- Email: [email protected]
Possible immune factors in spontaneous regression of bronchogenic carcinoma
CASE REPORTS
Possible Immune Factors in Spontaneous Regression of Bronchogenic Carcinoma Ten Year Survival in a Patient Treated with Minimal (1,200 r) Radiation Alone
J. W. BELL, MD, Seattle, Washington S p o n t a n e o u s r e g r e s s i o n of c a n c e r h a s been defined [ I ] as t h e p a r t i a l or c o m p l e t e d i s a p p e a r a n c e of a m a l i g n a n t t u m o r in t h e a b s e n c e of all t r e a t m e n t or in t h e p r e s e n c e of t h e r a p y w h i c h is c o n s i d e r e d ina d e q u a t e to. e x e r t a s i g n i f i c a n t influence on neop l a s t i c disease. I n 1964 t h e p a t i e n t r e p o r t e d h e r e i n w a s r e c o r d e d [2] as a f i v e - y e a r s u r v i v o r a f t e r app a r e n t s p o n t a n e o u s r e s o l u t i o n of a n e x t e n s i v e , p o o r l y ctifferentiated n e o p l a s m o f t h e l e f t lung, h a v i n g r e c e i v e d m i n i m a l (1,200 r ) r a d i a t i o n . T e n y e a r s a f t e r t h e initial e x p l o r a t o r y t h o r a c o t o m y , this case is n o w r e p o r t e d f o r t h e f o l l o w i n g o b s e r v a tions. T h i s p a t i e n t h a s c o n t i n u e d to s m o k e h e a v i l y a n d t h u s h a s been a t r i s k of r e { t o r r e n t l u n g c a n c e r b r m o r e likely det, e l o p m e n t of a n e w lesion. Second, ten y e a r s u r v i v a l of p a t i e n t s w i t h l u n g c a n c e r , even w h e n t r e a t e d w i t h c o n v e n t i o n a l m e a s u r e s , is uncommon. Finally, this patient has been demons t r a t e d to h a v e cellular i m m u n i t y a g a i n s t l u n g t u m o r s o f s i m i l a r histologic t ~ p e f r o m o t h e r patients.
Case Report On March 11, 1959, left thoracotomy on th~s thirtyseven year-old white man (JM) revealed an upper lobe tumor presenting on the visceral and parietal pleural surfaces. The tumor extended into the hium o f the tipper lobe and beneath the aortic arch. (Figure 1.) The probable origin of the tumor was believed to be in the apical-posterior segments. Because of t h e parietal and hitar extension of the tumor, no resection was considered possible. Frozen section was reported as a malignant neoplasm, probably poorly differentiated squamous carcinoma. (Figure 2.) During the first two postoperative weeks two events occurred which may have influenced the subsequent course. He was given a total tumor dose of 1,200 r through anterior and posterior portals. He manifested fever from 100 to 103°F during most of this period. At discharge there was no apparent change seen ~on'~the chest film. From the Department of Surgery, University o f Washington School of Medicine. and the Third University Surgical Service, Veterans Administration Hospital, Seattle, Washington.
804
Figure ] . Chest film taken on admission showing large tumor and pleural fluid in left hemithorax.
When seen five and a half months later, the patient had gained nearly 40 pounds, a n d t h e chest film revealed essentially con~plete' clearing of the previous lesion. (Figure 3.) The patient has been followed-up at yearly intervals thereafter, and the chest film has remained clear up to this ten-year interval. (Figure 4.)
Comments R y a n , M c D o n a l d , a n d C l a g e t t [3] f o u n d t h a t in f o r t y - o n e p a t i e n t s d y i n g o f c a n c e r o f t h e lung, t h e o p p o s i t e l u n g r e v e a l e d s q u a m o u s m e t a p l a s i a in 44 p e r c e n t a n d in situ o r f r a n k c a r c i n o m a in ] 2 p e r cent. A u e r b a c h a n d his a s s o c i a t e s [-4] in a s i m i l a r study of fifty-four lungs with bronchogenic carCinoma f o u n d c a r c i n o m a i n situ i n 89 p e r c e n t a n d e a r l y i n v a s i v e c a n c e r in 9 p e r cent. I t h a s b e e n Suggested t h a t Second lesions o f t h e l u n g would, d e v e l o p i f m o r e p a t i e n t s w e r e / t o s u r The American Journal o f Surgery
Spontaneous Regression of Bronchogenic Carcinoma
vive surgical o r radiologic t r e a t m e n t . Le Gal and B a u e r [5] believe the incidence of second p r i m a r y t u m o r s to be 6.4 p e r cent. S m i t h [6] d e t e r m i n e d a 6.8 p e r cent probability f o r development of a new p u l m o n a r y lesion a f t e r successful resection. Neptune, Woods, and Overholt [7] have r e p o r t e d f i g teen p a t i e n t s of 2,400 cases f r o m the Overholt Clinic who have had a second operation f o r bronchogenic carcinoma. It is a p p a r e n t t h a t in our paticnt, who has continued to smoke for the ten y e a r period a f t e r disa p p e a r a n c e of his tumor, t h e r e has been ample opp o r t u n i t y f o r a new t u m o r to p r e s e n t ; t h a t a new lesion has not developed suggests an acquired host immunity. F r o m animal e x p e r i m e n t s with both a u t o c h t h o n o u s and t r a n s p l a n t e d tumors, it has been shown t h a t i m m u n i t y a f t e r induced or spontaneous regression is more effective t h a n t h a t a f t e r surgical removal. Evidence is suggested in the review of experience with spontaneous regression in human subjects by E v e r s o n and Cole [1] and Boyd [8] t h a t a similar phenomenon m a y occur in man. In N o v e m b e r 1968, the p e r i p h e r a l lymphocytes of this p a t i e n t ( J M ) were collected by Dr. G. E. Pierce and tested f o r i m m u n e a c t i v i t y by the colony inhibition test in Hellstroms' l a b o r a t o r y [9]. This test: depends on a decrease in the plating efficiency of t u m o r t a r g e t cells which occurs a f t e r they have been incubated with s e r u m (and comp!emen t ) or lymphocytes f r o m specifically i m m u n e animals. Percentag'e reduction in the e x p e r i m e n t a l group with lymphocytes f r o m the p a t i e n t was calculated by c o m p a r i n g a n u m b e r of colonies in p e t r i dishes c o n t a i n i n g t a r g e t cells exposed to the patient's lymphocytes as compared to colonies in petri dishes exposed to lymphocytes f r o m o t h e r patients. W h e n the p e r i p h e r a l l y m p h o c y t e s of this p a t i e n t (JM) w e r e incubated with t a r g e t cells, f r o m a donor with undifferentiated bronchogenic carcinoma, t h e r e was a 52.1 p e r cent* reduction of Probability
Figure 2. Photomicrograph of biopsy specimen taken at thoracotomy, interpreted" as poorly differentiated broncho. genie carcinoma (original magnification × 100).
colony f o r m a t i o n . W h e n t h e s e l y m p h o e y t e s w e r e tested a g a i n s t cells of a d e n o c a r c i n o m a of the lung, t h e r e was a 23.2 p e r cent* inhibition of colony f o r mation. The slight nonspecific i n h i b i t i n g effect of the allogeneic l y m p h o c y t e s f r o m JM was seen by a 3.8 p e r cent inhibition when incubated w i t h norreal cells of the t u m o r cell donor. I t is i n t e r e s t i n g to speculate t h a t the a n a m n e s t i c response of this p a t i e n t ' s l y m p h o c y t e s to a cross t u m o r specific t r a n s p l a n t a t i o n a n t i g e n m a y b e a consequence of the regression of the original c a n ~er. F u r t h e r , the presence of these i m m u n e cells which a r e c y t o t o x i c m a y h a v e p r e v e n t e d r e c u r -
Figure 3; Roentgenogram taken six months after discharge shows complete clearing of the left.tung. FigUre 4, Chest film within normal iJrl~its at ten yeat follow-up study~ Volume 120, December 1970
'305
Bell
fence or development of a new t u m o r by an im~mnologic a t t a c k On c a r c i n o m a deyeloping in situ. E m e r s o n et al [10] have r e p o r t e d a p a t i e n t with a twelve y e a r survival f r o m proved bronchogenic carcinoma who died of carcinoma of t h e pancreas, Of special i n t e r e s t was t h e finding o f a b u n d a n t plasma cells and lymphocytes in the original biopsy specimen. Black and Speer [11] and o t h e r s have correlated prolonged survival with lymphocyte infiltration in the t u m o r and a d j a c e n t lymph nodes. T h e findings in this patient as welt as in our own suggest t h a t when i m m u n i t y is acquired by t u m o r regression, it tends to be essentially permanent and cell-type specific.
Summary A case is r e p o r t e d of ten y e a r survival a f t e r t h o r a c o t o m y f o r inoperable bronchogenic carcinoma, A p p a r e n t spontaneous regression has been followed by f r e e d o m f r o m development of a new p u l m o n a r y t u m o r in spite of the patient's continued smoking. Immunologic f a c t o r s affecting this course a r e suggested by the d e m o n s t r a t i o n of immune lymphocytes in the patient's peripheral blood which depres~ the g r o w t h of t u m o r cells f r o m a donor with lmig cancer.
Acknowledgment. I a m indebted to Drs Pierce.
806
Yang, and the HellstrSms f o r the immunologic findings.
References 1. Everson T. Cole WH: Spontaneous Regression of Cancer. Philadelphia, 1966, W B Saunders. 2, Bell JW, Jesseph JE, Leighton RS: Spontaneous regression of bronchogenic carcinoma with five.year survival. J Thorac Cardiovasc Sure 48: 984, 1964. 3. Ryan RF, McDonald JR, Clagett OT: Histopathological observations in bronchial epithelium with special reference to carcinoma of lung. J Thorac Sure 33: 264, 1957. 4. Auerbacb D, ~ Gere JB, Pawlowski JM. Muehsam GE. Smolin HJ, Stout AP: Carcinoma-in.situ and early invasive carcinoma occurring in the tracheobronchial trees in cases of bronchogenic carcinoma. J Thorac Sure 34: 298, 1957. 5. Le Gal Y. Bauer WC: Second ~primary bronchogenic carc=noma~ J Thorac Cardiovasc Sure 41: 114, 1961. 6. Smith RA: Development and treatment of fresh lung carcinoma alter successful tobectomy. Thorax 21: 1, 1966, 7. Neptune WB, Woods FM, Overholt RH: Reoperation for broncllogenic carcinoma. J Thorac Cardiovasc Surg 52: 342, 1966. 8. Boyd W: The Spontaneous RegressTon of Cancer. Springfield, 1966, Charles C Thomas. 9. Hellstrbm I, Hellstrbm KE. Pierce GE, Yang JPS: Cellular and humoral immunity t o different types of human neoplasms. Nature 220:352, 1968. 10. Emerson GL, Emerson MS. Sherwood CE, Terry R: Spontaneous regression of bronchogenic carcinoma. J Thorac Cardiovasc Sure 55: 225. 1968, ] 1. Black MM, Speer FD: Lymph node reactivity in cancer patients, Sure Gynec Obstet 110: 477, 1960.
The Amertcan Journli of Surgery
Possible Immune Factors in Spontaneous Regression of Bronchogenic Carcinoma Ten Year Survival in a Patient Treated with Minimal (1,200 r) Radiation Alone
J. W. BELL, MD, Seattle, Washington S p o n t a n e o u s r e g r e s s i o n of c a n c e r h a s been defined [ I ] as t h e p a r t i a l or c o m p l e t e d i s a p p e a r a n c e of a m a l i g n a n t t u m o r in t h e a b s e n c e of all t r e a t m e n t or in t h e p r e s e n c e of t h e r a p y w h i c h is c o n s i d e r e d ina d e q u a t e to. e x e r t a s i g n i f i c a n t influence on neop l a s t i c disease. I n 1964 t h e p a t i e n t r e p o r t e d h e r e i n w a s r e c o r d e d [2] as a f i v e - y e a r s u r v i v o r a f t e r app a r e n t s p o n t a n e o u s r e s o l u t i o n of a n e x t e n s i v e , p o o r l y ctifferentiated n e o p l a s m o f t h e l e f t lung, h a v i n g r e c e i v e d m i n i m a l (1,200 r ) r a d i a t i o n . T e n y e a r s a f t e r t h e initial e x p l o r a t o r y t h o r a c o t o m y , this case is n o w r e p o r t e d f o r t h e f o l l o w i n g o b s e r v a tions. T h i s p a t i e n t h a s c o n t i n u e d to s m o k e h e a v i l y a n d t h u s h a s been a t r i s k of r e { t o r r e n t l u n g c a n c e r b r m o r e likely det, e l o p m e n t of a n e w lesion. Second, ten y e a r s u r v i v a l of p a t i e n t s w i t h l u n g c a n c e r , even w h e n t r e a t e d w i t h c o n v e n t i o n a l m e a s u r e s , is uncommon. Finally, this patient has been demons t r a t e d to h a v e cellular i m m u n i t y a g a i n s t l u n g t u m o r s o f s i m i l a r histologic t ~ p e f r o m o t h e r patients.
Case Report On March 11, 1959, left thoracotomy on th~s thirtyseven year-old white man (JM) revealed an upper lobe tumor presenting on the visceral and parietal pleural surfaces. The tumor extended into the hium o f the tipper lobe and beneath the aortic arch. (Figure 1.) The probable origin of the tumor was believed to be in the apical-posterior segments. Because of t h e parietal and hitar extension of the tumor, no resection was considered possible. Frozen section was reported as a malignant neoplasm, probably poorly differentiated squamous carcinoma. (Figure 2.) During the first two postoperative weeks two events occurred which may have influenced the subsequent course. He was given a total tumor dose of 1,200 r through anterior and posterior portals. He manifested fever from 100 to 103°F during most of this period. At discharge there was no apparent change seen ~on'~the chest film. From the Department of Surgery, University o f Washington School of Medicine. and the Third University Surgical Service, Veterans Administration Hospital, Seattle, Washington.
804
Figure ] . Chest film taken on admission showing large tumor and pleural fluid in left hemithorax.
When seen five and a half months later, the patient had gained nearly 40 pounds, a n d t h e chest film revealed essentially con~plete' clearing of the previous lesion. (Figure 3.) The patient has been followed-up at yearly intervals thereafter, and the chest film has remained clear up to this ten-year interval. (Figure 4.)
Comments R y a n , M c D o n a l d , a n d C l a g e t t [3] f o u n d t h a t in f o r t y - o n e p a t i e n t s d y i n g o f c a n c e r o f t h e lung, t h e o p p o s i t e l u n g r e v e a l e d s q u a m o u s m e t a p l a s i a in 44 p e r c e n t a n d in situ o r f r a n k c a r c i n o m a in ] 2 p e r cent. A u e r b a c h a n d his a s s o c i a t e s [-4] in a s i m i l a r study of fifty-four lungs with bronchogenic carCinoma f o u n d c a r c i n o m a i n situ i n 89 p e r c e n t a n d e a r l y i n v a s i v e c a n c e r in 9 p e r cent. I t h a s b e e n Suggested t h a t Second lesions o f t h e l u n g would, d e v e l o p i f m o r e p a t i e n t s w e r e / t o s u r The American Journal o f Surgery
Spontaneous Regression of Bronchogenic Carcinoma
vive surgical o r radiologic t r e a t m e n t . Le Gal and B a u e r [5] believe the incidence of second p r i m a r y t u m o r s to be 6.4 p e r cent. S m i t h [6] d e t e r m i n e d a 6.8 p e r cent probability f o r development of a new p u l m o n a r y lesion a f t e r successful resection. Neptune, Woods, and Overholt [7] have r e p o r t e d f i g teen p a t i e n t s of 2,400 cases f r o m the Overholt Clinic who have had a second operation f o r bronchogenic carcinoma. It is a p p a r e n t t h a t in our paticnt, who has continued to smoke for the ten y e a r period a f t e r disa p p e a r a n c e of his tumor, t h e r e has been ample opp o r t u n i t y f o r a new t u m o r to p r e s e n t ; t h a t a new lesion has not developed suggests an acquired host immunity. F r o m animal e x p e r i m e n t s with both a u t o c h t h o n o u s and t r a n s p l a n t e d tumors, it has been shown t h a t i m m u n i t y a f t e r induced or spontaneous regression is more effective t h a n t h a t a f t e r surgical removal. Evidence is suggested in the review of experience with spontaneous regression in human subjects by E v e r s o n and Cole [1] and Boyd [8] t h a t a similar phenomenon m a y occur in man. In N o v e m b e r 1968, the p e r i p h e r a l lymphocytes of this p a t i e n t ( J M ) were collected by Dr. G. E. Pierce and tested f o r i m m u n e a c t i v i t y by the colony inhibition test in Hellstroms' l a b o r a t o r y [9]. This test: depends on a decrease in the plating efficiency of t u m o r t a r g e t cells which occurs a f t e r they have been incubated with s e r u m (and comp!emen t ) or lymphocytes f r o m specifically i m m u n e animals. Percentag'e reduction in the e x p e r i m e n t a l group with lymphocytes f r o m the p a t i e n t was calculated by c o m p a r i n g a n u m b e r of colonies in p e t r i dishes c o n t a i n i n g t a r g e t cells exposed to the patient's lymphocytes as compared to colonies in petri dishes exposed to lymphocytes f r o m o t h e r patients. W h e n the p e r i p h e r a l l y m p h o c y t e s of this p a t i e n t (JM) w e r e incubated with t a r g e t cells, f r o m a donor with undifferentiated bronchogenic carcinoma, t h e r e was a 52.1 p e r cent* reduction of Probability
Figure 2. Photomicrograph of biopsy specimen taken at thoracotomy, interpreted" as poorly differentiated broncho. genie carcinoma (original magnification × 100).
colony f o r m a t i o n . W h e n t h e s e l y m p h o e y t e s w e r e tested a g a i n s t cells of a d e n o c a r c i n o m a of the lung, t h e r e was a 23.2 p e r cent* inhibition of colony f o r mation. The slight nonspecific i n h i b i t i n g effect of the allogeneic l y m p h o c y t e s f r o m JM was seen by a 3.8 p e r cent inhibition when incubated w i t h norreal cells of the t u m o r cell donor. I t is i n t e r e s t i n g to speculate t h a t the a n a m n e s t i c response of this p a t i e n t ' s l y m p h o c y t e s to a cross t u m o r specific t r a n s p l a n t a t i o n a n t i g e n m a y b e a consequence of the regression of the original c a n ~er. F u r t h e r , the presence of these i m m u n e cells which a r e c y t o t o x i c m a y h a v e p r e v e n t e d r e c u r -
Figure 3; Roentgenogram taken six months after discharge shows complete clearing of the left.tung. FigUre 4, Chest film within normal iJrl~its at ten yeat follow-up study~ Volume 120, December 1970
'305
Bell
fence or development of a new t u m o r by an im~mnologic a t t a c k On c a r c i n o m a deyeloping in situ. E m e r s o n et al [10] have r e p o r t e d a p a t i e n t with a twelve y e a r survival f r o m proved bronchogenic carcinoma who died of carcinoma of t h e pancreas, Of special i n t e r e s t was t h e finding o f a b u n d a n t plasma cells and lymphocytes in the original biopsy specimen. Black and Speer [11] and o t h e r s have correlated prolonged survival with lymphocyte infiltration in the t u m o r and a d j a c e n t lymph nodes. T h e findings in this patient as welt as in our own suggest t h a t when i m m u n i t y is acquired by t u m o r regression, it tends to be essentially permanent and cell-type specific.
Summary A case is r e p o r t e d of ten y e a r survival a f t e r t h o r a c o t o m y f o r inoperable bronchogenic carcinoma, A p p a r e n t spontaneous regression has been followed by f r e e d o m f r o m development of a new p u l m o n a r y t u m o r in spite of the patient's continued smoking. Immunologic f a c t o r s affecting this course a r e suggested by the d e m o n s t r a t i o n of immune lymphocytes in the patient's peripheral blood which depres~ the g r o w t h of t u m o r cells f r o m a donor with lmig cancer.
Acknowledgment. I a m indebted to Drs Pierce.
806
Yang, and the HellstrSms f o r the immunologic findings.
References 1. Everson T. Cole WH: Spontaneous Regression of Cancer. Philadelphia, 1966, W B Saunders. 2, Bell JW, Jesseph JE, Leighton RS: Spontaneous regression of bronchogenic carcinoma with five.year survival. J Thorac Cardiovasc Sure 48: 984, 1964. 3. Ryan RF, McDonald JR, Clagett OT: Histopathological observations in bronchial epithelium with special reference to carcinoma of lung. J Thorac Sure 33: 264, 1957. 4. Auerbacb D, ~ Gere JB, Pawlowski JM. Muehsam GE. Smolin HJ, Stout AP: Carcinoma-in.situ and early invasive carcinoma occurring in the tracheobronchial trees in cases of bronchogenic carcinoma. J Thorac Sure 34: 298, 1957. 5. Le Gal Y. Bauer WC: Second ~primary bronchogenic carc=noma~ J Thorac Cardiovasc Sure 41: 114, 1961. 6. Smith RA: Development and treatment of fresh lung carcinoma alter successful tobectomy. Thorax 21: 1, 1966, 7. Neptune WB, Woods FM, Overholt RH: Reoperation for broncllogenic carcinoma. J Thorac Cardiovasc Surg 52: 342, 1966. 8. Boyd W: The Spontaneous RegressTon of Cancer. Springfield, 1966, Charles C Thomas. 9. Hellstrbm I, Hellstrbm KE. Pierce GE, Yang JPS: Cellular and humoral immunity t o different types of human neoplasms. Nature 220:352, 1968. 10. Emerson GL, Emerson MS. Sherwood CE, Terry R: Spontaneous regression of bronchogenic carcinoma. J Thorac Cardiovasc Sure 55: 225. 1968, ] 1. Black MM, Speer FD: Lymph node reactivity in cancer patients, Sure Gynec Obstet 110: 477, 1960.
The Amertcan Journli of Surgery