Clinical History: A 37-year-old woman with a history of methamphetamine use presented with a complaint of worsening shortness of breath. A frontal chest radiograph and thoracic CT were obtained. A ventilation-perfusion scintigram was interpreted as low probability for pulmonary embolism.
Figure 1. Frontal Chest Radiograph
What are the abnormalities?
Figure 2. Contrast-enhanced Axial CT
Compare the diameter of the main pulmonary artery with that of the aorta.
Figure 3. Contrast-enhanced Axial CT
Describe the abnormality of the right ventricle.
What is the differential diagnosis based on these 3 images?
Histologic sections of lung from a patient with the same diagnosis: A 52-year-old man with obstructive sleep apnea; hepatitis A, B, and C-positive serology; and a 20-year use of methamphetamine developed progressive dyspnea on exertion 3 years before death from progressive right heart failure.
Figure 4. Intra-acinar Vessel
The central vessel is accompanied by a proliferation of cells and slit-like vessels (at 5 o'clock). Dilated, thin-walled vessels partly surround this lesion.
Find the proliferation of cells and slit-like vessels.
Figure 5. Another Example of a Similar Lesion
Here, a parent artery branches at right angles. The origin of the branch is partly occluded by cells forming small lumens. More distally, the branch is patent and dilated.
Find the dark cells forming small lumens.
What are the lesions shown in figures 4 and 5? Answer
What is the histologic differential diagnosis? Answer
Scroll down after answering the questions.
Pulmonary Arterial Hypertension (PAH)
Introduction: Pulmonary arterial hypertension is defined as a persistent elevation of pulmonary arterial pressure above 25 mmHg at rest or above 30 mmHg with exercise, and a mean pulmonary capillary wedge pressure of less than 15 mmHg . The revised Evian Classification of pulmonary hypertension (2003) has clinical categories based on therapeutic similarities. Group l (PAH) includes idiopathic and familial forms, as well as forms associated with collagen vascular diseases, congenital systemic-pulmonary shunts, portal hypertension, HIV infection, certain drugs (including methamphetamine) or toxins, and other less frequent conditions. It also includes primary venous or capillary disease and persistent pulmonary hypertension of the newborn. Types of hypertension associated with left-sided heart disease, hypoxemia, thromboembolic disease, and inflammatory or neoplastic diseases that encroach on the pulmonary vessels are classified separately . Note: In the following, PAH will refer to Group 1 diseases excluding veno-occlusive disease, capillary hemangiomatosis and persistent pulmonary hypertension of the newborn.
Clinical Findings and Testing: Clinical symptoms include dyspnea on exertion, fatigue, syncope, and, with progression, signs of right heart failure. Diagnostic tests include EKG and transthoracic echocardiography to estimate pulmonary artery pressure and exclude heart disease . Laboratory tests for collagen vascular disease, liver or thyroid disease, and HIV; pulmonary function tests followed by HRCT, if indicated; and a sleep study, if suggested by history, may be helpful. Arterial hypoxemia is usually present . V/Q scans help to exclude thromboembolic disease . Right heart catheterization provides diagnostic information, and challenge with short-acting vasodilators helps to determine a response to therapy . Lung biopsy is not usually indicated .
General Imaging Manifestations of Pulmonary Hypertension: The characteristic findings of pulmonary hypertension on chest radiography (Figure 1 above), CT, or MRI are dilation of the main and central pulmonary arteries, with rapid tapering of the pulmonary vessels as they course peripherally, and enlargement of the right ventricle and right atrium. This pattern is present regardless of the etiology of the pulmonary hypertension. It has been suggested that pulmonary hypertension may be diagnosed on chest radiography if the transverse diameter of the right interlobar pulmonary artery exceeds 15 mm in women and 16 mm in men .
The main pulmonary arterial segment cannot be measured on chest radiography, but is easily measured on CT or MRI. The upper normal size limit for the main pulmonary arterial segment on axial CT or MR images is 29 mm. When the main pulmonary artery segment exceeds this size, pulmonary hypertension is usually, but not invariably, present. Furthermore, pulmonary hypertension may be present in patients with a normal-sized main pulmonary arterial segment. When the ratio of the main pulmonary artery to the aorta exceeds 1, elevated pulmonary pressures are usually present .
When pulmonary hypertension is prolonged and severe, calcification of the pulmonary arteries, usually affecting the main, right, and/or left pulmonary arteries, and less commonly, the lobar pulmonary arteries, may be present. These calcifications are associated with atherosclerotic plaques that develop in the proximal pulmonary vessels with hypertension .
V/Q scans may be normal with plexiform lesions or show patchy, nonsegmental abnormalities in microthrombotic disease, in contrast to lobar or segmental perfusion defects in thromboembolic disease .
HRCT: High resolution CT may demonstrate inhomogeneous lung opacity, representing differential pulmonary parenchymal perfusion. Irregular areas of decreased pulmonary parenchymal attenuation and smaller vessels alternate with areas of increased lung attenuation and larger vessels. The resulting mosaic perfusion pattern may also be observed in airway diseases. Vascular and airway causes of mosaic perfusion may be distinguished using postexpiratory imaging. When due to airway diseases, differences in lung attenuation become accentuated with postexpiratory imaging, whereas a proportional increase in attenuation in areas of both increased and decreased attenuation is expected for patients with pulmonary vascular disease .
Although chest radiography and CT may often suggest the presence of pulmonary hypertension, echocardiography is the most commonly obtained examination for the noninvasive assessment of possible pulmonary hypertension. Echocardiography, using continuous wave or pulsed Doppler, provides noninvasive measurement of pulmonary arterial pressures and also allows detailed morphological evaluation of the right ventricle. Further, echocardiography provides assessment of the hemodynamic response of the pulmonary arterial circulation in response to a variety of challenges, such as exercise or pharmacological agents: this technique is termed stress echocardiography.
MRI: It has been increasingly recognized that MRI can provide functional information equivalent to echocardiography (including stress echocardiography), such as direction and velocity of blood flow, in addition to specific anatomic information. MR techniques are well-suited to the evaluation of patients with pulmonary hypertension because they allow both a detailed anatomic and extensive functional examination of the cardiovascular system .
Histologic Findings: Histologic correlates are based on smooth muscle and endothelial-cell proliferation, thrombosis, and development of bronchial collaterals . Because there is no pathognomonic lesion of PAH, descriptive terms should be used.
Generalized distal arterial remodeling results in medial thickening of muscular arteries and extension of muscle into non-muscular arterioles. Along with the thickening is an eccentric or concentric, non-laminar intimal hyperplasia and fibrosis. Together, the medial thickening and intimal fibrosis constitute the most prevalent lesions of PAH and are believed to be reversible . Superimposed, irreversible, high-grade lesions consist of concentric, laminar intimal fibrosis; plexiform; dilation; and necrotizing lesions, which constitute the components of plexogenic angiopathy . The consequent luminal narrowing accounts for the loss of peripheral branching on angiography. Inflammatory infiltrates of T and B lymphocytes and macrophages are now considered to be a part of plexiform lesions . Further, periarterial adventitial fibrosis occurs, and veins typically show mild intimal and adventitial fibrosis . Another type of lesion, the microthrombus, is characterized by an intact vessel wall and a recanalized thrombus in a small artery . A frequent, non-specific change in the lung parenchyma is the cholesterol granuloma, which may reflect the residue of past hemorrhage.
Plexiform lesions occur at branch points of large, preacinar muscular pulmonary arteries (figure 5 above) as well as in smaller, intra-acinar arteries (figure 4 above). Pre-acinar lesions have been found to be statistically more frequent with congenital heart disease than in idiopathic pulmonary hypertension .
Experimental Production of Lesions: Plexiform and dilation lesions have been produced experimentally in dogs by anastomosing a single pulmonary segmental artery to the aorta and ligating the other branches. The dilation lesions surrounding or distal to the plexiform lesions were shown to be perfused by collateral vessels from the bronchial arteries as part of the expanded bronchial circulation that bypasses the obstructed pulmonary vessels in PAH . In the same study, necrotizing arteritis was found to precede the formation of plexiform lesions .
Prevalence of Histologic Vascular Lesions: In 5 series of patients (n=355) with PAH, 61% had plexiform lesions, 33% had microthrombotic lesions without plexiforms, and 6% had isolated medial thickening . Plexiform lesions often occur together with microthrombotic lesions and focal or concentric non-laminar intimal fibrosis. Nevertheless, plexiform lesions are infrequent in the lungs of patients with PAH, being found in 4-7% of vessels in biopsy or autopsy specimens . In a study of patients with the familial form of PAH, plexiform and microthrombotic lesions occurred in 14/23 (61%) cases, but 4 (17%) cases had microthrombotic, without plexiform, lesions. Both plexiform and microthrombotic lesions were rare, 3.4% and 2.7% of vessels, respectively . Both types of lesions are considered to be manifestations of the same disease process. We suggest the term thromboplexogenic angiopathy for this histologic constellation.
Large Thrombi Secondary to PAH: Infrequently, large thrombi in the main or segmental pulmonary arteries occur secondary to long-standing PAH . In addition, chronic thromboembolic pulmonary hypertension may be associated with the development of plexiform lesions, which may be present at the time of embolectomy or develop later .
Heart and Main Pulmonary Arteries: The heart shows right atrial dilation and right ventricular hypertrophy and dilation. Atherosclerosis frequently develops in the main pulmonary arteries, whereas with normal pressures in the pulmonary artery, atherosclerosis is absent even though it is present in the aorta. Remodeling of the elastic arteries results in focal destruction of the elastic fibers, medial hypertrophy and fibrosis, intimal thickening, as well as dilation. Occasionally compression of the recurrent laryngeal nerve between a dilated left pulmonary artery and the aorta produces hoarseness.
Pathogenetic Mechanisms: Multiple factors contribute to the development of PAH, but the primary cause is elusive. A genetic mutation in the bone morphogenetic protein receptor type 2 has been found in many with familial disease, as well as some with sporadic disease (probably genetic, but with unknown family history). The mutation is characterized by dominant inheritance, low penetrance, and genetic anticipation. In addition, an endothelial abnormality is thought to cause an imbalance of vascular regulators controlling vessel tone, cell proliferation, and clotting mechanisms. Central nervous system stimulants including methamphetamine are also implicated [1,19].
Treatment and Outcome: Treatment now prolongs survival and improves quality of life. A useful evaluation of therapy is based on the distance walked in 6 minutes. Treatments include diuresis, inhaled oxygen, anticoagulants, calcium channel blockers, prostacyclin or its analogues, endothelin-receptor antagonists, lung transplantation, and atrial septostomy .
Risk Factors for PAH in Patients in the Unknown: Use of methamphetamine (by both the 37-year-old woman and the 52-year-old man presented in the unknown) has been described as a risk factor, but the association is poorly documented, and PAH is infrequent despite widespread methamphetamine use . The woman received a lung transplant. In the man, sleep apnea is a possible contributing cause of pulmonary hypertension. However, it is usually associated with arterial medial and mild intimal thickening, but not with plexiform lesions. Non-cirrhotic chronic hepatitis and the absence of esophageal varices do not support a diagnosis of portopulmonary hypertension. The man's splenomegaly (475g, normal 150g) and ascites (2.3 L) could have been caused by chronic passive congestion from right heart failure. We do not know whether either patient had any related genetic abnormality.
Summary of Chest Radiographic Findings:
Computed Tomographic Findings:
Summary of Histologic Findings:
Diagnosis: Pulmonary Arterial Hypertension with Plexogenic Angiopathy
References: To return to reference section after viewing abstract, click here before clicking on "abstract".
1. Farber H, Loscalzo. Pulmonary arterial hypertension. N Engl J Med 2004;351:1655-1665.
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15. Pietra G, Edwards W, Kay J, Rich S, Kernis J, Schloo B, Ayres S, et al. Histopathology of primary pulmonary hypertension. A qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry. Circulation 1989; 80:1198-1206. Abstract
16. Loyd J, Atkinson J, Pietra G, Virmani R, Newman J. Heterogeneity of pathologic lesions in familial primary pulmonary hypertension. Am Rev Respir Dis 1988; 138:952-957. Abstract
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Answer: Enlargement of the main pulmonary artery segment (asterisk) and mild cardiomegaly, especially right atrial enlargement. Here, the whole right heart border represents right atrial enlargement. The right atrium makes up the right cardiac border on chest radiography, and when it protrudes laterally and extends cranially along the mediastinum more than normal, it represents right atrial enlargement.
Answer: The main pulmonary artery is larger than the ascending aorta. Normally, they are the same size or the aorta is slightly larger.
MPA = Main pulmonary artery
Asc Ao = Ascending aorta
SVC = Superior vena cava
Desc Ao = Descending aorta
Proliferation of cells and slit-like vessels
Dark cells forming small lumens
These are plexiform lesions. Note the accompanying dilation lesions.
Radiographic Differential Diagnosis: The images, which show enlargement of the pulmonary artery and right atrium and ventricle, indicate pulmonary hypertension. The differential diagnosis includes pulmonary arterial hypertension and pulmonary hypertension associated with left heart disease, lung diseases or hypoxemia, thromboembolic disease, or other conditions .
The differential diagnosis also includes those entities that cause bilateral hilar lymph node enlargement, which would simulate central pulmonary artery enlargement, including sarcoidosis, lymphoma, and metastatic disease. Enlargement of the pulmonary arteries usually appears as smooth hilar enlargement, whereas bilateral hilar lymphadenopathy presents a lobulated appearance. Additionally, lymph node enlargement can be readily distinguished from central pulmonary artery enlargement on the lateral radiograph, based on the location of the abnormal radiographic contour. Finally, pulmonary hypertension will produce enlargement of the main pulmonary artery segment, whereas etiologies of mediastinal and hilar lymph node enlargement will not produce enlargement of the main pulmonary artery segment.
Uncommon causes of central pulmonary arterial enlargement that may resemble pulmonary hypertension include acute pulmonary embolism or pulmonary arterial sarcoma; both of these entities usually cause unilateral central pulmonary arterial enlargement, as opposed to the bilateral symmetric pulmonary arterial enlargement characteristic of pulmonary hypertension. Rarely, bilateral pulmonary artery aneurysms may appear radiographically similar to the central pulmonary arterial enlargement typical of pulmonary hypertension.
Histologic Differential Diagnosis: Plexiform lesions are one type of lesion found in pulmonary arterial hypertension (PAH). The PAH may be idiopathic, familial, or associated with a number of other conditions (see discussion). Plexiform lesions may also occur in patients with chronic thromboembolic pulmonary hypertension, for which there was no evidence in these patients, and in patients with pulmonary sequestration (see Unknown 17).