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Pulmonary resection in the management of metastases from gestational choriocarcinoma
J
THoRAc CARDIOVASC SURG
81:830-834, 1981
Pulmonary resection in the management of metastases from gestational choriocarcinoma Case histories offive patients with pulmonary metastases from choriocarcinoma resistant to multidrug chemotherapy are presented. Thoracotomy was performed in all cases. All tumor was removed in three patients with no other site of active disease, and these patients are surviving with no evidence of recurrent disease. In one patient, the lesion could not be completely excised because of involvement of contiguous structures, and she died of progressive disease. A second patient, with liver metastases at the time ()f' thoracotomy, also died of progressive disease. The indications for performing thoracotomy in the management of pulmonary metastases of choriocarcinoma are discussed.
James D. Sink, M.D., Charles B. Hammond, M.D., and W. Glenn Young, Jr., M.D., Durham, N. C.
Gestational trophoblastic neoplasms (choriocarcinoma and related tumors) are malignant tumors arising from the trophoblast of human pregnancy. Prior to the advent of chemotherapy, the mortality rate was 60% for patients with nonmetastatic tumors and 98% for those with metastatic disease.'; however, Li, Hertz, and Spencer" at the National Institutes of Health reported in 1956 a patient with metastatic choriocarcinoma treated with methotrexate who had a sustained and complete remission. This report began an era of drug treatment which has resulted in progressive improvement in the salvage of patients with choriocarcinoma. At the present time, remission rates in excess of 90% can be expected when the disease is diagnosed early and treated vigorously. Even in the presence of brain or liver metastases, chemotherapy can result in remission rates in excess of 75%.1 Pulmonary metastases occur in approximately 70% of patients with choriocarcinoma." Although the successful surgical treatment of a solitary lung metastasis of choriocarcinoma was reported in 1947, 4 cytotoxic chemotherapy is presently the first line treatment of pulmonary metastasis. Thoracotomy is still indicated, however, in certain situations. In this paper, data are From the Departments of Surgery and Obstetrics and Gynecology, Duke University Medical Center, Durham. N. C. Received for publication Aug. 8, 1980. Accepted for publication Nov. 10, 1980. Address for reprints: W. Glenn Young, Jr., M.D .. Professor of Surgery, Box 2996, Duke University Medical Center, Durham, N. C. 27710.
830
reported on five patients who underwent thoracotomy for the management of pulmonary metastasis, and the indications for operation are discussed.
Patients and methods Since 1966, over 350 cases of gestational choriocarcinoma have been treated at the Southeastern Regional Trophoblastic Disease Center at Duke University Medical Center. Once the diagnosis of malignant trophoblastic disease was made, primary staging studies were done which included a general history and physical examination with pathology review, chest roentgenogram, liver and brain scans, electroencephalogram, ultrasound of the pelvis, hepatic and renal function tests, thyroid function evaluation, and initial quantitative gonadotropin assay (urine). Cytotoxic chemotherapy was initiated once the extent of disease had been assessed. Drugs included methotrexate, actinomycin D, chlorambucil, vinblastine S04 (Velban), and mercaptopurine in a variety of schedules which have been previously described.' Response to therapy was monitored by serial measurements of the beta subunit chain of human chorionic gonadotropin (HCG) in urine performed by radioimmunoassay. Treatment was continued until HCG titers had returned to a nondetectable level, and the diagnosis of remission was not made until three consecutive weekly normal HCG titers had been obtained. In most cases, an additional course of chemotherapy was administered after the first normal HCG titer in an attempt to reduce the risk of recurrence. HCG titers were monitored for detection of recurrent disease at 2 week intervals during the first 3 months
0022-5223/81/060830+05$00.50/0 © 1980 The C. V. Mosby Co.
Volume 81 Number 6
Gestational choriocarcinoma
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June, 1981
after termination of therapy, at I month intervals for the next 3 months, and at bimonthly intervals for the balance of I year. HCG titers were then followed at 6 month intervals. An elevation in HCG during the follow-up interval not explained by new pregnancy was considered an indication of recurrent disease, and the patient was re-evaluated for further treatment. Patients with demonstrable liver or brain metastases received whole brain or whole liver irradiation simultaneously with combination chemotherapy in an attempt to reduce the likelihood of hemorrhage in these lesions." Five patients during this period underwent thoracotomy for therapeutic purposes.
Case reports CASE I. A 24-year-old para 2-1-1 white woman underwent a hysterectomy for evaluation of a hydatidiform mole in September of 1972. Pulmonary metastasis was noted in December, 1972, and she was begun on weekly methotrexate therapy which was continued for approximately 18 months. By January of 1973, the chest x-ray film was reported as normal, and the patient's HCG titers confirmed that the disease was in remission. In November of 1975, however, irregular menstrual intervals and rectal pain developed. The woman was found to have a pelvic mass and a rapidly rising HCG titer, and she was referred to Duke University Medical Center. Upon admission to Duke, the patient had a normal chest x-ray film. In December, 1975, she underwent a total abdominal hysterectomy, a bilateral salpingo-oophorectomy, and excision of a large necrotic tumor mass involving the posterior cervix and extending down the rectovaginal septum to within 3 cm of the introitus. At operation, an 8 cm liver metastasis was noted. The patient received actinomycin-D and radiation therapy to the liver with a resulting decrease in the HCG titers. A chest roentgenogram in January of 1976 revealed bilateral pulmonary metastases which had not been discerned on earlier films (Fig. I). The patient's HCG titers also began to increase and chlorambucil and methotrexate were added to the chemotherapy regimen. Chemotherapy was continued for several months with resolution of the hepatic metastasis. Pulmonary metastases did not resolve, however, and in May 1976 the chemotherapy regimen was switched to a combination of vinblastine and actinomycin-D. By June, 1976, all of the patient's studies were completely normal except for the chest x-ray film, which showed a persistent lesion in the left upper lobe (Fig. 2). The patient then received radiation therapy to the pulmonary metastasis, but the lesion failed to resolve. A complete evaluation including arteriograms of the liver, kidneys, and pelvis demonstrated that the only site of residual disease was the left upper lobe nodule. The patient underwent a thoracotomy and partial lobectomy in December of 1976. Pathologic study confirmed metastatic choriocarcinoma. After operation, the HCG titers promptly fell to nondetectable levels (Fig. 3). The patient received three full courses of chemotherapy following the first normal HCG titer. The patient was discharged in February of 1976 in complete remission, and the HCG titers since discharge, with total follow-up of 4 years, have indicated no evidence of recurrence.
Fig. 1. Chest x-ray film taken in January, 1976, demonstrated bilateral pulmonary metastases (arrows). CA SE 2. A 27-year-old para 2-1-1 white woman was admitted to the Southeastern Regional Trophoblastic Disease Center at Duke University in February of 1975 with metastatic choriocarcinoma. The patient's history revealed that she had had a hydatidiform mole in 1971. She underwent an abdominal hysterectomy and several courses of multidrug chemotherapy. Remission was achieved, but on three separate occasions chemotherapy was again necessary owing to a rise in the HCG levels. The patient was readmitted to the hospital in September of 1977 with her fourth recurrence. Chest roentgenogram on admission revealed a nodule in the right middle lobe of the lung. Findings from an electrocardiogram, brain scan, liver scan, electroencephalogram, and intravenous pyelogram (IVP) were within normal limits. Chemotherapy was again initiated, and although the HCG levels declined they remained elevated. Chest tomography demonstrated that the pulmonary lesion had not regressed. In view of the patient's several episodes of recurrent disease, it was elected to remove the pulmonary metastatic lesion surgically, as the tumor was the patient's only known site of disease. On Oct. 24, 1977, the patient had a right thoracotomy and wedge resection of the right middle lobe mass. Pathologic examination confirmed choriocarcinoma of the lung. After the operation, the patient's HCG levels fell to nondetectable values. Prior to discharge, the patient received a 5 day course of actinomycin-D. Follow-up evaluations over the past 3 years have revealed normal HCG levels with no evidence of recurrent disease. CASE 3. In April of 1978, a 40-year-old para 3-0-3 white woman was admitted following a left thoracotomy in an outside hospital for a 10 cm lesion in the left upper lobe. The lesion had involved several ribs, which were resected with the tumor. Pathological diagnosis revealed choriocarcinoma. Of note is that the patient's last child was 15 years of age prior to admission. The patient did have irregular vaginal bleeding for
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The Journal of Thoracic and Cardiovascular Surgery
Fig. 2. Following several courses of chemotherapy, a single persistent nodule remained in the right upper lobe (arrows).
6 to 7 months prior to thoracotomy. On admission, a metastatic workup which included ultrasonographic studies of the pelvis, liver scan, IVP, and chest roentgenogram showed no abnormalities. HCG level at the time of admission was 33.8 mIUlml. During her hospitalization, the patient received four courses of methotrexate chemotherapy. HCG values fell to nondetectable levels and the patient was discharged in good condition. Follow-up reveals no evidence of recurrent disease. CASE 4. A 19-year-old white woman, para 1-1-0, had an incomplete abortion in January of 1973 and dilatation and curettage in October of 1973 for irregular bleeding. In Feburary of 1974 the patient had a total abdominal hysterectomy and bilateral salpingo-oophorectomy for choriocarcinoma. Multiple courses of chemotherapy were necessary on two separate occasions in 1974 for metastases, including multiple pulmonary lesions and metastases to the right side wall of the pelvis with obstruction of the right ureter. She was readmitted in 1975 because of hemoptysis. The HCG titer had risen from nondetectable levels to 32 mIU/ml by beta assay. On admission, the patient underwent staging studies including complete blood count, urinalysis, and hematologic and chemistry tests, all of which were normal. Chest x-ray film revealed a mass in the hilus of the left upper lobe. Liver and brain scans showed no abnormalities, results of the IVP were within normal limits. The patient was begun on combination triple drug chemotherapy including actinomycin-D, methotrexate, and chlorambucil. In addition to chemotherapy, the patient received radiation (2,000 rads) to the mediastinal area delivered in 10 treatment doses over a 2 week period. Despite several courses of multiple drug chemotherapy, the patient's
HCG titer remained in the 60 to 100 mIUlml range. Multiple selective arteriograms were carried out by a trans femoral approach, and none showed abnormalities. Lumbar puncture revealed an HCG level of less than 5 mIUlml in the cerebral spinal fluid. It was felt that the only site of disease was in the left hilar region; therefore, a thoracotomy was performed on June 16, 1975. At operation, a necrotic tumor mass was found contiguous to the aorta and superior vena cava. The lesion could not be completely excised, and examination of the partially resected specimen revealed metastatic choriocarcinoma. Following recovery from the operation, the patient received further triple drug chemotherapy and another course of whole lung irradiation (2,000 rads). Chemotherapy was complicated by leukopenia and thrombocytopenia necessitating multiple platelet transfusions. Toxicity to chemotherapeutic agents also was evidenced by transient oral ulceration, episodic nausea and vomiting, gastroenteritis, and episodes of fever accompanying leukopenia. Because of cumulative toxicity and severe depressive reaction, the patient chose to return home, and she died 3 months after discharge from the hospital. CASE 5. A 22-year-old black woman, para 1-1-0, had evacuation of a molar pegnancy in November, 1976. She became pregnant in 1977 and had a spontaneous vaginal delivery in January, 1978. She subsequently developed irregular bleeding. Dilatation and curettage revealed choriocarcinoma and she was referred to Duke University Medical Center. On admission, she had known disease in the pelvis, vagina, and metastatic disease to the lungs. She was started on multiagent chemotherapy. HCG titers remained elevated, however, and she underwent an abdominal hysterectomy, bilateral sal-
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Fig. 3. Following thoracotomy, HCG titers promptly fell to nondetectable levels. HCG. Human chorionic gonadotropin. pingo-oophorectomy , appendectomy, and resection of tumor nodules from the vagina and large bowel. Despite further chemotherapy, she continued to have elevated HCG titers. Arteriography revealed metastatic disease to the liver. Radiation therapy was initiated for the liver metastasis, but the pulmonary lesion continued to enlarge. Because of the rapidly enlarginglung lesion, increasing HCG titer, and the mistaken impression that the liver metastasis was under control, the right lower lobe was resected. The pathological diagnosis was choriocarcinoma. HCG titers remained elevated following pulmonary resection. One week following thoracotomy, she underwent emergency laparotomy for resection of an 8 cm nodulefrom the left lobe of the Iiver, which had ruptured. She had a protracted hospitalization, receiving multiple courses of chemotherapy. Her disease continued to progress, however, and she died in December, 1979.
Discussion Barney and Churchill" reported in 1939 the first series of patients with pulmonary resection for a solitary metastasis. The literature now contains many reports of successful resection of pulmonary metastatic nodules, with the longest survival reported to date being 30 years following the resection of a metastatic lung lesion. 7 Tumey and Haight 7 have summarized the experience of several centers reporting series of patients undergoing pulmonary resection for cure of metastatic neoplasms. The overall 5 year survival rate was 32.5% for 325 patients with a range of 22% to 47%. Although a direct relationship was demonstrated between long-term survival and the interval between treatment of primary neoplasm and the clinical appearance of pulmonary metastases, 30% of 5 year survivors
demonstrated pulmonary metastasis within 12 months of therapy for the primary neoplasm. These authors, therefore, state that operation should not be denied to an individual otherwise eligible for thoracotomy because of an early appearance of metastasis. Pulmonary metastases of choriocarcinoma may be miliary or embolic; however, it is the most common manifestation of metastatic disease, the discrete nodule, which lends itself to surgical excision." In most cases, pulmonary lesions rapidly resolve radiographically when subjected to cytotoxic drugs; often, they disappear before normal HCG titers are obtained. Tumor masses larger than 7 em in diameter have been reported to show only a moderate reduction in size when endocrine evidence indicates that all viable tumor has been eradicated. The assumption that any remaining lesion does not contain viable tumor is based on the long-term maintenance of normal HCG levels." Chemotherapy remains the first line treatment of pulmonary metastases of choriocarcinoma. Factors required to determine the response of metastatic lesions to cytotoxic agents include initial tumor size and the time interval between the incriminating pregnancy and diagnosis. Choriocarcinomas have no stroma and, therefore, get their blood supply from peripheral vessels. Edwards, Makey, and Bagshawe? have suggested that the central necrosis which often occurs may prevent effective concentrations of drugs from gaining access to larger lesions. The patients reported in this paper had metastatic lesions and elevated HCG titers which were resistant to
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multiple courses of combination chemotherapy. Prior to thoracotomy, it is important to ascertain as precisely as possible that no other areas of gross disease exist. Indicated studies include liver and brain scans, pulmonary tomograms, and arteriograms of the liver, kidneys, and pelvis. Newer studies have suggested that computerized axial tomography may be a more sensitive scanning technique for the detection of metastases of gestational choriocarcinoma, particularly to liver and brain. All the patients with totally resectable solitary pulmonary metastases reported in this series obtained complete remission following resection of their pulmonary lesions. One patient who died following operation had a nonresectable lesion, and the other had widespread metastases. Although long-term follow-up is not yet available, HCG titers are nondetectable and complete cure is believed to have been achieved. Edwards, Makey, and Bagshawe" have reported on six patients who had resection for pulmonary metastatic choriocarcinoma resistant to chemotherapy. Three patients were in complete remission 13, 7, and 2 years following thoracotomy. As in our series, one patient with a nonresectable tumor died of metastatic disease. Two other patients developed recurrent disease and died after refusing further therapy. Choriocarcinoma differs from other malignant tumors in that it is highly sensitive to cytotoxic agents, and the biological activity of the tumor can be precisely determined by monitoring HCG excretion. Excellent results can be expected from total surgical excision of pulmonary metastases if no other areas of gross disease exist. Successful surgical excision of all residual tumor should result in HCG levels returning to normal within 10 days after operation. However, we would recommend that all patients receive at least one course of chemotherapy following surgical excision of a metastatic pulmonary nodule in an attempt to eliminate possibly undetected metastatic foci or to reduce the Iikeli-
Thoracic and Cardiovascular Surgery
hood of hematogenous dissemination occurring from the surgical manipulation itself. In addition, all patients should be followed indefinitely with a beta subunit chain HCG radioimmunoassay. Chemotherapy is the treatment of choice for pulmonary metastatic lesions of choriocarcinoma, with remission rates in excess of 85% expected for isolated pulmonary nodules. Thoracotomy is indicated, however, when such lesions fail to respond to multiple courses of combination chemotherapy and no other areas of gross disease are demonstrable. Excellent results can be expected following total resection of these lesions. REFERENCES
2
3 4
5
6
7
8
9
Hammond CB, Schmidt HT, Parker RT: Gestational Trophoblastic Neoplasia, Gynecologic Oncology, L McGowan, ed., New York, 1977, Appleton-Century-Crofts Li MC, Hertz R. Spencer DB: Effect of methotrexate therapy upon choriocarcinoma and chorioadenoma. Proc Soc Exp Bioi Med 93:361-366, 1956 Tow WSH. Cheng WC: Recent trends in treatment of choriocarcinoma. Br Med J 4:521-523. 1967 Maier HC, Taylor HC Jr: Metastatic chorioepithelioma of the lung treated by lobectomy. Am J Obstet Gynecol 53:674-677, 1947 Hammond CB, Weed JC Jr, Currie JL: The role of operation in the current therapy of gestational trophoblastic disease. Am J Obstet Gynecol 136:844-858, 1980 Barney JD, Churchill ED: Adenocarcinoma of the kidney with metastasis to the lung cured by nephrectomy and lobectomy. J Urol 42:269-276, 1939 Turney SZ, Haight C: Pulmonary resection for metastatic neoplasms. J THoRAc CARDIOVASC SURG 61:784-794, 1971 Bagshawe KD, Garnett ES: Radiological changes in the lungs of patients with trophoblastic tumours. Br J Radiol 36: 673-679, 1963 Edwards JL. Makey AR, Bagshawe KD: The role of thoracotomy in the management of the pulmonary metastases of gestational choriocarcinoma. Clin Oncoll:329-339, 1975
THoRAc CARDIOVASC SURG
81:830-834, 1981
Pulmonary resection in the management of metastases from gestational choriocarcinoma Case histories offive patients with pulmonary metastases from choriocarcinoma resistant to multidrug chemotherapy are presented. Thoracotomy was performed in all cases. All tumor was removed in three patients with no other site of active disease, and these patients are surviving with no evidence of recurrent disease. In one patient, the lesion could not be completely excised because of involvement of contiguous structures, and she died of progressive disease. A second patient, with liver metastases at the time ()f' thoracotomy, also died of progressive disease. The indications for performing thoracotomy in the management of pulmonary metastases of choriocarcinoma are discussed.
James D. Sink, M.D., Charles B. Hammond, M.D., and W. Glenn Young, Jr., M.D., Durham, N. C.
Gestational trophoblastic neoplasms (choriocarcinoma and related tumors) are malignant tumors arising from the trophoblast of human pregnancy. Prior to the advent of chemotherapy, the mortality rate was 60% for patients with nonmetastatic tumors and 98% for those with metastatic disease.'; however, Li, Hertz, and Spencer" at the National Institutes of Health reported in 1956 a patient with metastatic choriocarcinoma treated with methotrexate who had a sustained and complete remission. This report began an era of drug treatment which has resulted in progressive improvement in the salvage of patients with choriocarcinoma. At the present time, remission rates in excess of 90% can be expected when the disease is diagnosed early and treated vigorously. Even in the presence of brain or liver metastases, chemotherapy can result in remission rates in excess of 75%.1 Pulmonary metastases occur in approximately 70% of patients with choriocarcinoma." Although the successful surgical treatment of a solitary lung metastasis of choriocarcinoma was reported in 1947, 4 cytotoxic chemotherapy is presently the first line treatment of pulmonary metastasis. Thoracotomy is still indicated, however, in certain situations. In this paper, data are From the Departments of Surgery and Obstetrics and Gynecology, Duke University Medical Center, Durham. N. C. Received for publication Aug. 8, 1980. Accepted for publication Nov. 10, 1980. Address for reprints: W. Glenn Young, Jr., M.D .. Professor of Surgery, Box 2996, Duke University Medical Center, Durham, N. C. 27710.
830
reported on five patients who underwent thoracotomy for the management of pulmonary metastasis, and the indications for operation are discussed.
Patients and methods Since 1966, over 350 cases of gestational choriocarcinoma have been treated at the Southeastern Regional Trophoblastic Disease Center at Duke University Medical Center. Once the diagnosis of malignant trophoblastic disease was made, primary staging studies were done which included a general history and physical examination with pathology review, chest roentgenogram, liver and brain scans, electroencephalogram, ultrasound of the pelvis, hepatic and renal function tests, thyroid function evaluation, and initial quantitative gonadotropin assay (urine). Cytotoxic chemotherapy was initiated once the extent of disease had been assessed. Drugs included methotrexate, actinomycin D, chlorambucil, vinblastine S04 (Velban), and mercaptopurine in a variety of schedules which have been previously described.' Response to therapy was monitored by serial measurements of the beta subunit chain of human chorionic gonadotropin (HCG) in urine performed by radioimmunoassay. Treatment was continued until HCG titers had returned to a nondetectable level, and the diagnosis of remission was not made until three consecutive weekly normal HCG titers had been obtained. In most cases, an additional course of chemotherapy was administered after the first normal HCG titer in an attempt to reduce the risk of recurrence. HCG titers were monitored for detection of recurrent disease at 2 week intervals during the first 3 months
0022-5223/81/060830+05$00.50/0 © 1980 The C. V. Mosby Co.
Volume 81 Number 6
Gestational choriocarcinoma
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June, 1981
after termination of therapy, at I month intervals for the next 3 months, and at bimonthly intervals for the balance of I year. HCG titers were then followed at 6 month intervals. An elevation in HCG during the follow-up interval not explained by new pregnancy was considered an indication of recurrent disease, and the patient was re-evaluated for further treatment. Patients with demonstrable liver or brain metastases received whole brain or whole liver irradiation simultaneously with combination chemotherapy in an attempt to reduce the likelihood of hemorrhage in these lesions." Five patients during this period underwent thoracotomy for therapeutic purposes.
Case reports CASE I. A 24-year-old para 2-1-1 white woman underwent a hysterectomy for evaluation of a hydatidiform mole in September of 1972. Pulmonary metastasis was noted in December, 1972, and she was begun on weekly methotrexate therapy which was continued for approximately 18 months. By January of 1973, the chest x-ray film was reported as normal, and the patient's HCG titers confirmed that the disease was in remission. In November of 1975, however, irregular menstrual intervals and rectal pain developed. The woman was found to have a pelvic mass and a rapidly rising HCG titer, and she was referred to Duke University Medical Center. Upon admission to Duke, the patient had a normal chest x-ray film. In December, 1975, she underwent a total abdominal hysterectomy, a bilateral salpingo-oophorectomy, and excision of a large necrotic tumor mass involving the posterior cervix and extending down the rectovaginal septum to within 3 cm of the introitus. At operation, an 8 cm liver metastasis was noted. The patient received actinomycin-D and radiation therapy to the liver with a resulting decrease in the HCG titers. A chest roentgenogram in January of 1976 revealed bilateral pulmonary metastases which had not been discerned on earlier films (Fig. I). The patient's HCG titers also began to increase and chlorambucil and methotrexate were added to the chemotherapy regimen. Chemotherapy was continued for several months with resolution of the hepatic metastasis. Pulmonary metastases did not resolve, however, and in May 1976 the chemotherapy regimen was switched to a combination of vinblastine and actinomycin-D. By June, 1976, all of the patient's studies were completely normal except for the chest x-ray film, which showed a persistent lesion in the left upper lobe (Fig. 2). The patient then received radiation therapy to the pulmonary metastasis, but the lesion failed to resolve. A complete evaluation including arteriograms of the liver, kidneys, and pelvis demonstrated that the only site of residual disease was the left upper lobe nodule. The patient underwent a thoracotomy and partial lobectomy in December of 1976. Pathologic study confirmed metastatic choriocarcinoma. After operation, the HCG titers promptly fell to nondetectable levels (Fig. 3). The patient received three full courses of chemotherapy following the first normal HCG titer. The patient was discharged in February of 1976 in complete remission, and the HCG titers since discharge, with total follow-up of 4 years, have indicated no evidence of recurrence.
Fig. 1. Chest x-ray film taken in January, 1976, demonstrated bilateral pulmonary metastases (arrows). CA SE 2. A 27-year-old para 2-1-1 white woman was admitted to the Southeastern Regional Trophoblastic Disease Center at Duke University in February of 1975 with metastatic choriocarcinoma. The patient's history revealed that she had had a hydatidiform mole in 1971. She underwent an abdominal hysterectomy and several courses of multidrug chemotherapy. Remission was achieved, but on three separate occasions chemotherapy was again necessary owing to a rise in the HCG levels. The patient was readmitted to the hospital in September of 1977 with her fourth recurrence. Chest roentgenogram on admission revealed a nodule in the right middle lobe of the lung. Findings from an electrocardiogram, brain scan, liver scan, electroencephalogram, and intravenous pyelogram (IVP) were within normal limits. Chemotherapy was again initiated, and although the HCG levels declined they remained elevated. Chest tomography demonstrated that the pulmonary lesion had not regressed. In view of the patient's several episodes of recurrent disease, it was elected to remove the pulmonary metastatic lesion surgically, as the tumor was the patient's only known site of disease. On Oct. 24, 1977, the patient had a right thoracotomy and wedge resection of the right middle lobe mass. Pathologic examination confirmed choriocarcinoma of the lung. After the operation, the patient's HCG levels fell to nondetectable values. Prior to discharge, the patient received a 5 day course of actinomycin-D. Follow-up evaluations over the past 3 years have revealed normal HCG levels with no evidence of recurrent disease. CASE 3. In April of 1978, a 40-year-old para 3-0-3 white woman was admitted following a left thoracotomy in an outside hospital for a 10 cm lesion in the left upper lobe. The lesion had involved several ribs, which were resected with the tumor. Pathological diagnosis revealed choriocarcinoma. Of note is that the patient's last child was 15 years of age prior to admission. The patient did have irregular vaginal bleeding for
832
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The Journal of Thoracic and Cardiovascular Surgery
Fig. 2. Following several courses of chemotherapy, a single persistent nodule remained in the right upper lobe (arrows).
6 to 7 months prior to thoracotomy. On admission, a metastatic workup which included ultrasonographic studies of the pelvis, liver scan, IVP, and chest roentgenogram showed no abnormalities. HCG level at the time of admission was 33.8 mIUlml. During her hospitalization, the patient received four courses of methotrexate chemotherapy. HCG values fell to nondetectable levels and the patient was discharged in good condition. Follow-up reveals no evidence of recurrent disease. CASE 4. A 19-year-old white woman, para 1-1-0, had an incomplete abortion in January of 1973 and dilatation and curettage in October of 1973 for irregular bleeding. In Feburary of 1974 the patient had a total abdominal hysterectomy and bilateral salpingo-oophorectomy for choriocarcinoma. Multiple courses of chemotherapy were necessary on two separate occasions in 1974 for metastases, including multiple pulmonary lesions and metastases to the right side wall of the pelvis with obstruction of the right ureter. She was readmitted in 1975 because of hemoptysis. The HCG titer had risen from nondetectable levels to 32 mIU/ml by beta assay. On admission, the patient underwent staging studies including complete blood count, urinalysis, and hematologic and chemistry tests, all of which were normal. Chest x-ray film revealed a mass in the hilus of the left upper lobe. Liver and brain scans showed no abnormalities, results of the IVP were within normal limits. The patient was begun on combination triple drug chemotherapy including actinomycin-D, methotrexate, and chlorambucil. In addition to chemotherapy, the patient received radiation (2,000 rads) to the mediastinal area delivered in 10 treatment doses over a 2 week period. Despite several courses of multiple drug chemotherapy, the patient's
HCG titer remained in the 60 to 100 mIUlml range. Multiple selective arteriograms were carried out by a trans femoral approach, and none showed abnormalities. Lumbar puncture revealed an HCG level of less than 5 mIUlml in the cerebral spinal fluid. It was felt that the only site of disease was in the left hilar region; therefore, a thoracotomy was performed on June 16, 1975. At operation, a necrotic tumor mass was found contiguous to the aorta and superior vena cava. The lesion could not be completely excised, and examination of the partially resected specimen revealed metastatic choriocarcinoma. Following recovery from the operation, the patient received further triple drug chemotherapy and another course of whole lung irradiation (2,000 rads). Chemotherapy was complicated by leukopenia and thrombocytopenia necessitating multiple platelet transfusions. Toxicity to chemotherapeutic agents also was evidenced by transient oral ulceration, episodic nausea and vomiting, gastroenteritis, and episodes of fever accompanying leukopenia. Because of cumulative toxicity and severe depressive reaction, the patient chose to return home, and she died 3 months after discharge from the hospital. CASE 5. A 22-year-old black woman, para 1-1-0, had evacuation of a molar pegnancy in November, 1976. She became pregnant in 1977 and had a spontaneous vaginal delivery in January, 1978. She subsequently developed irregular bleeding. Dilatation and curettage revealed choriocarcinoma and she was referred to Duke University Medical Center. On admission, she had known disease in the pelvis, vagina, and metastatic disease to the lungs. She was started on multiagent chemotherapy. HCG titers remained elevated, however, and she underwent an abdominal hysterectomy, bilateral sal-
Volume 81
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Number 6 June, 1981
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Fig. 3. Following thoracotomy, HCG titers promptly fell to nondetectable levels. HCG. Human chorionic gonadotropin. pingo-oophorectomy , appendectomy, and resection of tumor nodules from the vagina and large bowel. Despite further chemotherapy, she continued to have elevated HCG titers. Arteriography revealed metastatic disease to the liver. Radiation therapy was initiated for the liver metastasis, but the pulmonary lesion continued to enlarge. Because of the rapidly enlarginglung lesion, increasing HCG titer, and the mistaken impression that the liver metastasis was under control, the right lower lobe was resected. The pathological diagnosis was choriocarcinoma. HCG titers remained elevated following pulmonary resection. One week following thoracotomy, she underwent emergency laparotomy for resection of an 8 cm nodulefrom the left lobe of the Iiver, which had ruptured. She had a protracted hospitalization, receiving multiple courses of chemotherapy. Her disease continued to progress, however, and she died in December, 1979.
Discussion Barney and Churchill" reported in 1939 the first series of patients with pulmonary resection for a solitary metastasis. The literature now contains many reports of successful resection of pulmonary metastatic nodules, with the longest survival reported to date being 30 years following the resection of a metastatic lung lesion. 7 Tumey and Haight 7 have summarized the experience of several centers reporting series of patients undergoing pulmonary resection for cure of metastatic neoplasms. The overall 5 year survival rate was 32.5% for 325 patients with a range of 22% to 47%. Although a direct relationship was demonstrated between long-term survival and the interval between treatment of primary neoplasm and the clinical appearance of pulmonary metastases, 30% of 5 year survivors
demonstrated pulmonary metastasis within 12 months of therapy for the primary neoplasm. These authors, therefore, state that operation should not be denied to an individual otherwise eligible for thoracotomy because of an early appearance of metastasis. Pulmonary metastases of choriocarcinoma may be miliary or embolic; however, it is the most common manifestation of metastatic disease, the discrete nodule, which lends itself to surgical excision." In most cases, pulmonary lesions rapidly resolve radiographically when subjected to cytotoxic drugs; often, they disappear before normal HCG titers are obtained. Tumor masses larger than 7 em in diameter have been reported to show only a moderate reduction in size when endocrine evidence indicates that all viable tumor has been eradicated. The assumption that any remaining lesion does not contain viable tumor is based on the long-term maintenance of normal HCG levels." Chemotherapy remains the first line treatment of pulmonary metastases of choriocarcinoma. Factors required to determine the response of metastatic lesions to cytotoxic agents include initial tumor size and the time interval between the incriminating pregnancy and diagnosis. Choriocarcinomas have no stroma and, therefore, get their blood supply from peripheral vessels. Edwards, Makey, and Bagshawe? have suggested that the central necrosis which often occurs may prevent effective concentrations of drugs from gaining access to larger lesions. The patients reported in this paper had metastatic lesions and elevated HCG titers which were resistant to
The Journal of
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multiple courses of combination chemotherapy. Prior to thoracotomy, it is important to ascertain as precisely as possible that no other areas of gross disease exist. Indicated studies include liver and brain scans, pulmonary tomograms, and arteriograms of the liver, kidneys, and pelvis. Newer studies have suggested that computerized axial tomography may be a more sensitive scanning technique for the detection of metastases of gestational choriocarcinoma, particularly to liver and brain. All the patients with totally resectable solitary pulmonary metastases reported in this series obtained complete remission following resection of their pulmonary lesions. One patient who died following operation had a nonresectable lesion, and the other had widespread metastases. Although long-term follow-up is not yet available, HCG titers are nondetectable and complete cure is believed to have been achieved. Edwards, Makey, and Bagshawe" have reported on six patients who had resection for pulmonary metastatic choriocarcinoma resistant to chemotherapy. Three patients were in complete remission 13, 7, and 2 years following thoracotomy. As in our series, one patient with a nonresectable tumor died of metastatic disease. Two other patients developed recurrent disease and died after refusing further therapy. Choriocarcinoma differs from other malignant tumors in that it is highly sensitive to cytotoxic agents, and the biological activity of the tumor can be precisely determined by monitoring HCG excretion. Excellent results can be expected from total surgical excision of pulmonary metastases if no other areas of gross disease exist. Successful surgical excision of all residual tumor should result in HCG levels returning to normal within 10 days after operation. However, we would recommend that all patients receive at least one course of chemotherapy following surgical excision of a metastatic pulmonary nodule in an attempt to eliminate possibly undetected metastatic foci or to reduce the Iikeli-
Thoracic and Cardiovascular Surgery
hood of hematogenous dissemination occurring from the surgical manipulation itself. In addition, all patients should be followed indefinitely with a beta subunit chain HCG radioimmunoassay. Chemotherapy is the treatment of choice for pulmonary metastatic lesions of choriocarcinoma, with remission rates in excess of 85% expected for isolated pulmonary nodules. Thoracotomy is indicated, however, when such lesions fail to respond to multiple courses of combination chemotherapy and no other areas of gross disease are demonstrable. Excellent results can be expected following total resection of these lesions. REFERENCES
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Hammond CB, Schmidt HT, Parker RT: Gestational Trophoblastic Neoplasia, Gynecologic Oncology, L McGowan, ed., New York, 1977, Appleton-Century-Crofts Li MC, Hertz R. Spencer DB: Effect of methotrexate therapy upon choriocarcinoma and chorioadenoma. Proc Soc Exp Bioi Med 93:361-366, 1956 Tow WSH. Cheng WC: Recent trends in treatment of choriocarcinoma. Br Med J 4:521-523. 1967 Maier HC, Taylor HC Jr: Metastatic chorioepithelioma of the lung treated by lobectomy. Am J Obstet Gynecol 53:674-677, 1947 Hammond CB, Weed JC Jr, Currie JL: The role of operation in the current therapy of gestational trophoblastic disease. Am J Obstet Gynecol 136:844-858, 1980 Barney JD, Churchill ED: Adenocarcinoma of the kidney with metastasis to the lung cured by nephrectomy and lobectomy. J Urol 42:269-276, 1939 Turney SZ, Haight C: Pulmonary resection for metastatic neoplasms. J THoRAc CARDIOVASC SURG 61:784-794, 1971 Bagshawe KD, Garnett ES: Radiological changes in the lungs of patients with trophoblastic tumours. Br J Radiol 36: 673-679, 1963 Edwards JL. Makey AR, Bagshawe KD: The role of thoracotomy in the management of the pulmonary metastases of gestational choriocarcinoma. Clin Oncoll:329-339, 1975