The diagnostic challenge of pulmonary tumour thrombotic microangiopathy as a presentation for metastatic gastric cancer: a case report and review of the literature

PTTM is a rare clinico-pathological entity first described by von Herbay et al. in 1990. It is a complication of cancer characterised by widespread microscopic (usually non-occlusive) tumour emboli in the pulmonary arterioles. The distinction from conventional tumour emboli is that it features localised activation of coagulation pathways and the resultant histopathological finding of fibrocellular intimal proliferation with or without secondary thrombosis [2, 3].

For reasons that are not known, the clear majority of cases of PTTM arise from gastric adenocarcinomas, often those of the signet ring cell subtype. In reviewing all cases published in PubMed-indexed journals, we found that gastric cancer accounts for around 60 % of cases, with the remainder comprising lung cancer (9 %), cancer of unknown primary (6 %), breast cancer (3 %), and a few rarely-reported tumour sites.

The clinical presentation is typically of acute dyspnoea. There is a very rapid clinical course, progressing to death in a matter of hours to days. Echocardiography, if performed in a timely fashion, may show features of pulmonary hypertension and right heart strain (with raised pulmonary arterial pressure on right heart catheterisation) [4, 5]. The picture of rapidly progressive dyspnoea often prompts the team managing the patient to organise a CT scan of the thorax. If angiography is performed at the same time, it is usually negative for acute pulmonary embolism [1]. Instead, there are diffuse centrilobular nodular opacities in a tree-in-bud pattern throughout the lung fields, with the possible additional signs of acute cor pulmonale [6‐8].

A number of proteins have been implicated as mediators in the development of PTTM. Vascular endothelial growth factor [1, 9] and tissue factor [10] are expressed more frequently in cancer cells leading to PTTM than those with traditional tumour emboli. Platelet-derived growth factor (PDGF) is also expressed more frequently in PTTM-associated cancer cells [9], although the association may be more complex with PDGF overexpression also present in alveolar macrophages and PDGF receptor expression in the proliferating fibromuscular intimal cells [11]. Osteopontin has also been implicated [12, 13]. However, demonstrating overexpression of these factors falls short to construct a model for the pathogenesis of PTTM which remains to be elucidated.

As in our case, PTTM may well occur in patients hitherto unknown to be harbouring malignant disease. The combination of acute dyspnoea as the initial presentation for metastatic disease combined with a rapid deterioration makes ante mortem diagnosis a significant challenge [14]. Indeed, there are only ten case reports in the literature where the diagnosis of PTTM was made whilst the patient was still alive: five were diagnosed by transbronchial lung biopsy [15‐19], two by video-assisted thoracoscopic surgery [20, 21], one by CT-guided biopsy [22]; the final two were presumptive ante mortem diagnoses based on proven pulmonary hypertension and the finding of tumour cells from wedged pulmonary artery catheter aspiration [23, 24].

Early ante mortem diagnosis is, however, only the first step towards successful treatment. To date, there are only four case reports in the literature of patients who survived beyond the initial acute phase. The first was in 2007 when a patient with VATS biopsy-proven PTTM from gastric adenocarcinoma was treated with dexamethasone, warfarin, aspirin and fluoropyrimidine-based chemotherapy. The patient's symptoms and radiographic findings resolved, and she was well at six month follow-up [20].

The remaining three cases all experienced significant improvement following the administration of imatinib alongside other medications such as prostacyclin analogs and endothelial receptor antagonists to manage their pulmonary hypertension. These patients had improved pulmonary hypertension but died of either progressive disease [18, 23] or, in one case, influenza infection [24]. There are reports of imatinib being useful in pulmonary arterial hypertension in the non-PTTM setting [25], although its use is currently confined to clinical trials due to the IMPRES study which showed increased morbidity from adverse events despite an improvement in haemodynamics [26]. That imatinib appears to alter the natural history of PTTM lends credence to the theory that PDGF is involved in the pathophysiology. Disappointingly, although PDGF levels fell following imatinib therapy, Ogawa et al. did not actually find PDGF expression in either tumour cells or intimal cells. They hypothesised that this was because the biopsy specimen was taken after administration of imatinib and subsequent clinical improvement [18].

An earlier diagnosis (such as on her first hospital admission) is unlikely to have changed the prognosis in this lady with widespread carcinoma, but it should be remembered that definitive diagnosis is not purely an academic pursuit in terminal conditions. There is evidence to suggest that the act of providing information to cancer patients can reduce anxiety [27]. Knowledge of their illness is valuable in that it allows patients to contextualise life decisions [28, 29].