Thoracic Aortic Aneurysm Pathology
In the thoracic aorta, a diameter of 3 cm or greater is generally considered aneurysmal, although the average size of surgically corrected aneurysms is over 5cm. Thoracic aortic aneurysms (TAAs) can involve the aortic root, ascending aorta, arch, descending aorta, or a combination of these locations. The combination of aortic root dilatation and ascending aneurysm is termed “annuloaortic ectasia.” (Anatomically and radiologically, an aneurysm is defined as a dilatation at least 50% above the normal diameter of an artery.) (See the images below.)
Aortic dissections are frequently superimposed on noninflammatory TAAs; these aneurysms are often designated as “dissecting aneurysms.” However, aortic dissections may occur with medial degeneration in the absence of preexisting aneurysm.
Pseudoaneurysm denotes a ruptured aortic wall with healing of the extravasated blood and formation of the aneurysm wall by fibrous tissue.
Aortic aneurysms are a leading cause of the death in the United States. With improvements in screening and imaging techniques, the incidence of thoracic aortic aneurysm (TAA) has been increasing steadily in the last decades. Overall, the estimated incidence of TAA is 6 cases per 100,000 person years. Autopsy series have estimated its prevalence at 3-4% in patients over age 65 years.
The cause of TAA greatly affects the age at presentation. Patients with inherited disorders have TAAs at an early age, presenting in childhood or adolescence. Patients with idiopathic, noninflammatory aneurysms are typically adults and present with symptoms of aneurysm later than do those patients with identified connective tissue disorders. Patients with aortitis and aneurysms present at middle age or older, including advanced ages, especially in the case of giant cell aortitis.
Causes of thoracic aortic aneurysm (TAA) include inherited syndromes, atherosclerosis, noninfectious aortitis, and infections; however, a large number have no known cause. Idiopathic, noninflammatory aneurysms are associated with congenital conditions (bicuspid aortic valve) and acquired conditions (hypertension). Pathologically, noninflammatory aneurysms demonstrate degrees of cystic, medial degeneration, depending on etiology or association. The inherited syndromes causing TAA include Marfan syndrome, Loeys-Dietz syndrome, and Ehlers-Danlos syndrome.
Aneurysmal dilatation of the thoracic aorta can occur by various mechanisms. Most commonly, the pathogenesis of the aneurysms is due to noninflammatory, medial degeneration of the elastic aortic wall. However, inflammatory destruction secondary to syphilis, bacterial infection, noninfectious aortitis, or atherosclerosis can result in TAA. Pseudoaneurysms may result from aortic tears, typically due to blunt chest trauma, with healing of the extravasated blood and formation of fibrous tissue wall.
The etiology of TAA depends on the site of its occurrence in the aorta. Most surgically resected TAAs involve the ascending aorta. In a series of 513 ascending TAAs at the Mayo Clinic, 13% of patients had inherited connective tissue disease, mostly Marfan syndrome;  25% had bicuspid aortic valve with noninflammatory TAA; 11% had aortitis; and the remaining 51% had idiopathic noninflammatory aneurysms, with approximately 60% of this last group of patients being hypertensive.
Atherosclerosis accounts for only 1% of ascending TAAs;  however, 90% of descending TAAs are atherosclerotic,  with the remaining 10% being chronic dissections. Descending TAAs are less frequently resected than are ascending TAAs, as they are often treated medically (especially chronic dissections). 
Medial degeneration is the histologic substrate for most dissecting aneurysms and annuloaortic ectasia. Aortitis is divided clinically and pathologically in 2 major types, Takayasu arteritis and giant cell arteritis. 
The remaining etiologies account for less than 1-5% of surgical resections. Syphilitic aneurysms result in marked aortic root dilatation with ascending aneurysms but are extremely rare in industrialized countries.  Infectious bacterial aneurysms, still often termed mycotic aneurysms (after the designation given by Osler in the 1800s),  are frequently seen in patients with bacteremia due to infectious endocarditis. Most pseudoaneurysms are the result of trauma or ruptured atherosclerotic ulcers and may occur in any portion of the aorta, although they typically occur in the descending thoracic aorta. 
Marfan syndrome is an autosomal dominant disorder characterized by abnormalities of the eyes, skeleton, and cardiovascular system. Marfan syndrome is an autosomal dominant disease, with one quarter of patients having no family history of the condition and instead getting the disease from new mutations. Aortic root dilatation, aortic dissections, mitral valve prolapse, and other miscellaneous cardiovascular manifestations are seen in Marfan syndrome. Patients with Marfan syndrome have medial degeneration of the aorta, also referred to as cystic medial necrosis. The histologic medial degeneration tends to be prominent in patients with this syndrome, although it is not specific to the disease.
Loeys-Dietz syndrome is an autosomal dominant connective tissue disorder that is a rare cause of TAA. It results from genetic mutations in the transforming growth factor beta receptors 1 and 2 (TGFBR1 and TGFBR2). The syndrome is characterized phenotypically by hypertelorism, bifid uvula, and/or cleft palate, as well as by arterial tortuosity with aneurysms and dissections. Loeys-Dietz syndrome has a much more rapid clinical course than Marfan syndrome; thus, patients diagnosed with Loeys-Dietz syndrome are currently being recommended for prophylactic aortic root replacement at younger ages and with smaller aortic dimensions. Histologically, diffuse medial degeneration, which may be subtle, exists. 
Patients with Ehlers-Danlos syndrome type IV may also have TAAs; however, the typical complication is rupture in a normal caliber artery. Coronary artery dissections, aortic rupture, iliac and femoral rupture, and coronary and other muscular arterial aneurysms are among the different complications seen in these patients.
A significant clinical association with TAA with or without dissection is congenitally bicuspid aortic valve. Bicuspid aortic valve is a common congenital defect; it affects approximately 1.3% of the general population and 14% of patients with proximal aortic dissections. [10, 11, 12, 13]
The developmental defect underlying the association between aortic root dilatation and dissection is unknown, but both conditions have a hereditary component. It is currently accepted that the aneurysms are not due to flow-related disturbances secondary to valvar insufficiency or stenosis; for this reason, wrapping of the aorta to prevent progressive dilatation after valve repair is often advocated. 
Patients with bicuspid aortic valve and TAA present at a mean age of 56 +/-13 years. One half have aortic valve stenosis, and the other half have valve insufficiency, with or without stenosis; only a small number have normal valve function.  Valve insufficiency can be treated with ascending aortic aneurysm repair in two thirds of patients with TAA and aortic insufficiency; the rest of these patients require valve replacement. 
Infections are a rare cause of TAA. In industrialized countries, syphilitic aortitis is vanishingly rare, accounting for 0-1% in various series.  Bacterial (or myocytic) aneurysms are a rare type of ascending and descending TAA. In one series of 734 patients with aortic aneurysms, only 2.3% were caused by bacterial infection, and most occurred in the abdominal aorta. The most common pathogens were Salmonella and Staphylococcus species.  Many patients have a prior history of endocarditis.
Although most non-Marfan TAAs are sporadic, familial aggregation studies have suggested a higher prevalence in first-degree relatives. [16, 17] In a large study of 470 patients with TAAs and no history of Marfan syndrome, family history studies found an inherited pattern in 21.5% of patients. These patients were significantly younger than patients without a family history but older than patients with full-blown Marfan syndrome. In over 75% of families with multiple affected members, the disease is inherited in an autosomal dominant manner. Interestingly, an increased risk of abdominal aortic, cerebral, and other aneurysms exists.  Various loci have been associated with familial TAA, including TAAD1, FAA1, and FBN1, among others.
Another rare type of TAA, posttraumatic pseudoaneurysm, is most frequently seen in the proximal descending thoracic aorta at the site of the ligamentum arteriosum, when blunt chest trauma results in separation of the aortic wall.  Congenital TAA may occur in association with an aberrant right subclavian artery with diverticulum of Kommerell. 
The etiology of an aneurysm may affect the incidence of dissections. Atherosclerosis, when advanced, typically results in medial and adventitial fibrosis, which hampers the development of dissections. In some cases, an atherosclerotic plaque may ulcerate and result in limited dissection (a so-called penetrating atherosclerotic ulcer). These lesions are typically not aneurysmal but show imaging characteristics of intramural hematoma and usually occur in the descending thoracic aorta.
Dissections are common in Marfan syndrome, idiopathic TAA, and TAA associated with bicuspid aortic valve, because the medial degeneration is devoid of significant scarring and results in laminar weakness of the wall. Because rare examples of TAA with dissection lack an intimal tear, it is believed that the initiation of the dissection may involve leaking or ruptured vasa vasorum, which are present predominantly in the proximal aorta.
Inflammatory aortitides are associated with aneurysm, but the significant adventitial fibrosis that accompanies Takayasu aortitis inhibits dissections, despite the medial inflammation, whereas the aortitis of giant cell aortitis is more frequently associated with aneurysms, because fibrosis is less prominent.
A study by Pasta et al indicated that in dissection of the thoracic aorta in patients with an ascending TAA, the intimal portion of the aortic wall may fail before the adventitial portion does. The investigators also found evidence that, apparently due to a disorganized aortic microstructure, the aorta’s delimination strength in individuals with either a bicuspid or tricuspid aortic valve who have an ascending TAA is lower than that found in persons with a nonaneurysmal aorta. Moreover, among patients with an ascending TAA, those with a bicuspid valve had an even lower delamination strength than did patients with a tricuspid valve. 
The locations of thoracic aortic aneurysms (TAAs) vary by etiology and are of critical importance in approaches to surgical repair. The sites of involvement include the aortic root (including the sinuses of Valsalva and the fibrous annulus), the ascending aorta distal to the sinotubular junction, the transverse arch, and the distal thoracic aorta.
Ascending aortic aneurysms have several anatomic surgical subsets. Aortic root disease with or without ascending aortic involvement (annuloaortic ectasia) generally results in aortic insufficiency and requires valve replacement with valved ascending aortic graft (Bentall procedure). Aortic root dilatation is best determined by intraoperative transesophageal ultrasonography.
Valve-sparing aortic root repair with root reconstruction with or without valve reimplantation has been developed.  Ascending aortic aneurysms not involving the root may cause aortic insufficiency due to dilatation of the sinotubular junction, but aortic valve insufficiency is generally corrected by aneurysm repair only, with valve replacement being unnecessary. Ascending aneurysms may extend into the aortic arch, requiring partial or complete arch replacement; these aneurysms are often inflammatory or atherosclerotic.
Aneurysms of the distal arch and descending aorta are typically atherosclerotic. The other common types of aneurysm involving the descending thoracic aorta are healed dissecting aneurysms, infectious (mycotic) aneurysms, and traumatic pseudoaneurysms.
Noninflammatory aneurysms caused by Marfan syndrome almost always involve the aortic root, necessitating valve replacement or valve-sparing root repair. Noninflammatory aneurysms in older patients often spare the aortic valve and root. Syphilitic aortitis, as well as noninfectious aortitis, typically involves the aortic root, which requires valve replacement or root repair in over 50% of patients. [20, 21]
The location of the aneurysm also affects the prevalence of subtypes. Atherosclerotic lesions are most frequent in the descending aorta and the aortic arch. Aneurysms associated with medial degeneration are almost exclusively in the ascending segment, and dissecting aneurysms may be present either in the proximal or descending portion. Patients with aortitis tend to present with involvement of the ascending aorta. Infectious cases (mycotic mainly) are more frequent in the descending aorta.
A large percentage of patients with thoracic aortic aneurysm (TAA) are asymptomatic. Thoracic aneurysms are usually found incidentally after imaging studies. Symptoms develop in the setting of aortic insufficiency (aneurysms involving the aortic root or ascending aorta), dissection, or rupture. Rupture may occur in the thinned aneurysm wall or as rupture of the false lumen of a prior dissection. Symptoms from rupture include pain, hemopericardium (ascending aortic aneurysms), and hemothorax (descending aneurysms).
Dissections may cause symptoms via rupture of the false lumen or through extension of the dissection into arch vessels, causing cerebral ischemia, or coronary vessels, causing myocardial ischemia. Aneurysmal growth may be indolent, and debate exists as to the appropriate timing of surgical intervention, with suggestions ranging from as early as 3cm to as late as 6cm.
Symptomatic patients may experience symptoms of aortic insufficiency and heart failure, or they may feel epicardial pain with radiation to the neck and jaw. Back pain, located between the scapulae, is more likely to occur in patients with dissection of the descending aorta.
When rupture occurs, patients with TAA experience about the greatest pain ever felt, and medical attention should be sought immediately because mortality rates increase rapidly by the hour.
Uncomplicated thoracic aortic aneurysms (TAAs) can be divided grossly into saccular and fusiform. Fusiform aneurysms are most common; they affect the entire circumference of the aorta and have tapered borders (see the images below). Among the types of TAAs, only infectious (mycotic) aneurysms and posttraumatic pseudoaneurysms are typically saccular; both have a propensity for the distal thoracic aorta. Only rarely are aneurysms secondary to medial weakness due to medial degeneration saccular.
At autopsy, the gross appearance of a TAA depends on the type. Proximal TAAs demonstrate diffuse ectasia of the ascending aorta. Aneurysms of the proximal portion of the aorta may stretch the aortic ring, resulting in aortic insufficiency (annuloaortic ectasia). Involvement of the aortic root is typical of Marfan syndrome, syphilitic aneurysms, and a significant proportion of noninfectious aortitis. Syphilitic aneurysms tend to demonstrate massive formation, as well as marked thinning of the aortic wall. In noninflammatory aneurysms, the arch is generally spared, but aortic aneurysms and atherosclerotic aneurysms frequently extend to the arch vessels. 
Distal thoracic aneurysms are typically atherosclerotic and demonstrate diffuse ectasia of the lumen, with frequent extension across the diaphragm into the abdominal aorta (thoracoabdominal aortic aneurysm). Infectious aneurysms typically erode into adjacent structures with adhesions and tissue edema.
The adventitial appearance of a TAA is generally unremarkable unless the true or false lumen is ruptured, resulting in soft tissue hemorrhage, or if, in the case of infectious aneurysm, adhesions and edema exist.
The intimal surface of an aneurysm may be normal, as in the case of noninflammatory aneurysm; may demonstrate wrinkled appearance of the intima of a healed dissection; may demonstrate “tree-barking” of an aortic or syphilitic aneurysm; or may demonstrate atherosclerotic plaques, in the case of atherosclerotic aneurysm. Superimposed atherosclerotic change may be found in aneurysms of Takayasu aortitis. One form of aneurysm of the ascending aorta is the so-called “egg-shell” aorta, which occurs in cases of diffuse intimal calcification of atherosclerotic intima.
Dissecting aortic aneurysms represent one of the most dramatic specimens in gross pathology. The aneurysm involves the root in most cases of Marfan syndrome, but the root is typically spared in patients with a bicuspid aortic valve or idiopathic aneurysm. Aortic dissections have been studied extensively for centuries with uncountable descriptions in the medical and lay literature. The most commonly used classification was developed by DeBakey and colleagues.  Three major types of dissecting aortic aneurysm are described, as follows:
Dissection involving both the ascending and descending aorta (Type I)
Dissection only in the ascending aorta (Type II)
Dissection involving only the descending aorta (Type III)
A modified system refers to DeBakey types I and II as type A and type III as type B. Dissections are characterized by splitting of the aortic wall within the media, typically outer media, or the medial-adventitial interface. The blood flow dissects the new plane and forms a new path, called the false lumen. In the great majority of the cases, an intimal tear is seen on gross inspection; this is most often found in the proximal aorta, just distal to the aortic valve. The second most common location is just distal to the arch vessels, in the ascending aorta. The dissection plane can extend to any of the branches of the aorta, thoracic or abdominal, causing symptoms specific to that location. (See the images below.)
The outer wall of the false lumen is usually thinner than the inner dissected wall. Thus, rupture to adjacent structures (commonly causing hemopericardium, left pleural hemothorax, or extension of the blood into the mediastinum) is frequent. The distal portion of the false lumen will demonstrate a second communication with the true lumen, in the form of a reentry tear. The intimal tears associated with aortic dissections heal over time, in cases of prolonged survival, and have a white, fibrous surface.
The histopathologic hallmark of noninflammatory thoracic aortic aneurysms (TAAs) is cystic medial degeneration, or the pooling of proteoglycans (mucoid material) and pseudocyst formation in the media, accompanied by extensive loss of elastic lamellae. These changes result in the medial weakening that progresses to aneurysm, dissection, or both. A related histologic finding is so-called medionecrosis, which is also seen in aging aortas and in patients with hypertension. Medionecrosis, or laminar medial necrosis, is defined as coagulative necrosis of medial smooth muscle cells, resulting in loss of nuclei and collapse of the elastic lamellae;  this finding is not specific for any TAA etiology. (See the images below)
Aneurysms associated with unicuspid and bicuspid aortic valve disease usually show focal loss of elastic laminae and some associated intimal fibrosis, which is usually mild. Patients with Marfan syndrome usually have severe elastic fiber degeneration of the aortic media, which can be prominent at and around the sites of gross tears. If a healing process, such as remote tear, is present, intimal thickening and fibrosis can occur. The adventitia is usually normal in cases without a history of rupture.
Only a few reports of histologic findings in Ehlers-Danlos syndrome exist, and most show mild histologic change characterized by loss of elastic fibers and medionecrosis. The intima and adventitial layers are usually spared. Intimal tears are common and may cause intimal fibrosis, which is believed to occur posthealing.
The relationship between the extent of cystic medial necrosis and the etiology of TAA has been extensive studied. It has been shown that the greatest degrees of cystic medial necrosis occur in patients with Marfan syndrome, followed by individuals with non-Marfan familial dissection. Older patients with nonhereditary TAA or with TAA associated with bicuspid aortic valve have relatively small degrees of cystic medial necrosis.  Disorganized media in areas of healed aortitis may also show proteoglycan pooling very similar to that in cystic medial necrosis. [3, 6]
Takayasu disease (necrotizing aortitis) is characterized by intimal and adventitial fibrosis and inflammation, with areas of medial necrosis in varying phases of development. The histologic hallmark of Takayasu aortitis is multifocal medial laminar necrosis rimmed by macrophages and occasional giant cells. Loose granulomatous inflammation near necrotic areas is common. In late, healed cases, the intimal and adventitial fibrosis can be striking, and complete loss of elastic fibers in the media is appreciated. The degree of intimal fibrosis is usually greater than in cases of giant cell aortitis. The latter, in contrast, shows little medial destruction and minimal to no adventitial fibrosis. [6, 21] Calcification may be present in about 25% of cases. The adventitial fibrosis in aortitis is often accompanied by inflammation and obliteration of the adventitial vessels (endarteritis obliterans). (See the images below.)
Syphilitic aneurysms are similar histologically to those of Takayasu disease. Occasionally, gummatous inflammation occurs, and spirochetal organisms may be identified by silver impregnation stains. Endoarteritis obliterans is said to be common, as in cases of noninfectious aortitis.
This subtype of infectious aneurysm demonstrates destruction of the media, with acute and chronic inflammation and granulation tissue. Frequently, there is inflammation extending into adjacent structures, such as the pleura, pericardium, and lung.
Immunohistochemistry is of little use in the diagnosis of thoracic aortic aneurysm (TAA). In the case of noninflammatory TAA caused by Loeys-Dietz syndrome, positive staining for pSmad2 has been shown to be fairly specific.  Immunophenotyping of inflammatory infiltrates in aortitis has demonstrated a wide range of inflammatory cells. 
Thoracic aortic aneurysms (TAAs) can be divided into the following 5 main categories regarding their association with genetic diseases:
Sporadic cases with genetic imbalances and familial aggregation that may predispose an individual to the formation of a TAA
Cases associated with bicuspid valve disease with familial aggregation
Ehlers-Danlos syndrome type IV
Other genetic conditions predisposing an individual to a TAA
Many patients with aortic aneurysm and dissection do not fit any syndrome of collagen vascular disease, yet as many as 20% of these individuals have at least 1 first-degree family member with a known aneurysm in the arterial tree.  Radiologic screening in family members of patients presenting with aneurysms or with complications thereof have identified a pool of patients with asymptomatic aortic dilatation.  Three genomic loci for familial TAAs and dissections have been identified:
5q13–14 – Termed the TAAD1 locus
11q23–24 – Termed the FAA1 locus
3p24–25 – Termed the TAAD2 locus
The TAAD2 locus was sequenced for the transforming growth factor-β receptor type 2 (TGFBR2) gene, which may be responsible for 5% of familial TAAs. New studies have demonstrated unique polymorphisms in THBS2 as a risk for TAA, with some other variants being protective.  This area of research is rapidly advancing, and many other, more specific genes are expected to be identified and used in the screening of patients and family members. [25, 26]
Bicuspid aortic valve disease is a common congenital cardiac defect that is present in about 1% of the population. The much less common unicuspid aortic valve is also associated with TAAs. This condition happens in multiple members of the same family. Epidemiologic studies have pointed to an autosomal dominant inheritance, but no specific genetic aberration has been identified to date. 
Marfan syndrome has been extensive studied clinically and genetically. In the absence of surgical treatment, patients with Marfan disease have a 50% risk of developing aortic dissection during their lifetime. The aortic dilatation observed in Marfan syndrome is the result of defects in a specific component of the elastic fiber, fibrillin-1.  Mutations on the homologous gene, FBN1, are found on chromosome 15.
Mutations in the FBN2 gene, for fibrillin-2, also predispose patients to aortic dilatation, without a risk increase for dissection, as in patients with FBN1 mutations. A second, less prevalent locus was identified in Marfan syndrome – like patients at 3p24.2-p25, coded MFS2. Patients bearing this mutation do not meet the criteria for Marfan syndrome but seem to have a high incidence of TAA.
Ehlers-Danlos syndrome type IV (vascular type) is caused by defects in type III procollagen (COL3A1). This condition causes vascular fragility with aneurysm formation, rupture, and dissections. The aorta is involved in a small percentage of cases, since this disease most often affects smaller arteries. Usually, multiple rupture sites are found in the aorta.
Other, rarer genetic diseases that predispose patients to TAA are polycystic kidney disease and Ehlers-Danlos syndrome type VI (kyphoscoliotic type).
The prognosis of aortic aneurysms is dependent of the size of the aneurysm, which increases the risk for dissection and rupture. In cases of known Marfan syndrome, patients are followed, and elective surgery is performed with an aneurysm as small as 3cm in diameter (but generally, 4-6cm). [29, 30, 31, 32] In the case of a ruptured thoracic aortic aneurysm (TAA), the prognosis is quite poor without surgical intervention in cases of type I and II dissections, and surgery is considered a medical emergency.
In the case of type III dissection, over one half of patients survive with antihypertensive therapy for over 1 year.  The prognosis of surgery in ruptured type III dissections was dismal in the past, but newer surgical techniques and the development of aortic stent grafts show hope for the future.  Medical treatment of healed dissecting aneurysms of the distal thoracic aorta has been shown to lead to longer survival than does surgery. 
Of nonruptured TAAs, those with the worst prognosis are infectious (myocytic) aneurysms because of the high rate of sepsis. In one series, however, surgical resection was successful, with less than 25% operative mortality. 
A study by Ziganshin et al reported that routine genetic screening of patients with thoracic aortic aneurysm and dissection provides information that enables genetically personalized care and permits identification of novel mutations responsible for aortic pathology. [33, 34]
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Fabio R Tavora, MD, PhD Associate Medical Director, Argos Laboratory, Visiting Scientist, Paulista Medical School, Universidade Federal de São Paulo (EPM/UNIFESP), Brazil
Fabio R Tavora, MD, PhD is a member of the following medical societies: College of American Pathologists, United States and Canadian Academy of Pathology, International Society of Urological Pathology
Disclosure: Nothing to disclose.
Allen Patrick Burke, MD Associate Professor, Department of Pathology, University of Maryland School of Medicine; Chairman, Department of Cardiovascular Pathology, Armed Forces Institute of Pathology
Allen Patrick Burke, MD is a member of the following medical societies: American Academy of Forensic Sciences, American College of Cardiology, American College of Gastroenterology, American Medical Association, Society for Cardiovascular Pathology, United States and Canadian Academy of Pathology
Disclosure: Nothing to disclose.
Thoracic Aortic Aneurysm Pathology
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