemorrhage ( Fig. 8.1 ), the origin of which may be difficult to localize not only for the surgeon but also for the pathologist in biopsy material or at autopsy. The condition is likely underdiagnosed and is also referred to as Dieulafoy erosion.

Congenital arteriovenous fistula

Arteries and veins arise from the same embryonic vascular plexus and differentiate later, into distinctive vascular structures. Arteriovenous (AV) anastomoses are a normal aspect of development in certain sites in the body such as the palms, soles, terminal phalanges, nose, ears, eyelids, and tongue. Failure of proper differentiation of the embryonic vascular plexus may result in the formation of a congenital AV malformation containing numerous connections between arteries and veins. Such AV fistulas may be associated with hemangiomas and may be either localized or diffuse. Congenital AV fistulas can occur at essentially any site in the body, and may, uncommonly, result in significant shunting, causing high output cardiac failure, idiopathic cardiomegaly, pulmonary hypertension, and congestive heart failure .

Congenital pulmonary artery stenosis

The pulmonary arteries can manifest congenital stenoses anywhere from the main pulmonary artery to its smaller branches. Pulmonary artery stenosis may occur as an isolated abnormality or may be associated with congenital cardiac anomalies such as tetralogy of Fallot, in genetic syndromes such as Noonan or Williams syndromes, or with exposure of the fetus to teratogens such as rubella or toxoplasmosis . Such stenoses can be corrected by open surgical arterioplasty or by catheter-based balloon angioplasty and stenting. For branch pulmonary artery stenoses, balloon dilation and stenting have been reported to compare favorably with surgical repair, requiring fewer catheter intervention procedures on follow-up .

Unilateral absence of pulmonary artery

This is a rare congenital anomaly in which the pulmonary artery fails to develop properly, resulting in a single vessel only supplying one of the lungs . The lung lacking a pulmonary artery is supplied by a systemic arterial branch from the aorta, most commonly from bronchial arteries and less commonly from intercostal, subdiaphragmatic, subclavian, or coronary arteries. This condition is most often associated with congenital cardiac defects including tetralogy of Fallot, pulmonary atresia, atrial septal defects, truncus arteriosus, patent ductus arteriosus, and right-sided aortic arch, and is also often associated with pulmonary hypertension. Infants may present with significant pulmonary hypertension and right-sided heart failure. The condition can be fatal in childhood, but patients with isolated disease without cardiac defects are often asymptomatic into adulthood. Such adult patients may present with exercise intolerance, recurrent pulmonary infections, or hemoptysis, or the condition may be discovered incidentally on imaging. Histology of the lung lacking a pulmonary artery varies based on the caliber of the systemic artery supplying that lung. If the systemic artery is relatively small, the small intraparenchymal pulmonary arteries in the lung may be atrophic with thin walls. In contrast over perfusion of the lung by the systemic branch, artery may result in pulmonary hypertension in the lung lacking a pulmonary artery. However, the pathologic changes of pulmonary hypertension are most commonly seen in the lung being supplied by the pulmonary artery.

Scimitar syndrome

This is a rare syndrome with a prevalence of ~2/100,000 that is characterized by a partial, anomalous, pulmonary venous drainage of the right lung (or just the right middle and lower lobes) to the abdominal inferior vena cava by a single vein that traverses the diaphragm . This aberrant vein on imaging characteristically has the shape of a scimitar sword. In the scimitar syndrome, the right lung is hypoplastic and may show bronchiectasis. There may be associated dextroposition and dextrorotation of the heart. The right pulmonary artery may be small, or completely absent, with arterial supply of the right lung coming from one or more systemic arteries originating from the descending portion of the aorta. Some patients present in infancy with failure to thrive, respiratory distress, cyanosis and/or congestive heart failure. Alternatively, patients may be asymptomatic in infancy and present later in childhood or early adulthood with recurrent pulmonary infections, exertional dyspnea, cardiac murmur, and/or a deformation involving the right chest.

Anomalous pulmonary venous connection

In anomalous pulmonary venous connection, a pulmonary vein fails to drain into the left atrium, but rather drains into the right atrium or a systemic vein . In total anomalous pulmonary venous connection (TAPVC), none of the pulmonary veins drain into the left atrium. There are four types of TAPVC: supracardiac type (45% of cases), infracardiac type (25% of cases), cardiac type (25% of cases), and a mixed type (5% of cases). In the supracardiac type, the pulmonary veins drain to the brachiocephalic vein, superior vena cava, or azygos vein. In the infracardiac form, the pulmonary veins drain most often to the portal vein or a persistent embryonic ductus venosus, and less commonly to the gastric vein, hepatic vein, and/or inferior vena cava. In the cardiac form, the pulmonary veins drain to the right atrium or coronary sinus.

In hearts with TAPVC, there is abnormal histologic structure of the pulmonary veins and left atrium. The pulmonary veins lack a normal myocardial sleeve, and the left atrium is small, lacks a normal smooth muscle cell layer, and has thin hypoplastic walls.

Alkaptonuria

Alkaptonuria is an autosomal recessive disorder caused by a deficiency of the enzyme homogentisate 1,2-dioxygenase. This enzyme deficiency results in increased levels of homogentisic acid, a product of tyrosine and phenylalanine metabolism. In the urine, the homogentisic acid is oxidized to a melanin-like material, which causes the urine to acquire a blackened appearance. In the body, the homogentisic acid undergoes polymerization, causing it to accumulate in connective tissue and making the tissue blacken . Histologically, the pigment appears brown or ocher. The term ochronosis has been applied to alkaptonuria but also refers more generally to any deposition of an ocher-colored material in connective tissue. In patients with alkaptonuria, pigment can be found in heart valves, healed myocardial infarcts, atherosclerotic vascular lesions, and throughout nonatherosclerotic arterial walls. The material is deposited within various cells types including endothelial cells, macrophages, fibroblasts, and smooth muscle cells. The pigment is also found in the ECM. The pigment is Masson-Fontana positive, Prussian blue negative, and appears electron-dense ultrastructurally.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic small cerebral vascular disorder caused by mutations in the NOTCH3 gene, which encodes the Notch3 receptor . The age of onset is variable, but patients often present in mid-adulthood with migraine headaches followed by strokes. The disorder is inherited in an autosomal dominant fashion with the Notch3 receptor extracellular domain accumulating in arterial and arteriolar walls leading to vascular smooth muscle degeneration, scarring and vascular stenosis. The disorder predominantly affects the cerebral white matter. Histologically, the small arteries appear thickened with loss of smooth muscle cells and accumulation of PAS-positive material in the media.

Cutis laxa

Cutis laxa is a family of congenital and acquired disorders characterized by abnormal elastic fibers causing loose, redundant, and hypoelastic skin. The congenital forms may show an autosomal dominant, X-linked, or autosomal recessive pattern of inheritance. Several genes involved in elastic fiber biogenesis have been identified as harboring mutations including elastin, fibulin-4, fibulin-5, the vacuolar ATPase ATP6V0A2, pyrroline-5-carboxylate reductase 1, the copper transporter ATP7A, the glucose transporter GLUT10, latent TGF-β binding protein 4, and RIN2 . Tissue with elastic fibers throughout the body may be affected including the vasculature. Depending on the specific mutation involved, the patients may demonstrate aneurysms, tortuosity, or rupture of the aorta, pulmonary artery, or smaller arteries. Histologically, there may be loss and fragmentation of elastic fibers, accumulation of aggregates of dense granular material, and increased medial glycosoaminoglycans .

Pseudoxanthoma elasticum

Pseudoxanthoma elasticum is a genetic condition inherited in an autosomal recessive fashion due to mutations in the ABCC6 gene . This gene encodes an ATP-binding cassette transporter that is primarily expressed in the liver. It is thought that these patients have a metabolic disturbance that promotes calcification. In this disorder, elastic fibers in the skin, eyes, and cardiovascular system display fragmentation, clumping, and calcification. Skin lesions appear as yellow-orange papules resembling xanthomas, and are often found in the axillae, neck, and groin. Angioid streaks are often found in the ocular fundi, which result from mineralization and disruption of the elastic lamina of Bruch’s membrane. There may be stenosis or aneurysms of medium-sized arteries, which histologically demonstrate intimal thickening along with elastic fiber fragmentation and calcification ( Fig. 8.2 ) . The aorta is typically not involved. There may be accelerated atherosclerosis of atherosclerosis-prone arteries, as well as atherosclerosis of arterial beds that are typically resistant to developing atherosclerosis. Patients may present clinically with early-onset atherosclerosis in the absence of cutaneous manifestations .

Homocystinuria and hyperhomocysteinemia

Homocysteine is a sulfur-containing amino acid that is derived from the demethylation of methionine. In the serum, homocysteine occurs as two homocysteine molecules linked by a disulfide bond (homocystine), or as homocysteine disulfide-linked to cysteine. Homocysteine is metabolized to cystathionine by the enzyme cystathionine synthase, which uses vitamin B6 as a cofactor. Alternatively, homocysteine can be transformed back into methionine by the enzyme methionine synthase, which uses vitamin B12. The enzyme methylene tetrahydrofolate reductase generates 5-methyl tetrahydrofolate to serve as a carbon donor for methionine synthase.

Homozygous deficiencies of certain genes involved in methionine metabolism including cystathionine synthase or methylene tetrahydrofolate reductase results in the condition homocystinuria. Patients with this disorder have elevated serum concentrations of homocysteine and methionine. Patients are often mentally retarded, and may show skeletal abnormalities resembling those of Marfan syndrome as well as ectopia lentis. The patients are prone to thrombosis, and venous and arterial thrombosis often occurs before 30 years of age. The thrombosis is a major contributor to mortality in these patients.

In children with the disorder, the arteries histologically show fibrous intimal thickening, which may induce severe stenosis and cause tissue ischemia and infarction. There can also be splitting of the internal elastic lamina. Small, medium-sized, and large arteries are all involved . Aortic medial degeneration has also been reported. In some patients, the disorder has been linked with aneurysm formation in the coronary arteries and other arteries . Elevated plasma homocysteine levels are now considered to be a risk factor for coronary artery disease and myocardial infarction, even in patients without homocystinuria . It is thought the elevated levels of homocysteine may promote not only thrombosis but also vascular oxidative stress and endothelial dysfunction.

Neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is caused by mutations in the neurofibromin gene . NF1 is an autosomal dominant disorder associated with peripheral neurofibromas, pheochromocytoma, and vascular lesions. It has been associated with congenital valvular pulmonic stenosis and coarctation of the aorta . In addition, adventitial neurofibromas may compress arteries. In some NF1 patients, there is disordered architecture within the walls of small and medium-sized arteries, including proliferation of spindle cells within the intima and/or the media, intimal hyperplasia, intimal or medial fibrosis, loss of medial smooth muscle cells, and fragmentation of elastic fibers ( Fig. 8.3 ) . NF1 patients are prone to develop arterial aneurysms and venous varicosities throughout the body . When involving the renal arteries, the pathology of NF1 overlaps to some extent with that of the intimal fibroplasia form of fibromuscular dysplasia (see below) .

Myotonic dystrophy

Patients with myotonic dystrophy have microvascular tortuosity and increased vascular leakage in the anterior segment of the eye by fluorescein angiography . In the skeletal muscle, these patients have thinning of the capillary basement membrane . The significance of these microvascular changes is unclear. It has also been reported that these patients have impaired coronary reserve, possibly due to impairment of the vascular smooth muscle cells .

Sickle cell disease

Sickle cell disease is a hereditary hemoglobinopathy in which the red blood cells show decreased deformability, due to aggregation of the hemoglobin. This hemoglobin aggregation causes the red blood cells to acquire a sickled appearance and to be both stiff and sticky . These alterations lead to reduced microvascular blood flow and even microvascular occlusion with tissue ischemia and infarction. In the retina, these changes are associated with neovascular proliferation and are thus referred to as proliferative sickle cell retinopathy .

Fabry disease

Fabry disease is caused by deficiency of α-galactosidase, a lysosomal hydrolase. It shows an X-linked pattern of inheritance. The disease is characterized by the accumulation of trihexosylceramide (globotriaosylceramide) within multiple cell types including endothelial cells, vascular smooth muscle cells, cardiac myocytes, valve interstitial cells, renal glomerular cells, and renal tubular cells . The aorta, coronary arteries, and other arteries may be involved ( Fig. 8.4 ). Histologically, the involved cells are vacuolated, and contain birefringent deposits that stain positively with toluidine blue, periodic acid-Schiff (PAS) stain, or Sudan black B. The deposits appear as dense lamellar bodies by transmission electron microscopy. Definitive diagnosis is usually made by biochemical assay for α-galactosidase activity.

Menkes disease

Menkes disease is an X-linked disorder of copper transport causing a severe copper deficiency. The patients display kinky hair, neurologic symptoms, and connective tissue defects. These patients have abnormal arterial wall structure with arterial wall thinning, elastic fiber loss and fragmentation, intimal thickening, arterial tortuosity, and defects in vascular innervation . Arterial aneurysms may occur in which there is degeneration of the media with smooth muscle cell loss .

Mucopolysaccharidoses

The mucopolysaccharidoses are a group of hereditary disorders of proteoglycan metabolism in which mucopolysaccharides accumulate in the tissue . In addition to other cell types, mucopolysaccharides can accumulate in the arteries, including the coronary arteries. In Mucopolysaccharidosis type I (Hurler syndrome), there can be severe intimal thickening of the coronary arteries and aorta caused by the presence of collagen and vacuolated cells containing lamellar bodies by electron microscopy . In Mucopolysaccharidosis, type III (Sanfilippo syndrome) vacuolated cells are present in the coronary artery intima ( Fig. 8.5 ) . In Mucopolysaccharidosis, type IV (Morquio syndrome) vacuolated cells containing either lipid or finely granular material by electron microscopy are present in the coronary artery intima . Mucopolysaccharidosis type VII (Sly-Neufeld syndrome) can be associated with coronary artery stenosis, in which histologically there are vacuolated cells containing lamellar and filamentous material by electron microscopy .

Mucolipidoses

The mucolipidoses are hereditary storage disorders in which there is accumulation of mucopolysaccharides, sphingolipids, and glycolipids in the tissue, including in some cases, vascular cells. Mucolipidosis II, or I-cell disease, is an autosomal recessive disorder due to deficiency of N -acetylglucosamine-1-phosphotransferase, which results in a deficiency of lysosomal acid hydrolases. The disorder is named after fibroblasts with inclusion bodies, “I cells.” The inclusions measure 0.5–1 μm in diameter and contain lipid and mucopolysaccharide. The vacuoles stain positively with PAS and Sudan black stains, and by electron microscopy, they contain lamellar and granular material. In addition to other sites, vacuolated cells containing lamellar inclusions can be found within the coronary artery intima .

Osteogenesis imperfecta

Osteogenesis imperfecta is a group of inherited disorders that affects 1/10,000 of the population. The patients typically manifest bone fragility. The disorder causes either quantitative or qualitative changes in type I collagen. Patients may display a deficiency of collagen in the blood vessels . The disorder is associated with arterial aneurysms and dissections. Abnormalities have been observed in the microvasculature of the brain including perivascular nodules of calcifying ECM components, and endothelial proliferation with redundant basement membranes .

Hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia, or Osler-Weber-Rendu disease, is a group of autosomal dominant conditions characterized by telangiectasis and AV malformations primarily of the nose, skin, and gastrointestinal system . The patients may also develop lesions at other sites including the liver, lungs, and brain. The primary genes causing this condition include endoglin, SMAD4, and ACVRL1, and are involved in TGF-β signaling. The vascular lesions can cause hemorrhage and in some cases high output cardiac failure.

Klippel-Trenaunay syndrome

Klippel-Trenaunay syndrome is a syndrome characterized by cutaneous capillary malformations, varicose veins, and the hypertrophy of bone and soft tissue . The legs are most commonly affected but the arms, trunk, and even head and neck may be involved as well. Histologically, the cutaneous capillary malformations consist of dilated telangiectatic vessels in the upper dermis. The vascular malformations may extend to the underlying skeletal muscle or bone and may even involve visceral organs such as the pleura, liver, spleen, and colon. The vascular malformations are prone to hemorrhage. Varicosities are often present in infancy or childhood. The patients also often have anomalies of the deep veins, including absent, atretic, or hypoplastic veins, and the patients are predisposed to pulmonary emboli. The genetic changes casing the condition are not completely understood.

Diabetic vasculopathy

Diabetes mellitus is a group of disorders characterized by increased serum glucose levels or hyperglycemia. The level of glucose in the serum is regulated by insulin, which stimulates the uptake of glucose by target tissues, particularly skeletal muscle, adipose tissue, and the liver. Hyperglycemia can result from either deficient insulin secretion from the pancreas or impaired insulin action in target tissues such as skeletal muscle. In type 1 diabetes mellitus, there is an immune-mediated destruction of the β-cells in the pancreas, the cells that are responsible for secreting insulin into the blood. In adult-onset type 2 diabetes mellitus, genetic predisposition and/or obesity render target tissue relatively resistant to the effects of insulin. In type 2 diabetes, the pancreatic β-cells respond at first with compensatory hyperplasia and an overall increase in insulin production. However, eventually, the β-cells undergo failure, causing essentially an insulin deficiency in the setting of insulin resistance.

The vascular complications of diabetes encompass both macrovascular disease and microvascular disease. Pathologically, macrovascular disease is an accentuated atherosclerosis, which most severely affects the heart and the peripheral arteries in the legs. Diabetics are at increased risk for both myocardial infarction and peripheral vascular occlusive disease. Involvement of cerebral vessels makes diabetics more prone to strokes. In addition to accentuated atherosclerosis, diabetes also results in arteriosclerosis of small intraparenchymal arteries . The traditional microvascular disease of diabetes primarily affects capillaries and other small vessels. It most profoundly affects the kidneys, retina, and nerves causing the clinical manifestations of diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy respectively .

Although our understanding of the mechanisms underlying diabetic vascular disease continues to evolve, it appears most likely that these vascular complications are a result of the elevated levels of glucose. The elevated glucose levels lead to the formation of advanced glycation end products (AGEs). AGEs are formed by the nonenzymatic reaction of protein amino groups with glucose-derived metabolites such as glyoxal, methylglyoxal, and 3-deoxyglucosone. The ECM in the vessel wall is especially prone to development of AGEs, which can result in the crosslinking of the matrix proteins. The crosslinking of collagen makes the arteries stiffer and less elastic. It also alters shear stress and promotes endothelial activation and injury. Modification of the endothelial basement membrane by AGE formation impairs endothelial adhesion and increases permeability. The increased endothelial permeability allows for enhanced entry of serum proteins into the intima. Proteins with AGE modifications are relatively resistant to digestion by proteases. Since the quantity of a protein at any given time is determined by its rate of synthesis and degradation, the impaired degradation results in an increase in the amount of vascular ECM.

In diabetes, the abundant vascular ECM, with its AGE modifications, traps and retains serum proteins in the vessel wall. In large- and medium-sized arteries, this relatively abundant and cross-linked ECM fosters retention of LDL in the intima, promoting the development of atherosclerosis. In smaller arteries, which are relatively resistant to atherosclerosis, and in capillaries and other small vessels, the AGE-modified ECM binds and retains other plasma proteins including albumin, which have entered the intima in increased amounts due to the impaired endothelial permeability. The binding of plasma proteins to the ECM makes the vessel wall thicken and take on a glassy or hyalinized appearance ( Fig. 8.6 ). These changes can cause severe stenosis of the vessel and ischemia of downstream tissue. The affected vessels are more fragile and are susceptible to rupture. In the retina, diabetic vasculopathy causes the death of the pericytes around the capillaries, and the formation of microaneurysms. In the retina, the endothelial cells are activated and show increased proliferation, in some cases resulting in proliferative diabetic retinopathy.

Other extracellular proteins besides ECM can be modified by AGEs. Some of these modified proteins will bind to cellular surface receptors for AGEs, such as RAGE, on endothelial cells . Activation of RAGE promotes endothelial activation, and the increased secretion of reactive oxygen species, cytokines, and growth factors. Once released from the endothelial cells, these agents promote vascular smooth cell activation, resulting in an increased production of ECM. Small vessels with diabetic vasculopathy contain increased amounts of collagen, fibronectin, and laminin. Activation of RAGE also promotes the downregulation of glyoxalase-1 (Glo1), an enzyme that metabolizes methylglyoxal. Thus the interaction of AGE-modified proteins with RAGE fosters the accumulation of more methylglyoxal and more AGEs, setting up a vicious cycle.

Hypothyroidism

Hypothyroidism has been reported to be associated with a thickened capillary basement membrane in cardiac muscle and increased carbohydrate in the vascular media . The significance of these changes is unclear.

Introduction to vasculitis

The vasculitides are a heterogeneous group of disorders in which inflammation targets and damages blood vessels. The noninfectious vasculitides result from a direct attack on the vascular wall by the immune system. The classification of vasculitis is extremely important, since it forms the basis for how we approach these disorders for diagnosis, patient management, and research. It should be kept in mind that the vasculitides have the potential for being extremely diverse, perhaps as diverse as the complexity of the immune system itself, and thus no classification system is likely to perfectly classify the disease in all patients.

The most widely utilized scheme for classifying the vasculitides into distinct pathologic entities is the Chapel Hill Consensus Conference nomenclature . A primary feature of the Chapel Hill System is to first consider the sizes of the vessels that are involved, resulting in the three general vasculitic categories of large-vessel vasculitis, medium-vessel vasculitis, and small vessel vasculitis ( Table 8.1 ). Large vessels in this context refer primarily to the aorta, aortic arch branches, and distributing arteries in the extremities and head. Medium vessels refer to medium-sized arteries and veins throughout the body, which includes both distributing and proximal intraparenchymal vessels. Arterioles, capillaries, and venules are classified as small vessels. Small arteries and veins, represented by the distal intraparenchymal arteries and veins, were previously classified as medium vessels in the original Chapel Hill Classification System , but then reclassified as small vessels in the later revised Chapel Hill Classification System . This has led to some confusion in the field and difficulties with the interpretation of some of the literature. It is least ambiguous to reserve the term “small vessels” for arterioles, capillaries, and venules and to explicitly specify “small arteries” when referring to small arteries. Thus for this chapter, the term “small vessels” will refer only to arterioles, capillaries, and venules.

Many vasculitides can involve more than one size of vessel. For example, by Chapel Hill criteria, both large-vessel vasculitides and small-vessel vasculitides may also involve medium-sized vessels. Conditions in which no specific size of vessel is involved are referred to as variable-vessel vasculitis.

Small vessel vasculitis

The small vessel vasculitides are characterized by a neutrophil-predominant or leukocytoclastic vasculitis involving small vessels, thus arterioles, capillaries, and venules. The neutrophils often show fragmentation or leukocytoclasia. There is typically injury to the vessel wall, which may take the form of fibrinoid necrosis or red blood cell extravasation, and the vessel often shows evidence of luminal thrombosis. Hemorrhage from injured vessels may occur. The small vessel vasculitides are divided into those conditions associated with circulating antineutrophil cytoplasmic antibodies (ANCA), and those not associated with ANCA . Those conditions, which are not associated with ANCA, are associated with immune-complex deposition. The immune complexes activate complement, which results in the formation of chemotactic factors that attract neutrophils to the vessel wall. In contrast, the ANCA-associated vasculitides are often referred to as pauci-immune small vessel vasculitides, since they are not associated with a significant amount of immune-complex deposition. In contrast, in these conditions, the ANCA itself may play a role in amplification of the inflammatory response.

The ANCA-associated small-vessel vasculitides include three disorders: granulomatosis with polyangiitis (GPA, formerly known as Wegener’s granulomatosis), eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome), and microscopic polyangiitis (MPA). The immune-complex small vessel vasculitides can include any condition that results in immune-complex formation. The principal forms of immune-complex vasculitis are Henoch–Schönlein purpura (HSP), cryoglobulinemic vasculitis, and drug reactions. Other causes of immune-complex vasculitis include inflammatory bowel disease, systemic lupus erythematosus (SLE), paraneoplastic phenomena, and infections . Given the similarity of the vascular inflammation in both ANCA-associated and immune-complex small vessel vasculitis, it is not surprising that many of the manifestations of these disorders are very similar. For example, palpable purpura resulting from involvement of the superficial epidermal capillary plexus, hemoptysis resulting from pulmonary capillaritis, and hematuria resulting from glomerulonephritis can all be seen in many forms of small vessel vasculitis, particularly the ANCA-associated disorders. In addition, all small vessel vasculitides can also involve small and medium-sized arteries, which may result in aneurysms and thrombotic obstructions .

Granulomatosis with polyangiitis

GPA, along with the other ANCA-associated vasculitides, is small vessel vasculitis with a predilection for involving the lungs and kidneys . The ANCA-associated vasculitides are associated with circulating antibodies either to proteinase-3, which stains neutrophils in a cytoplasmic pattern (C-ANCA), or to myeloperoxidase, which stains neutrophils in a perinuclear pattern (P-ANCA). GPA is a relatively uncommon disease with an annual incidence of ~1 per 100,000 in European countries, but can afflict a wide age range of patients from children to the elderly . GPA may involve any organ, but has a propensity to involve the lungs, kidneys, upper respiratory tract and the ocular orbits. Chronic destruction of the nasal tissue can result in a characteristic saddle-nose deformity.

Pathologically, GPA is characterized by the presence of both a small vessel neutrophilic vasculitis and granulomatous inflammation ( Fig. 8.7 ). The granulomatous inflammation is largely extravascular, but in unusual cases it can result in a granulomatous vasculitis. GPA is thought to begin as a granulomatous disorder in the respiratory tract before becoming a widespread small vessel vasculitis . The granulomatous component primarily contains activated macrophages with scattered macrophage giant cells, and often shows areas of necrosis, which may occur as discrete collections of neutrophils (microabscesses). The granulomatous component may cause destructive mass forming lesions in the orbits, airways, and chest cavity. When the vasculitis involves medium-sized vessels, the inflammatory infiltrate will often have a more mixed cellular composition and fibrinoid necrosis is often present.

Eosinophilic granulomatosis with polyangiitis

EGPA is an ANCA-associated vasculitis that is closely related to GPA. An important distinction between the two conditions is that the patients with EGPA usually have asthma or allergic rhinitis and often demonstrate elevated levels of eosinophils circulating in the blood . In EGPA, only about 40% of patients develop ANCA in contrast to severe GPA in which >90% of patients will have ANCA. EGPA preferentially afflicts middle-aged adults. It is a rare disease having an annual incidence of around 2 per million per year.

EGPA can be separated into distinct phases. There is an initial prodromic phase consisting of allergic rhinitis or asthma, which is followed by a phase in which eosinophils are found within tissues along with granulomatous inflammation . This granulomatous phase is followed years later by a systemic small vessel vasculitis, which primarily affects the kidneys, lungs, skin, and peripheral nerves and less commonly other organs including the heart and brain. The pathology of EGPA is similar to that of GPA, except that in some cases increased numbers of eosinophils may be identified. It may be difficult if not impossible to distinguish the two conditions based solely on pathology, and clinical correlation is often required.

Microscopic polyangiitis

MPA is an ANCA-associated small vessel vasculitis. It lacks the granulomatous inflammation found in patients with GPA and EGPA. MPA was previously regarded as a variant of polyarteritis nodosa (PAN), and was often previously referred to as microscopic periarteritis and microscopic polyarteritis. About 75% of patients with MPA have ANCA in the blood . Like the GPA and EGPA, MPA frequently affects the kidneys and lungs. Kidney involvement often manifests as rapidly progressive glomerulonephritis. In addition to kidney and lung involvement, skin involvement, nerve involvement (mononeuritis multiplex), arthralgias and myalgias are also commonly seen in MPA. The annual incidence of MPA ranges from 2 to 12 per million per year in Europe, afflicting primarily middle-aged to older adults . Histologically the small vessel vasculitis seen in MPA is largely similar to that of GPA ( Fig. 8.8 ). While the absence of granulomatous inflammation helps to suggest the presence of MPA rather than GPA, the distinction often requires clinical-pathologic correlation.

Henoch–Schönlein purpura

HSP is an immune-complex small vessel vasculitis that results from the formation of immune complexes containing IgA . The disease is more common in children than adults. It is the most common vasculitis of childhood, having an annual incidence of 10 per 100,000 children per year. In about half of cases, the disease’s appearance is preceded by an upper respiratory tract infection, which suggests an infectious trigger in some patients. In other cases, environmental triggers such as medications may be involved. The classic presentation includes skin involvement in the form of palpable purpura, abdominal pain due to gastrointestinal involvement, and arthritis. Renal involvement with glomerulonephritis can also occur, especially in older children and adults. However, pulmonary hemorrhage is only rarely seen. The gastrointestinal involvement may present as hemoptysis or occult bleeding, and in rare occasions massive gastrointestinal hemorrhage. Elevated levels of IgA in the blood are seen in about half of patients.

Pathologically on routine hematoxylin and eosin-stained slides, HSP displays the features of a neutrophilic small-vessel vasculitis detailed above ( Fig. 8.9 ). In addition, by immunofluorescence, IgA containing immune complexes are present in the acute vascular lesions. The disease is often self-limited, typically lasting about 4 weeks. In about a third of patients, there will be recurrences of the disease over the next 4–6 months. The most common chronic complication of HSP is renal failure secondary to nephritis.

Cryoglobulinemic vasculitis

Cryoglobulins are immunoglobulins in the blood that precipitates when the serum is cooled below 37°C and that dissolves upon rewarming of the serum. Type I cryoglobulins are composed of monoclonal immunoglobulins and are most often encountered in the setting of a lymphoproliferative disorder. In contrast, type II cryoglobulins are composed of polyclonal IgG and monoclonal IgM rheumatoid factor. Type III cryoglobulins are composed of polyclonal IgG and polyclonal IgM rheumatoid factor. Type II and type III cryoglobulins are both often referred to as mixed cryoglobulins. Mixed cryoglobulinemia is associated with multiple infectious, rheumatologic, and neoplastic conditions including human immune deficiency virus, hepatitis C virus (HCV), endocarditis, Sjögren’s syndrome, SLE, and nonHodgkin’s lymphoma . When no underlying condition is identified, then the condition is classified as essential mixed cryoglobulinemia. Cryoglobulinemic vasculitis develops in about 10% of patients with mixed cryoglobulinemia due to deposition of immune complexes.

Upto 90% of patients with cryoglobulinemic vasculitis have chronic HCV infection . About half of patients infected with HCV have circulating mixed cryoglobulins, but only a minority of these patients, 5%–10%, will develop cryoglobulinemic vasculitis. Cryoglobulinemic vasculitis most commonly affects the skin, kidneys, nerves, and joints. These patients will frequently have additional laboratory abnormalities, including low levels of complement C4 and a positive rheumatoid factor.

Drug-induced vasculitis

Drug-induced small vessel vasculitis is often referred to as hypersensitivity vasculitis. It is the most common small vessel vasculitis in adults . As the name implies, drug-induced vasculitis is triggered by the administration of a drug. Agents that have been implicated in causing drug-induced vasculitis are diverse and include antibiotics, hydralazine, propylthiouracil, allopurinol, d -penicillamine, phenytoin, isotretinoin, and methotrexate . The drugs themselves are most often too small to serve as antigens for immune-complex formation. It is believed that in some cases the drugs become linked to proteins, and that the drug-protein complex then serves as an antigen for immune-complex formation. In other cases, the drugs appear to induce the formation of ANCA, which may itself be pathologic and cause small vessel vasculitis without extensive immune-complex formation .

The most common clinical manifestation of drug-induced vasculitis is skin involvement. The cutaneous leukocytoclastic vasculitis typically manifests as palpable purpura. However, other organs including kidneys, lungs, liver, and the gastrointestinal tract may less commonly be involved. By routine light microscopy, drug-induced vasculitis shows the features of a neutrophilic small vessel vasculitis detailed above. By immunofluorescence, immune complexes primarily composed of IgM or IgG are often present in the acute vascular lesions . This allows for a distinction from HSP, in which IgA containing immune complexes are seen. As with other forms of ANCA-associated vasculitis, extensive immune complexes are not typically observed when drug-induced ANCA is present.