CURRENT REVIEW. Tumors

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1 CURRENT REVIEW Primary Malignant of the Mediastinum Tumors David M. Conkle, M.D., and R. Benton Adkins, Jr., M.D. ABSTRACT Forty-three patients with primary malignant tumors of the rnediastinum are reviewed. An attempt has been made to correlate cell type and method of treatment with prognosis. The most prevalent cell types were found to be: malignant thymoma, lymphosarcoma, and undifferentiated carcinoma. Case reports of selected interesting patients are included to emphasize specific problems of management. The prognosis was found to be most favorable in those patients with malignant thymoma and tumor of neurogenic origin. The treatment of choice remains total excision of the tumor followed by irradiation. The 5-year survival rate in this series is 8 patients out of 31. P rimary malignant tumors of the mediastinum are a relatively rare entity. Due to the multiple cell types encountered and the difficulty often experienced in surgical excision, the acceptable mode of treatment has often been debated. The experience with these tumors at Vanderbilt University Hospital has been reviewed. Careful patient follow-up has allowed a critical evaluation of the modes of treatment employed and the results obtained. Clinical Material Forty-three patients with the diagnosis of a primary malignant mediastinal tumor have been admitted to Vanderbilt University Hospital from 1925 through Patients with primary esophageal lesions and those without a tissue diagnosis were excluded. Patient age ranged from 3 months to 82 years. The average age was 60 years. Twenty-eight patients were male, and 15 were female; ten tumor cell types were encountered (Table 1). From the Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tenn. Supported in part by U.S. Public Health Service Grant no. GM Address reprint requests to Dr. Adkins, Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tenn VOL. 14, NO. 5, NOVEMBER,

2 ~ TABLE 1. TUMOR TYPE WITH AGE AND SEX DISTRIBUTION IN 43 PATIENTS WITH PRIMARY MALIGNANT MEDIASTINAL NEOPLASMS No. of Sex Age Group (yr.) Tumor Type Patients M F k Malignant thymoma Lymphoma Undifferentiated carcinoma Neuroblas toma Neurogenic sarcoma Malignant teratoma Rhabdomyosarcoma Sympathicoblastoma Lymphangioendo thelioma Malignant paraganglioma Total

3 CURRENT REVIEW: Malignant Tumors of Mediastinum All 43 patients have been followed in the outpatient department by the surgical attending and resident staff. Assistance in this area was provided by the hospital s Tumor Registry. Diagnosis Thirty-nine of the 43 patients presented with the following symptoms (Table 2): a nonproductive chronic cough, dyspnea on exertion, chest or shoulder pain, dysphagia, and hoarseness. Twenty-nine of the patients presented with positive physical findings as well (see Table 2). Diagnostic procedures performed included chest roentgenogram with tomograms, esophagogram, angiography, bronchoscopy, esophagoscopy, and mediastinoscopy. Tissue diagnosis was established by the Surgical Pathology Department from specimens obtained at operation or postmortem examination. Treatment Total excision was possible in 12 of the 43 patients; 4 of these patients received postoperative irradiation. The surgical approach, depending on tumor location, was either a thoracotomy or a median sternotomy (Table 3). Thirty-one patients had unresectable tumor; this was determined by TABLE 2. SYMPTOMS AND SIGNS IN 43 PATIENTS WITH PRIMARY MALIGNANT MEDIASTJNAL TUMORS Findings No. of Patients Symptoms Cough 28 Dyspnea 18 Pain 14 Hoarseness 7 D ysphagia 7 No symptoms 4 Signs Weight loss Mediastinal widening to percussion Fever Superior vena cava obstruction Tracheal deviation Cyanosis Digital clubbing Horner s syndrome No signs VOL. 14, NO. 5, NOVEMBER,

4 CONKLE AND ADKINS TABLE 3. MODES OF TREATMENT IN 43 PATIENTS WITH PRIMARY MALIGNANT MEDIASTINAL TUMORS Total Irradia- Excision Partial tion Adjuncwith Excision Following tive Total Irradia- or Tissue Chemo- Tumor Type Excision tion Biopsy Diagnosis therapy Malignant thymoma Lymphoma Undifferentiated carcinoma Neuroblas toma 3 Neurogenic sarcoma 1 2 Malignant teratoma Rhabdom yosarcoma 1 S ympathicoblastoma 1 Lymphangio- 1 1 endothelioma Malignant 1 paraganglioma Total surgical exploration in 23 patients. The remaining 8 patients had metastatic disease at the time of their initial examination, and diagnosis was established by biopsy or at postmortem examination. Twenty-one of these patients received radiation therapy: 8 patients received chemotherapy as an adjunct to irradiation (see Table 3). There were 2 operative deaths. Eight patients developed postoperative complications which prolonged morbidity (Table 4). Follow-Up All 43 patients have been followed (Table 5). Thirty-one patients were eligible for a 5-year evaluation: 8 of the 31 patients are alive. Seven of these 8 patients had tumor excision for cure; their tumor types are listed in Table 5. At the present time, 6 of these 7 patients are free of tumor. The seventh patient had mediastinal recurrence of a malignant thymoma removed in 1969, the primary tumor having been resected in The eighth patient had an unresectable undifferentiated carcinoma of the anterior mediastinum. This patient has currently survived 8 years following radiation therapy without evidence of disease. Eleven patients have been followed for less than 5 years, and 4 of them are alive and well. Two patients who had malignant thymoma resected for cure are free of recurrence 3 and 4.8 years, respectively, after resection. A patient who has gone 4 years since resection and irradiation of a neuro- 556 THE ANNALS OF THORACIC SURGERY

5 CURRENT REVIEW: Malignant Tumors of Mediastinurn TABLE 4. POSTOPERATIVE MORBIDITY IN 43 PATIENTS WITH PRIMARY MALIGNANT MEDIASTINAL TUMORS Postoperative Complications No. of Patients Wound infection or hematoma 4 Pleural effusion 2 Horner s syndrome 2 Empyema 1 Pneumonia 1 Phlebitis 1 blastoma is without recurrence. A patient with mediastinal Hodgkin s disease is alive 2 years after biopsy. Comment Ten tumor types composed this series. Tumor cell type dictated the mode of treatment and the prognosis of each group. MALIGNANT THYMOMA Eleven of the 43 patients were found to have malignant thymoma. Eight of the 1 1 patients presented with symptoms-chronic nonproductive cough, dyspnea, and anterior chest pain being the prevalent complaints. Four patients presented with positive physical findings, 1 with palpable tumor in the cervical region and superior vena cava obstruction and 1 with muscle dysfunction secondary to advanced myasthenia gravis. Roentgeno- TABLE 5. FOLLOW-UP IN 43 PATIENTS WITH PRIMARY MALIGNANT MEDIASTINAL TUMORS Total Tumor Type No. of Patients No. of Survivors 5-Year Survivors Malignant thymoma Lymphoma 10 1 CJndifferentiated carcinoma Neuroblastoma Neurogenic sarcoma Malignant teratoma 2 0 Rhabdomyosarcoma 1 0 Sympathicoblastoma Lymphangioendo thelioma 1 0 Malignant paraganglioma Total VOL. 4, NO. 5, NOVEMBER,

6 CONKLE AND ADKINS graphic studies revealed all these tumors to be located in the anterior mediastinum. Nine of these 11 patients underwent surgical exploration. Five had total resection of their tumor for cure. One patient died in the immediate postoperative period. The 4 remaining patients are alive and well, although 1 had recurrence 7 years following resection of an encapsulated thymoma. This recurrent tumor was reexcised in 1969 except for a small focus involving the left atrium. Postoperative irradiation was administered, and the patient is currently free of demonstrable tumor. Thus, 4 of 5 patients who had tumor resected for cure have survived, 2 of them for 5 years. Of the remaining 6 patients with malignant thymoma, only 5 received treatment. The patient with myasthenia gravis died prior to the institution of treatment. These 5 patients had unresectable tumors and were treated with irradiation. In 3 instances, chemotherapy (nitrogen mustard or Cytoxan) was also employed. The average length of survival was 2 years, with the longest survivor living 3 years 8 months. In this series, excision for cure has proved to be the treatment of choice whenever possible. All patients without clinical evidence of widespread disease should be explored because excision is often possible in spite of surrounding tissue invasion. Sellors and associates [141 have noted this in stating that pleural, pericardial, phrenic nerve, and innominate vein invasion are not contraindications for resection. Postoperative irradiation was only employed in 1 patient who had had resection for cure, and he shows no evidence of recurrence. Legg and Brady [lo] and Sellors and his associates [14] believe that all patients with thymoma should receive irradiation. In their experience, most thymomas have proved to be radiosensitive with marked palliation being obtained. Legg and Brady [lo] reported a 40% 5-year survival with radiation therapy; unfortunately, this was not our experience when irradiation alone was used. Patient 1. A 67-year-old man entered Vanderbilt University Hospital for evaluation of an asymptomatic anterior mediastinal mass discovered on routine chest roentgenogram. A chest film 1 year prior to admission had shown no abnormalities. Physical examination was within normal limits. Fluoroscopy revealed a pulsatile mass in the anterior mediastinum. Angiography revealed the mass to be independent from the heart and great vessels. A 9 cm. mass was found in the arch of the aorta. This structure was excised. Microscopical examination (Fig. 1) revealed a thymoma which was believed to have malignant characteristics (reviewed by Dr. Frank Foote). This patient has currently survived 10 years since resection and is without recurrence. LYMPHOMA Ten of the 43 patients had lymphoma localized to the mediastinum. The cell types identified were lymphosarcoma (8 patients) and Hodgkin s disease (2 patients). Symptoms were present in all patients and consisted of 558 THE ANNALS OF THORACIC SURGERY

7 CURRENT REVIEW: Malignant Tumors of Mediastinum FIG. 1. Microscopical appearance of tumor from Patient 1 shows both lymphocytic and epithelial components of the tumor. (H&E, X20.1 chronic cough, progressive dyspnea, fever, and weight loss. A predilection for the young, as proposed by Heuer and Andrus [SI, was demonstrated; 8 of the 10 patients were less than 30 years of age. Roentgenographic studies demonstrated all 10 tumors to be located in the anterior mediastinum as described by Sabiston and Scott [13]. Surgical excision was attempted in 9 of the 10 patients; the remaining patient had biopsy of a supraclavicular mass which extended from the mediastinum. Successful resection was possible in only 1 instance; the remaining tumors were found to be invading surrounding structures, making total resection impossible. There was 1 operative death-a 9-year-old girl who presented with extreme respiratory distress and superior vena cava obstruction. She underwent an emergency median sternotomy and died during induction of anesthesia. This experience corresponds with that of Boyd and Midell [23, who found such lesions to be rarely resectable. Radiation therapy was given to 6 of the 10 patients following tissue diagnosis. Their survival time was not appreciably greater than that of the 3 patients who received no irradiation. Chemotherapy was employed in 3 patients whose tumor showed no response to irradiation. Again, no appreciable response was obtained. VOL. 14, NO. 5, NOVEMBER,

8 CONKLE AND ADKINS The current mode of therapy for lymphoma is irradiation. As stated by Burke and his colleagues [3], operative excision followed by cobalt therapy still offers the best opportunity for cure. This proves especially true in those patients with localized disease and with sclerosing Hodgkin s disease. The results in our small series have been disappointing, with only 1 patient surviving more than 2 years. This patient had unresectable sclerosing Hodgkin s disease localized to the mediastinum. The remaining 9 patients have all experienced a rapid death, with the average length of survival being 6 months. UNDIFFERENTIATED CARCINOMA Ten of the 43 patients had undifferentiated carcinoma of the mediastinum. Clinical and roentgenographic studies suggested that these tumors were primary mediastinal lesions. Although the tumors were of epithelial origin, there was no evidence that they were metastatic, thymic, or pulmonary neoplasms [71. Nine of the 10 patients presented with symptoms, nonproductive cough and anterior chest pain being predominant. Physical findings were present in 9 patients, supraclavicular adenopathy (6 patients) and superior vena cava obstruction (3 patients) being the most prevalent. Roentgenographic studies revealed all the lesions to be in the superior or anterior mediastinum. Tissue diagnosis was established at thoracotomy (5 patients) or by tissue biopsy of a metastatic lesion. No patient had resectable disease. Eight of the 10 patients received radiation therapy; 2 patients died prior to the institution of therapy. Chemotherapy was employed in 1 patient following radiation therapy; no improvement was obtained. Nine patients died. Their average survival following diagnosis was 1 year. One patient is alive 8 years after biopsy and irradiation (see case report on Patient 2). The prognosis for this tumor appears to be poor at present. The tumor usually proves to be unresectable, and only a rare success is achieved with radiation therapy. Patient 2. A 30-year-old man was found to have a superior mediastinal tumor on routine chest roentgenogram (Fig. 2). He had no symptoms or abnormal physical findings. Bone marrow biopsy and scalene node biopsy were not diagnostic. Exploratory thoracotomy revealed an unresectable tumor. Microscopical sections (Fig. 3) revealed an undifferentiated carcinoma. Postoperatively the patient received 4,000 R to the superior mediastinum. Serial roentgenograms demonstrated complete tumor regression. The patient has currently survived 8 years after irradiation without evidence of recurrence. TUMORS OF NEUROGENIC ORIGIN Three of the 43 patients had the microscopical diagnosis of neurogenic sarcoma (malignant neurolemmoma). Stewart and Copeland [ 151 say that 560 THE ANNALS OF THORACIC SURGERY

9 CURRENT REVIEW: Malignant Tumors of Mediastinurn FIG. 2. Routine chest roentgenogram showing mediastinal mass which occupies the superior mediastinum. No primary lesion outside the mediastinum is seen (Patient 2). FIG. 3. Microscopical appearance of tumor from Patient 2 showing undifferentiated carcinoma. (H&E, X 50.) VOL. 14, NO. 5, NOVEMBER,

10 CONKLE AND ADKINS this tumor is characteristically solitary, anaplastic, hypercellular, and circumscribed. This was not the case in our small series. Two tumors were unresectable, invading vital structures, and 1 of these tumors was multifocal. All 3 tumors were in the posterior mediastinum. One tumor was resected, and the patient is still alive (see case report on Patient 3). The other 2 patients died in less than 1 year; irradiation and chemotherapy were not employed. Patient 3. A 64-year-old woman noted the gradual onset of neck vein distention and paresthesia of the right arm. Physical examination revealed superior vena cava obstruction. A chest roentgenogram (Fig. 4) revealed a posterior mediastinal mass. The patient underwent a right posterolateral thoracotomy, and a large, firm, circumscribed tumor was excised from the posterior mediastinum (see Fig. 4). Microscopical examination (Fig. 5) demonstrated a malignant neurolemmoma. This patient is alive and well 14 years after resection. Three patients had mediastinal neuroblastomas. These patients were all less than 1% years of age. Symptoms and signs were present in 2 patients, 1 presenting with cyanosis and wheezing and the other with lower extremity paralysis of rapid onset. Roentgenograms revealed posterior mediastinal masses; calcification and rib erosion were present in 2 instances. All 3 patients had resections and postoperative irradiation; 1 patient required a thoracic laminectomy to remove that portion of a dumbbell tumor which had extended into the neural canal. The 3 patients are alive without evidence of recurrence; the survival period ranges from 4% to l l years. Patient 4. A 15-month-old boy presented with failure to thrive. There FIG. 4. Chest roentgenogram showing large posterior mediastinal mass with pressure upon esophagus and superior vena caua. The excised tumor mass is upon the chest roentgenogram (Patient 3.) 562 THE ANNALS OF THORACIC SURGERY

11 CURRENT REVIEW: Malignant Tumors of Mediastinum FIG. 5. Microscopical appearance of malignant neurolemmoma from tumor mass shown in Figure 4 (Patient 3). (Hb.E, X50.) were dullness and decreased breath sounds over the left chest. A roentgenogram (Fig. 6) demonstrated a mass in the left posterior hemithorax. At thoracotomy this mass was found to arise from the posterior mediastinum and involved the third and fourth intercostal nerves. The tumor was resected, and microscopical sections (Fig. 7) revealed a neuroblastoma. Irradiation of 5,000 R was given to the mediastinum. The patient has currently survived 10 years after resection without recurrence. One patient was found at thoracotomy to have a sympathicoblastoma. This tumor was located in the superior mediastinum, unlike those reported by Chandler and Norcross [41 which arose in the posterior mediastinum. Patient 5. A 4-month-old girl was admitted with Horner s syndrome on the left side. A chest roentgenogram revealed a homogeneous mass in the superior mediastinum. Left thoracotomy exposed an encapsulated tumor extending from the superior mediastinum into the base of the neck. Resection was possible. Microscopical sections (Fig. 8) revealed a sympathicoblastoma. This tumor was excised, and the patient has currently survived 18 years after resection without recurrence. At the age of 2 years 3 months, 1 patient was found on routine chest roentgenogram to have a mass located in the posterior mediastinum. At the VOL. 14, NO. 5, NOVEMBER,

12 CONKLE AND ADKINS FIG. 6. Chest roentgenogram showing a large mass in the left hemithorax. This tumor arose from the posterior mediastinum and involved the chest wall and intercostal nerves. (Patient 4.) time of thoracotomy this was found to be a malignant paraganglioma. Invasion was present, but resection was possible. This patient has currently survived 10 years after resection without recurrence. Kent and his co-work- FZG. 7. Microscopical appearance of neuroblastoma in Patient 4. (H&E, X20.) 564 THE ANNALS OF THORACIC SURGERY

13 CURRENT REVIEW: Malignant Tumors of Mediastinum FIG. 8. Microscopical appearance of sympathicoblastoma from tumor removed as described in Patient 5. (Hb.E, X.20.) ers [91 describe this tumor as being the second most frequent neurogenic tumor of the mediastinum. Neurofibroma is the most common. This tumor is usually benign, but invasion has been reported. Treatment consists of resection; irradiation is not of value. In our series of malignant neurogenic tumors, resection has often been possible and the survival rate-a total of 6 patients out of 8-has been favorable. Irradiation alone was not attempted in this series, and only its reported lack of success [9, 111 can be cited. Postoperative irradiation in patients with neuroblastoma was employed in accordance with the mode of therapy discussed by Gross [5]. MALIGNANT TERATOMA Two of the 43 patients were found to have malignant teratoma. Both presented with symptoms of respiratory distress; 1 patient had signs of superior vena cava obstruction. Roentgenograms revealed anterior mediastinal masses, and calcification was present in 1 patient. The patient with superior vena cava obstruction died prior to operative intervention. His tumor was found to invade both lungs, the superior vena cava, and the pericardial sac. The other patient underwent exploratory thoracotomy ; the VOL. 14, NO. 5, NOVEMBER,

14 CONKLE AND ADKINS tumor was found to be invading surrounding structures, making resection impossible. Postoperatively he received 6,000 R of irradiation and nitrogen mustard chemotherapy. He survived 5 months. Tumors of this cell type are seldom resectable, and irradiation is stated to be of no benefit [12]. They do, however, present in a benign form that is amenable to operative excision. Many believe that all malignant teratomas arise from benign lesions which, over the course of years, have an increasing potential to undergo malignant degeneration [ 121. This tumor usually presents in the young adult, and symptoms secondary to pressure on surrounding structures predominate. Roentgenograms reveal an anterior mediastinal mass often containing teeth, bone, and fluid levels. The origin of the tumor is still debated; the current theory is that it arises from embryonic rest cells that descended into the mediastinum with the branchial arches. Rusby [12] gives an excellent account of the medical history associated with this tumor. LYMPHANGIOENDOTHELIOMA One of the 43 patients was found to have an extremely vascular tumor occupying the anterior mediastinum. Resection proved impossible. Microscopical sections revealed the tumor to be composed of numerous sinuses lined with epithelial cells. The tumor was thought to be a lymphangioendothelioma. The patient received postoperative irradiation without tumor regression and died 4 months after diagnosis. A review of vascular neoplasms of the mediastinum was published by Balbaa and Chestermann [l] in They refer to these tumors as angiosarcoma and state that they usually occupy the anterior mediastinum but occasionally are found in other areas of the mediastinum. They invade surrounding structures early, and hence excision is usually impossible; however, Balbaa and Chestermann recommend total excision followed by irradiation. Survival following tumor diagnosis is poor; only 1 survivor was reported in their series. RHABDOMYOSARCOMA The occurrence of this tumor in the mediastinum is very rare. Heimburger and Battersby [6] reported 1 such Occurrence in a 2-year-old girl who died prior to treatment. At postmortem examination an extensive embryonal rhabdomyosarcoma was found. In our series, a 5-year-old girl presented to Dr. Alfred Blalock in March, 1933, with shortness of breath, a productive cough, and left chest pain. Physical examination revealed prominence of the left chest and tracheal deviation to the right. A chest roentgenogram revealed a mass obliterating the left hemithorax. A left thoracotomy was performed, and a large mediastinal mass was found which was incompletely resected. Microscopical sections revealed a rhabdomyosarcoma. The child survived approximately 1% months. 566 THE ANNALS OF THORACIC SURGERY

15 CURRENT REVIEW: Malignant Tumors of Mediastinum References Balbaa, A., and Chestermann, J. T. Neoplasms of vascular origin in the mediastinum. Br. J. Surg. 44:545, Boyd, D. P., and Midell, A. I. Mediastinal cysts and tumors. Surg. Clin. North Am. 48:493, Burke, W. A., Burford, T. H., and Dorfman, R. F. Hodgkin s disease of the mediastinum. Ann. Thorac. Surg. 3:287, Chandler, F. A., and Norcross, J. R. Sympathicoblastoma. J.A.M.A. 114: 112, Gross, R. E. The Surgery of Infancy and Childhood. Philadelphia: Saunders, Heimburger, I., and Battersby, J. S. Primary mediastinal tumors of childhood. J. Thorac. Cardiovasc. Surg. 50:92, Heimburger, I., Battersby, J. S., and Vellios, F. Primary neoplasms of the mediastinum. Arch. Surg. 76:978, Heuer, G. J., and Andrus, W. D. The surgery of mediastinal tumors. Am. J. Surg. 50:146, Kent, E. M., Blades, B., Valle, R. A., and Graham, E. Intrathoracic neurogenic tumors. J. Thorac. Surg. 1 3:116, Legg, M. A., and Brady, W. J. Pathology and clinical behavior of thymomas. Cancer 18:1131, LeRoux, B. T. Primary intrathoracic neural tumors. Thorax 15:339, Rusby, N. L. Dermoid cysts and teratomata of the mediastinum. J. Thorac. Surg. 13:169, I Sabiston, D. C., Jr., and Scott, H. W., Jr. Primary neoplasms and cysts of the mediastinum. Ann. Surg. 123:777, Sellors, T. H., Thachray, A. C., and Thomson, A. D. Tumors of the thymus. Thorax 22: 193, Stewart, F. W., and Copeland, M. M. Neurogenic sarcoma. Am. J. Cancer 15:1235, VOL. 14, NO. 5, NOVEMBER,

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