THE Jour·a'-T1tL 01:· UROLOGY
Copyright © 1977 by The '1Villia1ns & Vlilkins Co.
EXTRARENAL MANIFESTATION'S OF RENAL CELL FRAY F. MARSHALL
AND
PATRICK C. WALSH
From the Department of Urology, Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, Maryland
ABSTRACT
Renal cell adenocarcinoma can be one of the great masqueraders in medicine. More common extrarenal manifestations of renal cell carcinoma include fever, anemia and gastrointestinal symptoms. Other rarer systemic symptoms are caused by amyloidosis, neuromyopathy and tumor thrombus. Humoral manifestations include polycythemia, hypercalcemia, galactorrhea and Cushing's syndrome. Metastatic disease commonly presents as the initial symptom. Syphilis and tuberculosis have been recognized as 2 of the great imitators in medicine. Presently, infectious disease is controlled better and often neoplastic disease, such as carcinoma of the lung, pancreas or kidney, can present with perplexing symptoms apparently unrelated to the primary involved organ. For the urologist renal cell carcinoma can be difficult to diagnose even after a complete evaluation, including an angiogram. Extrarenal manifestations of renal cell carcinoma are far more common than is realized. Classically, the triad ofhematuria, flank pain and a flank mass has been described but this triad has been reported more recently in only 16 per cent of the cases. 1 In l large series a third of the patients with renal cell carcinoma presented without any of the 3 elements of the classic triad. 2 The extrarenal manifestations of renal cell carcinoma can best be divided into 2 categories. The first group consists of patients with a variety of systemic manifestations of the neoplastic disease. The second, less common group, is composed of patients with hormonal manifestations secondary to the tumor. In the first group fever is one of the more common extrarenal manifestations of renal cell carcinoma. Malignancies are known to be a common source of fever in large series of patients with fever of unknown origin. As many as 20 per cent of the patients with hypemephroma will have a fever at some time during their course and in 3 per cent of the patients fever will be only initial presenting symptom. 3 Rarely are urinary tract infections the source of the fever. Formerly, necrosis and hemorrhage of the tumor have been thought to cause an elevated temperature but evidence for the release of endogenous pyrogens in renal cell carcinoma has been substantiated.4 Gastrointestinal disturbances have been reported in a sixth of patients with hypernephroma. 1 Nausea, vomiting, anorexia, constipation and abdominal pain have been described. Hypercalcemia, pressure effects or direct tumor involvement may be related to the symptoms. In addition, nephrogenic hepatopathy or hepatic dysfunction associated with renal cell carcinoma is a well recognized entity. 3 Hepatic dysfunction is measured by the usual liver function tests, including bilirubin, alkaline phosphatase, prothrombin time, protein electrophoresis and bromsulphalein tests. Although the exact incidence is not known hepatic dysfunction is not an extremely rare phenomenon. In many of the reported patients liver function tests reverted to normal after resection of the hypernephroma. Therefore, hepatic dysfunction associated with renal cell carcinoma does not necessarily contraindicate an operation. Although polycythemia is known to be associated with hypernephroma anemia is far more common. As many as a quarter of the patients will have anemia, which does not Accepted for publication July 30, 1976.
appear to be secondary to blood loss and is generally normochromic and normocytic. 2 Although anemia has not been characterized fully it appears to be associated with malignancy and secondary to marrow depression. In some cases the hematocrit has returned to normal after resection of the primary tumor. Amyloidosis has been associated with as many as 3 per cent of the patients with renal cell carcinoma.'·" Some patients have presented with diffuse symptoms suggestive of a collagen vascular disease and have had no genitourinary symptoms. Many organs have been involved with amyloidosis, including the opposite kidney, heart, spleen and liver. Generally, the prognosis has been poor in these patients. Renal cell carcinoma also tends to invade the renal veins frequently. In more extensive cases a tumor thrombus may extend into the vena cava. 7 Occlusion of the vena cava may produce edema of the lower extremities. If the tumor thrombus extends to the hepatic veins a Budd-Chiari-like syndrome may ensue, and ascites and abnormal liver function tests may result from hepatic venous obstruction. In the most severe cases the tumor thrombus may extend into the right atrium. Resection of the vena cava has been done for a right-sided lesion with direct involvement of the vena cava. Other rare entities have been associated with hypernephroma. A polyneuromyopathy has been reported. 8 One patient experienced complete resolution of the neuropathy after resection of the tumor. A leukemoid reaction with a high white blood count resembling leukemia has been reported in 1 instance. 9 In addition, the association of renal cell carcinoma with von Hippel-Lindau's disease is well recognized. 10 Various hormonal syndromes have been associated with neoplastic disease. 11 Symptoms have been the result of hormone by the ueuµ,aa,c1c tissue. Renal cell carcinoma is one of the common non-endocrine tumors that is associated vvith hormone production. On the other hand, it has become apparent in recent years that the kidney is an endo· crine organ and is involved in calcium metabolism and the maintenance of a normal hematocrit. Polycythemia, or more appropriately erythrocytosis, is associated with approximately 3 per cent of the patients with hypernephroma. 2 Erythrocytosis is the appropriate term because usually there is not the associated leukocytosis or increase in platelet count. Some patients have been treated initially for polycythemia and were found subsequently to have a renal cell carcinoma. Although several hypotheses have been suggested an erythropoietic stimulating substance, or erythropoietin, 12 has been isolated from the tumors of some patients. The erythropoietin isolated from these tumors appears to be similar to normal erythropoietin. Hypercalcemia also is well recognized to occur with renal cell carcinoma. Sometimes hypercalcemia is secondary to osteolytic metastases, with resultant increase in serum calcium levels. In other instances, however, hypercalcemia may be
439
440
MARSHALL AND WALSH
present without any evidence of bone involvement. A variety of humoral agents has been implicated in the hypercalcemia of malignancy. These substances include parathormone, vitamin D, vitamin D metabolites, prostaglandins and osteoclast activating factors. 13 In several patients with hypernephroma ectopic hyperparathyroidism has been reported. 14 Elevated parathormone levels have been found by radioimmunoassay techniques. 15 This hormone was indistinguishable from normal parathormone. In other patients with hypercalcemia elevated parathormone levels were not detectable. 16 In 1 reported case the patient responded to indomethacin therapy after all other treatment for hypercalcemia had failed. 17 A prostaglandin E and F-like factor was isolated from this tumor. It becomes apparent, then, that the pathogenesis of the hypercalcemia associated with renal cell carcinoma is quite diverse. As many as a quarter of the patients with hypernephroma will have some element of hypertension. 18 Arteriovenous fistulas have been implicated in some patients. 19 Some patients may have hypertension solely on an idiopathic basis but, recently, a renin-secreting tumor has been identified. 20 Renin secretion also has been reported previously with other renal neoplasms. 21 One patient was reported to have a tumor with an apparent hypotensive effect. Prostaglandin A levels were found to be markedly elevated in the tumor tissue. 22 Prostaglandin A is a known potent vasodilator. Other much rarer clinical endocrine syndromes have been reported with hypernephroma. Several patients have been identified with Cushing's syndrome thought to be secondary to ectopic adrenocorticotropic hormone production by a hypernephroma. 23 These patients do not always have the typical body habitus of Cushing's syndrome but hypokalemia is usually a prominent feature of the disease. One patient has been reported with galactorrhea and renal cell carcinoma. Prolactin was demonstrated in tissue culture of the tumor. 24 Immunologic studies revealed a hormone identical to normal prolactin. In other cases an enteropathy associated with glucagon-like activity in a renal cell carcinoma was reported. 25 In addition, gynecomastia and loss of libido have been demonstrated in a patient with hypernephroma and an ectopic gonadotropin production. 26 Initial symptoms of renal cell carcinoma often can present from metastatic disease. Metastatic disease from the thyroid27 to the testicle28 has been reported as the initial site of symptoms. The 3 most common sites of metastatic disease are lung, brain and bone. Some chest lesions have been found by serendipity. Bone pain may be an initial symptom. We have had 2 patients in the last year present initially with brain lesions who were found later to have a primary renal cell carcinoma. The extrarenal manifestations of renal cell carcinoma can be exceedingly varied and can imitate many other diseases. REFERENCES
1. Tveter, H. J.: Unusual manifestations of renal carcinoma. A review of the literature. Acta Chir. Scand., 139: 401, 1973. 2. Melicow, M. M. and Uson, A. C.: Nonurologic symptoms in patients with renal cancer. J.A.M.A., 172: 146, 1960. 3. Berger, L. and Sinkoff, M. W.: Systemic manifestations of hypernephroma. A review of273 cases. Amer. J. Med., 22: 791, 1957. 4. Cranston, W. I., Luff, R. H., Owen, D. and Rawlins, M. D.: Studies on the pathogenesis of fever in renal carcinoma. Clin. Sci. Mol. Med., 45: 459, 1973.
5. Walsh, P. N. and Kissane, J.M.: Nonmetastatic hypernephroma with reversible hepatic dysfunction. Arch. Intern. Med., 122: 214, 1968. 6. Svane, S.: Hypernephroma and systemic amyloidosis. A report on 3 cases. Acta Chir. Scand., 136: 68, 1970. 7. Svane, S.: Tumor thrombus of the inferior vena cava resulting from renal carcinoma. A report on 12 autopsied cases. Scand. J. Urol. Nephrol., 3: 245, 1969. 8. Alanis, B. F. and Flanagan, J. F.: Myopathy and hypercalcemia occurring with carcinoma of the kidney. J.A.M.A., 171: 2076, 1959. 9. Reiss, 0.: Leukemoid reaction due to hypernephroma. J.A.M.A., 180: 1126, 1962. 10. Malek, R. S. and Greene, L. F.: Urologic aspects of HippelLindau syndrome. J. Urol., 106: 800, 1971. 11. Liddle, G. W., Nicholson, W. E., Island, D. P., Orth, D. N., Abe, K. and Lowder, S. C.: Clinical and laboratory studies of ectopic humoral syndromes. Recent Progr. Hormone Res., 25: 283, 1969. 12. Murphy, G. P., Kenny, G. M. and Mirand, E. A.: Erythropoietin levels in patients with renal tumors or cysts. Cancer, 26: 191, 1970. 13. Tashjian, A. H., Jr.: Tumor humors and the hypercalcemias of cancer. New Engl. J. Med., 290: 905, 1974. 14. Blair, A. J., Jr., Hawker, C. D. and Utiger, R. D.: Ectopic hyperparathyroidism in a patient with metastatic hypernephroma. Metabolism, 22: 147, 1973. 15. Lytton, B., Rosof, B. and Evans, J. S.: Parathyroid hormone-like activity in a renal carcinoma producing hypercalcemia. J. Urol., 93: 127, 1965. 16. Powell, D., Singer, F. R., Murray, T. M., Minkin, C. and Potts, J. T., Jr.: Nonparathyroid humoral hypercalcemia in patients wih neoplastic diseases. New Engl. J. Med., 289: 176, 1973. 17. Brereton, H. D., Halushka, P. V., Alexander, R. W., Mason, D. M., Keiser, H. R. and DeVita, V. T., Jr.: Indomethacin-responsive hypercalcemia in a patient with renal-cell adenocarcinoma. New Engl. J. Med., 291: 83, 1974. 18. Griffiths, I. H. and Thackray, A. C.: Parenchymal carcinoma of the kidney. Brit. J. Urol., 21: 128, 1949. 19. Rodgers, M. V., Moss, A. J., Hoffman, M. and Lipchik, E. 0.: Arteriovenous fistulae secondary to renal cell carcinoma. Clinical and cardiovascular manifestations: report of a case. Circulation, 52: 345, 1975. 20. Hollifield, J. W., Page, D. L., Smith, C., Michelakis, A. M., Staab, E. and Rhamy, R.: Renin-secreting clear cell carcinoma of the kidney. Arch. Intern. Med., 135: 859, 1975. 21. Eddy, R. L. and Sanchez, S. A.: Renin-secreting renal neoplasm and hypertension with hypokalemia. Ann. Intern. Med., 75: 725, 1971. 22. Zusman, R. M., Snider, J. J., Cline, A., Caldwell, B. V. and Speroff, L.: Antihypertensive function of a renal-cell carcinoma. Evidence for a prostaglandin-A-secreting tumor. New Engl. J. Med., 290: 843, 1974. 23. Riggs, B. L., Jr. and Sprague, R. G.: Association of Cushing's syndrome and neoplastic disease: observations in 232 cases of Cushing's syndrome and review of the literature. Arch. Intern. Med., 108: 841, 1961. 24. Turkington, R. W.: Ectopic production ofprolactin. New Engl. J. Med., 285: 1455, 1971. 25. Gleeson, M. H., Bloom, S. R., Polak, J. M., Henry, K. and Dowling, R. H.: An endocrine tumour in kidney affecting small bowel structure, motility, and function. GUT, 11: 1060, 1970. 26. Case records of Massachusetts General Hospital: Case 13-1972. New Engl. J. Med., 286: 713, 1972. 27. Gault, E.W., Leung, T. H. and Thomas, D. P.: Clear cell renal carcinoma masquerading as thyroid enlargement. J. Path., 113: 21, 1974. 28. Talerman, A. and Kniestedt, W. F.: Testicular tumor as the first manifestation of renal carcinoma. J. Urol., 111: 584, 1974.
Copyright © 1977 by The '1Villia1ns & Vlilkins Co.
EXTRARENAL MANIFESTATION'S OF RENAL CELL FRAY F. MARSHALL
AND
PATRICK C. WALSH
From the Department of Urology, Brady Urological Institute, The Johns Hopkins Hospital, Baltimore, Maryland
ABSTRACT
Renal cell adenocarcinoma can be one of the great masqueraders in medicine. More common extrarenal manifestations of renal cell carcinoma include fever, anemia and gastrointestinal symptoms. Other rarer systemic symptoms are caused by amyloidosis, neuromyopathy and tumor thrombus. Humoral manifestations include polycythemia, hypercalcemia, galactorrhea and Cushing's syndrome. Metastatic disease commonly presents as the initial symptom. Syphilis and tuberculosis have been recognized as 2 of the great imitators in medicine. Presently, infectious disease is controlled better and often neoplastic disease, such as carcinoma of the lung, pancreas or kidney, can present with perplexing symptoms apparently unrelated to the primary involved organ. For the urologist renal cell carcinoma can be difficult to diagnose even after a complete evaluation, including an angiogram. Extrarenal manifestations of renal cell carcinoma are far more common than is realized. Classically, the triad ofhematuria, flank pain and a flank mass has been described but this triad has been reported more recently in only 16 per cent of the cases. 1 In l large series a third of the patients with renal cell carcinoma presented without any of the 3 elements of the classic triad. 2 The extrarenal manifestations of renal cell carcinoma can best be divided into 2 categories. The first group consists of patients with a variety of systemic manifestations of the neoplastic disease. The second, less common group, is composed of patients with hormonal manifestations secondary to the tumor. In the first group fever is one of the more common extrarenal manifestations of renal cell carcinoma. Malignancies are known to be a common source of fever in large series of patients with fever of unknown origin. As many as 20 per cent of the patients with hypemephroma will have a fever at some time during their course and in 3 per cent of the patients fever will be only initial presenting symptom. 3 Rarely are urinary tract infections the source of the fever. Formerly, necrosis and hemorrhage of the tumor have been thought to cause an elevated temperature but evidence for the release of endogenous pyrogens in renal cell carcinoma has been substantiated.4 Gastrointestinal disturbances have been reported in a sixth of patients with hypernephroma. 1 Nausea, vomiting, anorexia, constipation and abdominal pain have been described. Hypercalcemia, pressure effects or direct tumor involvement may be related to the symptoms. In addition, nephrogenic hepatopathy or hepatic dysfunction associated with renal cell carcinoma is a well recognized entity. 3 Hepatic dysfunction is measured by the usual liver function tests, including bilirubin, alkaline phosphatase, prothrombin time, protein electrophoresis and bromsulphalein tests. Although the exact incidence is not known hepatic dysfunction is not an extremely rare phenomenon. In many of the reported patients liver function tests reverted to normal after resection of the hypernephroma. Therefore, hepatic dysfunction associated with renal cell carcinoma does not necessarily contraindicate an operation. Although polycythemia is known to be associated with hypernephroma anemia is far more common. As many as a quarter of the patients will have anemia, which does not Accepted for publication July 30, 1976.
appear to be secondary to blood loss and is generally normochromic and normocytic. 2 Although anemia has not been characterized fully it appears to be associated with malignancy and secondary to marrow depression. In some cases the hematocrit has returned to normal after resection of the primary tumor. Amyloidosis has been associated with as many as 3 per cent of the patients with renal cell carcinoma.'·" Some patients have presented with diffuse symptoms suggestive of a collagen vascular disease and have had no genitourinary symptoms. Many organs have been involved with amyloidosis, including the opposite kidney, heart, spleen and liver. Generally, the prognosis has been poor in these patients. Renal cell carcinoma also tends to invade the renal veins frequently. In more extensive cases a tumor thrombus may extend into the vena cava. 7 Occlusion of the vena cava may produce edema of the lower extremities. If the tumor thrombus extends to the hepatic veins a Budd-Chiari-like syndrome may ensue, and ascites and abnormal liver function tests may result from hepatic venous obstruction. In the most severe cases the tumor thrombus may extend into the right atrium. Resection of the vena cava has been done for a right-sided lesion with direct involvement of the vena cava. Other rare entities have been associated with hypernephroma. A polyneuromyopathy has been reported. 8 One patient experienced complete resolution of the neuropathy after resection of the tumor. A leukemoid reaction with a high white blood count resembling leukemia has been reported in 1 instance. 9 In addition, the association of renal cell carcinoma with von Hippel-Lindau's disease is well recognized. 10 Various hormonal syndromes have been associated with neoplastic disease. 11 Symptoms have been the result of hormone by the ueuµ,aa,c1c tissue. Renal cell carcinoma is one of the common non-endocrine tumors that is associated vvith hormone production. On the other hand, it has become apparent in recent years that the kidney is an endo· crine organ and is involved in calcium metabolism and the maintenance of a normal hematocrit. Polycythemia, or more appropriately erythrocytosis, is associated with approximately 3 per cent of the patients with hypernephroma. 2 Erythrocytosis is the appropriate term because usually there is not the associated leukocytosis or increase in platelet count. Some patients have been treated initially for polycythemia and were found subsequently to have a renal cell carcinoma. Although several hypotheses have been suggested an erythropoietic stimulating substance, or erythropoietin, 12 has been isolated from the tumors of some patients. The erythropoietin isolated from these tumors appears to be similar to normal erythropoietin. Hypercalcemia also is well recognized to occur with renal cell carcinoma. Sometimes hypercalcemia is secondary to osteolytic metastases, with resultant increase in serum calcium levels. In other instances, however, hypercalcemia may be
439
440
MARSHALL AND WALSH
present without any evidence of bone involvement. A variety of humoral agents has been implicated in the hypercalcemia of malignancy. These substances include parathormone, vitamin D, vitamin D metabolites, prostaglandins and osteoclast activating factors. 13 In several patients with hypernephroma ectopic hyperparathyroidism has been reported. 14 Elevated parathormone levels have been found by radioimmunoassay techniques. 15 This hormone was indistinguishable from normal parathormone. In other patients with hypercalcemia elevated parathormone levels were not detectable. 16 In 1 reported case the patient responded to indomethacin therapy after all other treatment for hypercalcemia had failed. 17 A prostaglandin E and F-like factor was isolated from this tumor. It becomes apparent, then, that the pathogenesis of the hypercalcemia associated with renal cell carcinoma is quite diverse. As many as a quarter of the patients with hypernephroma will have some element of hypertension. 18 Arteriovenous fistulas have been implicated in some patients. 19 Some patients may have hypertension solely on an idiopathic basis but, recently, a renin-secreting tumor has been identified. 20 Renin secretion also has been reported previously with other renal neoplasms. 21 One patient was reported to have a tumor with an apparent hypotensive effect. Prostaglandin A levels were found to be markedly elevated in the tumor tissue. 22 Prostaglandin A is a known potent vasodilator. Other much rarer clinical endocrine syndromes have been reported with hypernephroma. Several patients have been identified with Cushing's syndrome thought to be secondary to ectopic adrenocorticotropic hormone production by a hypernephroma. 23 These patients do not always have the typical body habitus of Cushing's syndrome but hypokalemia is usually a prominent feature of the disease. One patient has been reported with galactorrhea and renal cell carcinoma. Prolactin was demonstrated in tissue culture of the tumor. 24 Immunologic studies revealed a hormone identical to normal prolactin. In other cases an enteropathy associated with glucagon-like activity in a renal cell carcinoma was reported. 25 In addition, gynecomastia and loss of libido have been demonstrated in a patient with hypernephroma and an ectopic gonadotropin production. 26 Initial symptoms of renal cell carcinoma often can present from metastatic disease. Metastatic disease from the thyroid27 to the testicle28 has been reported as the initial site of symptoms. The 3 most common sites of metastatic disease are lung, brain and bone. Some chest lesions have been found by serendipity. Bone pain may be an initial symptom. We have had 2 patients in the last year present initially with brain lesions who were found later to have a primary renal cell carcinoma. The extrarenal manifestations of renal cell carcinoma can be exceedingly varied and can imitate many other diseases. REFERENCES
1. Tveter, H. J.: Unusual manifestations of renal carcinoma. A review of the literature. Acta Chir. Scand., 139: 401, 1973. 2. Melicow, M. M. and Uson, A. C.: Nonurologic symptoms in patients with renal cancer. J.A.M.A., 172: 146, 1960. 3. Berger, L. and Sinkoff, M. W.: Systemic manifestations of hypernephroma. A review of273 cases. Amer. J. Med., 22: 791, 1957. 4. Cranston, W. I., Luff, R. H., Owen, D. and Rawlins, M. D.: Studies on the pathogenesis of fever in renal carcinoma. Clin. Sci. Mol. Med., 45: 459, 1973.
5. Walsh, P. N. and Kissane, J.M.: Nonmetastatic hypernephroma with reversible hepatic dysfunction. Arch. Intern. Med., 122: 214, 1968. 6. Svane, S.: Hypernephroma and systemic amyloidosis. A report on 3 cases. Acta Chir. Scand., 136: 68, 1970. 7. Svane, S.: Tumor thrombus of the inferior vena cava resulting from renal carcinoma. A report on 12 autopsied cases. Scand. J. Urol. Nephrol., 3: 245, 1969. 8. Alanis, B. F. and Flanagan, J. F.: Myopathy and hypercalcemia occurring with carcinoma of the kidney. J.A.M.A., 171: 2076, 1959. 9. Reiss, 0.: Leukemoid reaction due to hypernephroma. J.A.M.A., 180: 1126, 1962. 10. Malek, R. S. and Greene, L. F.: Urologic aspects of HippelLindau syndrome. J. Urol., 106: 800, 1971. 11. Liddle, G. W., Nicholson, W. E., Island, D. P., Orth, D. N., Abe, K. and Lowder, S. C.: Clinical and laboratory studies of ectopic humoral syndromes. Recent Progr. Hormone Res., 25: 283, 1969. 12. Murphy, G. P., Kenny, G. M. and Mirand, E. A.: Erythropoietin levels in patients with renal tumors or cysts. Cancer, 26: 191, 1970. 13. Tashjian, A. H., Jr.: Tumor humors and the hypercalcemias of cancer. New Engl. J. Med., 290: 905, 1974. 14. Blair, A. J., Jr., Hawker, C. D. and Utiger, R. D.: Ectopic hyperparathyroidism in a patient with metastatic hypernephroma. Metabolism, 22: 147, 1973. 15. Lytton, B., Rosof, B. and Evans, J. S.: Parathyroid hormone-like activity in a renal carcinoma producing hypercalcemia. J. Urol., 93: 127, 1965. 16. Powell, D., Singer, F. R., Murray, T. M., Minkin, C. and Potts, J. T., Jr.: Nonparathyroid humoral hypercalcemia in patients wih neoplastic diseases. New Engl. J. Med., 289: 176, 1973. 17. Brereton, H. D., Halushka, P. V., Alexander, R. W., Mason, D. M., Keiser, H. R. and DeVita, V. T., Jr.: Indomethacin-responsive hypercalcemia in a patient with renal-cell adenocarcinoma. New Engl. J. Med., 291: 83, 1974. 18. Griffiths, I. H. and Thackray, A. C.: Parenchymal carcinoma of the kidney. Brit. J. Urol., 21: 128, 1949. 19. Rodgers, M. V., Moss, A. J., Hoffman, M. and Lipchik, E. 0.: Arteriovenous fistulae secondary to renal cell carcinoma. Clinical and cardiovascular manifestations: report of a case. Circulation, 52: 345, 1975. 20. Hollifield, J. W., Page, D. L., Smith, C., Michelakis, A. M., Staab, E. and Rhamy, R.: Renin-secreting clear cell carcinoma of the kidney. Arch. Intern. Med., 135: 859, 1975. 21. Eddy, R. L. and Sanchez, S. A.: Renin-secreting renal neoplasm and hypertension with hypokalemia. Ann. Intern. Med., 75: 725, 1971. 22. Zusman, R. M., Snider, J. J., Cline, A., Caldwell, B. V. and Speroff, L.: Antihypertensive function of a renal-cell carcinoma. Evidence for a prostaglandin-A-secreting tumor. New Engl. J. Med., 290: 843, 1974. 23. Riggs, B. L., Jr. and Sprague, R. G.: Association of Cushing's syndrome and neoplastic disease: observations in 232 cases of Cushing's syndrome and review of the literature. Arch. Intern. Med., 108: 841, 1961. 24. Turkington, R. W.: Ectopic production ofprolactin. New Engl. J. Med., 285: 1455, 1971. 25. Gleeson, M. H., Bloom, S. R., Polak, J. M., Henry, K. and Dowling, R. H.: An endocrine tumour in kidney affecting small bowel structure, motility, and function. GUT, 11: 1060, 1970. 26. Case records of Massachusetts General Hospital: Case 13-1972. New Engl. J. Med., 286: 713, 1972. 27. Gault, E.W., Leung, T. H. and Thomas, D. P.: Clear cell renal carcinoma masquerading as thyroid enlargement. J. Path., 113: 21, 1974. 28. Talerman, A. and Kniestedt, W. F.: Testicular tumor as the first manifestation of renal carcinoma. J. Urol., 111: 584, 1974.
