Mitomycin-Induced Pulmonary Veno-Occlusive Disease

Abstract

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

The cancer theory of pulmonary arterial hypertension

“…In all the tested species, cyclophosphamide was shown to induce severe PH in mice associated with pulmonary venous remodeling reminiscent of pulmonary veno-occlusive disease (PVOD), an uncommon form of PH. 132 In direct connection with this, mitomycin-C therapy was also identified as a potent inducer of PVOD in humans and rats, 133 further supporting the fact that, in the early stage of the disease, DNA damaging agents pose a significant genomic stress contributing to endothelial cell apoptosis and PAH development, but in advanced stages of the disease, it may induce stress overload of the DDR pathway, improving vascular remodeling. 48,53 Nevertheless, the current evidence suggests that there is no place for these agents in PAH therapy.…”

Hematological disorders and pulmonary hypertension

“…A number of alkylating agents including cyclophosphamide, bleomycin, mitomycin used for hematological diseases have been shown to lead to PVOD and PH[11,120]. Other therapeutic measures used for hematological disorders such as tyrosine kinase inhibitor dasatinib, interferon, splenectomy, bone marrow transplantation (BMT) and radiation also contribute to PH as discussed below.…”

EIF2AK4 mutation in pulmonary veno-occlusive disease

“…[20] Previous studies have indicated that the exposure to toxins, such as cigarette smoke and chemotherapeutic agents, is associated with the development of PVOD. [5,21,22] Mitomycin-C (MMC) therapy was reported to be a potent inducer of PVOD in humans and rats. In rats, MMC administration was associated with the dose-dependent depletion of pulmonary EIF2AK4 content and decreased smad1/5/8 signaling.…”

“…Amifostine prevented the development of MMC-induced PVOD. [21] Another report reviewed 37 cases of chemotherapy-associated PVOD from the French PH network and literature. They found that 83.8% of the exposure in the cases was to alkylating agents, mostly represented by cyclophosphamide (43.2%).…”