Arterial lesions

Isolated medial hypertrophy 
This abnormality of the vessel wall can be observed in all subgroups of PAH and may even be encountered in other forms of PH, e.g. in mitral valve stenosis. The lesion corresponds to a smooth muscle cell proliferation and / or recruitment within the tunica media; the histological criterion of hypertrophy / hyperplasia is fulfilled, when the diameter of a single medial layer, delimited by its internal and external elastic lamina, exceeds 10 per cent of the arteries cross-sectional diameter (Figure 2A). Isolated hypertrophy of the medial layer may be considered as an early and even reversible event as it has been shown in PH due to hypoxia in high altitude [171]. However, medial hypertrophy is usually associated with other PAH-lesions.
Figure 2  Pulmonary arteries of the muscular type displaying obstructive arteriopathy in lungs of patients with PAH. A Medial hypertrophy with smooth muscle cell proliferation and pronounced adventitial fibrosis. Magnification x200, Weigert-hematoxylin-phloxine-saffron staining (WHPS). B Concentric non-laminar intimal fibrosis comprising numerous myofibroblasts (arrows). C Eccentric intimal fibrosis corresponding to organized thrombotic material. Br: bronchus, Ar: pulmonary artery. Magnification x100, HES staining. D Thrombotic lesion, so called "colander-like lesion", with partial recanalization by microvessels. Note the similarity to plexiform lesions (F). Magnification x100, HES. E Concentric laminar intimal fibrosis, so called „onion-skin lesion“. Magnification × 200, HES. F Plexiform lesion with proliferation of small sinusoid-like vessels on a fibrotic matrix. Note surrounding dilated vessels. Magnification x100, HES. G Multiple dilation lesions being the sentinel of the centrally located plexiform lesion. Magnification × 40, Elastica-van-Gieson staining (EvG). H The same plexiform lesion after immunohistochemical staining with anti-CD3, a T-lymphocytic marker. Note the perivascular distribution of the inflammatory infiltrate. Magnification x100.

Concentric and eccentric non-laminar intimal fibrosis 
Fibrotic lesions of the intimal layer are frequent in PAH-diseased lungs. The intima may be thickened by proliferation and recruitment of fibroblasts, myofibroblasts and other connective tissue cells, and consequently by the interstitial deposition of collagen (Figure 2B, C). In a purely descriptive approach, this thickening may be uniform and concentric, or focally predominating and eccentric. However, the eccentric intimal thickening is frequently observed in cases with thrombotic events and could represent residues of wall-adherent, organized thrombi. Thrombotic lesions, or so called in situ thrombosis, are a frequent pattern in different PAH-subgroups: organization and recanalization of totally occluding thrombotic material may lead to bizarre, fibrotic multi-channel lesions (so called “colander-like” lesions) which can be easily confounded with proliferative complex lesions (see below) (Figure 2D). Frequently, adventitial fibrosis is associated to intimal modifications (Figure 2A, B).

Concentric laminar intimal fibrosis 
This morphologically conspicuous phenotype of intimal fibrosis is also known as “onion-skin” or “onion-bulb” lesion. Numerous concentrically arranged fibrotic layers occlude the arterial lumen of small (diameter: 100–200 μm) arteries (Figure 2E). The scary, cell-lacking morphology of this lesion is frequently found in patients suffering from idiopathic PAH and PAH associated to CTD [172]. Nevertheless, immunohistochemical analysis reveals fibroblasts, myofibroblasts and smooth muscle cells.

Complex lesions 
The pathological classification of the World Symposium meetings in Venice and in Dana Point comprises three patterns, plexiform lesion, dilation lesion and arteritis. The plexiform lesion probably represents the most illustrious form of vascular lesions in PAH and affects various vascular compartments: focal intimal thickening of small pulmonary arteries, preferably beyond branching points and exuberant endothelial cell proliferation, leading to the formation of capillary-like, sinusoidal channels on a smooth muscle cell and collagen-rich matrix within the native arterial lumen and resulting in obstruction [173,174]. This glomeruloid-like arterial zone feeds into dilated, vein-like congestive vessels, which are perceivable at low magnification (Figure 2F). The latter vein-like vessels are also known as dilation lesions and may predominate the histological pattern (Figure 2G). Classical arteritis with transmural inflammation and fibrinoid necrosis, as first described by Heath and Edwards for PAH associated to congenital cardiac disease (Eisenmenger), is not a regular finding in PAH [175]. Nevertheless, perivascular inflammatory infiltrates of diseased pulmonary arteries in PAH-patients, consisting mainly of T- and B-lymphocytes, dendritic cells, mast-cells and macrophages can be regularly found [141,148,176] (Figure 2H). It has not been elucidated until now, whether this inflammatory pattern is of pathogenetic importance, or if it represents a pure epiphenomenon within disease evolution. The reported evidence of proinflammatory mediators, so called chemokines, released by altered endothelial cells of PAH-lungs strongly indicates a self-supporting and self-amplifying process [145,177].

Venous and venular lesions (Pulmonary veno-occlusive disease and pulmonary hemangiomatosis) 
A clear-cut differentiation between pre-and post-capillary pulmonary vascular lesions is sometimes difficult to make: lesions frequently concern veins and arteries in lungs of patients with PVOD, and vice-versa veins may be strongly involved in some subgroups of PAH. This is not contradictory because the clinical approach to ‘difficult-to-treat’ PAH-groups may be similar to clinical management of PVOD and PVOD-patients are frequently treated – under great precaution – with pulmonary arterial dilators, e.g. prostanoids. Recent reports, for example, indicate that CTD associated PAH, classically being considered as pre-capillary PH, simultaneously displays a PVOD-like pattern in histology [178,179]. Like in PVOD, the observed post-capillary lesions concern septal veins and pre-septal venules and usually consist of a loose and pauci-cellular and cushion-like intimal fibrosis that may totally occlude the lumen. A muscularization of both, septal veins and pre-septal venules may be observed (Figure 3A, B). Importantly, occult pulmonary hemorrhage regularly occurs in patients displaying PVOD. This particularity, which is certainly due to the post-capillary bloc, is of diagnostic importance, as bronchio-alveolar lavage can reveal an occult hemorrhage. The degree of hemorrhage can be evaluated semi-quantitatively and qualitatively using the Golde Score, which takes number and Perls-Prussian-Blue staining-degree of intra-alveolar siderophages into consideration (Figure 3C) [180]. Pulmonary capillary hemangiomatosis has been historically described as an aggressive capillary proliferation with patchy distribution within the pulmonary parenchyma: alveolar septa are thickened by 3 to 4 capillary layers, and infiltration of venous and bronchiolar structures with secondary occlusion may be present (Figure 3D). It is thought, that a clinically relevant post-capillary bloc is owed to this angiomatoid expansion. Occult hemorrhage or hemosiderosis, therefore, is frequently found [181]. However, Lantuejoul and co-workers have shown in a remarkable retrospective histological analysis, that capillary hemangiomatosis-pattern is virtually always present in PVOD, and vein-remodelling is constantly observed in case with a primary diagnosis of PCH [54]. The authors suggest the possibility, that PVOD and PCH might be the same disease, with a vein- or a capillary-predominating pattern. We fully support this view, and in our experience from the French National PH Reference Center, no clinical distinction is made between both conditions.
Figure 3  Pulmonary veins with obstructive venopathy in lungs of patients with PVOD and a case of pulmonary capillary hemangiomatosis. A Longitudinally dissected septal vein with asymmetric intimal and partially occlusive fibrosis. Note the intra-alveolar hemorrhage due to the post-capillary block on the upper half of the photograph. Magnification × 100, EvG. B Pre-septal venule with occlusive intimal fibrosis. Magnification × 100, EvG. C Bronchio-alveolar lavage in a PVOD-patient. Perls-Prussian-Blue staining. Note the siderophages displaying gradually different color-shades (see text). Magnification × 400. D Excessively proliferating alveolar capillaries in a patient with pulmonary capillary hemangiomatosis. Note protrusion of ectatic lumina into the alveoli. Magnification × 200, anti-CD31 staining.

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