Andrew Churg, MD, and Joanne L. Wright, MD
Biopsy for evaluation of pulmonary hypertension (PH) is relatively uncommon, in part because of the dangers of fatal arrhythmias in such patients, and has sometimes been viewed as offering little therapeutic benefit. As argued by Wagenvoort,1 however, biopsy in patients with PH serves three purposes:
1. It can establish the nature of the underlying lesion. This is potentially important information because patients with purely thrombotic lesions appear to have a much better prognosis than patients with plexogenic arteriopathy or venoocclusive disease.2
2. Occasionally, the lung lesions shed light on the type of underlying congenital cardiac abnormality.
3. The lesions seen in the lung biopsy specimen can provide an indication of potential reversibility. This information is important in deciding whether to perform corrective surgery in congenital heart disease1 and appears to be of value in predicting response to vasodilator therapy.2,3
Morphologic Features of the Pulmonary Vasculature
Pulmonary Arteries
Any diagnosis of PH requires recognition of the different types of vessels seen in the lung. This is aided by the use of elastic tissue stains, which should be a routine approach when a biopsy or larger specimen shows potential vascular disease. Knowledge of the structure of the normal pulmonary vascular bed is important in assessing biopsy material.4,5 Branches of the pulmonary artery run with the bronchi and then the bronchioles. Arteries associated with the bronchi are typically larger than 1 mm in diameter and have a fairly extensive elastic fiber meshwork in their walls. Muscular pulmonary arteries (Fig. 12.1) are usually associated with bronchioles and measure between 100 and 1000 μm. They are frequently abnormal in PH. Elastic stain (Fig. 12.2) shows that they have both an internal and an external elastic lamina. In the normal lung the diameter of a muscular pulmonary artery and its accompanying airway should be about the same. Below a diameter of about 100 μm, the pulmonary artery branches lose the internal elastica and are termed arterioles. Arterioles run adjacent to the alveolar ducts and can be found as a corner vessel by the alveolar saccules, but should not be found in alveolar walls. A well-defined mesh of capillaries arranged in a single layer of rings and spokes forms the gas exchange system in the alveoli (Fig. 12.3).6
Figure 12.1 Normal muscular pulmonary artery branches accompanying a bronchiole.
Figure 12.2 Elastic stain of a normal small muscular pulmonary artery showing double elastic laminae surrounding a fairly thin muscular layer. The intima is unobtrusive.
Figure 12.3 Scanning electron micrograph showing a methacrylate vascular cast of an alveolus showing the mesh of capillaries.
Pulmonary Veins
Normal pulmonary veins have only a single elastica and a thin layer of muscle. Veins are best identified by anatomic location. Larger pulmonary veins run in the interlobular septa (Fig. 12.4). Smaller veins are found associated with the alveolar saccules and are indistinguishable by morphology from pulmonary arterioles; thus the identification of a small vessel as a vein often requires tracing it back through several sections until it joins a definite vein in an interlobular septum. Of note, in pulmonary venous hypertension, the larger veins may acquire both a double elastica and additional muscle and resemble muscular arteries, but the location in the septa indicates their true nature.
Bronchial Arteries
Bronchial arteries are found in the walls of the larger bronchi. They usually are heavily muscularized and have a prominent internal elastica and a less well-defined external elastica. Bronchial arteries may develop longitudinal muscle bands, a feature helpful in identification. Bronchial arteries are systemic vessels at systemic pressure, and areas where they anastomose with the pulmonary circulation (around bronchiectatic foci, in plexogenic arteriopathy) may be foci of hemorrhage.
Figure 12.4 Elastic stain of a normal pulmonary vein running in the interlobular septum. Note the single elastica, a characteristic finding of pulmonary veins.
Recognition of Right Ventricular Hypertrophy
Significant degrees of PH are usually associated with right ventricular hypertrophy. A quick, but relatively inaccurate, determination of ventricular hypertrophy can be made by simple measurement of the right ventricular wall muscle thickness (Fig. 12.5). Wall thickness in the normal adult population should be approximately 2 to 3 mm, with measurements greater than 5 mm thought to represent hypertrophy.7
Figure 12.5 Cross section of heart at autopsy from a patient with pulmonary hypertension secondary to fenfluramine-phentermine use. Note the markedly thickened right ventricle.
Partitioning of the heart into right ventricle and left ventricle plus septum8 provides a sensitive estimation of ventricular hypertrophy, with a right ventricular weight of 65 g or greater considered abnormal.7 Although a portion of the septum will enlarge with the right ventricle, a ratio of left ventricular weight to right ventricular weight of less than 1.9 is considered to represent right ventricular hypertrophy. Obviously, such ratios are only useful if There is no enlargement of the left ventricle.
Microscopic examination of the right ventricle does not show the generalized increase of fibrosis that can be found in left ventricular hypertrophy. Detailed measurement of the myocardiocytes will demonstrate enlarged fiber diameters,9 but this finding may be too subtle to recognize visually.
Definition of Pulmonary Hypertension
The normal pressure in the pulmonary artery is 20/12 mm Hg (mean, 15 mm Hg) at sea level and 38/14 mm Hg (mean, 25 mm Hg) at an altitude of approximately 15,000 feet. In general, a mean arterial pressure of 20 mm Hg at sea level is considered abnormal, whereas at 15,000 feet, a pressure of 25 mm Hg is considered abnormal. PH is defined clinically as a mean pulmonary artery pressure at rest of greater than 25 mm Hg. For a diagnosis of pulmonary arterial hypertension (PAH) specifically, the pulmonary arterial wedge pressure must be less than 15 mm Hg, and the pulmonary vascular resistance greater than 3 Wood units.10
Classification of Pulmonary Hypertension
A variety of schemes for classifying PH have been proposed.2,11-17 Table 12.1 shows the most recent clinical classification adopted by the fifth World Symposium on Pulmonary Hypertension, commonly called the Nice classification.17 the term primary pulmonary hypertension is no longer used: such cases are now a subcategory of PAH (Nice Group 1) and are called either idiopathic PAH, or heritable PAH; about 80% of cases in the latter category are associated with mutations in BMPR2, and much smaller numbers with mutations in ALK-1, endoglin, caveolin-1, or KCKN3.17
Table 12.1 the Nice Clinical Classification of Pulmonary Hypertension
1. Pulmonary Arterial Hypertension (PAH)
1.1 Idiopathic PAH
1.2 Heritable PAH
1.2.1 BMPR2 mutation
1.2.2 ALK-1, endoglin, Smad9, caveolin-1, KCNK3 mutation
1.2.3 Unknown
1.3 Drug and toxin induced
1.4 Associated with:
1.4.1 Connective tissue disease
1.4.2 Human immunodeficiency virus infection
1.4.3 Portal hypertension
1.4.4 Congenital heart disease
1.4.5 Schistosomiasis
1' Pulmonary venoocclusive disease and/or pulmonary capillary hemangiomatosis
1" Persistent pulmonary hypertension of the newborn
2. Pulmonary hypertension due to left heart disease
2.1 Left ventricular systolic dysfunction
2.2 Left ventricular diastolic dysfunction
2.3 Valvular disease
2.4 Congenital/acquired left heart inflow/outflow tract obstruction and congenital
Cardiomyopathies
3. Pulmonary hypertension due to lung diseases and/or hypoxia
3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease
3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern
3.4 Sleep-disordered breathing
3.5 Alveolar hypoventilation disorders
3.6 Chronic exposure to high altitude
3.7 Developmental lung diseases
4. Chronic thromboembolic pulmonary hypertension
5. Pulmonary hypertension with unclear multifactorial mechanisms
5.1 Hematologic disorders, chronic hemolytic anemia, myeloproliferative disorders,
Splenectomy
5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, lymphangioleiomyomatosis
5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders
5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal failure, segmental pulmonary hypertension
From Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Col Cardiol. 2013;62(suppl):D34-D41.
The Nice classification is comprehensive in terms of listing known associations and patterns of PH. However, from the point of view of pathologic diagnosis, a problematic aspect of this classification is the inclusion of pulmonary venoocclusive disease (PVOD)/pulmonary capillary hemangiomatosis (PCH) in the general category of PAH (Group 1) because of dubious claims that these entities can show all the changes of classic idiopathic PAH, including plexiform lesions (see the section Pulmonary Venous Hypertension later in the chapter), and on the basis of a handful of reports of PVOD cases with BMPR2 mutations,18 the latter a typical finding in familial PAH. Morphologically, cases of PVOD and what has been called PCH (but is probably just PVOD, see later in this chapter; we will indicate this as PVOD [PCH]) show changes of pulmonary venous hypertension and are distinctly different from most cases of PAH. In general, PVOD (PCH) patients also have a different set of mutations in familial cases (EIF2AK4,19 and see later in this chapter). Most important, PVOD (PCH) patients often develop pulmonary edema after vasodilator therapy and have a worse outcome than patients in Nice category 118 (see the section Pathogenesis and Treatment of Pulmonary Hypertension later in the chapter).
For these reasons we will discuss PVOD (PCH) under the general heading of pulmonary venous hypertension (see later in this chapter) and we use the older and more generally useful (for pathologists) pathologic classification scheme shown in Table 12.2. It should be borne
Table 12.2 Pathologic Classification of Pulmonary Hypertension Plexogenic Arteriopathy
• Idiopathic or familial
• Associated with congenital heart disease with left-to-right shunts
• Associated with connective tissue
• Associated with cirrhosis (portal hypertension)
• Secondary to drugs and toxins (Table 12.4)
• Associated with human immunodeficiency virus infection
• Associated with thyroid disorders, glycogen storage diseases, and other uncommon causes of pulmonary hypertension in group 5 of the Nice 2013 classification
• Rarely in chronic obstructive pulmonary disease (COPD), sarcoid, thromboembolic hypertension, and possibly venoocclusive disease
Thromboembolic Pulmonary Hypertension
• Associated with recurrent thromboemboli or in situ thromboses
• Affecting proximal pulmonary arteries (surgically resectable)
• Affecting distal pulmonary arteries
• Associated with sickle cell disease
• Associated with IV drug abuse (injection of insoluble foreign particles)
• Associated with tumor emboli
• Pulmonary tumor thrombotic microangiopathy
Pulmonary Venous Hypertension
• Left-sided cardiac diseases
• Atrial myxomas
• Sclerosing mediastinitis
• Congenital cardiac malformations affecting venous outflow
• Pulmonary venoocclusive disease/pulmonary capillary hemangiomatosis
Associated with interstitial lung disease, COPD, or other intrinsic lung diseases Associated with chronic hypoxia in mind that, in terms of pathologic diagnosis, the various etiologies/ associations in each group of the Nice classification, particularly those in PAH, Group 1, are usually not separable on the basis of morphology alone; clinical and sometimes radiologic information is important in making a final diagnosis.
Table 12.3 Etiologies of Pulmonary Hypertension in a Series of 483 Patients
|
Left-sided heart disease |
79% |
|
Intrinsic lung disease |
10% |
|
Pulmonary arterial hypertension |
4% |
|
Thromboembolic hypertension |
0.6% |
|
Undefined |
7% |
Data from Galiè N, Palazzini M, Manes A. Pulmonary hypertension and pulmonary arterial hypertension: a clarification is needed. Eur Respir J. 2010;36:986-990.
Although the Nice classification might be taken to imply that PAH entities represent the majority of cases of PH, in fact this is not true. As shown in Table 12.3, by far the most common cause of PH is left-sided heart disease, followed by intrinsic lung disease. Overall, PAH is relatively uncommon.
Biomarkers of Pulmonary Hypertension
A variety of attempts have been made to find serum biomarkers of PH. At this point There are no generally accepted or utilized markers, but a recent report found that a combination of soluble VEGF receptor 1, more commonly called soluble fms-like tyrosine kinase 1, and placental growth factor discriminated between PH and controls with a sensitivity of 84% and a specificity of 100%.20 These biomarkers did not separate different types of PH. High levels of serum endostatin, which appears to reflect cardiac dysfunction, have been associated with a worse prognosis in PH.21
Table 12.4 Drugs Associated With Pulmonary Arterial Hypertension
|
• Established Association |
Possible Association |
|
• Aminorex |
Cocaine |
|
• Fenfluramine |
Phenylpropanolamine |
|
• Dexfenfluramine |
St. John's Wort |
|
• Toxic rapeseed oil |
Chemotherapeutic agents |
|
• Benfluorex |
Selective serotonin reuptake inhibitors |
|
• Dasatinib (tyrosine kinase inhibitor [TKI]) |
Pergolide |
|
Probable Association |
|
|
Amphetamines |
|
|
Methamphetamines |
|
|
L-Tryptophan |
|
Data from Montani D, Seferian A, Savale L, Simonneau G, Humbert M. Drug-induced pulmonary arterial hypertension: a recent outbreak. Eur Respir Rev. 2013;22:244-250.
Pathologic Features of Pulmonary Hypertension
Plexogenic Arteriopathy
We use the term plexogenic arteriopathy, first coined by Wagenvoort and Wagenvoort,11 to describe a set of morphologic lesions running from muscular hyperplasia to necrotizing arteritis to plexiform lesions. In general, plexogenic arteriopathy is the pathologic finding associated with PAH (Nice Group 1), but plexiform lesions have rarely (and not always accurately) been reported in patients with PH of other types in patients with extremely high pulmonary artery pressures.22-25
Clinical and Etiologic Features
The clinical features of PH in general, and PAH specifically, are very nonspecific. Patients typically describe progressive shortness of breath, which is particularly marked during exercise. Syncopal episodes, presumably related to cardiac arrhythmias, may occur. Chest pain is usually a sign of right-sided cardiac ischemia and is seen late in the course in those who develop cor pulmonale. Similarly, abdominal discomfort is a sign of right-sided heart failure with progressive liver congestion.
The pathologic features of plexogenic arteriopathy are similar for any etiology and generally not separable by histologic examination. An exception is plexogenic arteriopathy associated with schistosome infection where intravascular schistosome eggs and perivascular granulomas can be found.26 In plexogenic arteriopathy associated with anorectic agents, the pulmonary vascular lesions are sometimes accompanied by cardiac valvular lesions, predominately on the left side of the heart.27,28 PAH associated with most connective tissue diseases is morphologically indistinguishable from idiopathic PAH29; however, patients with systemic sclerosis may have distinctive mucoid thickening or intimal proliferation of their pulmonary arteries and tend not to develop plexiform lesions.30
A variety of drugs have been reported to produce PAH with varying degrees of certainty; these drugs are listed Table 12.4.
Imaging Features
Plain chest film early in the disease may be totally normal in appearance. With more advanced PAH (and PH in general), enlarged pulmonary arteries become apparent, and with the development of cor pulmonale, the right ventricle may be visibly enlarged. With long-standing PH, calcification of the large arteries, presumably representing atherosclerosis, can be seen. Computed tomography (CT) scanning allows measurements of the diameters of the main pulmonary artery; as a rule, if the diameter of the pulmonary artery is larger than that of the ascending aorta—strictly speaking, if the diameter of the main pulmonary artery at the level of its bifurcation is greater than 29 mm (Fig. 12.6)—There is a high probability of PH.31 Angiography classically demonstrates vascular pruning, in which the vessels have a simplified branching pattern.
Morphologic Features
Plexiform lesions were first clearly characterized by Heath and Edwards.16 the term plexogenic pulmonary arteriopathy was coined by Wagenvoort and Wagenvoort11 to describe a morphologic response pattern that sometimes, but not always, is characterized by the formation of peculiar thrombi with multiple small channels—plexiform lesions. Such lesions are the end result of a series of vascular changes, however, and a given case of plexogenic arteriopathy may show only the lower-grade changes without formation of plexiform lesions.
Plexogenic arteriopathy primarily affects muscular arteries and arterioles, but larger arteries may demonstrate increased atherosclerosis, a finding that can be seen in PH of any cause or in the absence of PH (statistically, the most common cause of atherosclerosis in the pulmonary artery is severe systemic atherosclerosis).32
The vascular changes in the muscular arteries and arterioles in plexogenic arteriopathy appear to reflect, in general, the level of pulmonary artery pressure29 and, to a lesser extent, the length of time hypertension has been present; thus in a broad sense, higher-grade lesions (see later on) are found in individuals with higher pulmonary artery pressures. The correlations are not exact, however, and only lower-grade lesions may be found in some patients with quite marked PH. There is also some controversy about the order in which different lesions develop.2,13,14,16 It is our belief that the original Heath and Edwards classification16 is incorrect and that the actual sequence of changes is that proposed by Wagenvoort and Wagenvoort11 as follows.
Grade I: Muscular Hypertrophy
Muscular hypertrophy appears as thickening of the walls of muscular arteries, often with obvious narrowing of the lumina (Fig. 12.7). Elastic stain shows that the space between the internal and external elastica has become widened by the new muscle. Normal preacinar muscular pulmonary arteries should have, in the fully distended state, a medial thickness that is 1% to 2% of the vessel diameter, although in the smaller muscular arteries (30-100 pm in external diameter), the medial thickness may be up to 5%. However, these values are based on arteries fixed by inflation, and in ordinary specimens, allowance needs to be made for the fact that uninflated vessels will normally have thicker-appearing walls than inflated vessels.
Figure 12.6 Computed tomography scan from a patient with scleroderma and pulmonary hypertension. Note the markedly dilated main pulmonary artery and left and right branches.
Muscular hypertrophy in small arteries is often accompanied by muscularization of arterioles, such that the arteriole acquires both a double elastica and muscle between the elasticas (Fig. 12.8). Thus muscularized arterioles come to resemble ordinary muscular arteries but are found in the lung parenchyma rather than next to bronchioles; this finding is a clue to the correct diagnosis because arteries are normally present only next to accompanying airways.
Grade II: Intimai Proliferation
In this stage, proliferation of intimal cells leads to a thickened intima superimposed on a thickened muscular media (Fig. 12.9). The intimal cells do not show any special organization, but the process generally affects the whole circumference of the vessel.
Grade III: Concentric Laminar Intimal Fibrosis
In this stage, the intima is markedly thickened and organized in a series of concentric bands of collagen and spindle-shaped cells, which lend a whorled appearance (Fig. 12.10). The lumen is often dramatically narrowed.
Grade IV: Necrotizing Vasculitis
As a result of markedly increased pressure or a marked cytokine reaction, the arterial wall may become necrotic. The typical pattern is that of fibrinoid necrosis with eosinophilic granular necrotic material replacing the normal arterial wall (Fig. 12.11). Inflammatory cells, usually polymorphonuclear leukocytes but sometimes eosinophils, may be present. Elastic stains show that, typically, the internal elastic is destroyed.
Grade V: Plexiform Lesions
Plexiform lesions are usually found in small muscular arteries at branch points. The artery immediately proximal to the plexiform lesion frequently shows marked muscular hypertrophy and concentric intimal hyperplasia. In the plexiform lesion itself, the artery is often dilated and the lumen is characteristically filled with capillary channels that very much resemble a fairly cellular organizing thrombus (Fig. 12.12). However, in contradistinction to most thrombi, where the elastic laminae of the artery are intact,2 elastic stains show that the inner elastica is typically destroyed in the region of the plexiform lesion (Fig. 12.12B), and this feature is useful when a question of thrombotic PH versus plexogenic arteriopathy arises. This set of findings reflects the fact that plexiform lesions, in our view, are actually the result of necrosis of the vessel, with subsequent thrombosis and organization.
The acute plexiform lesions may show small fibrin thrombi and small numbers of inflammatory cells in the capillary channels; as the lesions age, they scar and become paucicellular. Plexiform lesions are usually not very numerous and can be widely scattered within the lung parenchyma; thus a certain amount of hunting may be required to demonstrate them. It has been suggested that in plexogenic arteri- opathy associated with congenital left-to-right shunts, the plexiform lesions occur in arteries 100 to 200 pm in external diameter; whereas in other forms of PAH, the lesions occur in arteries smaller than 100 μm.33
Figure 12.7 Muscular hypertrophy in pulmonary hypertension. (A) Muscular pulmonary artery branches showing muscular hypertrophy. In normal bronchovascular bundles, airways and vessels are about the same size; here, the vessel is larger and very thick-walled. Note the obviously increased muscle area on the elastic stain (C). Muscular hypertrophy of this type may be seen in pulmonary hypertension of any cause and by itself does not indicate a diagnosis of plexogenic arteriopathy. (B) Thickened muscular media is very obvious at higher magnification. (C) Increase in muscle well demonstrated on elastic stain. (D) Occasionally smooth muscle proliferation occurs in the intima in pulmonary hypertension; when this occurs, the muscle bundles run longitudinally, as here (smooth muscle actin stain).
Grade VI: Dilatation and Angiomatoid Lesions
These arterial lesions are located distal to plexiform lesions and probably are related to changes in flow produced by the plexiform lesions. They consist of thin-walled, often dilated and tortuous channels with a single elastica; these channels do not have an obvious arterial structure, but their origin can be proved by tracing back through serial sections (Fig. 12.13). Dilatation and angiomatoid lesions may rupture with resulting pulmonary hemorrhage, and in some instances they appear to anastomose with the bronchial circulation, thus exposing these relatively weak structures to systemic arterial pressures.
Clinical Correlations
As noted earlier, assessment of reversibility or potential for response to treatment is an important reason for performing lung biopsies in patients with PH. However, the question of what features actually predict reversibility is controversial. As a first approximation, lesions can be separated as shown in Table 12.5: muscular hypertrophy, intimal proliferation, and mild degrees of concentric intimal fibrosis are potentially reversible, while the higher grades of plexogenic arteriopathy are not.
Wagenvoort12,13 and Palevsky and associates3 have suggested that simple qualitative assessment of the types of lesions present may be inadequate by itself for predicting response, and that quantitative measurements can give better information, particularly measurements of intimal proliferation. For example, Palevsky’s group3 found that an average intimal area of more than 18% of the vascular cross section predicted a poor response to therapy (and see Refs. 2, 3, 13, 34). Intriguing evidence for reversibility comes from a study published in 2013 of 62 explanted lungs from patients with PAH.29 These patients had received modern treatments for PAH, and in many of them the degree of muscular hypertrophy or intimal proliferation overlapped a set of non-PH control lungs; however the PAH lungs still had plexiform lesions. Although the authors took these findings to imply that muscular hypertrophy and intimal proliferation are not mandatory features of plexogenic arteri- opathy, we believe the more likely explanation is that treatment led to regression of that muscular hypertrophy and intimal proliferation, but could not affect plexiform lesions.
Figure 12.8 (A) Severe muscular hypertrophy in a very small arterial branch. (B) Smooth muscle actin stain of alveolar corner arterioles, showing complete muscular media in a case of pulmonary hypertension. Ordinarily these vessels do not have a complete muscular media.
Figure 12.9 (A and B) Mild intimal proliferation. The elastic stain (B) is required to separate this process from pure muscular hypertrophy.
Figure 12.11 Necrotizing vasculitis. (A) Note the combination of inflammatory cells and pink material (fibrinoid necrosis) in the vessel wall. (B) Partial loss of the internal elastica in the matching section.
Figure 12.11, cont'd (C) A small thrombus is present in the lumen. (D) the process is shown at higher magnification.
Figure 12.12 Plexiform lesions. (A) Low-power view showing fibrinoid necrosis in one branch of the artery at left; concentric laminar intimal fibrosis in the small vessel in the middle of the field, and a plexiform lesion cut in longitudinal section at right. (B) Elastic stain of plexiform lesion showing the typical combination of multiple small capillary channels and loss of the internal elastica. (C) Similar image on hematoxylin and eosin (H&E) stain. (D) Plexiform lesion seen in cross section. The plexiform lesion appears to represent organization and thrombosis in arteries that have developed necrotizing vasculitis.
Figure 12.13 Dilatation lesions. (A and B) Dilatation lesions appear as thin-walled, blood-filled channels. Dilatation lesions develop distal to plexiform lesions, present here at the top of the field. (B) Elastic stain.
Table 12.5 Reversibility and Morphologic Findings in Plexogenic Arteriopathy Potentially Reversible
Muscular hypertrophy
Intimal proliferation
Mild concentric lamellar fibrosis
Not Reversible
Marked concentric lamellar fibrosis Fibrinoid necrosis Plexiform lesions
Dilatation and angiomatoid lesions
Data from Wagenvoort CA, Wagenvoort N, Draulans-Noë Y. Reversibility of plexogenic pulmonary arteriopathy following banding of the pulmonary artery. /Thorac Cardiovasc Surg. 1984;87:876-886.
Differential Diagnosis
Higher-grade lesions in the plexogenic arteriopathy group are distinctive and not easily confused with other diseases, although occasionally it is necessary to resort to elastic stains to separate plexiform lesions from organized thrombi as discussed previously. In this situation, the presence of other arteries with concentric intimal fibrosis strongly favors plexogenic arteriopathy. Systemic necrotizing vasculitis (microscopic polyangiitis, Wegener granulomatosis) may produce fibrinoid necrosis of vessels but is not associated with lower-grade vascular changes or with plexiform lesions.
It is important to remember that some degree of arterial muscular hypertrophy and often mild intimal proliferation is seen not only in plexogenic arteriopathy but in virtually all forms of PH, including thromboembolic hypertension, venous hypertension, and hypertension secondary to intrinsic lung disease.2,11,34 Thus the finding of muscular hypertrophy as the only vascular abnormality does not necessarily mean that the patient has plexogenic arteriopathy. Equally important, low-grade morphologic changes, especially isolated muscular hypertrophy, are not necessarily predictors of the degree of PH; some patients with only muscular hypertrophy, nonetheless, can have quite high pulmonary artery pressures.
A further problem in interpretation is that thrombotic lesions, presumably reflecting in situ thromboses caused by abnormal flow, are now recognized as a finding in many different morphologic types of PH2,3,29,35 (see morphologic description in the next section) and certainly may be found in plexogenic arteriopathy; indeed, Stacher et al.29 found evidence of thromboses in 50% of cases. This does not invalidate the notion that plexogenic arteriopathy is morphologically separate from thrombotic hypertension.35
Thrombotic and Embolic Hypertension
Clinical Features
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by the insidious onset of shortness of breath without clinical evidence of current pulmonary emboli (hence, thrombotic hypertension is sometimes included in the differential diagnosis for primary pulmonary hypertension). However, there may be a history of prior events that suggest the diagnosis—for example, recurrent sickle crises, a history of intravenous drug abuse, or known episodes of thromboembolism. Other risk factors for CTEPH include splenectomy, atrioventricular shunts for hydrocephalus, infected pacemakers, thyroid replacement therapy, and malignancy.36
Statistically, previous pulmonary emboli are the most common cause of CTEPH and can be documented in about 50% of cases. It has been estimated that anywhere from 0.1% to 9% of patients diagnosed with pulmonary emboli will go on to develop CTEPH within 2 years.36
Radiologic Features
The radiologic features of CTEPH are not specific, but angiography or CT with contrast enhancement may reveal large emboli, or sometimes evidence of multiple small thrombi with apparent abrupt vascular cutoffs.
Pathologic Findings
Pathologic findings in CTEPH vary with the type of underlying lesion. In classic thrombotic or thromboembolic hypertension, thrombi in various stages of organization, mostly old, are seen in branches of the small muscular pulmonary arteries. Of note, both elastic laminae are usually intact in thrombotic disease, as opposed to the destruction of the internal elastic in plexiform lesions.2 Larger arteries may show webs (Fig. 12.14), which are simply organized thrombi with channels large enough to be seen grossly. In some cases of thrombotic or embolic hypertension, thrombi are only found in the main branches of the pulmonary artery, sometimes with webs as well; it has been suggested that these patients often have underlying (nonhypertensive) lung disease or left-sided cardiac disease, as well as systemic peripheral vascular thromboses.
A helpful feature that should alert the pathologist to the presence of thrombi and emboli is the finding of eccentric intimal proliferation or intimal fibrosis in arterial vessels (Fig. 12.15); these lesions sometimes represent old small organizing thrombi. However, both eccentric lesions and recanalized thrombi may be seen in PH of other causes.37
Figure 12.14 Appearance of organized thrombi. (A) Gross appearance of a web (arrow) in a large pulmonary artery. The main pulmonary artery also contains an organized thrombus. (B and C) Hematoxylin and eosin and elastic stains of another web in a large pulmonary artery branch. Note that the original elastic lamellae of the artery are intact. (D and E) Organized thrombus in a muscular pulmonary artery showing numerous channels. Note again the preservation of the normal elastic structure in the arterial wall. Most thrombi do not disturb the arterial wall structure, as opposed to the destructive process that leads to plexiform lesions.
Patients with sickle cell disease may develop thrombi in their distal pulmonary arterial or venous branches during sickle crises, and recurrent episodes can lead to a form of thrombotic PH; this appears to be a relatively common event because the prevalence of catheterization- confirmed PH in adult sickle cell disease patients is 6% to 11%.38 the lesions look like organizing thrombi, but close examination reveals the presence of sickled cells (Fig. 12.16).
Intravenous injection of licit drugs intended for oral use, or sometimes of illicit drugs such as heroin or cocaine,39,40 tends to produce deposits of insoluble filler material from the drug in the small muscular arteries. In mild disease, small numbers of birefringent particles are seen in the lumina or in the arterial walls (Fig. 12.17), presumably having been incorporated into organizing thrombi. With injection of large amounts of drug, the inflammatory and thrombotic reaction to the particles leads to thrombus-like formations with capillary channels called angiothrombotic lesions.40 These are probably just peculiar in situ thrombi caused by large numbers of particles. They more or less completely obstruct the arterial branch, and accumulation of such lesions leads to PH. Polarized light examination is often useful in demonstrating the particulate matter. Under polarized light, starch appears as Maltese cross-like images; talc as brightly birefringent plates; microcrystalline cellulose as periodic acid/Schiff-positive rectangular crystals that are also birefringent; and crospovidone as deeply basophilic coral-like particles.41 With illicit drugs, exact identification of the filler may not be possible.
Figure 12.15 Eccentric intimal proliferation representing an old thrombus. Compare with the concentric intimal proliferation of plexogenic arteriopathy in Figs. 12.10C and 12.12A.
Figure 12.16 Thrombosis in a patient with sickle cell disease. (A) Acute thrombus. (B and C) Organized thrombus showing multiple channels. This appearance in itself is not specific for etiology, but sickle cells are seen at high power in part (D).
Figure 12.17 Organized thrombus and biréfringent particles in a muscular pulmonary artery from an intravenous drug abuser.
Figure 12.18 Tumor thrombotic microangiopathy. A pulmonary artery branch contains a few tumor cells and extensive thrombus with complete occlusion of the lumen.
PH may develop as a result of filling of the small arterial branches with tumor emboli. Metastases that are grossly visible radiologically or pathologically may or may not be present. PH in this setting has been most commonly reported with lung, breast, stomach, ovarian, and hepatocellular carcinomas.42
An unusual form of tumor-associated PH is pulmonary tumor thrombotic microangiopathy43 in which the tumor elicits a marked intimal proliferation/local thrombosis with only small numbers of tumor cells present (Fig. 12.18).
Clinical Correlations
When CTEPH is caused by large vessel (main, lobar, and segmental pulmonary artery branches) thrombi without significant small vessel thrombi, surgical removal of the thrombi may reverse the hypertension. However, some CTEPH patients have a mixture of large and small vessel thrombi or only small vessel thrombi. Recently riociguat (a soluble guanylate cyclase stimulator) has been shown to be beneficial in such cases.44
Table 12.6 Etiologies of Pulmonary Venoocclusive Disease (Pulmonary Capillary Hemangiomatosis)
Familial (EIF2AK4 or BMPR2 mutations)
Cigare The smoking
Systemic sclerosis
Solvent exposure, especially trichloroethylene
Chemotherapeutic drugs
Anticardiolipin antibodies
Data from Montani D, Lau EM, Descatha A, et al. Occupational exposure to organic solvents: a risk factor for pulmonary veno-occlusive disease. Eur Respir J. 2015;46:1721-1731; Lantuéjoul S, Sheppard MN, Corrin B, Burke MM, Nicholson AG. Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis: a clinicopathologic study of 35 cases. Am J Surg Pathol. 2006;30:850-857; Lombard C, Churg A, Winokur A. Pulmonary veno-occlusive disease following therapy for malignant neoplasms. Chest. 1987;92:871-876; Dorfmüller P, Humbert M, Perros F, et al. Fibrous remodeling of the pulmonary venous system in pulmonary arterial hypertension associated with connective tissue diseases. Hum Pathol. 2007;38:893-902.
Differential Diagnosis
As noted, scattered thrombi are fairly common in other types of PH, such as plexogenic arteriopathy, and the presence of thrombi or eccentric intimal lesions does not automatically indicate a diagnosis of CTEPH. Although it has been claimed that plexiform lesions can rarely be seen in thrombotic and embolic hypertension,25 we believe that most such cases, in fact, represent plexogenic arteriopathy with more than the usual number of thrombi, or occasionally, confusion of organized thrombi with plexiform lesions.45 Thus it is important to be sure that typical plexogenic lesions are not present and to demonstrate the presence of multiple thrombi or emboli when making a diagnosis of thrombi or embolic hypertension.
Pulmonary Venous Hypertension
Clinical Features
In previous editions we discussed PVOD and PCH as separate topics. However, because of increasing evidence that these lesions are the same entity or very closely related (see later in this chapter), we have chosen to treat them together under the heading PVOD (PCH), consistent with the usage in the Nice classification.
Like other forms of PH, pulmonary venous hypertension is characterized by the insidious onset of shortness of breath, sometimes associated with a nonproductive cough. The vast majority of patients with pulmonary venous hypertension have left-sided heart disease; other associations are shown in Table 12.2. For PVOD (PCH) There is a wide age range of affected subjects, with a mean age of less than 50 years, and a significant proportion of children. Patients with PVOD (PCH) do not have clinical evidence of thrombotic or embolic disease, but may have small hemop- tyses. Clubbing has been identified in some patients with PVOD (PCH).
PVOD can be familial, with disease appearing as a recessive trait, or sporadic. A recent report described mutations in EIF2AK4 in 13/13 families with PVOD as well as 25% of sporadic cases.19 Similarly, EIF2AK4 mutations were found in 6/6 familial PCH and 2/10 sporadic PCH cases.46 These findings support the idea that PVOD and PCH are the same or very closely related.47 As noted previously, a few cases of PVOD with BMPR2 mutations have been described.18
Apart from familial cases, a number of etiologic associations have been described for PVOD (Table 12.6).48-51
Radiologic Features
On plain films, patients with advanced disease show pulmonary artery enlargement and, with cor pulmonale, right ventricular hypertrophy; depending on etiology, they may also have left ventricular enlargement or other cardiac abnormalities, or evidence of sclerosing mediastinitis. A helpful finding in PVOD is the presence of prominent Kerley B lines and mild to moderate interstitial infiltrates. The CT scan shows distinctly thickened interlobular septa.52
Pathologic Findings
In pulmonary venous hypertension of any cause, the most common findings are intimal fibrosis in the small pulmonary veins and venules, mild interstitial inflammation and edema, occasionally fine interstitial fibrosis, prominent lymphatics in the interlobular septa, and small alveolar hemorrhages, typically manifest as hemosiderin-laden macrophages (Fig. 12.19). Ferrugination of vascular elastic fibers (sometimes called endogenous pneumoconiosis) can be seen with sufficient hemorrhage. Dystrophic ossification is common (Fig. 12.19). Muscular hypertrophy in the small pulmonary arterial branches may be present as well (Fig. 12.19). With sufficiently increased venous pressure, the veins in the interlobular septa become arterialized; that is, the normal single elastica is reduplicated to produce a double (and occasionally more than double) elastica, mimicking pulmonary arteries. However, by definition, true venous thrombosis/ obliteration is only seen in PVOD (PCH).
The fundamental lesion in PVOD (PCH) is thrombosis, typically old thrombosis, of small pulmonary veins and venules, although a recent report documented venulitis in a small proportion of cases.49 ’ttrombosis is most easily seen in veins in the interlobular septa (Fig. 12.20) where the location ensures that the structure is indeed a vein. Arterialization of veins is common (Fig. 12.20C), and such veins are distinguishable from arteries only by their location.
The venules in PVOD (PCH) are often thrombosed as well, but this may be difficult to document because the lumen of small venules may simply be obliterated by fibrous tissue (Fig. 12.21). Use of elastic stains is mandatory to find such vessels, and once small vessels with apparent luminal obliteration are found, they may need to be traced back through several sections until they connect with a vein in an interlobular septum, thus proving their nature. The diagnosis of PVOD (PCH) can be exceedingly difficult when only small venules are affected.
Venous thrombosis in PVOD (PCH) is accompanied by other changes typical of venous hypertension, but often to a much greater degree. The interlobular septa are generally edematous and the lymphatics prominently dilated (Fig. 12.20). A peculiar, usually mild, form of interstitial fibrosis that tends to be more marked in the very periphery of the lung under the pleura (Fig. 12.22) is common in PVOD (47% of cases in a recent large series).49 the fibrosis is fairly homogeneous, typically paucicellular, and raises the morphologic question of a chronic interstitial pneumonia; such cases can be mistaken for fibrotic nonspecific interstitial pneumonia (NSIP). Accompanying the fibrosis are usually small foci of acute or old hemorrhage with hemosiderin-laden macrophages (Fig. 12.22B) and sometimes extensive ferruginization of elastic fibers (Fig. 12.22C). The combination of mild homogeneous fibrosis and small hemorrhages or ferruginization should bring the diagnosis of PVOD to mind and prompt examination of the veins in the interlobular septa to look for thrombi.
The alveolar capillaries in PVOD may be dilated and very prominent and sometimes appear to be located on both sides of the alveolar walls or reduplicated. This is the typical finding that has been described in PCH, which is defined by proliferation of dilated capillary-sized channels along and in the alveolar walls (Fig. 12.23). In this respect it resembles a very severe form of passive congestion, but careful examination shows that There appear to be duplicate or multiple capillary channels in an alveolar wall, something not present in passive congestion.52,53 the proliferating capillary channels extend into arterioles and venules, producing a peculiar pattern of capillary vessels within the walls of the larger vessel with resulting luminal narrowing or obliteration. Often There is an admixture of very abnormal areas of lung with extensive capillary proliferation combined with perfectly normal-appearing lung, again a helpful finding in separating this process from passive congestion (The latter should be more homogeneous).
Although this set of features has been claimed to be pathognomonic of PCH, careful review of a large series of cases has shown that the same phenomenon can be found in PVOD.49 Conversely, venous thromboses can be found in cases identified as PCH.49 At this point the weight of the evidence suggests that PVOD and PCH are probably the same, and the nomenclature PVOD is preferable because venous occlusion is the fundamental pathologic abnormality.
Arterial changes may be present in PVOD (PCH) and consist of muscular hypertrophy and sometimes mild intimal fibrosis. Although it has been claimed that plexiform lesions can be seen in PVOD,33 in our experience this is not true, and plexiform lesions were not seen in 30 patients reported by Lantuéjoul et al.49
Clinical Correlations
As mentioned previously, vasodilator therapy of PVOD (PCH) must be approached with caution because it may induce severe pulmonary edema. Many patients require lung transplantation. Further comments are provided later in the section Pathogenesis and Treatment of Pulmonary Hypertension.
Differential Diagnosis
PVOD (PCH) must be separated from other causes of venous hypertension. Venous thromboses are only seen in PVOD (PCH), and the degree of subpleural interstitial fibrosis that can be present in PVOD (PCH) is often much greater than that found in other types of venous hypertension. In a shallow biopsy, separation of PVOD (PCH) from fibrotic NSIP can be problematic; however, evidence of hemorrhage and fer- rugination of elastic tissue should not be present in NSIP, nor should venous thromboses. In deeper biopsies, the fibrosis of PVOD (PCH) often can be seen to be confined to the subpleural regions and then stop abruptly deeper in the lung, whereas the fibrosis of NSIP by definition is quite diffuse.
Pulmonary Hypertension Secondary to Intrinsic Lung Disease or Hypoxia
PH is commonly found associated with different forms of nonvascular intrinsic lung disease or conditions that produce chronic hypoxia, including sleep apnea, morbid obesity, chronic obstructive lung disease, bronchiectasis, usual interstitial pneumonia, and other forms of interstitial lung disease that lead to extensive scarring of the parenchyma (Tables 12.1 and 12.2). In emphysema, claims have been made that hypertension is secondary to loss of capillary bed, although this may not be correct, and vascular changes may be caused by direct effects of cigare The smoke on the vasculature resulting in endothelial dysfunction or by local hypoxic vasoconstriction.54
PH is increasingly being recognized as an important complication of usual interstitial pneumonia; it was seen in 46% of a large series of patients with usual interstitial pneumonia awaiting transplantation.55 PH is also extremely common in combined pulmonary fibrosis with emphysema (30%-50% of patients),56 advanced sarcoidosis (75% of sarcoidosis patients awaiting transplant),57 and Langerhans cell histiocytosis.57 High levels of PH (pulmonary artery pressure >35 mm Hg) are associated with greatly increased mortality.57
In all of these settings, the typical vascular changes consist of muscular hypertrophy of the small pulmonary arteries, often with extension of muscle into the arterioles. Sometimes, mild intimal proliferation is present. Rare cases with plexiform lesions have been reported.
Morphologic Mimics of Pulmonary Hypertension
In our experience, biopsies from patients with interstitial lung disease frequently show what at first glance appears to be arterial muscular hypertrophy, and this same phenomenon is sometimes seen in normal or near-normal lung. However, in many such instances elastic stain reveals that this is actually intimal proliferation and that the muscular layer is not really thickened (Fig. 12.24). Intimal fibrosis also increases as a normal function of age.58 ’Hius considerable caution should be exercised in the individual case when interpreting what appear to be low-grade hypertensive changes when the morphologic changes occur in a clinical or pathologic setting not suggestive of PH.
Pathogenesis and Treatment of Pulmonary Hypertension
The pathophysiology of PH is complex and involves multiple pathways. New therapeutic approaches have been specifically directed toward these pathways, either as single drugs or more recently as dual or even triple therapies.59 A recent conference has divided translational targets and therapies into several groups.60
1. Vasomotion imbalance: Endothelial dysfunction, defined as an imbalance between vasoconstricting and vasodilating agents produced by the vascular endothelium or acting on the vascular endothelium, results from an increase in the production of vasoconstrictor mediators and/or a decrease in the activity of vasorelaxant mediators. Endothelin is the major identified vasoconstrictor target with development of drugs directed toward antagonists of the dual (endothelin [ET]-A&B) or selective (ET-A) endothelin receptors. Serotonin (5-hydroxytryptamine) was implicated in the pathogenesis of aminorex-induced PH and has since been identified to work at the 5-HT(1B) receptor resulting in vasoconstriction and cellular proliferation. Although There are potential 5-HT antagonists in development, these have not been included in recent clinical trials.
Mediators of vasorelaxation include nitric oxide (NO) and prostacyclin (PGI2), both of which are important therapeutic targets. NO is often given as an inhalation challenge to determine whether the vasculature is sensitive to an increase in NO, helping to determine therapy. Downstream NO can be enhanced by activation of soluble guanylate cyclase. PDE5 inhibitors prevent the breakdown of cyclic guanosine monophosphate (cGMP). Prostanoids can be inhaled in various forms, injected, or taken orally. An oral PHI2 receptor agonist has also been developed. All of these agents have been parts of clinical trials, either singly or in various combinations.
Figure 12.23 Pulmonary venoocclusive disease (PVOD)/pulmonary capillary hemangiomatosis (PCH). (A) Low-power view showing what at first glance appears to be marked congestion. (B) Higher-power image demonstrates thickened alveolar walls caused by markedly dilated capillaries. (C) Dilated capillary channels, better demonstrated by reticulin staining, appear to invade the walls of a small vein (arrow). (D) Reticulin staining shows capillaries in the wall of an airway (arrow). All of these changes have been described as characteristic of PCH, but are now recognized to occur in PVOD, and it is likely that PCH is not a separate entity.
2. Interruption of cellular proliferation. This concept is based upon the observation that many cytokines and vasoactive mediators are associated with smooth muscle or fibroblast proliferation. Platelet- derived growth factor a exerts its cellular proliferative effect via the receptor tyrosine kinase (RTK) signaling pathway. A clinical trial of the RTK inhibitor imatinib resulted in some significant improvement in vascular function, but also had increased adverse effects (subdural hematoma). Use of broad-spectrum multikinase inhibition or downstream signaling inhibition targets are currently under preclinical investigation.
3. Antiinflammatory strategies. A variety of inflammatory cytokines are increased in PH, and these cytokines may have proliferative effects. Furthermore, there is evidence to support an autoimmune component in some forms of PH. No specific therapies have been clinically tested to support these theories.
4. Modulation of epigenome and regulation of mitochondrial redox. Histone acetylation is important in cell proliferation regulation. Histone deacetylase inhibition has shown positive results in a hypoxia-induced PH animal model. There is recent evidence that microRNAs (miRs) are altered in PH, and animal models of miR inhibitors have shown some promise.
5. BMPR2 repair. Familial PH and some sporadic PH populations are associated with BMPR2 mutation with reduced expression. Tacrolimus appears to be able to activate the signaling pathway, providing a potential therapy, but this has not been tested beyond an animal model.
Currently, a variety of approved drugs exist for treatment of Group 1 PAH. These typically act by promoting vasodilation through inhibition of vasoconstrictors such as endothelin and/or enhancing production of vasodilators such as NO and PGI2, as well as reducing cell proliferation.
Figure 12.24 Thick-walled pulmonary artery branch from a case of bronchiolitis obliterans organizing pneumonia mimicking changes of pulmonary hypertension. At first glance the vessel appears to show muscular hyperplasia, but typically an elastic stain will demonstrate that most of the wall thickness is actually intimal proliferation and that There is no muscular hyperplasia. Changes of this type are common in lungs with interstitial lung disease and should not be overinterpreted as evidence of pulmonary hypertension unless muscular hyperplasia is actually demonstrable on elastic stain.
At present the armamentarium includes calcium channel blockers, prostanoids, endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and soluble guanylate cyclase stimulators. ^e soluble guanylate cyclase stimulator, riociguat, has also been found to be effective in CTEPH.44,59 Combinations of agents are often used (reviewed in Galie et al.).59 Although these treatments improve the quality of life and improve survival,61 they are not curative. Some patients are treated by lung transplantation.
A variety of agents have been used in PH secondary to left heart failure, but clinical trials directed specifically to this have been unsuccessful, and an approved specific therapy is lacking.62 Similarly, there are no valid data to support the use of vasodilators in PH complicating chronic obstructive pulmonary disease (COPD).57 In lung fibrosis- associated PH, trials using the dual ET receptor antagonist bosentan have either not achieved end point criteria or are in progress, and trials using the selective ET-A antagonist ambrisentan or macitentan had negative results.57
Self-assessment questions related to this chapter can be found online at ExpertConsult.com.
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1. Which of the following statements concerning surgical lung biopsy in the assessment of pulmonary hypertension is/are TRUE?
A. It is uncommonly used.
B. It can provide important information about the nature of the disease.
C. It may shed light on the type of underlying congenital cardiac pathology.
D. It may have implications for therapy.
E. All of the above.
ANSWER: E
2. Which of the following statements about the muscular pulmonary arteries is FALSE?
A. An elastic tissue stain is essential for accurate evaluation.
B. They run in parallel with the pulmonary veins.
C. They cannot easily be distinguished from veins within the acinus.
D. They have internal and external elastic lamina.
E. They are important in pulmonary hypertension.
ANSWER: B
3. Which of the following statements about pulmonary hypertension is TRUE?
A. It is defined as a mean arterial pressure greater than 20 mm Hg at sea level.
B. It may be primary or secondary.
C. It is frequently associated with secondary thrombosis.
D. It is often difficult to diagnose on clinical grounds.
E. All of the above
ANSWER: E
4. Which of the following statements about plexiform lesions is TRUE?
A. They were first described by Wagenvoort.
B. They may occur in both primary (idiopathic) or secondary forms of pulmonary hypertension.
C. They are thought to be a sign of reversible disease.
D. They occur in both arteries and veins.
E. All of the above.
ANSWER: B
5. Which of the following statements about thrombotic and embolic hypertension is FALSE?
A. It has an insidious clinical onset.
B. It is claimed to be rarely associated with plexiform lesions.
C. It may occur in intravenous drug users.
D. There is frequently a history of pulmonary embolism.
E. All of the above.
ANSWER: E
6. Which of the following statements about patients with pulmonary venoocclusive disease (PVOD) is TRUE?
A. Most often they are younger than 50 years of age.
B. They have characteristic clinical features of disease at presentation.
C. They are exclusively female.
D. They frequently respond well to corticosteroids.
E. None of the above.
ANSWER: A
7. Radiologic findings of pulmonary hypertension include:
A. Right heart enlargement
B. Normal plain films in early disease
C. A pulmonary artery trunk larger than aorta in the mid-mediastinum
D. Peripheral pulmonary arteries larger than their respective associated airways
E. All of the above
ANSWER: E
8. Which of the following sequences best characterizes the morphologic progression of grades in pulmonary hypertension according to Wagenvoort and Wagenvoort?
A. Muscular hypertrophy, plexiform lesions, dilation lesions, concentric laminar intimal fibrosis, intimal proliferation, necrotizing vasculitis
B. Necrotizing vasculitis, plexiform lesions, muscular hypertrophy, dilation lesions, concentric laminar intimal fibrosis, intimal proliferation
C. Intimal proliferation, muscular hypertrophy, plexiform lesions, dilation lesions, concentric laminar intimal fibrosis, necrotizing vasculitis
D. Dilation lesions, muscular hypertrophy, concentric laminar intimal fibrosis, intimal proliferation, necrotizing vasculitis, plexiform lesions
E. Muscular hypertrophy, intimal proliferation, concentric laminar intimal fibrosis, necrotizing vasculitis, plexiform lesions, dilation lesions
ANSWER: E
9. Pulmonary capillary hemangiomatosis (PCH) is probably the same disease as pulmonary venoocclusive disease (PVOD) because:
A. Morphologic changes thought to be those of PCH can be found in PVOD.
B. Surgical lung biopsy shows features that somewhat resemble those of severe chronic passive congestion in both PVOD and PCH.
C. Mutations in EIF2AK4 can be found in both conditions.
D. All of the above.
ANSWER: D
10. Which of the following findings most strongly favors a diagnosis of pulmonary hypertension over other diffuse lung diseases?
A. Interstitial fibrosis
B. Granulomas
C. Plexiform lesions
D. Kerley B lines
E. Arterial muscular thickening and vessel tortuosity
ANSWER: C
11. True or false: In most patients, pulmonary hypertension is a straightforward clinical diagnosis.
A. True
B. False
ANSWER: B
12. True or false: Many of the vascular lesions of pulmonary hypertension are thought to be reversible.
A. True
B. False
ANSWER: A
13. True or false: Patients with sickle cell disease may develop thrombotic pulmonary hypertension.
A. True
B. False
ANSWER: A
14. True or false: Thrombotic lesions may occur in many different morphologic forms of pulmonary hypertension.
A. True
B. False
ANSWER: A
15. True or false: Arterial muscular hypertrophy, in isolation, is a poor predictor of elevated pulmonary artery pressure.
A. True
B. False
ANSWER: A
16. What is this?
A. Pulmonary embolus
B. Venoocclusive disease
C. Severe arterial muscular hypertrophy
D. Secondary amyloidosis
E. None of the above
ANSWER: C
17. What grade (Wagenvoort and Wagenvoort) of pulmonary hypertension does this vascular abnormality represent?
A. Grade I
B. Grade II
C. Grade III
D. Grade IV
E. Grade V
F. Grade VI
ANSWER: D
18. What grade (Wagenvoort and Wagenvoort) of pulmonary hypertension does this vascular abnormality represent?
A. Grade I
B. Grade II
C. Grade III
D. Grade IV
E. Grade V
F. Grade VI
ANSWER: F
19. What is this?
A. Pulmonary embolus
B. Recanalized thromboembolus
C. Dilatation lesion
D. Plexiform lesion
E. None of the above
ANSWER: B
20. What is this?
A. Talc embolus
B. Angiopathic carcinoma
C. Dilatation lesion
D. Plexiform lesion
E. None of the above
ANSWER: D