P ulmonary veno-occlusive disease (PVOD) is a rare and devastating cause of pulmonary hypertension (PH). PVOD is characterized by widespread fibrous intimal proliferation of septal veins and preseptal venules, and is frequently associated with pulmonary capillary dilatation and proliferation.
1Although the pathology firmly confirms PVOD, a noninvasive diagnostic approach is usually favored in these fragile patients in whom a lung biopsy carries a high risk of lifethreatening complications. Decreased diffusing capacity of the lung for carbon monoxide, severe hypoxemia, radiological abnormalities on high-resolution computed tomography (CT) scans of the chest, and the occurrence of pulmonary edema after starting pulmonary vasodilator therapy strongly argue for PVOD.1,2 PVOD is a difficult form of PH to diagnose; it is frequently misclassified as idiopathic pulmonary arterial hypertension (PAH). Thus, the true incidence of PVOD is not known precisely, but is considered to represent 10% of cases of PAH Background-Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension characterized by the obstruction of small pulmonary veins and a dismal prognosis. PVOD may be sporadic or heritable because of biallelic mutations of the EIF2AK4 gene coding for GCN2. Isolated case reports suggest that chemotherapy may be a risk factor for PVOD. Methods and Results-We reported on the clinical, functional, and hemodynamic characteristics and outcomes of 7 cases of PVOD induced by mitomycin-C (MMC) therapy from the French Pulmonary Hypertension Registry. All patients displayed squamous anal cancer and were treated with MMC alone or MMC plus 5-fluoruracil. The estimated annual incidence of PVOD in the French population that have anal cancer is 3.9 of 1000 patients, which is much higher than the incidence of PVOD in the general population (0.5/million per year). In rats, intraperitoneal administration of MMC induced PVOD, as demonstrated by pulmonary hypertension at right-heart catheterization at days 21 to 35 and major remodeling of small pulmonary veins associated with foci of intense microvascular endothelial-cell proliferation of the capillary bed. In rats, MMC administration was associated with dose-dependent depletion of pulmonary GCN2 content and decreased smad1/5/8 signaling. Amifostine prevented the development of MMC-induced PVOD in rats. Key Words: alkylating agents ◼ antineoplastic agents ◼ complications ◼ drug-related side effects and adverse reactions ◼ GCN2 ◼ hypertension, pulmonary ◼ pulmonary veno-occlusive disease
Conclusions-MMC