Aggressive Slurgical Management of Testicular Carcinoma Metastatic to Lungs and Mediastinurn

Aggressive Slurgical Management of Testicular Carcinoma Metastatic to Lungs and Mediastinurn Isadore Mandelbaum, M.D., Stephen D. Williams, M.D., and Lawrence H. Einhorn, M.D. ABSTRACT During the past six years, more than 200 patients were treated with chemotherapy for disseminated testicular cancer with a 70% complete remission rate. In 22 patients who were 17 to 46 years old, there was persistent thoracic disease, which was treated surgically. Six required a median stemotomy for bilateral pulmonary involvement or mediastinal metastasis. In 8 patients, chemotherapy had altered the histological appearance of the metastases from that of an undifferentiated primary tumor to a mature cystic teratoma. Five patients had nodules in the lungs, which were necrotic and fibrosed with no evidence of tumor. Nine showed embryonal cell carcinoma metastases in the lungs. All who had cystic teratoma are alive and free from disease. Three of the 5 with nodules and 1 of the 9 with metastases are currently free from disease. Aggressive surgical intervention is important in this unique group of patients in order to determine the precise pathological category of the lesions, to remove intrathoracic malignancy, and to assess the need for additional chemotherapy. An operative mortality of zero and a low morbidity justify this approach. Surgical management of metastatic pulmonary lesions from various primary sites have been reported previously and favorable prognostic factors defined [7, 81. With improved chemotherapy and close cooperation between oncologist and thoracic surgeon, it has been possible to apply these principles and to formulate new ones in the treatment of metastatic tes- From the Departments of Surgery, Division of Cardiothoracic Surgery, and Hematology-Oncology, Indiana University School of Medicine, Indianapolis, IN. Supported in part by a grant from the Indiana Chapter, American Lung Association. Presented at the Sixteenth Annual Meeting of The Society of Thoracic Surgeons, Jan 21-23, 1980, Atlanta, GA. Address reprint requests to Dr. Mandelbaum, Department of Surgery, Indiana University Medical Center, 1100 W Michigan St, Indianapolis, IN 46223. ticular carcinoma of germ cell origin to the chest [I]. Testicular carcinoma is a disease of young men, and more than 200 patients with this type of disseminated cancer were treated at Indiana University Medical Center from 1974 through 1979. Twenty-one with metastases to the chest and I with metastasis to the supraclavicular area were selected for surgical treatment and constitute a unique and interesting subgroup. The purpose of this paper is to present the results of combined thoracic surgical and chemotherapy treatment in these patients. Those with primary mediastinal carcinoma of germ cell origin are not included in this series. Material and Methods Since April, 1975,22 patients with metastases to the chest or supraclavicular area from testicular carcinoma of germ cell origin were treated surgically. They ranged from 17 to 46 years old (mean, 26 years; median, 23 years). The primary tumor had arisen in the testis in 21 patients and as a primary retroperitoneal germ cell tumor in 1. Most patients had no pulmonary symptoms, but were seen with roentgenographic evidence of thoracic metastases. One patient had chest wall pain due to an extrapleural lesion with rib involvement, and 1 had hemoptysis due to pulmonary metastases. The histological picture of the primary tumor was usually mixed and consisted of embryonal, teratocarcinomatous, and choriocarcinomatous elements. When initially seen, all patients had advanced disease and were classified in Stage 111. All patients had had a radical orchiectomy, and 13 had had a previous retroperitoneal lymph node dissection before they were seen for chemotherapy. Patients were evaluated by physical examination, posteroanterior and lateral chest roentgenograms, whole-lung tomograms, abdominal ultrasound and abdominal computerized axial 224 0003-4975/80/090224-06$01.25 @ 1980 by The Society of Thoracic Surgeons

225 Mandelbaum, Williams, and Einhorn: Testicular Carcinoma Metastatic to Lungs and Mediastinum tomograms (CAT scans), and determinations of serum beta subunit human chorionic gonadotropin (HCG) and a-fetoprotein levels. Selected patients had thoracic CAT scans. All patients had received intensive courses of platinum, vinblastine, and bleomycin therapy following excision of the primary germ cell carcinoma. The exact chemotherapy schedule was detailed in a previous paper [la]. Specific indications for thoracic procedures were limited to patients with (1) thoracic lesions and no other anatomical evidence of tumor, (2) thoracic lesions persisting after a full course of chemotherapy, (3) a solitary pulmonary lesion that had recurred after an initial chemotherapyinduced complete remission, and (4) good general health without any other systemic disease. The operation was performed one month or longer after the last chemotherapy treatment to allow full recovery from the toxicity of the chemotherapeutic agents. Results Since 1975,21 patients with thoracic lesions and 1 with a supraclavicular lesion have been treated surgically. Five with bilateral lesions and a single patient with a solitary mediastinal lesion had a median sternotomy incision. Thirteen patients with a solitary lesion and 3 with multiple lesions limited to one lung were approached by a posterolateral thoracotomy or by excision of a supraclavicular mass (1 patient). The primary aim was to preserve as much normal pulmonary tissue as possible, and, therefore, most patients had wedge resection for each pulmonary lesion. As many as thirty lesions were removed in a single patient. In 3 patients, a lobectomy was carried out because of the central location of the lesion. In 1, pneumonectomy was performed because of hilar involvement. There was no operative mortality and minimal morbidity. Fourteen patients had solitary lesions. Five were in the right lung, one in the right lung with extension into the extrapleural space and ribs, six in the left lung, one in the mediastinum, and one in the left supraclavicular area. Of these 14 patients, 6 had mature teratoma, 6 had embryonal carcinoma, and 2 had a necrotic, fibrotic area without evidence of tumor. Fig I. Solitary mass in the right lower lobe proved to be a mature teratoma. Eight patients had multiple lesions. Three had involvement of one lung and 5 had bilateral involvement. The lesions consisted of embryonal carcinoma in 1 patient, three mature teratomas in 1, necrotic and fibrotic areas in 3 patients, a mature teratoma and an embryonal carcinoma in 1 patient, a mature teratoma and separate necrotic fibrotic tissue in 1, and embryonal carcinoma with separate fibrotic tissue in 1. There was excellent correlation among CAT scans, whole-lung tomograms, and operative and histological findings. In only 1 patient was a lesion visualized with chest CAT scan not apparent on whole-lung tomography. In another patient, one lesion in the right lower lobe was diagnosed preoperatively, but an additional one each in the right lower and right middle lobes was found at operation. No preoperative roentgenographic study predicted accurately the type of histological lesion that was excised-teratoma, embryonal carcinoma, or fibrotic masses (Figs 1-3). Four patients underwent thoracic resection within six months of resection of the primary testicular cancer. Three were operated on from between seven and twelve months; 8 from thirteen to twenty-four months, 6 from twenty-five to thirty-six months, and 1 was operated on eight years following testicular re-

226 The Annals of Thoracic Surgery Vol 30 No 3 September 1980 8 6 Fig 2. The solitary mass in the right upper lobe consisted of a discrete area of fibrosis and necrosis without any evidence of tumor. VI I- z Y I- 2 u 4 I K w L 6 12 18 24 30 36 96 M O N T H S Fig 4. Fifteen patients (68%) were operated on for thoracic lesions within two years of resection of the primary testicular cancer. Fig 3. Solitary lesion in the right lower lobe proved to be metastatic embryonal carcinoma. section. Of 8 patients with mature teratoma, 1 had thoracic resection three months after radical orchiectomy, 5 were resected thirteen to twenty-four months after removal of the primary lesion, and 2 from twenty-five to thirtysix months later (Fig 4). At the present time, 12 patients are alive with no evidence of tumor from four months to two years following thoracic resection. Eight had had benign teratomas, 3 had had areas of fibrosis, and 1 had had a solitary embryonal carcinoma. Seven of 9 patients with embryonal carcinoma died. One is free from disease, and 1 had a cerebral metastasis, which was resected recently. Two of 5 patients who had areas of fibrosis without evidence of tumor died of cerebral metastases. The HCG and a-fetoprotein serum levels were elevated prior to thoracic resection in 7 patients and were normal in 15. Four with elevated levels were discovered to have embryonal carcinoma, and 3 had discrete areas of fibrosis without evidence of tumor. However, in the latter 3 patients, embryonal carcinoma developed subsequently in the central nervous system in 2 and in the retroperitoneum in 1. Therefore, elevated HCG and a-fetoprotein serum levels correlated well with the finding of viabie carcinoma in the chest or with the occult presence of embryonal carcinoma in other anatomical sites. The HCG and a-fetoprotein levels were normal in all patients with teratoma who had no other evidence of malignancy, in 2 patients with fibrotic areas, and in 5 with embryonal carcinoma of the chest. While abnormal preoperative serum levels of HCG and a-

227 Mandelbaum, Williams, and Einhorn: Testicular Carcinoma Metastatic to Lungs and Mediastinum fetoprotein correlated well with the presence of cancer, normal levels did not rule it out [5]. Comment Many patients with thoracic metastases due to testicular cancer of germ cell origin have been treated effectively with chemotherapy without needing any operative intervention [la, 61. Our 22 patients were selected critically from more than 200 patients. After intensive chemotherapy, the criteria for thoracic surgery have been disease limited to the thorax or recurrence of disease, and no other major systemic disability. The time interval between resection of the primary carcinoma and resection of pulmonary metastases as well as the number of metastatic nodules plays an important role in the prognosis of patients who have had carcinoma of the colon or uterus [7,81, for example. These factors may not be as important in patients with thoracic metastases due to germ cell testicular cancer because of the results achieved with chemotherapy in these patients. Resection of multiple lesions in 8 patients resulted in 3 being alive free from disease for as long as twenty-one months, 2 are alive with disease, and 3 have died. Furthermore, thoracic resection was performed with excellent results in about 70% of our patients earlier than two years after removal of the primary testicular cancer. Of greater prognostic importance in this series is the type of histological lesion found at the time of thoracic resection. If the lesion has been altered by chemotherapy so that a mature teratoma is present without any other malignant lesion [9], the patient has not died in this series. The finding of metastatic embryonal carcinoma in the chest, on the other hand, has been associated with death in 7 patients and recurrent cancer in 1. Only 1 of the 9 patients in this group is currently free from disease. In those patients with primarily fibrotic lesions, 3 are alive and free from disease, and 2 have recurrent embryonal cancer in the central nervous system. Retroperitoneal cancer developed in another patient, who underwent an additional operation, and is currently free from disease. These last 3 patients all demonstrated elevated HCG and a-fetoprotein serum levels. It is evident from this unique group of pa- tients that chemotherapy plays an important role in either eradicating all evidence of metastatic disease or in altering the histological characteristics of a substantial number of lesions from those of a wildly malignant tumor to either a mature teratoma or to an area of fibrosis and necrosis without evidence of viable carcinoma. Since there is no precise preoperative diagnostic technique differentiating among these three histological types, thoracic resection is important in order to remove every lesion and to obtain an exact diagnosis. There has been considerable controversy concerning the finding of mature teratoma and the importance of this particular lesion [9]. Some regard it as a true malignant metastasis. Whether it is or not, since mature teratoma in other parts of the body has the potential to undergo malignant degeneration, we consider excision of this lesion mandatory. A late follow-up in our patients who have had mature teratoma resected without any evidence of malignancy indicates no other evidence of disease. Why all metastatic lesions from germ cell testicular cancer are not altered into mature teratoma remains an unanswered question. It is possible that some embryonal cancer metastases are resistant initially to chemotherapy or, more likely, that there is an initial response followed by cellular resistance. This latter explanation would seem to be more plausible in view of the fact that in most patients, as a result of chemotherapy, there is some regression of pulmonary metastases followed by recurrent embryonal cancer in some. There have been reports of oxygen toxicity in patients who are operated on for thoracic metastases due to testicular cancer of germ cell origin [21. Our patients were treated with the usual methods of respiratory support and with the usual concentrations of oxygen both during anesthesia and in the early postoperative period, without any evidence of pulmonary insufficiency. The reason for this discrepancy between our series and those reported in the literature remains speculative. Rarely, germ cell cancers may arise primarily in the mediastinum and should be differentiated from metastatic lesions of testicular origin [31. In our series, metastasis to the

228 The Annals of Thoracic Surgery Vol 30 No 3 September 1980 mediastinum secondary to a germ cell testicular cancer occurred in only 1 patient. Nevertheless, patients with mediastinal germ cell cancers must be screened carefully in order to rule out primary testicular carcinomas [41. The psychological aspects are of extreme importance in the care of these young men. All have had alopecia due to chemotherapy, and all have had previous operation-radical orchiectomy and additional retroperitoneal node dissection in most. Many are married and are concerned about unknown factors such as the nature of the histological thoracic lesion, the possible disability following thoracotomy, the prognosis, and other personal problems. A team approach has helped us to understand these problems in each individual patient and to psychologically support the patient and family during the trying preoperative and postoperative periods. At present, the cure rate for patients with disseminated testicular cancer is approaching 70%. The majority of patients with pulmonary metastasis do not require operation since they most frequently achieve complete remission with chemotherapy alone. It has been a source of personal gratification that in a disease that was almost universally fatal and is the most common cause of cancer in the young adult male, our combination of chemotherapy and surgical intervention in these selected patients has resulted in no operative mortality and minimal morbidity. Also, 12 of 22 patients (54%) currently are alive and disease-free. After completing this study, we arrived at the following conclusions: 1. In a series of 22 patients with thoracic metastases due to germ cell carcinoma of testicular origin, complete excision of the thoracic lesions was carried out utilizing either a median sternotomy incision or in unilateral lesions, a posterolateral thoracotomy. Limited resections are desirable. In 1 patient, a supraclavicular mass was excised. 2. Before surgical intervention is considered, these patients should receive an intensive course of chemotherapy. 3. In patients with persistent thoracic lesions or with recurrent lesions, three types of his- tological pictures are observed-mature teratoma, fibrosis and necrosis without evidlence of tumor, and embryonal cell carcinoma. 4. Preoperative roentgenographic diagnostic methods do not differentiate among these three histopathological forms. 5. In all patients with elevated serum HCG and at-fetoprotein levels, there was embryonal cell cancer in the chest or it subsequently developed in the abdomen or brain. The levels were normal in all patients with teratoma and in 5 patients with embryonal cancer of the chest. 6. In contradistinction to pulmonary metastases from nontesticular primaries, the presence of solitary or multiple lesions and the time interval between resection of the primary germ cell cancer of testicular origin and the pulmonary lesions have no bearing on the ultimate prognosis. 7. Aggressive surgical intervention is important in this unique group of patients in order to determine the precise pathological category of the lesions, to remove intrathoracic malignancy, and to assess the need for additional chemotherapy. 8. This approach is justified by three chief results: an operative mortality of zero, a low morbidity, and a cancer-free rate of 54%. Addendum Since submission of this paper, 10 additional patients have been operated on for testicular germ cell cancer metastatic to the chest. Five had a median sternotomy for bilateral lesions, and 2 had thoracotomy for unilateral ones. Three additional patients had a median sternotomy for bilateral disease performed at the same time of retroperitoneal dissection. Of these 10 patients, 3 had mature teratoma, 4 had areas of fibrosis and necrosis, and 3 had metastatic cancer. Postoperative morbidity was minimal, and again, no mortality was observed. References 1. Bains MS, McCormack PM, Cvitkovic E, et al: Results of combined chemosurgical therapy for pulmonary metastases from testicular carcinoma. Cancer 41350, 1978 la. EIinhorn LH, Donahue J: Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. Ann Int Med 87293, 1977

229 Mandelbaum, Williams, and Einhorn: Testicular Carcinoma Metastatic to Lungs and Mediastinum 2. Goldiner PL, Schweizer 0: The hazards of anesthesia and surgery in bleomycin-treated patients. Semin Oncol 6:121, 1979 3. Martini N, Golbey R, Hadju SI, et al: Primary mediastinal germ cell tumors. Cancer 33:763, 1974 4. Meares EM Jr, Briggs EM: Occult seminoma of the testis masquerading as primary extragonadal germinal neoplasms. Cancer 30:300, 1972 5. Schultz H, Sell A, et al: Serum AFP and HCG as markers for the effect of postoperative radiation therapy and/or chemotherapy in testicular cancer. Cancer 42:2182, 1978 6. Stoter G, Vendrik CPJ, et al: Combination chemotherapy with cis-diammine-dichloroplatinum, vinblastine, and bleomycin in advanced testicular non-seminoma. Lancet 1:941, 1979 7. Takita H, Merrin C, Didolkar MS, et al.: The surgical management of multiple lung metastases. Ann Thorac Surg 24:359, 1977 8. Thomford NR, Woolner LB, Clagett OT: The surgical treatment of metastatic tumors in the lungs. J Thorac Cardiovasc Surg 49:357, 1965 9. Willis GW, Hajdu SI: Histologically benign teratoid metastasis of testicular embryonal carcinoma. Am J Clin Pathol 59:338, 1973 Discussion DR. EDWARD J. BEATTIE, JR. (New York, NY): I had the privilege of reading Dr. Mandelbaum s paper and enjoyed it very much. This report on metastatic germ cell tumors, of which the embryonal cell carcinomas primarily are the bad actors, is the most exciting study of cancer in adults to be presented in the past ten years. Dr. Mandelbaum s paper is very timely indeed. Ten years ago I saw a patient who had embryonal cell carcinoma in the chest. He was dead in 6 months despite use of the best known therapy-three operations, internal radiotherapy, external radiotherapy, and chemotherapy. A Stage I11 embryonal cell carcinoma of the testicle with metastases to the abdomen, chest, and neck resulted in death before 12 months. So what you are hearing today is truly revolu tionary. I have shown survival curves supplied by Dr. Robert Golbey, Chief of Chemotherapy at Memorial Hospital, and obtained with our VAB Program. It,began with VAB I. We are now up to VAB VIII, which contains seven drugs. You will see that VAB I resulted in a cure rate at five years of up to 30%. We now expect to cure almost 80% of patients with Stage I11 embryonal cell carcinomas. That is really spectacular. The important thing stressed by Dr. Mandelbaum is that only 22, or lo%, of his patients had to have chest operation. This is because the chemotherapy was so good. He demonstrated very well that the lesions cannot be identified properly until they are looked at under the microscope. An important concept today is in vivo chemotherapy sensitivity testing. He demonstrated that when chemotherapy killed the cancers, the patients all survived unless there was cancer someplace other than in the chest. Patients with metastases in the lungs who are alive and well 24 months later have, in our experience, all been cured. So, the 24-month period is critical. One final point I think is important. In his paper, Dr. Mandelbaum mentioned respiratory failure following chest operation in patients who were on intensive chemotherapy. He had none in his series. However, there are some patients receiving intensive chemotherapy, particularly with high doses of bleomycin, who do go into respiratory failure following thoracotomy. The anesthetists at Memorial Hospital have demonstrated the cause to my satisfaction. They believe the cause is oxygen toxicity from the standard high-dose oxygen usually used during thoracotomy, especially if the patient is considered a bad risk. In our patients with lung cancer who have had chemotherapy, the oxygen concentration is kept to 24% or less during operation. No respiratory distress syndromes after operation have been seen in these patients. Dr. Mandelbaum stated he used usual oxygen. What is usual oxygen in Indiana? DR. MANDELBAUM: I thank Dr. Beattie very much for his kind comments. He, of course, has led the field in the treatment of metastatic disease to the chest. This unique group of patients was presented today because it represents an unusual type of response of malignancy to chemotherapy. Perhaps it illustrates what the future holds in terms of treatment of other metastatic disease and the possibility of combining operation with other therapeutic modalities. Dr. Beattie and his group have guided us all in this direction. As for oxygen toxicity, I have been aware of this in the literature and am alert to the possibility of it occurring. However, I have not encountered this problem in the present series. I don t know the precise explanation. Perhaps at our center we operate on patients who have not had as much chemotherapy as those reported in other groups with oxygen toxicity. At Indiana University Medical Center, the usual oxygen concentrations in patients during the operative and early postoperative periods range from an Fro, of 30 to 45%.