Is there hope of improving the prognosis of pulmonary tumour thrombotic microangiopathy?

To the Editor:

We read with interest the letter by Kumar et al. [1] reporting two new cases of fatal pulmonary tumour thrombotic microangiopathy (PTTM). As discussed by the authors, ante mortem diagnosis of PTTM is difficult to confirm because of a rapid progression of the disease. The disease is characterised histopathologically by microscopic tumour emboli and remodelling of the pulmonary vasculature, leading to right heart failure, severe hypoxaemia and, ultimately, death in the very short term, within a few hours or days following admission.

However, some cases have also been reported in the literature with higher survival of a few months that were not analysed in detail by Kumar et al. [1], who cited only one of these cases [2]. After reviewing all cases published in PubMed-indexed journals, since the original description by von Herbay et al. [3], we found six additional observations of such prolonged survival after a diagnosis of PTTM (table 1) [4–9]. These cases drew our attention because they could also be interesting to highlight the physiopathological mechanisms of PTTM and identify potential targeted therapies for this fatal condition.

One of these cases reported prolonged survival of a patient treated for a colorectal cancer with chemotherapy including bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody [7]. VEGF is known to have a specific role in angiogenic endothelial cells and, thereby, in promoting the proliferation of endothelium involved in embryonic development and tumour angiogenesis. A recent clinical analysis of 30 autopsy cases observed that the immunohistochemistry of tumour cells located within the tumour emboli was positive for VEGF, suggesting that this pathway could be an interesting option to treat PTTM [10]. However, the effect of anti-VEGF antibody in this condition has to be evaluated in light of side-effects of this treatment, including thromboembolic events. In addition, four other patients were treated with imatinib, a tyrosine kinase inhibitor that inhibits platelet-derived growth factor (PDGF) receptors, at different dosages [2, 7–9]. Imatinib was associated in three cases with other chemotherapies acting on the VEGF pathway. In these patients, a survival of 12 months was reported, which is exceptional in PTTM. An immunohistochemical study reported PDGF and PDGF receptor expression in cancerous cells and pulmonary endothelial cells in lesions of PTTM caused by gastric carcinoma. In two cases, imatinib treatment lead to a decrease in serum PDGF concentration, which was associated with a decrease in D-dimer concentrations, despite the absence of anticoagulation [2, 9]. Interestingly, in one case, a sustained clinical response after weaning from imatinib was observed, probably related to the efficacy of adjunct chemotherapy [2]. Again, the effect of this drug has to be evaluated in light of its side-effects. We have to remember that the risk/benefit ratio was recently considered unfavourable for the treatment of idiopathic pulmonary artery hypertension.

Based on these observations, we can hope that a better understanding of the pathophysiology of PTTM could result in specific targeted therapies that should improve prognosis of this vascular condition.