Answers

Short Answers

1 Thromboembolic disease, cardiogenic pulmonary oedema, infection, hypersensitivity reaction to the colloid, pulmonary haemorrhage, or (the diagnosis in this case) acute lung injury secondary to chemotherapy.

2 Give supportive management, use systemic steroids, and stop the chemotherapy regimen

3 A thrombus or a neoplasm. In this case, the filling defect was a leiomyosarcoma from haematogenous spread.

Long answers
1 Diagnosis
Her breathlessness was caused by an acute lung injury associated with chemotherapy.

From a more detailed history it was apparent the intermittent breathlessness occurred after each chemotherapy cycle, with increasing severity. The clinical presentation could have been in keeping with thromboembolic disease, respiratory infection, cardiogenic pulmonary oedema, pulmonary haemorrhage, or a acute lung injury associated with chemotherapy. Acute lung injury associated with chemotherapy is a diagnosis of exclusion. In this case the computed tomography pulmonary angiogram had excluded pulmonary thromboembolic disease. Her echocardiogram showed normal biventricular and valvular function, hence cardiogenic pulmonary oedema was not suspected. Pulmonary haemorrhage was unlikely to have caused her breathlessness because she had no history of haemoptysis or coagulopathy. Respiratory infection was thought not to be the main cause of her intermittent breathlessness because she did not have a cough or associated fevers.

These features, however, are non-specific and may occur in acute lung injury. To help confirm the diagnosis of acute lung injury, a high resolution computed tomography scan was performed. This showed bilateral diffuse ground glass opacities, which are usually seen in acute lung injury and any disease process that causes an accumulation of fluid in the alveoli. At presentation the patient was too hypoxic to have a bronchoscopic alveolar lavage or a lung biopsy. These tests are helpful in excluding other differential diagnoses.

The diagnosis of acute lung injury associated with chemotherapy was strengthened by her dramatic response to high dose intravenous steroids. Within 24 hours her oxygen requirements fell from 15 l/min to 8 l/min. She was discharged from the hospital five days after admission and started a new chemotherapy regimen.

Gemcitabine and docetaxel are common chemotherapy drugs. Gemcitabine is used for solid cancers such as lung, breast, pancreas, bladder, and soft tissue sarcomas. Docetaxel is mainly used for breast, ovarian, and lung cancers. Few chemotherapy drugs are effective in leiomyosarcoma, although small studies have found that gemcitabine and docetaxel in combination have tolerability and response.^{1 2} Acute lung injury associated with gemcitabine is a rare but potentially fatal side effect. The incidence of pulmonary toxicity in analysis of pooled data varies from 0.02% to 0.27%, but some reports show that acute lung injury occurs in up to 14% of patients.³ Acute lung injury secondary to docetaxel alone is not reported as often as injury secondary to gemcitabine alone. Chemotherapy drugs given in addition to gemcitabine are thought to increase the likelihood of acute lung injuries. Case reports suggest a mortality of up to 44% in gemcitabine associated acute lung injury.⁴ Clinical features of chemotherapy associated acute lung injury include dyspnoea, cough, fever, and raised inflammatory markers.^{4 5} [ref numbering out of sequence]The predominant pattern seen on a chest radiograph is diffuse bilateral interstitial infiltrates. Gemcitabine associated acute lung injury can present from the first day that a drug is given, or up to one and half years later.⁴

2 Treatment
The mainstay of treatment for chemotherapy associated acute lung injury is to stop the potentially offending drug and administer systemic corticosteroids. Many reports document a good response with complete reversal of the acute lung injury.⁴ Some studies have reported clinical improvement with the addition of diuretics.⁴

The pathophysiological mechanism behind acute lung injury associated with gemcitabine is thought to be an abnormal permeability of the alveolar capillary wall that is mediated by cytokines. Gemcitabine induces the release of proinflammatory cytokines and any chemotherapy drugs given at the same time can augment this proinflammatory cascade.⁶ The mechanism behind acute lung injury associated with docetaxel is not known.

View larger version (90K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1 Computed tomography scan shows multiple pulmonary metastases, diffuse bilateral infiltrates, small bilateral pleural effusions, and a large filling defect in right ventricle [figure not referred to in text]

On echocardiography the right ventricle lesion did not obstruct the outflow tract and had features suggesting a sarcoma not a thrombus. Primary cardiac tumours have an incidence of less than 0.1% and about 75% are benign. Of these benign tumours about 75% are atrial myxomas. Secondary cardiac tumours are more common. In the largest series of postmortem examinations performed on patients with cancer (1900) 8% had cardiac metastases.⁷ The metastases are usually carcinomas rather than sarcomas. The type of cancer and whether it is malignant or benign might be predicted from the appearance of the metastases on echocardiograms.

Sarcomas are a rare form of endometrial cancer and account for less than 4% of uterine malignancies. Endometrial carcinomas are the most common form of uterine malignancy. The sarcomas arise from the endometrial lining of the uterus or myometrium and behave more aggressively and carry a worse prognosis than the endometrial carcinomas. About a third of uterine sarcomas are leiomyosarcomas. These cancers arise from the endometrial smooth muscle. Leiomyosarcomas account for only 7% of all soft tissue sarcomas, of which the most common primaries are stomach, retroperitoneum, and the small intestine. Leiomyosarcoma metastases to the heart are exceptional, and the diagnosis is often made after a postmortem examination.⁸ An increase in the frequency of case reports makes it seem that cardiac leiomyosarcoma metastases are on the rise, possibly because of the prolonged survival of cancer patients. Treatment is difficult as most cardiac metastases cannot be removed completely because of local spread or distant metastases. Chemotherapy and radiotherapy have been used to control symptoms, with limited success.

References

Cite this as: BMJ 2008;337:a1405