1313
CLINICAL
PRACTICE
Pulmonary embolism, pulmonary hypertension, and choriocarcinoma
A
of
pulmonary embolism and pulmonary artery hypertension in young women is choriocarcinoma growing in the pulmonary artery. This growth is reversible, and the disorder can be cured. We describe three patients with this feature who have been treated with appropriate high-risk chemotherapy and who are now in remission. Contrast-enhanced computed tomography can be used to identify major emboli, and progress of the disease can be monitored by serial ventilation/ perfusion scans and measurement of serum human chorionic gonadotropin. Recognition of this rare syndrome is important because of the generally excellent outlook with appropriate treatment. rare
cause
Introduction If untreated, choriocarcinoma is a fatal tumour in women childbearing age. Current chemotherapy regimens can cure almost all patients with gestational trophoblastic disease after hydatidiform mole1 and over 80% of patients with high-risk disease.2 The incidence of hydatidiform molar pregnancies in the UK is about 1.5 per 1000 livebirths. These patients are screened for potential malignant sequelae, therefore few present with advanced disease. However, trophoplastic tumours can occur after abortions and rarely after normal pregnancies (incidence 1 per 40 000 to 50 000). All tumours that occur after a normal pregnancy are histologically choriocarcinomas. We still have patients presenting to our centre with advanced disease, in whom the diagnosis of choriocarcinoma has not been considered earlier, usually because the obstetric history did not suggest an abnormal pregnancy. Some of these patients have presented to their local hospitals with recurrent pulmonary emboli, major pulmonary artery obstruction, and pulmonary artery hypertension (PAH). 30 years ago Bagshawe3reported that choriocarcinoma could be found at necropsy in the pulmonary tree in patients who died of PAH. He was the first to recognise this tumour as a potentially reversible cause of PAH. There are probably still deaths every year from choriocarcinoma embolism to the pulmonary tree that are never recognised. Unless the pulmonary thrombus is examined histologically, tumour in the pulmonary artery can be mistaken for blood clot. Many textbooks of medicine omit choriocarcinoma as a cause of pulmonary emboli and PAH. We describe the successful treatment of three patients with choriocarcinoma embolising to the pulmonary tree. of
Case-reports Patient 1 After a spontaneous abortion at age 19 this woman took oral contraceptives for 4 years. 5 months after she stopped the oral contraceptives irregular heavy vaginal bleeding developed. Over the next 18 months four pregnancy tests were positive but were ignored by her physicians, since two pelvic ultrasound examinations showed no abnormalities. A gynaecological diagnosis of dysfunctional uterine bleeding was made, and clomiphene was prescribed. 1 month later right-sided pleuritic chest pain and exertional dyspnoea developed. During the next 6 weeks the patient became dyspnoeic at rest, and a further pregnancy test was strongly positive. She was transferred to our hospital for further management 3 months after her first pulmonary embolus. On examination, she had tachypnoea at rest, tachycardia (130 bpm) with a blood pressure of 110/60 mm Hg, a left parasternal heave, a loud pulmonary second sound, and a high jugular venous pressure. Her POz was 37 mm Hg on air, chest radiography showed many peripheral wedge shadows compatible with pulmonary infarcts, and the electrocardiogram showed right heart strain. A ventilation perfusion (V/Q) scan showed no perfusion of the right lung and multiple defects of the left lung with normal ventilation. Dynamic computed tomography showed occlusion of the right pulmonary artery (fig 1). On admission, the human chorionic gonadotropin (HCG) concentration was 103 200 IU/1 (the normal concentration is below 2 IU/1). Ultrasound and doppler examination of the pelvis showed no abnormalities. We started treatment with our high-risk chemotherapy protocol, alternating etoposide, methotrexate, and actinomycin D every week with vincristine and cyclophosphamide, and heparin for anticoagulation. The HCG concentration fell rapidly, and chemotherapy was discontinued after 4 months. Serial V/Q scans showed an improvement in perfusion to the left lung, but the right remained largely unperfused. The signs of PAH disappeared during the first few weeks of therapy. 4 years later, the patient is well and has had two subsequent
uncomplicated pregnancies. ADDRESSES. Departments of Medical Oncology (M. J. Seckl, MRCP, G. J. S. Rustin, MRCP, Prof E. S Newlands, FRCP), Radiology (S J. Gwyther, FRCR), and Nuclear Medicine (J Bomanji, MRCP), Charing Cross Hospital, London, UK. Correspondence to Prof Edward S. Newlands, Department of Medical Oncology, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK
1314
Fig 1-Contrast-enhanced CT scan of thorax pulmonary arteries in patient 1. Note filling defect in right
mam
at level of main
pulmonary artery (arrow)
Patient 2 A 24-year-old woman had a spontaneous abortion, followed by heavy and irregular periods. 2 months later intermittent pleuritic chest pains developed and were treated with several different antibiotics. The pains persisted and a year later the patient was admitted to her local hospital with haemoptysis and progressive dyspnoea at rest. She had signs of PAH and was profoundly hypoxic even on 40% oxygen. The electrocardiograph showed right heart strain. A chest radiograph showed nodular shadows and an oligaemic left lung. Computed tomography of the chest showed bilateral nodular shadowing throughout the lung fields. Computed tomography and ultrasound examinations of the abdomen and pelvis were normal. A pregnancy test was strongly positive, and the patient was referred to our care before an intended lung biopsy was carried out. On admission, the HCG concentration was 280 000 IU/1. A V/Q scan showed normal ventilation but no perfusion of the left lung and many perfusion defects of the
right (fig 2).
A
dynamic computed tomography
scan
confirmed occlusion of the left main pulmonary artery. Treatment with our high-risk chemotherapy protocol plus heparin was started. The patient required oxygen support with continuous positive airway pressure for 2 weeks and signs of PAH settled over this period. Serial V/Q scans have shown a return of normal perfusion of most of the right lung and part of the left lung. The HCG concentration has fallen to normal and the patient is completing the final 2 months of
chemotherapy. Patient 3 spontaneous abortion this 30-year-old woman noticed intermittent chest pains. Because of a positive pregnancy test and menorrhagia, she underwent dilatation and curettage; no abnormalities were found. Several months later the patient was admitted with a pulmonary embolism, and a V/Q scan showed no perfusion of the right lung. A month later she had a further pulmonary embolus, and angiography showed occlusion of the right upper and middle lobe pulmonary arteries, which was slightly reduced by streptokinase. Previous pelvic 8 months after
a
Fig 2-V/Q scan
in
No perfusion of left ventilation
patient 2 (posterior views). lung and multiple defects
m
right lung with normal
venography was negative. Despite warfarin therapy her dyspnoea grew worse. An ultrasound examination showed a right adnexal mass. Two further pregnancy tests were strongly positive, and the patient was transferred to our care 6 months after her first pulmonary embolism. On examination, she had signs of PAH and the electrocardiogram showed right heart strain. A V/Q scan was compatible with multiple pulmonary emboli. Her initial HCG was 132300 IU/1. She received our high-risk chemotherapy protocol and continued anticoagulant treatment first with heparin and then with warfarin, completing treatment after 4 months. Serial V/Q scans showed gradual resolution of the perfusion abnormalities, and the patient has remained well for the past 8 years.
1315
Discussion
Although most physicians, gynaecologists, radiologists, and pathologists are aware of choriocarcinoma, not many know that this disorder can present with PAH. This feature is secondary to tumour embolism and thrombus in either the pulmonary artery or the distal pulmonary tree. Other tumours can embolise to the lung, but choriocarcinoma is unusual for several reasons shown by the cases described. Firstly, and most importantly, it can be cured. Secondly, primary growth in the uterus or any other site may not be apparent. Thirdly, choriocarcinoma always produces HCG. Thus, a high urinary or serum HCG concentration when pregnancy cannot be confirmed by ultrasound should alert the attending doctors to the possibility of choriocarcinoma.4 The time between the causal pregnancy and the onset of symptoms may be several years. The chest radiograph may show none of the usual signs of metastatic disease, such as cannonball secondaries. V/Q scanning confirms multiple pulmonary emboli. Pulmonary angiography could be fatal, since the catheter could dislodge tumour. The cases we have described show that contrast-enhanced computed tomography scanning can identify embolus within the main pulmonary trunk and that serial V/Q scans can document improvements in perfusion. Colour doppler studies may in future allow non-invasive measurements of pulmonary artery pressure. Once the diagnosis is suspected, further management should be discussed immediately with a centre that treats choriocarcinoma. The diagnosis is highly likely on clinical grounds if the HCG is high in a non-pregnant patient when other features compatible with this syndrome are present. Appropriate life-saving chemotherapy must be started as soon as possible. Disease progress is monitored both clinically and by serial HCG measurements. Choriocarcinoma is unusual in that definitive histology is
always required before treatment. Indeed, biopsy of suspicious lung nodules is contraindicated because of the vascularity of these tumours, and the resultant haemothorax in a patient whose cardiorespiratory status is already compromised may lead to death. Streptokinase treatment of the tumour embolism is potentially dangerous because of the risk of haemorrhage, but heparin treatment to prevent not
thrombus extension on the tumour has not caused complications in the patients treated so far. Formal ventilation of patients with choriocarcinoma has resulted in 100% mortality from barotrauma-induced damaged Such trauma can be avoided by means of continuous positive airway pressure mask support. Although rare, choriocarcinoma should be considered in the differential diagnosis of fertile women presenting with pulmonary embolism or PAH because unnecessary death will result unless appropriate treatment is started. This work was supported by the Cancer Research Campaign. We thank Prof K. D. Bagshawe for helpful discussion.
REFERENCES Dent J, Newlands ES, Begent RHJ, Rustin GJS. The role of low-dose methotrexate and folinic acid in gestational trophoblastic tumours (GTT). Br J Obstet Gynaecol 1989; 96: 775-802. 2. Newlands ES, Bagshawe KD, Begent RHJ, Rustin GJS, Holden L. Results with the EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) regimen in high risk gestational trophoblastic tumours, 1979 to 1989. Br J Obstet Gynaecol 1991; 98: 550-57. 3. Bagshawe KD, Brooks WDW. Subacute pulmonary hypertension due to chorionepithelioma. Lancet 1959; i: 653-58. 4. Smith DB, Rustin GJS, Bagshawe K. Don’t ignore a positive pregnancy test. Br Med J 1988; 297: 1119-20. 5. Kelly MP, Rustin GJS, Ivory C, Phillips P, Bagshawe KDB. Respiratory failure due to choriocarcinoma: a study of 103 dyspnoeic patients. Gynecol Oncol 1990; 38: 149-54.
1. Bagshawe KD,
HYPOTHESIS
chemotherapy and cure of childhood acute lymphoblastic leukaemia
Maintenance
Maintenance chemotherapy with 6-mercaptopurine and methotrexate, widely believed an essential contribution to the high cure rates achieved in children with acute lymphoblastic leukaemia (ALL), is thought to work by killing the leukaemia cells that remain after intensive chemotherapy. We suggest instead that ALL commonly arises in precursor B cells normally programmed to die, and that maintenance chemotherapy does not kill these cells but controls growth of the leukaemia clone so that programmed death can occur. A similar approach may apply to other cancers in which programmed death is intrinsic to the normal counterparts of the neoplastic cells.
Cure of childhood acute lymphoblastic leukaemia (ALL) of the most impressive accomplishments of modem cancer chemotherapy.1-5 Most haematologists believe that maintenance chemotherapy with low doses of 6-mercaptopurine and methotrexate is important for curebut are there convincing data that maintenance chemotherapy is effective? And, if it is effective, how does maintenance chemotherapy work? is
one
ADDRESSES. Department of Medicine, Division of Hematology and Oncology, UCLA School of Medicine, Los Angeles, California 90024, USA (R P Gale, MD) and Department of Paediatrics, Division of Haematology and Oncology, University of Parma, Parma 43100, Italy (A Buttunni, MD). Correspondence to Dr R P. Gale, Department of Medicine, Division of Hematology-Oncology, UCLA School of Medicine, Los Angeles, CA 90024-1678, USA
CLINICAL
PRACTICE
Pulmonary embolism, pulmonary hypertension, and choriocarcinoma
A
of
pulmonary embolism and pulmonary artery hypertension in young women is choriocarcinoma growing in the pulmonary artery. This growth is reversible, and the disorder can be cured. We describe three patients with this feature who have been treated with appropriate high-risk chemotherapy and who are now in remission. Contrast-enhanced computed tomography can be used to identify major emboli, and progress of the disease can be monitored by serial ventilation/ perfusion scans and measurement of serum human chorionic gonadotropin. Recognition of this rare syndrome is important because of the generally excellent outlook with appropriate treatment. rare
cause
Introduction If untreated, choriocarcinoma is a fatal tumour in women childbearing age. Current chemotherapy regimens can cure almost all patients with gestational trophoblastic disease after hydatidiform mole1 and over 80% of patients with high-risk disease.2 The incidence of hydatidiform molar pregnancies in the UK is about 1.5 per 1000 livebirths. These patients are screened for potential malignant sequelae, therefore few present with advanced disease. However, trophoplastic tumours can occur after abortions and rarely after normal pregnancies (incidence 1 per 40 000 to 50 000). All tumours that occur after a normal pregnancy are histologically choriocarcinomas. We still have patients presenting to our centre with advanced disease, in whom the diagnosis of choriocarcinoma has not been considered earlier, usually because the obstetric history did not suggest an abnormal pregnancy. Some of these patients have presented to their local hospitals with recurrent pulmonary emboli, major pulmonary artery obstruction, and pulmonary artery hypertension (PAH). 30 years ago Bagshawe3reported that choriocarcinoma could be found at necropsy in the pulmonary tree in patients who died of PAH. He was the first to recognise this tumour as a potentially reversible cause of PAH. There are probably still deaths every year from choriocarcinoma embolism to the pulmonary tree that are never recognised. Unless the pulmonary thrombus is examined histologically, tumour in the pulmonary artery can be mistaken for blood clot. Many textbooks of medicine omit choriocarcinoma as a cause of pulmonary emboli and PAH. We describe the successful treatment of three patients with choriocarcinoma embolising to the pulmonary tree. of
Case-reports Patient 1 After a spontaneous abortion at age 19 this woman took oral contraceptives for 4 years. 5 months after she stopped the oral contraceptives irregular heavy vaginal bleeding developed. Over the next 18 months four pregnancy tests were positive but were ignored by her physicians, since two pelvic ultrasound examinations showed no abnormalities. A gynaecological diagnosis of dysfunctional uterine bleeding was made, and clomiphene was prescribed. 1 month later right-sided pleuritic chest pain and exertional dyspnoea developed. During the next 6 weeks the patient became dyspnoeic at rest, and a further pregnancy test was strongly positive. She was transferred to our hospital for further management 3 months after her first pulmonary embolus. On examination, she had tachypnoea at rest, tachycardia (130 bpm) with a blood pressure of 110/60 mm Hg, a left parasternal heave, a loud pulmonary second sound, and a high jugular venous pressure. Her POz was 37 mm Hg on air, chest radiography showed many peripheral wedge shadows compatible with pulmonary infarcts, and the electrocardiogram showed right heart strain. A ventilation perfusion (V/Q) scan showed no perfusion of the right lung and multiple defects of the left lung with normal ventilation. Dynamic computed tomography showed occlusion of the right pulmonary artery (fig 1). On admission, the human chorionic gonadotropin (HCG) concentration was 103 200 IU/1 (the normal concentration is below 2 IU/1). Ultrasound and doppler examination of the pelvis showed no abnormalities. We started treatment with our high-risk chemotherapy protocol, alternating etoposide, methotrexate, and actinomycin D every week with vincristine and cyclophosphamide, and heparin for anticoagulation. The HCG concentration fell rapidly, and chemotherapy was discontinued after 4 months. Serial V/Q scans showed an improvement in perfusion to the left lung, but the right remained largely unperfused. The signs of PAH disappeared during the first few weeks of therapy. 4 years later, the patient is well and has had two subsequent
uncomplicated pregnancies. ADDRESSES. Departments of Medical Oncology (M. J. Seckl, MRCP, G. J. S. Rustin, MRCP, Prof E. S Newlands, FRCP), Radiology (S J. Gwyther, FRCR), and Nuclear Medicine (J Bomanji, MRCP), Charing Cross Hospital, London, UK. Correspondence to Prof Edward S. Newlands, Department of Medical Oncology, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK
1314
Fig 1-Contrast-enhanced CT scan of thorax pulmonary arteries in patient 1. Note filling defect in right
mam
at level of main
pulmonary artery (arrow)
Patient 2 A 24-year-old woman had a spontaneous abortion, followed by heavy and irregular periods. 2 months later intermittent pleuritic chest pains developed and were treated with several different antibiotics. The pains persisted and a year later the patient was admitted to her local hospital with haemoptysis and progressive dyspnoea at rest. She had signs of PAH and was profoundly hypoxic even on 40% oxygen. The electrocardiograph showed right heart strain. A chest radiograph showed nodular shadows and an oligaemic left lung. Computed tomography of the chest showed bilateral nodular shadowing throughout the lung fields. Computed tomography and ultrasound examinations of the abdomen and pelvis were normal. A pregnancy test was strongly positive, and the patient was referred to our care before an intended lung biopsy was carried out. On admission, the HCG concentration was 280 000 IU/1. A V/Q scan showed normal ventilation but no perfusion of the left lung and many perfusion defects of the
right (fig 2).
A
dynamic computed tomography
scan
confirmed occlusion of the left main pulmonary artery. Treatment with our high-risk chemotherapy protocol plus heparin was started. The patient required oxygen support with continuous positive airway pressure for 2 weeks and signs of PAH settled over this period. Serial V/Q scans have shown a return of normal perfusion of most of the right lung and part of the left lung. The HCG concentration has fallen to normal and the patient is completing the final 2 months of
chemotherapy. Patient 3 spontaneous abortion this 30-year-old woman noticed intermittent chest pains. Because of a positive pregnancy test and menorrhagia, she underwent dilatation and curettage; no abnormalities were found. Several months later the patient was admitted with a pulmonary embolism, and a V/Q scan showed no perfusion of the right lung. A month later she had a further pulmonary embolus, and angiography showed occlusion of the right upper and middle lobe pulmonary arteries, which was slightly reduced by streptokinase. Previous pelvic 8 months after
a
Fig 2-V/Q scan
in
No perfusion of left ventilation
patient 2 (posterior views). lung and multiple defects
m
right lung with normal
venography was negative. Despite warfarin therapy her dyspnoea grew worse. An ultrasound examination showed a right adnexal mass. Two further pregnancy tests were strongly positive, and the patient was transferred to our care 6 months after her first pulmonary embolism. On examination, she had signs of PAH and the electrocardiogram showed right heart strain. A V/Q scan was compatible with multiple pulmonary emboli. Her initial HCG was 132300 IU/1. She received our high-risk chemotherapy protocol and continued anticoagulant treatment first with heparin and then with warfarin, completing treatment after 4 months. Serial V/Q scans showed gradual resolution of the perfusion abnormalities, and the patient has remained well for the past 8 years.
1315
Discussion
Although most physicians, gynaecologists, radiologists, and pathologists are aware of choriocarcinoma, not many know that this disorder can present with PAH. This feature is secondary to tumour embolism and thrombus in either the pulmonary artery or the distal pulmonary tree. Other tumours can embolise to the lung, but choriocarcinoma is unusual for several reasons shown by the cases described. Firstly, and most importantly, it can be cured. Secondly, primary growth in the uterus or any other site may not be apparent. Thirdly, choriocarcinoma always produces HCG. Thus, a high urinary or serum HCG concentration when pregnancy cannot be confirmed by ultrasound should alert the attending doctors to the possibility of choriocarcinoma.4 The time between the causal pregnancy and the onset of symptoms may be several years. The chest radiograph may show none of the usual signs of metastatic disease, such as cannonball secondaries. V/Q scanning confirms multiple pulmonary emboli. Pulmonary angiography could be fatal, since the catheter could dislodge tumour. The cases we have described show that contrast-enhanced computed tomography scanning can identify embolus within the main pulmonary trunk and that serial V/Q scans can document improvements in perfusion. Colour doppler studies may in future allow non-invasive measurements of pulmonary artery pressure. Once the diagnosis is suspected, further management should be discussed immediately with a centre that treats choriocarcinoma. The diagnosis is highly likely on clinical grounds if the HCG is high in a non-pregnant patient when other features compatible with this syndrome are present. Appropriate life-saving chemotherapy must be started as soon as possible. Disease progress is monitored both clinically and by serial HCG measurements. Choriocarcinoma is unusual in that definitive histology is
always required before treatment. Indeed, biopsy of suspicious lung nodules is contraindicated because of the vascularity of these tumours, and the resultant haemothorax in a patient whose cardiorespiratory status is already compromised may lead to death. Streptokinase treatment of the tumour embolism is potentially dangerous because of the risk of haemorrhage, but heparin treatment to prevent not
thrombus extension on the tumour has not caused complications in the patients treated so far. Formal ventilation of patients with choriocarcinoma has resulted in 100% mortality from barotrauma-induced damaged Such trauma can be avoided by means of continuous positive airway pressure mask support. Although rare, choriocarcinoma should be considered in the differential diagnosis of fertile women presenting with pulmonary embolism or PAH because unnecessary death will result unless appropriate treatment is started. This work was supported by the Cancer Research Campaign. We thank Prof K. D. Bagshawe for helpful discussion.
REFERENCES Dent J, Newlands ES, Begent RHJ, Rustin GJS. The role of low-dose methotrexate and folinic acid in gestational trophoblastic tumours (GTT). Br J Obstet Gynaecol 1989; 96: 775-802. 2. Newlands ES, Bagshawe KD, Begent RHJ, Rustin GJS, Holden L. Results with the EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) regimen in high risk gestational trophoblastic tumours, 1979 to 1989. Br J Obstet Gynaecol 1991; 98: 550-57. 3. Bagshawe KD, Brooks WDW. Subacute pulmonary hypertension due to chorionepithelioma. Lancet 1959; i: 653-58. 4. Smith DB, Rustin GJS, Bagshawe K. Don’t ignore a positive pregnancy test. Br Med J 1988; 297: 1119-20. 5. Kelly MP, Rustin GJS, Ivory C, Phillips P, Bagshawe KDB. Respiratory failure due to choriocarcinoma: a study of 103 dyspnoeic patients. Gynecol Oncol 1990; 38: 149-54.
1. Bagshawe KD,
HYPOTHESIS
chemotherapy and cure of childhood acute lymphoblastic leukaemia
Maintenance
Maintenance chemotherapy with 6-mercaptopurine and methotrexate, widely believed an essential contribution to the high cure rates achieved in children with acute lymphoblastic leukaemia (ALL), is thought to work by killing the leukaemia cells that remain after intensive chemotherapy. We suggest instead that ALL commonly arises in precursor B cells normally programmed to die, and that maintenance chemotherapy does not kill these cells but controls growth of the leukaemia clone so that programmed death can occur. A similar approach may apply to other cancers in which programmed death is intrinsic to the normal counterparts of the neoplastic cells.
Cure of childhood acute lymphoblastic leukaemia (ALL) of the most impressive accomplishments of modem cancer chemotherapy.1-5 Most haematologists believe that maintenance chemotherapy with low doses of 6-mercaptopurine and methotrexate is important for curebut are there convincing data that maintenance chemotherapy is effective? And, if it is effective, how does maintenance chemotherapy work? is
one
ADDRESSES. Department of Medicine, Division of Hematology and Oncology, UCLA School of Medicine, Los Angeles, California 90024, USA (R P Gale, MD) and Department of Paediatrics, Division of Haematology and Oncology, University of Parma, Parma 43100, Italy (A Buttunni, MD). Correspondence to Dr R P. Gale, Department of Medicine, Division of Hematology-Oncology, UCLA School of Medicine, Los Angeles, CA 90024-1678, USA
