Am J Pathol. 2015 Feb;185(2):356-71

Am J Pathol. 2015 Feb;185(2):356-71. doi: 10.1016/j.ajpath.2014.10.021. Epub 2014 Dec 11.
Chemotherapy-induced pulmonary hypertension: role of alkylating agents.
Ranchoux B1, Günther S2, Quarck R3, Chaumais MC4, Dorfmüller P5, Antigny F1, Dumas SJ1, Raymond N5, Lau E2, Savale L2, Jaïs X2, Sitbon O2, Simonneau G2, Stenmark K6, Cohen-Kaminsky S1, Humbert M2, Montani D2, Perros F7.

Abstract

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents.

PMID: 25497573