Dyspnoea is not uncommon in patients with a cancer diagnosis, and can represent several differential diagnostic possibilities. We describe a case of persistent and increasing dyspnoea in a woman in her 40s who previously had been treated for breast cancer with metastasis to lymph nodes.
Dyspnoea is not unusual in cancer patients, and several differential diagnoses may be possible, such as infection, thromboembolic disease, tumour emboli, solitary lung metastases, carcinomatous lymphangitis, side effects of chemotherapy, heart failure, cardiac tamponade etc.
Because of her history of illness with dyspnoea and elevated D-dimer, a pulmonary embolism was suspected. A CT of the pulmonary arteries did not reveal pulmonary emboli, but because of the suspicion of peripheral pulmonary emboli, lung scintigraphy was also carried out.
The possibility of heart/coronary affection due to previous chemotherapy and radiation near the heart was also considered. As part of the assessment, the patient was also referred for spirometry and a walking test with the lung specialist.
Pulmonary embolism was still regarded as the most probable diagnosis.
Experience shows that warfarin can be difficult to monitor with metastatic disease and can intereact with chemotherapy. Warfarin was therefore discontinued. Treatment with a therapeutic dose of low-molecular heparin was continued. The suspected metastatic lesions were considered to be too small to explain the patient’s dyspnoea and chest pain, and supplementary CT abdomen showed no other metastases. The patient reported subjective improvement after the start of anti-coagulation treatment, and the diagnosis of pulmonary embolism was retained. The patient had a strong wish to go abroad on holiday, and it was therefore decided to postpone chemotherapy until she returned.
A bronchial infection was considered the most probable cause of the patient’s problems.
The X-ray finding caused suspicion of pulmonary hypertension, and this was assumed to be associated with pulmonary emboli.
According to the discharge summary from abroad, her condition was perceived as an acute asthma attack complicated by concomitant infection. She was treated with broad-spectrum antibiotics, anti-obstructive drugs and prednisolone. Elevated liver markers were also found, and believed to be due to possible acute hepatitis due to the use of low-molecular heparin. This was therefore discontinued.
Her condition was considered to be heparin-induced thrombocytopaenia, and low-molecular heparin was therefore replaced with an inhibitor of factor X/Xa, fondaparinux (Arixtra). Bone marrow smears and crista biopsy yielded normal findings. Disseminated intravascular coagulation (DIC) was also considered as a possible cause of thrombocytopaenia, but the blood tests yielded no evidence to support this.
Because of clinically dominant dyspnoea without improvement, the CT images of the thorax were reviewed by the radiologist on suspicion of carcinomatous lymphangitis. No evidence was found for this, or for significant progression in the patient’s cancer.
Figure 1 Volume CT thorax with intravenous contrast taken during the first admission to hospital. The truncus pulmonalis has normal dimensions
Figure 2 Volume CT thorax with intravenous contrast taken during last hospitalisations shows pronounced truncus pulmonalis with diameter 37 mm causing suspicion of pulmonary hypertension
An autopsy was ordered to investigate the cause of the patient’s persistent dyspnoea, hypoxia and subsequent death.
Figure 3 Small pulmonary artery with tumour cells in the lumen (haematoxylin erythrosine saffron (HES))
Figure 4 Artery with intimal fibrosis, recanalisation and tumour thrombi in both artery and associated veins/lymph vessels (HES)
Figure 5 Small pulmonary artery with eccentric intimal fibrosis (HES)
The vascular changes that were found are consistent with pulmonary arterial hypertension, WHO Group 5 (1), with tumour emboli in small pulmonary vessels as underlying causes. All in all, this is consistent with pulmonary tumour thrombotic microangiopathy (PTTM).
Pulmonary tumour thrombotic microangiopathy is difficult to diagnose and often misinterpreted as thromboembolic disease. Other designations used are carcinomatous microangiopathy, carcinomatous arteriopathy, carcinomatous endarteritis and pulmonary tumour emboli. This condition differs from ordinary tumour emboli in that there are also vascular changes as with pulmonary hypertension.
The histopathological changes differ little from changes associated with pulmonary hypertension as a consequence of thromboembolic disease. Characteristically, eccentric, but also concentric, intimal fibrosis is seen (2), mild or absent hypertrophy of muscularis media (as opposed to idiopathic pulmonary arterial hypertension), and recanalisation of tumour thrombi. The condition was first described by Brill & Robertson in 1937, as rapid development of right-sided heart failure due to tumour emboli (3). The typical patient often has pronounced dyspnoea (3, 4), while clinical and imaging diagnostic findings may be relatively limited.
The condition is seldom diagnosed ante mortem, and is normally found at autopsy. In an autopsy study of 630 patients with adenocarcinoma, the disease was found in 3.3 % of patients with solitary tumours (5). In another autopsy study of patients with carcinoma, tumour emboli were found in the lungs of 40 % of those who were autopsied (6), but in this study the number who also had changes as in PTTM is not reported.
The condition has been described with several types of cancer, but is most commonly associated with primary tumour in lung, breast or stomach (4, 5). The frequent association between breast and lung cancer can probably be attributed to the fact that they are two of the most common forms of cancer (7). The pathophysiological mechanisms underlying the development of pulmonary hypertension secondarily to tumour emboli in lungs is largely unknown, but two hypotheses have been described. First, dysregulation of signal pathways that are normally activated by ordinary emboli, may result in remodelling of vasculature and thereby contribute to the development of pulmonary hypertension. The other hypothesis describes increased vascular resistance as a result of mechanical occlusion of arterial pulmonary vessels due to tumour emboli. When the obstruction has reached a certain threshold level, the capacity of the pulmonary vessels to compensate is weakened and symptoms arise (7).
Chest X-rays can provide information about any infections, solitary lung metastasis, interstitial fibrosis and any carcinomatous lymphangitis, but findings that may indicate pulmonary hypertension and cor pulmonale are seen in fewer than 50 % of the patients with PTTM (4, 8). CT thorax also contributes little, but in a few cases may show changes peripherally in the pulmonary arteries, particularly subsegmentally, in the form of dilation and beading of peripheral blood vessels (9). Pulmonary angiography is often normal (7, 10). Lung scintigraphy can show characteristic, abundant, symmetrical and peripheral, often subsegmental perfusion defects (11).
Multifocal abnormal absorption of fluorodeoxyglucose (FDG) has been described in connection with positron emission tomography (PET), and this is a test that may be useful in assessing cases of suspected PTTM (12). However, there is very limited information on the use of PET for such an assessment. Lung biopsy is very useful for diagnosis, but is contra-indicated with pulmonary hypertension because of the risk of haemorrhaging (13, 14). Right-side heart catheterisation is necessary for diagnosing pulmonary arterial hypertension, for determining the degree of affection of the right ventricle pumping function and for testing the vasoreactivity of pulmonary circulation to, for example, nitric oxide. With a pulmonary arterial catheter it is also possible to aspirate blood from pulmonary microvasculature for cytological testing (15 – 17). A pathologist with cytology experience should be consulted in advance, so that the material can be optimally secured and prepared. Smears and cell blocks can be made from the material. If there are sufficient tumour cells in a cell block, supplementary special staining, immunohistochemical and molecular pathology tests are possible. In conventional smears, the tumour cells tend to lie peripherally, so that they may be difficult to detect. It must be borne in mind that there may be relatively abundant megacaryocytes in pulmonary vasculature, and that these may be mistakenly identified as tumour cells (16).
PTTM is an aggressive disease with rapid progression. The median survival from the onset of symptoms with dyspnoea until death is estimated at 4 – 12 weeks (2). There is no established treatment for the condition. We assume that early diagnosis may enable more aggressive, tumour-focused treatment, and that reduction of tumour cells in the pulmonary circulation may possibly limit the risk of fibrointimal proliferation and the development of pulmonary hypertension. However there are no reliable studies that can confirm this, although a case of successful treatment of a patient with adenocarcinoma in the ventricle has been described (18).
Dyspnoea in cancer patients is not unusual, and offers many diagnostic possibilities. On suspicion of pulmonary emboli, with or without signs of pulmonary hypertension, the possibility of tumour thrombi must be considered in the event of lack of response to treatment if there is no consistency between the patient’s symptoms and the diagnostic imaging findings. The possibility of PTTM should also be considered in patients with persistent dyspnoea who do not have known cancer. Even though the patients often have advanced cancer, efforts should be made to achieve rapid assessment. We regard cross-disciplinary cooperation early in the course as essential, both in order to establish a diagnosis as quickly as possible and to avoid unnecessary assessment and treatment of other conditions.