036IS3016/79/112059-04$02.00/O
Int. J. Radiation Oncology Biol. Phys.,, Vol. 5, pp. 205%2062 0 Pergamon Press Ltd., 1979. Printed m the U.S.A.
??Brief Communication
THYMOMA: THERAPY AND PROGNOSIS AS RELATED TO OPERATIVE STAGING DONALD
G.NORDSTROM,M.D.,HAMED H.TEwFIK,M.B.,CH.B.,M.D. HOWARDB.LATOURETTE,M.D.
Department
of Radiation
Therapy,
University
of Iowa Hospitals
and
& Clinics, Iowa City, Iowa 52242
Fifty-three patients were seen and treated for thymoma at the University of Iowa Hospitals. Staging of patients was based upon invasion. Stage I and Stage II patients had a 100% survival when surgery was the only method of treatment. With Stage III disease, 50% survivaI was noted at five years; combined surgery and radiation therapy was the treatment of choice. Thymoma, Staging, Radiation therapy.
INTRODUCTION
(41%). Myasthenia gravis was present in eleven (21%); the remainder of the patients presented with dysphagia (lo%), weakness (6%), chest pain (8%), cough (6%), superior vena cava syndrome (4%), fatigue or hemoptysis, one case each. All patients underwent thoracotomy either to attempt complete resection or to obtain tissue for diagnosis. The extent of disease was recorded at operation. The patients have been classified retrospectively by stage as described by Bergh et ~1.~ Thymus specific epithelial cells, together with the varying number of lymphocytes, are necessary in order for disease to be classified as thymoma.2 The pathological claissifcation followed that of Bernatz, et ~1.~ which had four categories: lymphocytic, epithelial, mixed and spindle cell. Table 1 presents a breakdown of our patients. Radiation therapy was employed in selected patients. Doses varied from 2100 rad in 2 weeks to 5000 rad in 5 weeks; all but four patients received at least 4000 rad in 4 weeks. Cobalt teletherapy was utilized in all but two patients when either 250 KV X-ray or a linear accelerator with 10 MV photons were employed. All patients were treated using anterior posterior portals and the fraction size was either 200 rad or 180 rad.
A good deal has been written about thymoma, particularly regarding classification and prognosis. Some of the articles have discussed the differential between benign and malignant thymomas as criteria for the choice of therapy. The number of articles indicates the uncertainty of clinico-pathological status as it is related to appropriate management. This study evaluates the prognosis of patients with thymoma based upon operative staging of the neoplasm; particular emphasis is placed on survival as it relates to stage and treatment.
METHODSANDMATERIALS During the period from 1949 to 1976, a total of sixty-two patients with thymoma were seen at the University of Iowa Hospitals; the diagnosis was obtained at autopsy in four patients in this group. One patient died of leukemia before she received treatment; one patient received radiation therapy without a biopsy; in three patients, the diagnosis was changed to lymphoma. This left a total of fifty-three patients who received surgicd resection or biopsy which led to the diagnosis of thymoma. Selected patients received postoperative radiation therapy in the course of their treatment. The average age of our patients was forty-six; their ages ranged from one to seventy-one years. There were twenty-nine males and twenty-four females. An incidental finding of a mass on a chest X-ray led to the diagnosis in twenty-two patients
RESULTS Follow-up was obtained on all patients with a minimum of one year. Twenty-six of the patients had Stage I disease,
Reprint requests to: Donald G. Nordstrom, M.D., 1417 So. Minnesota Avenue, Sioux Falls, South Dakota 57105.
Accepted for publication 2059
21 August 1979.
2060
Radiation Oncology 0 Biology 0 Physics
i.e., intact capsule or growth within the capsule. Treatment consisted of surgical resection of the entire lesion in all cases; one patient received immediate postoperative radiation therapy. No thymoma related deaths occurred in patients with Stage I disease; four patients died of other causes, one of pulmonary embolism, one of chronic bronchiectasis and the other two of unknown causes. But thymoma was not a cause of death in these four patients. Only one recurrence was observed in a patient with lymphocytic type who developed pleural recurrences four years and six years post resection, but who was alive at eighteen years with radiation therapy control of her recurrent lesions. Thus, as Fig. 1 shows, for Stage I disease, at 2 y. followup, 25 patients were at risk; at four years 23 patients were at risk, at five years 21 patients were at risk. By five years we had lost two patients because of other diseases; three patients were removed because of insufficient follow-up time. At ten years 12 patients were alive and well with no evidence of disease (NED). Seven patients had Stage II disease, i.e., invasion of the capsule into the pericapsule fat. Complete surgical resection of all tumor tissue was attempted. Two patients received postoperative radiation therapy. Three non-thymoma related deaths were observed; one death resulted from cardiac arrest, one death from pneumonia and one death from respiratory failure. Four patients were alive and well with NED from one to twenty-four years (Fig. 1). A total of twenty patients were found to have invasive growth of their thymoma, i.e., Stage III; all but one patient in this category received radiation therapy. One died of GI bleeding; one died of radiation complications; two died of pneumonia; and one died of emphysema. The patient who died from radiation complications died three years after radiation therapy to the abdomen because of abdominal metastases. He died because of GI radiation complications but autopsy showed NED. Nine patients, including the one who did not receive radiation, died of their tumor. A tenth patient died of pneumonia; however, at the time of death, he did have metastasis to the right humerus five years and five months after initial diagnosis. Among patients with Stage III disease, (Fig. l), nine patients were alive and well with NED and one patient was alive at five years but with metastases to the right humerus; at six and seven years follow-up, six patients were alive and well with NED; at nine years five patients were alive and well with NED; 10 years four patients were alive and well with NED. The five year survival for this stage was lo/20 (50%) with nine patients free of disease. The survival curve shows only those patients at
November-December 1979, Vol. 5, No. 11 and No. 12
a.....*
-m
??
-A
stage I StageII stage
Ill
100 3 .-> ? S E g : n.
75 50 25 0
I
I
1
I
I
1
012345676
1
I
1
1
,
9
10
Years Fig. 1. Five and ten year determinant survival for patients with stage J, II & III thymoma; adjusted for patient death from non-thymoma causes or no evidence of disease (NED) but at risk for less than 10 years.
risk of recurrence of thymoma. At each point on the graph, the patient survival was calculated only for those patients who are at risk of recurrence of thymoma. Any patient who died of intercurrent disease or other than thymoma related causes were deleted; also, all patients with insufficient time for follow-up were deleted from the curve for this particular point on the graph. Evaluation of those dying of thymoma revealed that one death occurred in the patient who did not receive postoperative radiation therapy; four tumors were found to have a high number of mitotic figures and four were described as anaplastic. Six patient deaths were related to metastatic spread of their thymoma; review of the pathology showed four to be epithelial and two of mixed cell type. Of these, three were described as having a high ratio of mitotic cells and two were anaplastic in nature. Two additional patients also had numerous mitotic figures but complete resection was attempted in addition to the radiation therapy and they were free of disease at this writing. Myasthenia gravis was seen in eleven patients (21%) in this series. Review of pathological classification found one epithelial, five lymphocytic and five mixed cell types in patients with myasthenia gravis. In Stage I and II disease, good control of myasthenia gravis was obtained in four patients following surgical resection, and one patient died from complications of bronchiectasis. In Stage II disease, two obtained good control, myasthenia crises occurred in two patients, and two deaths were observed, related to extensive tumor involvement.
Thymoma: Therapy and prognosis 0 D. G. NORDSTROM
Table 1. Classification
Lymphocytic Epithelial Mixed Spindle Undifferentiated Total
et al.
of patients by stage and histological Stage I
Stage II
11 5 9 0 1 26
3 1 3 0 0 7
2061
type
Stage III
Totals
9 1 3 20
15 12 21 1 4 53
Stage I=Intact capsule or growth within capsule. Stage II=Pericapsular growth into the mediastinal fat tissue. Stage III=Invasive growth into surrounding organs, intrathoracic metastases, or both
DISCUSSION Previous studies have investigated the factors related to the prognosis of patients with thymoma. Jain and Frable5 described benign thymomas having a capsule, usually with a nodular pattern, and sometimes containing calcification. Infiltration, lost lobulations, necrosis, degeneration and mitotic figures were assigned to malignant thymomas; however, differentiation of tumors by this criteria were not always good predictors. Likewise, the cytologic evidence of a malignant thymoma is not dependable. A more accurate predictor of prognosis is the absence or presence of invasion of the surrounding tissue. The staging system by Bergh et a1.2 is consistent with our observation that invasion is the single most important determinant of prognosis; this agrees with other studies.3*4,6*7*11 Batata et al.’ state that superior vena cava syndrome, pleural effusion, supraclavicular lymph nodes, dysphagia and myasthenia gravis indicate poor prognosis; all are related to invasion by the thymoma. Bernatz, et af.3 separated their patients into those with and without invasion and noted no difference in histology in each category. The finding was confirmed by others.8,11 Our study found 100% survival in Stage I and II disease with surgical resection as the therapeutic management. Results indicate that postoperative radiation is not necessary if resection is complete. Only one of thirty-three patients developed a local recurrence; this was well controlled with radiation to known sites of disease. Bergh, et al.” also noted
1.
complete control of Stage I and Stage II disease; they recommended surgery for Stage I and II disease. Of thirty-seven patients in Salyer and Eggleston’s” review, thymoma did not recur in patients who did not have invasion. Postoperative radiation therapy is of definite value in the case of Stage III thymoma with growth into surrounding tissue. In eleven of twenty patients, disease was locally controlled; in ten of twenty patients, survival was greater than five years in our series. In the remaining patients, extent of disease or anaplastic nature of the lesion precluded poor survival. Bergh, et al.’ noted control of disease in five of seven patients at five years in study. Two patients failed with doses below 4000 rad; we feel 5000 rad in five weeks is necessary for control of these lesions when invasion is noted. Marks et a1.g stated that 4000 rad in twenty fractions is the minimum recommended dose and suggest that 4000 rad is required if residual disease is present. With these doses, they found 100% local control. Penn and Hope-Stone “) had seven patients with curative doses of 4000 rad; three of four were alive at ten years. Patients with a lower dose did not survive. In summary, we feel that invasion is the best factor for evaluation of prognosis and predictor of survival. If there is an intact capsule or growth into pericapsule fat, i.e. Stage I or Stage II, and resection was complete, surgery is sufficient treatment; good results can be expected. If invasion is present, postoperative radiation therapy can be of benefit and may produce long-term survivors.
REFERENCES Batata, M.A., Martini, N., Huvos, A.G., Aguilar, R.I., Ridell, B.: Tumors of the thymus and thymic region: I.
Beattie, E.J., Jr.: Thymomas: Clinicopathologic features, therapy, and prognosis. Cancer 34: 389-396, 1974. 2. Bergh, N.P., Gatzinsky, P., Larsson, S., Lundin, P.,
Ann. Clinicopathological studies on thymomas. Thoracic Surg. 25(2): 91-98, 1978. 3. Bernatz, P.E., Harrison, E.G., Clagett, O.T.: Thymoma: A clinicopathologic study. J. Zhrac. Car-
Radiation Oncology 0 Biology 0 Physics
2062
diovasc. Surg. 42: 424-444,
1961. of the thymus gland. In Atlas of Tumor Pathology, Sec. 5, Fax. 19. Washington, D.C., Armed Forces Institute of Pathology, 1955, pp. 53-56. 5. Jain, U., Frable, W.J.: Thymoma: Analysis of benign and malignant criteria. J. Thorac. Cardiovasc. Surg.
4. Castleman,
B.: Tumors
67: 310-321, 1974. 6. Lattes, R.: Thymoma
and other tumors of the thymus: An analysis of 107 cases. Cancer 15: 1224-1260, 1962. 7. Legg, M.A., Brady, W.J.: Pathology and clinical behavior of thymomas: A survey of 51 cases. Cancer 18:
November-December 1979, Vol. 5, No. 11 and No. 12
1131-1144, 1965. 8. LeGolvan, D.P., Abell, M.R.: Thymomas. 2142-2157, 9. Marks,
Cancer
39:
1977.
R.D., Jr., Wallace, K.M., Pettit, H.S.: Radiation therapy control of nine patients with malignant thymoma. Cancer 41: 117-119, 1978. 10. Penn, C.R.H., Hope-Stone, H.F.: The role of in the mamagement of malignant radiotherapy thymoma. &it. J. Surg. 59(7), 1972. 11. Salyer, W.R., Eggleston, J.C.: Thymoma: A clinical and pathological study of 65 cases. Cancer 37: 229249, 1976.
Int. J. Radiation Oncology Biol. Phys.,, Vol. 5, pp. 205%2062 0 Pergamon Press Ltd., 1979. Printed m the U.S.A.
??Brief Communication
THYMOMA: THERAPY AND PROGNOSIS AS RELATED TO OPERATIVE STAGING DONALD
G.NORDSTROM,M.D.,HAMED H.TEwFIK,M.B.,CH.B.,M.D. HOWARDB.LATOURETTE,M.D.
Department
of Radiation
Therapy,
University
of Iowa Hospitals
and
& Clinics, Iowa City, Iowa 52242
Fifty-three patients were seen and treated for thymoma at the University of Iowa Hospitals. Staging of patients was based upon invasion. Stage I and Stage II patients had a 100% survival when surgery was the only method of treatment. With Stage III disease, 50% survivaI was noted at five years; combined surgery and radiation therapy was the treatment of choice. Thymoma, Staging, Radiation therapy.
INTRODUCTION
(41%). Myasthenia gravis was present in eleven (21%); the remainder of the patients presented with dysphagia (lo%), weakness (6%), chest pain (8%), cough (6%), superior vena cava syndrome (4%), fatigue or hemoptysis, one case each. All patients underwent thoracotomy either to attempt complete resection or to obtain tissue for diagnosis. The extent of disease was recorded at operation. The patients have been classified retrospectively by stage as described by Bergh et ~1.~ Thymus specific epithelial cells, together with the varying number of lymphocytes, are necessary in order for disease to be classified as thymoma.2 The pathological claissifcation followed that of Bernatz, et ~1.~ which had four categories: lymphocytic, epithelial, mixed and spindle cell. Table 1 presents a breakdown of our patients. Radiation therapy was employed in selected patients. Doses varied from 2100 rad in 2 weeks to 5000 rad in 5 weeks; all but four patients received at least 4000 rad in 4 weeks. Cobalt teletherapy was utilized in all but two patients when either 250 KV X-ray or a linear accelerator with 10 MV photons were employed. All patients were treated using anterior posterior portals and the fraction size was either 200 rad or 180 rad.
A good deal has been written about thymoma, particularly regarding classification and prognosis. Some of the articles have discussed the differential between benign and malignant thymomas as criteria for the choice of therapy. The number of articles indicates the uncertainty of clinico-pathological status as it is related to appropriate management. This study evaluates the prognosis of patients with thymoma based upon operative staging of the neoplasm; particular emphasis is placed on survival as it relates to stage and treatment.
METHODSANDMATERIALS During the period from 1949 to 1976, a total of sixty-two patients with thymoma were seen at the University of Iowa Hospitals; the diagnosis was obtained at autopsy in four patients in this group. One patient died of leukemia before she received treatment; one patient received radiation therapy without a biopsy; in three patients, the diagnosis was changed to lymphoma. This left a total of fifty-three patients who received surgicd resection or biopsy which led to the diagnosis of thymoma. Selected patients received postoperative radiation therapy in the course of their treatment. The average age of our patients was forty-six; their ages ranged from one to seventy-one years. There were twenty-nine males and twenty-four females. An incidental finding of a mass on a chest X-ray led to the diagnosis in twenty-two patients
RESULTS Follow-up was obtained on all patients with a minimum of one year. Twenty-six of the patients had Stage I disease,
Reprint requests to: Donald G. Nordstrom, M.D., 1417 So. Minnesota Avenue, Sioux Falls, South Dakota 57105.
Accepted for publication 2059
21 August 1979.
2060
Radiation Oncology 0 Biology 0 Physics
i.e., intact capsule or growth within the capsule. Treatment consisted of surgical resection of the entire lesion in all cases; one patient received immediate postoperative radiation therapy. No thymoma related deaths occurred in patients with Stage I disease; four patients died of other causes, one of pulmonary embolism, one of chronic bronchiectasis and the other two of unknown causes. But thymoma was not a cause of death in these four patients. Only one recurrence was observed in a patient with lymphocytic type who developed pleural recurrences four years and six years post resection, but who was alive at eighteen years with radiation therapy control of her recurrent lesions. Thus, as Fig. 1 shows, for Stage I disease, at 2 y. followup, 25 patients were at risk; at four years 23 patients were at risk, at five years 21 patients were at risk. By five years we had lost two patients because of other diseases; three patients were removed because of insufficient follow-up time. At ten years 12 patients were alive and well with no evidence of disease (NED). Seven patients had Stage II disease, i.e., invasion of the capsule into the pericapsule fat. Complete surgical resection of all tumor tissue was attempted. Two patients received postoperative radiation therapy. Three non-thymoma related deaths were observed; one death resulted from cardiac arrest, one death from pneumonia and one death from respiratory failure. Four patients were alive and well with NED from one to twenty-four years (Fig. 1). A total of twenty patients were found to have invasive growth of their thymoma, i.e., Stage III; all but one patient in this category received radiation therapy. One died of GI bleeding; one died of radiation complications; two died of pneumonia; and one died of emphysema. The patient who died from radiation complications died three years after radiation therapy to the abdomen because of abdominal metastases. He died because of GI radiation complications but autopsy showed NED. Nine patients, including the one who did not receive radiation, died of their tumor. A tenth patient died of pneumonia; however, at the time of death, he did have metastasis to the right humerus five years and five months after initial diagnosis. Among patients with Stage III disease, (Fig. l), nine patients were alive and well with NED and one patient was alive at five years but with metastases to the right humerus; at six and seven years follow-up, six patients were alive and well with NED; at nine years five patients were alive and well with NED; 10 years four patients were alive and well with NED. The five year survival for this stage was lo/20 (50%) with nine patients free of disease. The survival curve shows only those patients at
November-December 1979, Vol. 5, No. 11 and No. 12
a.....*
-m
??
-A
stage I StageII stage
Ill
100 3 .-> ? S E g : n.
75 50 25 0
I
I
1
I
I
1
012345676
1
I
1
1
,
9
10
Years Fig. 1. Five and ten year determinant survival for patients with stage J, II & III thymoma; adjusted for patient death from non-thymoma causes or no evidence of disease (NED) but at risk for less than 10 years.
risk of recurrence of thymoma. At each point on the graph, the patient survival was calculated only for those patients who are at risk of recurrence of thymoma. Any patient who died of intercurrent disease or other than thymoma related causes were deleted; also, all patients with insufficient time for follow-up were deleted from the curve for this particular point on the graph. Evaluation of those dying of thymoma revealed that one death occurred in the patient who did not receive postoperative radiation therapy; four tumors were found to have a high number of mitotic figures and four were described as anaplastic. Six patient deaths were related to metastatic spread of their thymoma; review of the pathology showed four to be epithelial and two of mixed cell type. Of these, three were described as having a high ratio of mitotic cells and two were anaplastic in nature. Two additional patients also had numerous mitotic figures but complete resection was attempted in addition to the radiation therapy and they were free of disease at this writing. Myasthenia gravis was seen in eleven patients (21%) in this series. Review of pathological classification found one epithelial, five lymphocytic and five mixed cell types in patients with myasthenia gravis. In Stage I and II disease, good control of myasthenia gravis was obtained in four patients following surgical resection, and one patient died from complications of bronchiectasis. In Stage II disease, two obtained good control, myasthenia crises occurred in two patients, and two deaths were observed, related to extensive tumor involvement.
Thymoma: Therapy and prognosis 0 D. G. NORDSTROM
Table 1. Classification
Lymphocytic Epithelial Mixed Spindle Undifferentiated Total
et al.
of patients by stage and histological Stage I
Stage II
11 5 9 0 1 26
3 1 3 0 0 7
2061
type
Stage III
Totals
9 1 3 20
15 12 21 1 4 53
Stage I=Intact capsule or growth within capsule. Stage II=Pericapsular growth into the mediastinal fat tissue. Stage III=Invasive growth into surrounding organs, intrathoracic metastases, or both
DISCUSSION Previous studies have investigated the factors related to the prognosis of patients with thymoma. Jain and Frable5 described benign thymomas having a capsule, usually with a nodular pattern, and sometimes containing calcification. Infiltration, lost lobulations, necrosis, degeneration and mitotic figures were assigned to malignant thymomas; however, differentiation of tumors by this criteria were not always good predictors. Likewise, the cytologic evidence of a malignant thymoma is not dependable. A more accurate predictor of prognosis is the absence or presence of invasion of the surrounding tissue. The staging system by Bergh et a1.2 is consistent with our observation that invasion is the single most important determinant of prognosis; this agrees with other studies.3*4,6*7*11 Batata et al.’ state that superior vena cava syndrome, pleural effusion, supraclavicular lymph nodes, dysphagia and myasthenia gravis indicate poor prognosis; all are related to invasion by the thymoma. Bernatz, et af.3 separated their patients into those with and without invasion and noted no difference in histology in each category. The finding was confirmed by others.8,11 Our study found 100% survival in Stage I and II disease with surgical resection as the therapeutic management. Results indicate that postoperative radiation is not necessary if resection is complete. Only one of thirty-three patients developed a local recurrence; this was well controlled with radiation to known sites of disease. Bergh, et al.” also noted
1.
complete control of Stage I and Stage II disease; they recommended surgery for Stage I and II disease. Of thirty-seven patients in Salyer and Eggleston’s” review, thymoma did not recur in patients who did not have invasion. Postoperative radiation therapy is of definite value in the case of Stage III thymoma with growth into surrounding tissue. In eleven of twenty patients, disease was locally controlled; in ten of twenty patients, survival was greater than five years in our series. In the remaining patients, extent of disease or anaplastic nature of the lesion precluded poor survival. Bergh, et al.’ noted control of disease in five of seven patients at five years in study. Two patients failed with doses below 4000 rad; we feel 5000 rad in five weeks is necessary for control of these lesions when invasion is noted. Marks et a1.g stated that 4000 rad in twenty fractions is the minimum recommended dose and suggest that 4000 rad is required if residual disease is present. With these doses, they found 100% local control. Penn and Hope-Stone “) had seven patients with curative doses of 4000 rad; three of four were alive at ten years. Patients with a lower dose did not survive. In summary, we feel that invasion is the best factor for evaluation of prognosis and predictor of survival. If there is an intact capsule or growth into pericapsule fat, i.e. Stage I or Stage II, and resection was complete, surgery is sufficient treatment; good results can be expected. If invasion is present, postoperative radiation therapy can be of benefit and may produce long-term survivors.
REFERENCES Batata, M.A., Martini, N., Huvos, A.G., Aguilar, R.I., Ridell, B.: Tumors of the thymus and thymic region: I.
Beattie, E.J., Jr.: Thymomas: Clinicopathologic features, therapy, and prognosis. Cancer 34: 389-396, 1974. 2. Bergh, N.P., Gatzinsky, P., Larsson, S., Lundin, P.,
Ann. Clinicopathological studies on thymomas. Thoracic Surg. 25(2): 91-98, 1978. 3. Bernatz, P.E., Harrison, E.G., Clagett, O.T.: Thymoma: A clinicopathologic study. J. Zhrac. Car-
Radiation Oncology 0 Biology 0 Physics
2062
diovasc. Surg. 42: 424-444,
1961. of the thymus gland. In Atlas of Tumor Pathology, Sec. 5, Fax. 19. Washington, D.C., Armed Forces Institute of Pathology, 1955, pp. 53-56. 5. Jain, U., Frable, W.J.: Thymoma: Analysis of benign and malignant criteria. J. Thorac. Cardiovasc. Surg.
4. Castleman,
B.: Tumors
67: 310-321, 1974. 6. Lattes, R.: Thymoma
and other tumors of the thymus: An analysis of 107 cases. Cancer 15: 1224-1260, 1962. 7. Legg, M.A., Brady, W.J.: Pathology and clinical behavior of thymomas: A survey of 51 cases. Cancer 18:
November-December 1979, Vol. 5, No. 11 and No. 12
1131-1144, 1965. 8. LeGolvan, D.P., Abell, M.R.: Thymomas. 2142-2157, 9. Marks,
Cancer
39:
1977.
R.D., Jr., Wallace, K.M., Pettit, H.S.: Radiation therapy control of nine patients with malignant thymoma. Cancer 41: 117-119, 1978. 10. Penn, C.R.H., Hope-Stone, H.F.: The role of in the mamagement of malignant radiotherapy thymoma. &it. J. Surg. 59(7), 1972. 11. Salyer, W.R., Eggleston, J.C.: Thymoma: A clinical and pathological study of 65 cases. Cancer 37: 229249, 1976.
