Oncology 31: 280-287 (1975)
Multiple Primary Malignancies in Patients with Alcoholic Liver Disease A Report of Two Cases
Anastasios A. Mihas and Wilhelm G. Doos' Thorndike Memorial Laboratory, Harvard Medical Unit, Boston City Hospital and Department of Medicine, Harvard Medical School and Mallory Institute of Pathology, Boston City Hospital, Boston, Mass.
Key Words. Cirrhosis • Cellular immunity • Ca of thyroid • Ca of breast • Ca of colon • Ca of esophagus Abstract. Two patients, each with three primary malignant neoplasms are presented. In an effort to identify a possible common denominator of induction of these tumors, it was found that both patients were alcoholics with liver disease, and that both had impaired delayed hypersensitivity reactions. The possibility of an increased susceptibility to cancer among alcoholics with liver disease is noted and the need for careful follow-up of these patients is suggested.
The occurrence of multiple primary neoplasms in the same patient was first described by Billroth in 1889 (3). The subject has been increasingly studied in the hope of finding factors which may initiate the neoplastic process or may identify those likely to develop cancer. The occurrence of more than one pri mary malignant neoplasm in a patient is not rare, frequency varying from 2 to 12 % (13, 20, 22) with double primaries being the most common. The number of patients with more than two is smaller. In addition, some or all of the tumors were not diagnosed until postmortem examination in most of the published series (2, 9, 21). This is a report of two patients who each developed three primary malignant tumors, all of which were diagnosed ante mortem.
Patient I. A 66-year-old Caucasian male was admitted to the hospital with a 3-month history of weakness, anorexia and 30 lb. weight loss. 20 years before this admission he had had an amputation of his left leg for a lipomyxosarcoma (fig. 1). Two years prior to Clinical Fellow of the American Cancer Society.
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Case Reports
281
Fig. 1. Liposarcoma showing lipoblasts with foamy and vacuolated cytoplasm (marked ly positive with fat stains) intermingled with a myxomatous tissue of stellate and spindle cells with a very loose and clear interstitium. Fig. 2. Basal cell carcinoma (epithelioma) of the skin showing nests of neoplastic cells in the dermis which are composed of small tightly packed aggregates with peripheral pali sading.
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Mihas/Doos
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282
3
Fig. 3. Adenocarcinoma of colon showing submucosal pool of mucus containing mucin producing carcinoma cells. The serosa and regional lymph nodes were involved by tumor. Fig. 4. Thyroid carcinoma showing trabecular and microfollicular pattern. Vascular invasion was not present.
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4
283
Fig. 5. Infiltrating ductal carcinoma of the breast with scirrous reaction and ‘Indian filling’ of carcinoma cells. Three lymph nodes (of 18) showed métastasés. Fig. 6. Esophageal biopsy showing squamous cell carcinoma with keratohyalin pearl formation and intercellular bridges.
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Multiple Malignancies in Alcoholics
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admission he was found to have a large basal cell carcinoma of the left preauricular area which was treated with local excision and X-radiation therapy (fig. 2). Six months later he underwent a right hemicolectomy with ileo-transverse colostomy for an adenocarcinoma of the hepatic flexure (fig. 3). One year prior to this admission he was operated on for a ventral hernia repair; the operating surgeon found the liver and peritoneum free of any metastatic deposits. Other pertinent past history revealed that the patient was a heavy alcoholic; laboratory tests and liver scan were suggestive of chronic liver disease, probably cirrhosis. Physical examina tion revealed an elderly male, cachectic and extremely pale. Other pertinent findings were a grade 3 of 6 ejection type systolic murmur in the aortic area and a palpable spleen. Labora tory values showed an hematocrit of 21 with microcytic hypochromic indices; prothrombin time 15.3 sec with control of 12.3, bilirubin 2.3/mg/100 ml, albumin 2.1 g/100 ml, SGOT 20 IU and alkaline phosphatase 92 IU. A stool specimen was guaiac positive. Intradermal skin tests with: PPD (1st and 2nd strength), trichophytin and mumps were all negative. The hospital course was complicated by the development of an empyema of the gallbladder which was treated with drainage through a cholecystostomy tube and antibiotics. Again the surgeon was unable to detect any metastases to the liver or peritoneum. A cholecystogram via the cholecystostomy tube showed no evidence of obstruction of the cystic or common bile duct. The patient recovered fully from this insult and subsequent work-up included duodenoscopy which revealed the presence of a tumor in the second portion of the duode num distal to the papilla of Vater. Biopsies were obtained and histologic examination disclosed an adenocarcinoma. His poor general condition and nutritional status, as well as the extensive procedure indicated (Whipple’s operation) were decisive factors for not operating on this patient. He expired a few weeks later; autopsy was not granted. Patient II. A 66-year-old Caucasian female presented with a 2-month history of dys phagia and hematemesis 1 day prior to admission. Three years prior to admission she was found to have a follicular carcinoma of the thyroid requiring subtotal thyroidectomy (fig. 4). One year later she was admitted to the hospital for evaluation of a lump in the right breast; this was proven to be a ductal carcinoma, for which she underwent radical mastec tomy followed by cobalt teletherapy (fig. 5). The patient was also known to be a heavy alcoholic for many years with biopsy proven Laennec’s cirrhosis. Physical examination was unremarkable except for signs of peripheral neuropathy. Laboratory values revealed a normal hematocrit and chemistry profile. Liver function tests were within normal limits except for a mildly elevated alkaline phosphatase (105 IU) and marked hypoalbuminemia (2.0 g/100 ml). Tuberculin skin test (first and second strength) was twice negative. An upper gastrointestinal series revealed a large ulcerating mass in the distal esophagus. Surgery was performed (esophagogastrectomy) and an ulcerated mass measuring 3.5 X 1.5 cm was removed from the distal esophagus. Histologic examination revealed an infiltrating welldifferentiated squamous cell carcinoma of the esophagus with metastasis to the periesopha geal lymph nodes (fig. 6). The patient expired on the 10th postoperative day secondary to cardio-respiratory failure. Autopsy permission was not obtained.
The criteria for multiple primary malignancy proposed by Warren and Gares in 1932 (22) have been widely accepted: (1) each of the tumors must represent a definite picture of malignancy; (2) each tumor must be distinct histologically, and (3) the probability of one being a metastasis of the other must be excluded.
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Comment
285
All three primary malignant tumors in each of our patients fulfill these criteria. In our first case report a fourth primary malignant neoplasm - adenocarcinoma of the second portion of the duodenum — was strongly suspected; exploratory laparotomy, 1 year and a second one a few days before the duodenoscopy was performed, failed to reveal any metastatic deposits. However, (a) the histologic similarity of this tumor with the previously resected adenocarcinoma of the colon, and (b) the lack of a postmortem examination were decisive factors for not considering this duodenal tumor as a fourth primary malignancy. There is an accumulating body of evidence that the risk of the development of a second primary malignant neoplasm in a person with one malignant neo plasm is greater than the risk of the development of the initial malignancy in any given population (5, 8, 22). In most of the published series the authors found a relatively high incidence of multiple primary malignant tumors and all attributed them to a susceptibility or predisposition to cancer. Peller (14), however, presenting statistical material from 5,876 cancer cases concluded that the real incidence for multiple malignancies was less than the expected rate and he hypothesized that a cured cancer secured protection against the appearance of another cancer. These conflicting conclusions reflect the lack of adequate control groups against which to compare the patient populations studied. The disclosure of common denominators of tumor induction in certain patient groups would be of great assistance to the clinician in his dealing with diagnostic and therapeutic problems of malignancy. Much evidence has accumulated during the past decade to support the concept that there exists in animals and in man a cellular mechanism for recognition and ultimate destruction of host cells under going dysplastic change (6, 10). The efficiency of an immune surveillance system of this kind may determine resistance or susceptibility to tumor development and similar events may be capable of altering the growth of established tumors (7, 17). Furthermore, it is well known that patients with immunologic defi ciency as well as patients treated with immunosuppressives are more prone to develop malignant tumors than are others (4, 11, 15). High incidence of neoplasms among patients with liver disease has not been reported with the exception of hepatoma especially in patients with underlying alcoholic cirrhosis (16). On the other hand, it has been known that patients with alcoholic liver disease are unusually susceptible to infections and impaired immunity has been suggested as a significant factor for this susceptibility (19). In recent years there is emerging evidence that patients with alcoholic liver disease show a high incidence of altered cellular immunity, although it is not clear whether this immunologic abnormality is the consequence or the cause of the disease (7, 12, 18). In a study of 177 cases of multiple primary malignancies the authors found that more than 50% of the cases showed significant cirrhosis of the liver (9). Both of our cases were known alcoholics with liver disease and both demon
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Multiple Malignancies in Alcoholics
Mihas/Doos
286
strated impaired cell-mediated immunity when skin-tested although the second patient was only tested with PPD. It should be noted that this impaired delayed hypersensitivity reaction was shown well in advance of the detection of the second and third primary tumors in these patients. It is attractive to speculate that patients with alcoholic liver disease may be more prone to develop malignancies than the general population. Coincidence, however, could be the only factor involved in the development of multiple primary malignant tumors in two patients who also had alcoholic liver disease. It would be useful to have our observation confirmed with data from other sources and a study of autopsy material among patients with alcoholic liver disease might be revealing. In the meantime, we suggest that patients with chronic liver disease should be carefully followed for possible development of a malignant neoplasm other than hepatoma. It is striking that among 177 cases of multiple primary malignancies only nine were diagnosed before the postmortem examina tion and no cancer was diagnosed (or suspected) in roughly one fourth of them (9).
1 Berenyi, M.R.; Straus, B., and Cruz, D.: In vitro and in vivo studies of cellular immuni ty in alcoholic cirrhosis. Am. J. dig. Dis. 19: 199-205 (1974). 2 Berg, J.W.: The incidence of multiple primary cancers. I. Development of further cancers in patients with lymphomas, leukemias and myeloma. J. natn. Cancer Inst. 38: 741-752(1967). 3 Billroth, T.: Die allgemeine chirurgische Pathologic und Therapie in 51 Vorlesungen, p. 908 (Reimer, Berlin 1889). 4 Brown, R.S.; Schiff, M., and Mitchell, M.S.: Reticulum-cell sarcoma of host origin arising in a transplanted kidney. Ann. intern. Med. 80: 459-463 (1974). 5 Bugher, J.C.: The probability of the chance occurrence of multiple malignant neo plasms. Am. J. Cancer 21: 809-824 (1934). 6 Burnet, F.M.: Immunological recognition of self. Science, N.Y. 133: 307-311 (1961). 7 Burnet, F.M.: The concept of immunological surveillance. Prog. exp. Tumor Res., vol. 13, pp. 1-27 (Karger, Basel 1970). 8 Gaudin, H.: Multiple primary malignant tumours. N.7.. med. J. 40: 367—374 (1941). 9 Hajdu, S.I. and Hajdu, E.D.: Multiple primary malignant tumors. J. Am. Geriat. Soc. 16: 16-26 (1968). 10 Hellstrom, I. and Hellstrom, K.E.: Some aspects of the immune defense against cancer. II. In vitro studies on human tumors. Cancer 28: 1269-1271 (1971). 11 Hermans, P.E. and Juizenga, K.A.: Association of gastric carcinoma with idiopathic late onset immunoglobulin deficiency. Ann. intern. Med. 76: 605-609 (1972). 12 Hsu, C.C.S. and Leevy, C.M.: Inhibition of PHA stimulated lymphocyte transformation by plasma from patients with advanced alcoholic cirrhosis. Clin. exp. Immunol. 8: 749-760(1971). 13 Moertel, C.G.; Dockerty, M.B., and Baggenstos, A.H.: Multiple primary malignant neoplasms. I. Introduction and presentation of data. II. Tumors of different tissues and organ. Cancer 14: 221-237 (1961).
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References
Multiple Malignancies in Alcoholics
287
Dr. A. Mihas, University of Alabama Medical Center, Birmingham, AL 35294 (USA)
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14 Peller, S.: Metachronous multiple malignancies in 5,876 cancer patients. Am. J. Hyg. 34: 1-11 (1941). 15 Penn, I.: Hammond, W.; Brettsclmeider, L., and Staril, T.E.: Malignant lymphomas in transplantation patients. Transplant Proc. 1: 106-112 (1969). 16 Purtilo, D.T. and Gottlieb, L.S.: Cirrhosis and hepatoma occurring at Boston City Hospital. Cancer 32: 458-462 (1973). 17 Smith, R.T.: Possibility and problems of immunologic intervention in cancer. New Engl. J. Med. 287: 439-450 (1972). 18 Straus, B B e r e n y i , M.R.; Huang, J.M., and Straus, E.: Delayed hypersensitivity in alcoholic cirrhosis. Am. J. dig. Dis. 16: 509-516 (1971). 19 Straus, B. and Berenyi, M.R.: Infection and immunity in alcoholic cirrhosis. Mount Sinai J. Med. 40: 631-640 (1973). 20 Thoma, G.W.: The incidence and significance of multiple primary malignant tumors. I. A study of 2,346 necropsies from a cancer research hospital. Am. J. med. Sci. 77: 427-430(1964). 21 Tullis, J.L.: Multiple primary malignant lesions. J. Lab. clin. Med. 27: 588-594 (1942). 22 Warren, S. and Gores, O.: Multiple primary malignant tumors: a survey of the literature and statistical study. Am. J. Cancer 16: 1358-1414 (1932).
Multiple Primary Malignancies in Patients with Alcoholic Liver Disease A Report of Two Cases
Anastasios A. Mihas and Wilhelm G. Doos' Thorndike Memorial Laboratory, Harvard Medical Unit, Boston City Hospital and Department of Medicine, Harvard Medical School and Mallory Institute of Pathology, Boston City Hospital, Boston, Mass.
Key Words. Cirrhosis • Cellular immunity • Ca of thyroid • Ca of breast • Ca of colon • Ca of esophagus Abstract. Two patients, each with three primary malignant neoplasms are presented. In an effort to identify a possible common denominator of induction of these tumors, it was found that both patients were alcoholics with liver disease, and that both had impaired delayed hypersensitivity reactions. The possibility of an increased susceptibility to cancer among alcoholics with liver disease is noted and the need for careful follow-up of these patients is suggested.
The occurrence of multiple primary neoplasms in the same patient was first described by Billroth in 1889 (3). The subject has been increasingly studied in the hope of finding factors which may initiate the neoplastic process or may identify those likely to develop cancer. The occurrence of more than one pri mary malignant neoplasm in a patient is not rare, frequency varying from 2 to 12 % (13, 20, 22) with double primaries being the most common. The number of patients with more than two is smaller. In addition, some or all of the tumors were not diagnosed until postmortem examination in most of the published series (2, 9, 21). This is a report of two patients who each developed three primary malignant tumors, all of which were diagnosed ante mortem.
Patient I. A 66-year-old Caucasian male was admitted to the hospital with a 3-month history of weakness, anorexia and 30 lb. weight loss. 20 years before this admission he had had an amputation of his left leg for a lipomyxosarcoma (fig. 1). Two years prior to Clinical Fellow of the American Cancer Society.
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Case Reports
281
Fig. 1. Liposarcoma showing lipoblasts with foamy and vacuolated cytoplasm (marked ly positive with fat stains) intermingled with a myxomatous tissue of stellate and spindle cells with a very loose and clear interstitium. Fig. 2. Basal cell carcinoma (epithelioma) of the skin showing nests of neoplastic cells in the dermis which are composed of small tightly packed aggregates with peripheral pali sading.
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Mihas/Doos
Milias/Doos
282
3
Fig. 3. Adenocarcinoma of colon showing submucosal pool of mucus containing mucin producing carcinoma cells. The serosa and regional lymph nodes were involved by tumor. Fig. 4. Thyroid carcinoma showing trabecular and microfollicular pattern. Vascular invasion was not present.
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4
283
Fig. 5. Infiltrating ductal carcinoma of the breast with scirrous reaction and ‘Indian filling’ of carcinoma cells. Three lymph nodes (of 18) showed métastasés. Fig. 6. Esophageal biopsy showing squamous cell carcinoma with keratohyalin pearl formation and intercellular bridges.
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Multiple Malignancies in Alcoholics
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admission he was found to have a large basal cell carcinoma of the left preauricular area which was treated with local excision and X-radiation therapy (fig. 2). Six months later he underwent a right hemicolectomy with ileo-transverse colostomy for an adenocarcinoma of the hepatic flexure (fig. 3). One year prior to this admission he was operated on for a ventral hernia repair; the operating surgeon found the liver and peritoneum free of any metastatic deposits. Other pertinent past history revealed that the patient was a heavy alcoholic; laboratory tests and liver scan were suggestive of chronic liver disease, probably cirrhosis. Physical examina tion revealed an elderly male, cachectic and extremely pale. Other pertinent findings were a grade 3 of 6 ejection type systolic murmur in the aortic area and a palpable spleen. Labora tory values showed an hematocrit of 21 with microcytic hypochromic indices; prothrombin time 15.3 sec with control of 12.3, bilirubin 2.3/mg/100 ml, albumin 2.1 g/100 ml, SGOT 20 IU and alkaline phosphatase 92 IU. A stool specimen was guaiac positive. Intradermal skin tests with: PPD (1st and 2nd strength), trichophytin and mumps were all negative. The hospital course was complicated by the development of an empyema of the gallbladder which was treated with drainage through a cholecystostomy tube and antibiotics. Again the surgeon was unable to detect any metastases to the liver or peritoneum. A cholecystogram via the cholecystostomy tube showed no evidence of obstruction of the cystic or common bile duct. The patient recovered fully from this insult and subsequent work-up included duodenoscopy which revealed the presence of a tumor in the second portion of the duode num distal to the papilla of Vater. Biopsies were obtained and histologic examination disclosed an adenocarcinoma. His poor general condition and nutritional status, as well as the extensive procedure indicated (Whipple’s operation) were decisive factors for not operating on this patient. He expired a few weeks later; autopsy was not granted. Patient II. A 66-year-old Caucasian female presented with a 2-month history of dys phagia and hematemesis 1 day prior to admission. Three years prior to admission she was found to have a follicular carcinoma of the thyroid requiring subtotal thyroidectomy (fig. 4). One year later she was admitted to the hospital for evaluation of a lump in the right breast; this was proven to be a ductal carcinoma, for which she underwent radical mastec tomy followed by cobalt teletherapy (fig. 5). The patient was also known to be a heavy alcoholic for many years with biopsy proven Laennec’s cirrhosis. Physical examination was unremarkable except for signs of peripheral neuropathy. Laboratory values revealed a normal hematocrit and chemistry profile. Liver function tests were within normal limits except for a mildly elevated alkaline phosphatase (105 IU) and marked hypoalbuminemia (2.0 g/100 ml). Tuberculin skin test (first and second strength) was twice negative. An upper gastrointestinal series revealed a large ulcerating mass in the distal esophagus. Surgery was performed (esophagogastrectomy) and an ulcerated mass measuring 3.5 X 1.5 cm was removed from the distal esophagus. Histologic examination revealed an infiltrating welldifferentiated squamous cell carcinoma of the esophagus with metastasis to the periesopha geal lymph nodes (fig. 6). The patient expired on the 10th postoperative day secondary to cardio-respiratory failure. Autopsy permission was not obtained.
The criteria for multiple primary malignancy proposed by Warren and Gares in 1932 (22) have been widely accepted: (1) each of the tumors must represent a definite picture of malignancy; (2) each tumor must be distinct histologically, and (3) the probability of one being a metastasis of the other must be excluded.
Downloaded by: Access provided by the University of Michigan Library 141.216.78.40 - 1/10/2019 11:47:21 AM
Comment
285
All three primary malignant tumors in each of our patients fulfill these criteria. In our first case report a fourth primary malignant neoplasm - adenocarcinoma of the second portion of the duodenum — was strongly suspected; exploratory laparotomy, 1 year and a second one a few days before the duodenoscopy was performed, failed to reveal any metastatic deposits. However, (a) the histologic similarity of this tumor with the previously resected adenocarcinoma of the colon, and (b) the lack of a postmortem examination were decisive factors for not considering this duodenal tumor as a fourth primary malignancy. There is an accumulating body of evidence that the risk of the development of a second primary malignant neoplasm in a person with one malignant neo plasm is greater than the risk of the development of the initial malignancy in any given population (5, 8, 22). In most of the published series the authors found a relatively high incidence of multiple primary malignant tumors and all attributed them to a susceptibility or predisposition to cancer. Peller (14), however, presenting statistical material from 5,876 cancer cases concluded that the real incidence for multiple malignancies was less than the expected rate and he hypothesized that a cured cancer secured protection against the appearance of another cancer. These conflicting conclusions reflect the lack of adequate control groups against which to compare the patient populations studied. The disclosure of common denominators of tumor induction in certain patient groups would be of great assistance to the clinician in his dealing with diagnostic and therapeutic problems of malignancy. Much evidence has accumulated during the past decade to support the concept that there exists in animals and in man a cellular mechanism for recognition and ultimate destruction of host cells under going dysplastic change (6, 10). The efficiency of an immune surveillance system of this kind may determine resistance or susceptibility to tumor development and similar events may be capable of altering the growth of established tumors (7, 17). Furthermore, it is well known that patients with immunologic defi ciency as well as patients treated with immunosuppressives are more prone to develop malignant tumors than are others (4, 11, 15). High incidence of neoplasms among patients with liver disease has not been reported with the exception of hepatoma especially in patients with underlying alcoholic cirrhosis (16). On the other hand, it has been known that patients with alcoholic liver disease are unusually susceptible to infections and impaired immunity has been suggested as a significant factor for this susceptibility (19). In recent years there is emerging evidence that patients with alcoholic liver disease show a high incidence of altered cellular immunity, although it is not clear whether this immunologic abnormality is the consequence or the cause of the disease (7, 12, 18). In a study of 177 cases of multiple primary malignancies the authors found that more than 50% of the cases showed significant cirrhosis of the liver (9). Both of our cases were known alcoholics with liver disease and both demon
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Multiple Malignancies in Alcoholics
Mihas/Doos
286
strated impaired cell-mediated immunity when skin-tested although the second patient was only tested with PPD. It should be noted that this impaired delayed hypersensitivity reaction was shown well in advance of the detection of the second and third primary tumors in these patients. It is attractive to speculate that patients with alcoholic liver disease may be more prone to develop malignancies than the general population. Coincidence, however, could be the only factor involved in the development of multiple primary malignant tumors in two patients who also had alcoholic liver disease. It would be useful to have our observation confirmed with data from other sources and a study of autopsy material among patients with alcoholic liver disease might be revealing. In the meantime, we suggest that patients with chronic liver disease should be carefully followed for possible development of a malignant neoplasm other than hepatoma. It is striking that among 177 cases of multiple primary malignancies only nine were diagnosed before the postmortem examina tion and no cancer was diagnosed (or suspected) in roughly one fourth of them (9).
1 Berenyi, M.R.; Straus, B., and Cruz, D.: In vitro and in vivo studies of cellular immuni ty in alcoholic cirrhosis. Am. J. dig. Dis. 19: 199-205 (1974). 2 Berg, J.W.: The incidence of multiple primary cancers. I. Development of further cancers in patients with lymphomas, leukemias and myeloma. J. natn. Cancer Inst. 38: 741-752(1967). 3 Billroth, T.: Die allgemeine chirurgische Pathologic und Therapie in 51 Vorlesungen, p. 908 (Reimer, Berlin 1889). 4 Brown, R.S.; Schiff, M., and Mitchell, M.S.: Reticulum-cell sarcoma of host origin arising in a transplanted kidney. Ann. intern. Med. 80: 459-463 (1974). 5 Bugher, J.C.: The probability of the chance occurrence of multiple malignant neo plasms. Am. J. Cancer 21: 809-824 (1934). 6 Burnet, F.M.: Immunological recognition of self. Science, N.Y. 133: 307-311 (1961). 7 Burnet, F.M.: The concept of immunological surveillance. Prog. exp. Tumor Res., vol. 13, pp. 1-27 (Karger, Basel 1970). 8 Gaudin, H.: Multiple primary malignant tumours. N.7.. med. J. 40: 367—374 (1941). 9 Hajdu, S.I. and Hajdu, E.D.: Multiple primary malignant tumors. J. Am. Geriat. Soc. 16: 16-26 (1968). 10 Hellstrom, I. and Hellstrom, K.E.: Some aspects of the immune defense against cancer. II. In vitro studies on human tumors. Cancer 28: 1269-1271 (1971). 11 Hermans, P.E. and Juizenga, K.A.: Association of gastric carcinoma with idiopathic late onset immunoglobulin deficiency. Ann. intern. Med. 76: 605-609 (1972). 12 Hsu, C.C.S. and Leevy, C.M.: Inhibition of PHA stimulated lymphocyte transformation by plasma from patients with advanced alcoholic cirrhosis. Clin. exp. Immunol. 8: 749-760(1971). 13 Moertel, C.G.; Dockerty, M.B., and Baggenstos, A.H.: Multiple primary malignant neoplasms. I. Introduction and presentation of data. II. Tumors of different tissues and organ. Cancer 14: 221-237 (1961).
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References
Multiple Malignancies in Alcoholics
287
Dr. A. Mihas, University of Alabama Medical Center, Birmingham, AL 35294 (USA)
Downloaded by: Access provided by the University of Michigan Library 141.216.78.40 - 1/10/2019 11:47:21 AM
14 Peller, S.: Metachronous multiple malignancies in 5,876 cancer patients. Am. J. Hyg. 34: 1-11 (1941). 15 Penn, I.: Hammond, W.; Brettsclmeider, L., and Staril, T.E.: Malignant lymphomas in transplantation patients. Transplant Proc. 1: 106-112 (1969). 16 Purtilo, D.T. and Gottlieb, L.S.: Cirrhosis and hepatoma occurring at Boston City Hospital. Cancer 32: 458-462 (1973). 17 Smith, R.T.: Possibility and problems of immunologic intervention in cancer. New Engl. J. Med. 287: 439-450 (1972). 18 Straus, B B e r e n y i , M.R.; Huang, J.M., and Straus, E.: Delayed hypersensitivity in alcoholic cirrhosis. Am. J. dig. Dis. 16: 509-516 (1971). 19 Straus, B. and Berenyi, M.R.: Infection and immunity in alcoholic cirrhosis. Mount Sinai J. Med. 40: 631-640 (1973). 20 Thoma, G.W.: The incidence and significance of multiple primary malignant tumors. I. A study of 2,346 necropsies from a cancer research hospital. Am. J. med. Sci. 77: 427-430(1964). 21 Tullis, J.L.: Multiple primary malignant lesions. J. Lab. clin. Med. 27: 588-594 (1942). 22 Warren, S. and Gores, O.: Multiple primary malignant tumors: a survey of the literature and statistical study. Am. J. Cancer 16: 1358-1414 (1932).
