Plexiform Vasculopathy in Chronic Thromboembolic Pulmonary Hypertension

A 64-year-old white woman was admitted with distal severe chronic thromboembolic pulmonary hypertension. Pulmonary angiography revealed an irregular pattern of organized, recanalized thromboembolisms with abrupt, frequently angular narrowing of the major pulmonary arteries and complete obstruction of main, lobar, and segmental vessels (Figure 1A). The patient was discussed in a multidisciplinary conference and was not considered a candidate for pulmonary endarterectomy because of severe hemodynamic impairment and predominantly distal distribution of the pulmonary vascular lesions. She received medical therapy with riociguat, a soluble guanylate cyclase stimulator, and underwent a total of six balloon pulmonary angioplasties. However, because of progressive hemodynamic and clinical deterioration (see online supplement), she eventually underwent bilateral lung transplantation. Histopathological examination of the explanted lungs revealed multifocal complete or incomplete thromboembolic obstructions in different stages of reorganization in various subsequent segmental precapillary vessels. These vessels showed severe, focally calcified fibrous changes with prominent widening of the tunica intima, medial hypertrophy, as well as multifocal formation of concentric, angiomatoid, and plexiform lesions (PLs; Heath-Edwards grade 5; Figure 2) (1, 2). The latter represent complex vascular neoformations originating from remodeled pulmonary arteries presumably due to endothelial-mesenchymal transition in an attempt to restore the integrity of the endothelial barrier, resulting in a release of inflammatory cytokines and endothelial dysfunction (2-4). The impact of this remodeling-associated microvascular neoangiogenesis in PLs has not yet been reported in the literature. PLs are convoluted glomeruloid-like vascular malformations, exclusively diagnosed by histopathological examination and arising largely independent of the underlying cause of pulmonary hypertension (4). The objective of our study was to characterize plexiform changes three-dimensionally by microvascular corrosion casting. Immunohistochemical analysis of PLs illustrated the arrangement of vascular channels expressing markers of endothelial differentiation (CD31, CD34), surrounded and supported by specialized smooth muscle cells (Figure 3). Freshly harvested lung tissue was analyzed by microvascular corrosion casting (5), and the vascular architecture was studied two-and three-dimensionally. The small vessels showed chaotic arrangement with abnormal capillary elongations, missing vascular hierarchy, and tortuous sinusoidal vessels, changes generally associated with microvascular architecture in neoplasms (Figure 4A and B). The expansion of the PL was principally brought about by vasodilation and increased incidence of intussusceptive pillars (Figure 4C). Intussusceptive angiogenesis is pivotal in various proliferative and inflammatory diseases (5). The morphogenetic feature of intussusceptive angiogenesis is the development of intravascular pillars, which bridge the opposing lumina without requiring cellular proliferation, but by incorporation of CD34-positive endothelial progenitor cells (5). In summary, our study provides the first evidence that the formation of PLs is driven by sprouting and intussusceptive angiogenesis. Our architectural findings may suggest that plexiform vascular changes interact as a collateral circulation, overcoming the restricted local perfusion caused-in our patient-by vasculopathy and remodeling of the distal pulmonary arteries.