Pulmonary Tumour Thrombotic Microangiopathy

Pulmonary tumour thrombotic microangiopathy (PTTM) is a rare, fatal complication of cancer in which tumour cell emboli lodge in small pulmonary arteries and arterioles and trigger local coagulation and fibrocellular intimal proliferation. This produces progressive obstruction and severe pulmonary hypertension within days to weeks.

It is mostly linked to adenocarcinoma, particularly gastric (signet ring cell) cancer, then breast, lung, prostate, pancreas, liver and renal cancers. It is found in 0.9 to 3.3% of autopsies of patients with carcinoma, and is under diagnosed in life. The primary tumour may not be known at presentation.

Pathophysiology. Tumour cells reach the pulmonary microvasculature and activate the clotting cascade, with release of vascular endothelial growth factor, platelet derived growth factor, tissue factor and osteopontin. These stimulate intimal fibrocellular proliferation, thrombosis and luminal narrowing, and lead to a sharp rise in pulmonary vascular resistance, right ventricular failure and hypoxaemia.

Rapidly progressive dyspnoea over days to weeks (nearly all), dry cough, hypoxaemia, tachycardia, chest pain, and right heart failure with syncope. Examination shows tachypnoea, a loud pulmonary second sound, a raised jugular venous pressure, and oedema. Fever and features of disseminated intravascular coagulation (bleeding, petechiae) and microangiopathic haemolysis may occur. Many have a known cancer, and others have non-specific signs of malignancy (weight loss, anaemia).

Rapid respiratory failure with pulmonary hypertension in a patient with cancer needs urgent assessment and early palliative planning.

• Clinical suspicion in a cancer patient with subacute pulmonary hypertension, with the main finding that CT pulmonary angiography shows no large emboli.
• Chest CT: often subtle, with ground glass opacity, septal thickening, centrilobular nodules or tree-in-bud pattern, mosaic attenuation, and enlarged pulmonary arteries. Lymph node enlargement and a primary tumour are sought.
• Echocardiography: high pulmonary artery pressure (often over 50 to 60 mmHg), dilated right heart, and a flattened septum.
• Ventilation perfusion scan: multiple subsegmental mismatched peripheral perfusion defects.
• Blood tests: raised D-dimer, thrombocytopenia, anaemia, raised lactate dehydrogenase, schistocytes on the film, and tumour markers.
• Definitive diagnosis is histological (autopsy or lung biopsy), showing tumour emboli with fibrocellular intimal thickening and microthrombi. In life, pulmonary microvascular cytology from a wedged pulmonary artery catheter blood sample may show tumour cells, though wedging carries a risk.
• Bone marrow or primary tumour biopsy to establish the cancer type.

Differential diagnosis.

• Acute or chronic pulmonary embolism
• Lymphangitic carcinomatosis
• Pulmonary arterial hypertension (idiopathic or from drugs)
• Pulmonary veno occlusive disease
• Pneumonia, including opportunistic infection
• Heart failure

• Treatment is mainly palliative, since median survival after symptoms is days to a few weeks. Establish goals of care early with the patient and family.
• Treat the cancer where possible: chemotherapy directed by the primary tumour (for example, a platinum based regimen for gastric cancer), which has produced improvement in a minority.
• Reported agents in case series: imatinib 200 to 400 mg daily (platelet derived growth factor inhibition) with some responses, corticosteroid (dexamethasone 8 mg daily or prednisolone 1 mg/kg), and anticoagulation with low-molecular-weight heparin (enoxaparin 1 mg/kg twice daily), though evidence is anecdotal.
• Supportive care: oxygen (target saturation 92 to 96%), non-invasive ventilation or high flow oxygen in line with the patient's goals, diuretics with caution for right heart failure, and cautious use of vasodilators, since systemic hypotension is a danger.
• Symptom control: morphine 2.5 to 5 mg orally every 4 hours for breathlessness, midazolam for anxiety, and early palliative care involvement.
• Avoid pulmonary hypertension drugs unless specialists advise, since reports show worsening oedema and shunt.

Complications and prognosis. Right heart failure, respiratory failure, disseminated intravascular coagulation and death. Median survival from the onset of symptoms is about 1 to 2 weeks (range days to a few months).

Monitoring. Daily clinical review, oxygen saturation, haemoglobin, platelets and coagulation while symptoms are being treated.

Referral and escalation. Refer to oncology and palliative care at presentation, and to pulmonary hypertension specialists for diagnostic doubt.