Pulmonary Hypertension: Classification and General Histologic Features
Allen P. Burke, M.D.
Joseph J. Maleszewski, M.D.
Definition
Pulmonary hypertension is defined clinically as a mean pulmonary artery pressure of ≥25 mm Hg at rest. The normal mean pulmonary pressure is between 9 and 18 mm Hg, and levels between 18 and 25 are considered borderline and may indicate increased mortality in patients with associated conditions, such as interstitial lung disease. Right heart catheterization is the gold standard for measuring pressures, though echocardiography with Doppler is sometimes used as a surrogate, though the correlations are not particularly good.1 Pulmonary hypertension is caused by a variety of conditions that originate in the arteries (precapillary), veins (postcapillary), or capillaries.
Classification
The clinical classification of pulmonary hypertension has evolved appreciably over time. Initially, the classification was dichotomous and based on whether or not an identifiable cause for the hypertension was present. The term primary pulmonary hypertension was used when no cause for the elevated pressures could be identified, and the term secondary pulmonary hypertension was used when a cause was identified. Pulmonary hypertension has been classified according to site of obstruction (precapillary, capillary, or postcapillary).
In 1998, the World Health Organization revamped the clinical classification to better reflect etiology and mechanism.2 The new classification allows for classification of pulmonary hypertension into five basic groups (Table 62.1). Group 1 (pulmonary arterial hypertension) includes idiopathic pulmonary arterial hypertension, familial pulmonary arterial hypertension, and pulmonary arterial hypertension due to drugs, toxins, connective tissue diseases, infection, portal hypertension, and congenital heart disease. Group 2 (left heart disease) are those cases of pulmonary hypertension owing to underlying structural heart disease (e.g., ischemic heart disease, valvular heart disease, hypertensive heart disease, and cardiomyopathy). Group 3 (lung disease) is pulmonary hypertension caused by lung disease and/or chronic hypoxemia (e.g., chronic obstructive pulmonary disease, interstitial lung disease, obstructive sleep apnea, etc.). Group 4 (thromboembolic disease) is arterial hypertension secondary to chronic thromboembolic occlusion of the pulmonary vessels. Group 5 (multifactorial) is a category reserved for those with unclear mechanisms such as in the setting of metabolic disorders, chronic renal failure, or hemolytic anemia. Pulmonary hypertension in the newborn setting and in pulmonary veno-occlusive disease (PVOD) have been given their own subgrouping (groups 1″ and 1′, respectively).
TABLE 62.1 World Health Organization Classification of Pulmonary Hypertensiona | |||||||||||||||||||||||||||
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Although the above classification system is useful and widely used clinically, it is more common for pathologists to group the changes into one that describes the location of the identified histopathologic changes. Recognizing that it is not uncommon to identify changes in the absence of elevated pressures and vice versa, it is important to indicate that identified changes (or lack thereof) should be correlated with pressures for comprehensive interpretation. Precapillary pulmonary hypertension includes those in which arterial changes are identified in the setting of either primary or secondary pulmonary hypertension. Post-capillary-type pulmonary hypertension will include PVOD and pulmonary venous hypertension (owing to left-sided heart disease). Arterial hypertensive changes in the setting of interstitial lung disease occur typically in a background of fibrosis and parenchymal distortion. Thrombotic/embolic changes include those that arise in the setting of thromboembolic disease. Hypertensive changes can also be seen in the setting of sarcoidosis, infection, and other miscellaneous conditions.
Histologic Changes Associated with Precapillary Pulmonary Hypertension
Approach to Histologic Evaluation
Arterial and venous abnormalities are most easily appreciated with the use of elastic stains. Pulmonary arteries travel within the bronchovascular bundles, and are usually near airways. Muscular arteries, unlike veins and systemic arteries, have a distinct internal and external elastic lamina. Elastic arteries are easily distinguished by parallel elastic layers. Pulmonary veins travel within interlobular septa. Bronchial arteries, which supply oxygenated blood to larger airways, originate from the aortic arch and intercostal arteries. Of note, bronchial arteries do not have a distinct external elastic membrane, but rather have a fragmented elastic layer like other systemic arteries. Bronchial arteries are more easily identified in cases of bronchial artery embolization, which is used for patients with intractable hemoptysis (see Chapter 61).
Interpretation and Specificity of Findings
There is a poor correlation between extent of histologic vascular changes and actual arterial pressures measured by catheterization. This discrepancy is likely related to sampling and lack of histologic
manifestations of vasoconstriction, which is an important component contributing to increased pulmonary resistance. Therefore, a diagnosis of “pulmonary hypertension” is not appropriate on a surgical pathology report, rather “changes of pulmonary arterial hypertension” with an appropriate comment indicating that necessity of correlation with hemodynamic data. Historical grading systems based on histologic findings (i.e., Heath et al.,3 which were devised for preoperative evaluation of patients with congenital right-to-left cardiac shunts) are no longer in use.
manifestations of vasoconstriction, which is an important component contributing to increased pulmonary resistance. Therefore, a diagnosis of “pulmonary hypertension” is not appropriate on a surgical pathology report, rather “changes of pulmonary arterial hypertension” with an appropriate comment indicating that necessity of correlation with hemodynamic data. Historical grading systems based on histologic findings (i.e., Heath et al.,3 which were devised for preoperative evaluation of patients with congenital right-to-left cardiac shunts) are no longer in use.
In general, plexiform lesions are present only in a subset of conditions, including idiopathic pulmonary artery hypertension, familial pulmonary hypertension, and pulmonary arterial hypertension associated with autoimmune connective tissue disorders, congenital rightto-left shunts, portal hypertension, and certain drugs and toxins (e.g., fenfluoramine and monocrotaline). Careful evaluation for such, with a histopathologic diagnosis of “plexogenic pulmonary arteriopathy” can be useful in refining the clinical diagnosis.
The most common condition associated with histologic changes of pulmonary hypertension (other than plexiform lesions) is fibrotic lung disease. Intimal arterial thickening is common in wedge biopsies with interstitial lung disease (over 90%),4 and patients with idiopathic pulmonary fibrosis demonstrate increased pulmonary arterial pressures in up to one-third of cases.5
Muscularization of Arterioles
In general, arterial pulmonary vessels <100 µm in diameter are considered arterioles. They continue to progressively arborize and lose their muscular walls with very little muscle usually identified in vessels <20 µm in diameter. A distinct muscular wall in vessels of this size is abnormal. In infants, vessels even smaller than this can be seen with a muscular wall in cases of abnormal shunts or persistent pulmonary hypertension of the newborn (see Chapter 13).
Muscular Hypertrophy of the Pulmonary Arteries
Muscular (medial) hypertrophy of muscular arteries has been defined as thickening of the muscular arterial wall (distance between the elastic layers) of >10%.6 The mean medial thickness of normal pulmonary arteries is 5% of the vessel diameter and normally is <8% to 10%. The percentage is calculated from measuring the medial thickness, multiplying by two, and dividing by the external diameter of the vessel. Medial hypertrophy is nonspecific and may be seen in pre- and postcapillary hypertension, interstitial lung disease, and as an incidental finding (usually focally) (Fig. 62.1). It is commonly associated with intimal thickening.
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