Pathology of pulmonary hypertension

Abstract

The secondary role of pathology in the present clinical management of pulmonary hypertension (PH) reflects to some extent the limitations of the current understanding of the disease. Ample room exists for the diagnostic translation of the pathobiologic studies, with the goal of improving the diagnostic and prognostic power of the pathologic assessment of pulmonary vascular remodeling. This article seeks to show the complementarities of the pathology and pathobiology of PH.

Figure 1

Histopathology of endothelial cell lesions in IPAH. A. Pulmonary artery showing medial hypertrophy and lined by a single layer of endothelial cells, as outlined by Factor VIII related antigen immunostaining (arrow). Plexiform lesion (outlined by the rim of arrowheads) with the proximal vascular arterial segment with marked intimal and medial thickening by smooth muscle cells (arrow). Note the proliferation of endothelial cells with the outer edge (3–5 o’clock) occupied by dilated blood vessel-like structures. C. Cross section of a plexiform lesion, outlined by arrowheads. Note perilesional inflammatory infiltrate (arrow). D. High magnification histology of plexiform lesions shown slit-like vascular channels lined by hyperchromatic and cuboidal endothelial cells. Cells in the core do not display distinct cytoplamic borders. E. Low magnification immunohistology with Factor VIII related antigen immunohistochemistry of different endothelial cell based vascular lesions. This area has re-vascularized lesions (possibly an organized thrombus), with well-formed and distinct small capillaries/vessels (arrowhead), a plexiform lesion (arrow), and dilated/angiomatoid lesions (between arrowheads). F. High magnification immunohistology of cellular plexiform lesion stained with Factor VIII related antigen (arrowheads). G and H. Histological identification of plexiform and dilation lesions (G) is markedly improved by Factor VIII related antigen immunohistochemistry (H) (arrowheads), while the parent vessel (arrow) shows mild medial remodeling. I. Highlight of vascular dilation/angiomatoid lesions with Factor VIII related antigen immunohistochemistry. J. Endothelial cells in plexiform lesion is highlighted by CD34 immunohisochemistry (arrowheads). Proximal pulmonary artery with marked intima and medial thickening is highlighted by the arrow. K and I. Endothelial cells are highlighted by CD31 immunohistochemistyr (arrowheads). Note that capillary endothelial cells express CD31 as well (arrow in I),

Figure 2

Histological patterns of endothelial cell injury and lesions in IPAH. (A–C). Plexiform lesion (B) with high magnification of proliferated endothelial cells in A. A luminal projection of endothelial cells is highlighted by an arrowhead while cells in cellular core are marked by an arrow. In B, the proximal segment is shown in high magnification, highlighting the atypical endothelial cell (arrowheads) facing the vascular lumen, while a myxoid component organized as concentric layers of smooth muscle cells is highlighted by the arrow. D. A similar pattern of abnormal endothelial cells (arrowhead) and the myxoid subendothelial layer (arrow) are highlighted. E. An intimal projection is highlighted (arrowhead). F. Increased number of endothelial cells (arrowheads) in the intima while the myxoid subintimal layer is highlighted by the arrow. These lesions (B, D–F) contain usually endothelial cells that can be highlighted by Factor VIII related antigen immunohistochemistry. The cluster of endothelial cells possibly represents early plexiform lesions. G. Shown is a concentric lesion (arrowhead) with adjacent smooth muscle-like cells (arrow).

Figure 3

A. Fibrotic, relatively paucicellular intima thickening (outlined by arrowheads) in a pulmonary artery with the media highlighted with the arrow. B. Marked intima remodeling with almost complete obliteration by fibrous tissue with a marked intravascular and perivascular inflammatory infiltrate (arrows). C. Smooth muscle cell hypertrophy, with prominent thickening of medial layer (arrow). D. Highlight of medial hypertrophy with smooth muscle α actin immunohistochemistry. E. Markedly remodeled pulmonary artery with endothelial cell layer highlighted by Factor VIII related antigen immunohistochemistry. Note that the intima and medial smooth muscle cells are negative for Factor VIII related antigen reactivity. F. Ingrowth of smooth muscle cells in a plexiform lesions, highlighted by smooth muscle cell α actin immunohistochemistry (arrow).

Figure 4

Distribution of collagen IV, a component of basement membrane of endothelial cells (arrows) in PH pulmonary arteries. A and B. Plexiform lesion. C. Pulmonary artery with medial thickening. The collagen IV basement membrane of alveolar capillaries shows the clear demarcation of capillary basement membrane.

Figure 5

Veno-occlusive PH. A. Low-power histological view of thickened pulmonary veins running into the lung parenchyma from the pleural surface (left edge) (arrows). Note marked vein wall thickening and decreased lumen. Adjacent alveoli are filled with blood and show septal thickening with engorged capillaries (arrowhead). B. Marked vein thickening with intimal projection probably representing organized thrombus (arrow). Alveolar hemorrhage and septal thickening are highlighted with arrowhead. C and D. Movat stained pulmonary vein showing arterialization pattern with internal and external elastic layers (arrow). The vein shows marked intima thickening with organized thrombus (arrowheads).

Figure 6

Inflammatory cell infiltrate in severe PH. A. Lymphomonuclear cells positive for CD45RO (arrow), surrounding a plexiform lesion (PA). B. Clustering of CD4 lymphocytes around a pulmonary artery (PA) with concentric thickening (arrow). C. Clustering of CD8 lymphocytes around a remodeled pulmonary artery (PA) (arrow). D. Few cells stain positively for CD45RA marker (indicative of naïve T cell cells).

Figure 7

HIV-1 Nef localization in HIV-1 associated PH. A. Normal precapillary vessels (methyl green). B. Localization of Factor VIII related antigen stained with Alexa Fluor 488 (green) and Nef stained with Vector Red. Note lack of expression of Nef in normal pulmonary arteries, resulting in a green signal in the endothelial cells (arrow). C. Markedly remodeled pulmonary artery with concentric/plexiform lesion (arrow, methyl green). D. Co-localization of Factor VIII related antigen (green) with Nef (red), resulting in a yellow signal (arrow). E. Plexiform lesion in HIV-1 associated PH (arrow, methyl green). F. Co-localization of Factor VIII related antigen (green) with Nef (red), resulting in a yellow signal (arrow) in endothelial cells of pulmonary arteries with mild remodeling (arrow). G and H. Lymph node of an SIV infected monkey, showing extensive expression of Nef (red in G and brown in H, arrows) in a hilar lymph node. (Reproduced from Marecki, J. C., et al. “HIV-1 Nef is Associated with Complex Pulmonary Vascular Lesions in SHIV-nef-infected Macaques.” Am.J Respir Crit Care Med. 174.4 (2006): 437-45, with permission.)