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Non-Metastatic Hepatic Dysfunction Associated with Renal Carcinoma
0022-534 7/78/1194-0468.$02. 00/ 0 Vol. 119, April Printed in U.S.A.
THE JOURNAL OF UROWGY
Copyright © 1978 by The Williams & Wilkins Co.
NON-METASTATIC HEPATIC DYSFUNCTION ASSOCIATED WITH RENAL CARCINOMA RICHARD J. BOXER,* JERRY WAISMAN, MICHAEL M. LIEBER, FRANCISCO M. MAMPASO AND DONALD G. SKINNER From the Division of Urology, Department of Surgery, and Department of Pathology, University of California, Los Angeles, California
ABSTRACT
A retrospective computer analysis of 102 patients treated for renal tubular carcinoma revealed 7 patients who presented with non-metastatic hepatic dysfunction. Of these 7 patients 5 also had the triad of fever, weight loss and fatigue. Only 1 patient survived more than 10 years after nephrectomy. A review of the literature on non-metastatic hepatic dysfunction revealed a significant interval between onset of symptoms and detection of the underlying renal malignancy, as well as a poor over-all survival rate if the syndrome persisted after nephrectomy. Renal tubular carcinoma or renal cell carcinoma, henceforth referred to as renal carcinoma, may present with a wide variety of symptoms and signs, ranging from the classic triad of hematuria, flank pain and palpable abdominal mass occurring in 10 per cent of the cases 1 to common but more obtuse signs, such as fever, 2• 3 fatigue, weight loss, weakness and anemia. 4 • 5 These neoplasms also may secrete parathormone, thus causing symptoms and signs of hyperparathyroidism, erythropoietin causing erythrocytosis or renin-producing hypertension. 6 • 7 Because of the wide range of unusual and nonspecific presenting features the detection of a renal carcinoma often is difficult and delayed. In 1935 Creevy described 3 patients with renal carcinoma who presented with a clinical picture simulating hepatic cirrhosis. 8 However, it was not until 1961 that Stauffer reported the syndrome of reversible hepatic dysfunction associated with renal carcinoma. 9 None of his 5 patients had liver metastases at the time of nephrectomy but preoperative liver function studies included retention of bromsulphthalein, an elevated serum alkaline phosphatase level, an increased prothrombin time, an elevated a-2-globulin fraction of the blood proteins and an abnormal thymol turbidity test. These abnormal liver function studies reverted to normal after nephrectomy but long-term surveillance of these patients was not reported. This syndrome of reversible hepatic dysfunction associated with renal carcinoma subsequently has been noted by others and to date 95 cases have been reported. 10-2 :1 Long-term observation has been recorded in 39 patients and only 17 of them have survived 2 years. Warren and associates reported on 13 patients in whom the syndrome persisted postoperatively and only 4 were alive at 2 years. 24 Of 13 patients whose liver function tests returned to normal postoperatively 11 survived 2 years. 24 The syndrome also has been reported in patients with xanthogranulomatous pyelonephritis stimulating renal carcinoma25 and localized cancer of the gastrointestinal tract, 26 as well as in a 10-month-old infant with renal carcinoma. 27 A humoral etiology has been suggested but not proved by isolation of an active substance or by experimental models. 28 During a 20-year period 7 patients with hepatic dysfunction Accepted for publication May 13, 1977. Read at annual meeting of Western Section, American Urological Association, San Francisco, California, March 13-17, 1977. Supported in part by the Blalock Foundation, University of California, Los Angeles, California. *Requests for reprints: c/o Editor's Office, Department of Surgery, University of California at Los Angeles, Los Angeles, California 90024.
associated with renal carcinoma were treated at our hospital. Herein we relate the clinical, radiographic and survival data, and describe the features of the renal specimens from these patients compared to similar patients with renal carcinoma but without hepatic dysfunction. MATERIALS AND METHODS
The clinical reports and operative specimens of 102 patients who underwent nephrectomy for renal carcinoma at our hospital were reviewed and coded for analysis by computer. Thirty-five symptoms, 20 physical and radiological signs, 35 features of the kidneys and the neoplasms, and 12 therapeutic modalities were annotated for each patient. The tumor specimens were reviewed independently by 2 pathologists (J. W. and F. M. M.) without knowledge of the clinical data, and 17 gross and 18 microscopic characteristics of each specimen were obtained. Analysis of the data was performed by computer and each feature was related to survival data by the Fisher exact test and the chi-square test. Survival data were computed by the life table analysis method. 29 In this study hepatic dysfunction was determined by an elevation of blood alkaline phosphatase level, retention of bromsulphthalein, albumin:globulin ratio of less than 1, elevated serum haptoglobin (a-2-globulin) level and increased serum prothrombin time. Of the 102 patients 76 had 2 or more of the enumerated tests of hepatic dysfunction. The 7 patients described herein had abnormal results of at least 3 of the aforementioned tests, indicating liver dysfunction. CASE REPORT
A 44-year-old white man was in excellent health until March 1965 when he noticed the sudden onset of fever (contant at lOOF), malaise, weight loss and fatigue. A heterophil test and blood culture were normal and, after 3 months of symptoms, the man was hospitalized. History included an abdominal perineal resection for carcinoma of the rectum. Physical examination revealed an enlarged firm liver but a barium enema, upper gastrointestinal series, cholecystogram and hepatic scan were within normal limits. Laboratory data indicated liver dysfunction (table 1), while a needle biopsy of the liver showed normal histology. The patient was transferred to our hospital for further laboratory tests. A bone marrow aspirate, repeat hepatic scan and isotope scan of the brain were normal, as well as other tests of urine and serum chemistry studies. The urinary sediment showed 4 red blood cells per high power field and an excretory urogram revealed a mass in the upper pole of the right kidney. Subsequently, a radical nephrectomy and liver biopsy were performed.
468
NON-METASTATIC HEPATIC DYSFUNCTION ASSOCIATED WITH RENAL CARCINOMA TABLE
Date
BromsulDhthalein at 45 Minutes (% retention)
Alkaline Phosphatase Level (King-Armstrong units; normal 1-4)
16.6 17.9
9.9* 21
6/22/65 8/22/65
1. Laboratory data from the case report
Prothrombin Time (sec.)
SerumGluAlbumin: a-2-Globulin tamic OxaloaRatio (% serum protein, cetic Transami- Globulin (gm.) normal 7-11) nase (units)
16 (control = 12.5) 18.5 (control = 13.5)
24 29
3.0:4.1 3.0:4.2
16% (1.1 gm.) 17.5% (1.3 gm.)
SedimentationRate (mm./hr.)
Liver Biopsy
Normal
32
Slight periportal fibrosis
8/30/65t 9/22/65 10/20/65 7/25/66
0.1
5.6 4.9 6.9
12 32
13 (control = 13)
5.0:2.5
10% (0. 75 gm.)
23 18
* Bodansky units, normal 1-4. t Rt. radical nephrectomy.
A, renal carcinoma with sheets of cells separated by delicate vascular stroma. H & E, reduced from x250. H, neoplastic cells have granular cytoplasm. Reduced from x675. TABLE
2. Significant features of renal carcinoma compared in
patients with and without hepatic dysfunction* Feature Flank pain Gross hematuria Fever Weight loss Fatigue No symptoms Anemia Splenomegaly Solid (>90%) patternt Tubular ( <5%) patternt Triad (fever, fatigue, weight loss)
Hepatic Dysfunction (%) No= 7 0 0 71
86 86 0 71
17 100 86 72
No Hepatic Dysfunction(%) No= 69 30 31 10 26 25 30 20 0
56 52 9
p Value <0.10 <0.10 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.05 <0.10 <0.0005
* Two or more tests of hepatic function available. t The over-all microscopic appearance of the tumors was grouped into solid, cystic, tubular and papillary patterns.
A renal carcinoma was present with the characteristic gross appearance. The renal tumor contained 90 per cent granular cells, 10 per cent clear cells and 10 per cent fusiform (spindleshaped) cells (see figure). There were no giant or foam cells. Ninety per cent of the tumor showed a solid pattern and 10 per cent was cystic. The over-all grade of the carcinoma was 3 (poorly differentiated), while the nuclear grade1 was 2 (inter-
mediate). There was microscopic invasion of the veins and hilus but not of the main renal vein, capsule, pelvis or regional lymph nodes, thus indicating a stage I tumor. The liver biopsy showed slight periportal fibrosis and inflammation. Convalescence was uneventful and the patient was discharged from the hospital 7 days postoperatively. Subsequent liver function studies reverted to normal and in July 1975, 10 years after nephrectomy, the patient was well without evidence of residual recurrent disease. RESULTS
The average age of the 7 patients with hepatic dysfunction was 55. 7 years, exactly the same as the group without the syndrome. There were 3 men (43 per cent) and 4 women (57 per cent) with this syndrome, whereas the general population with renal carcinoma contained 31 per cent women and 69 per cent men. None of the patients with the syndrome had evidence of liver metastases by clinical or radiologic tests. The significant variables are listed in table 2. Fever, fatigue, weight loss and anemia were statistically more common in patients with hepatic dysfunction than in those without this syndrome (p < 0.01). Of the 7 patients 5 (71 per cent) with hepatic dysfunction had the symptom complex of fever, fatigue and weight loss, whereas 5 (7.2 per cent) of69 patients without hepatic dysfunction had the triad. This difference is
470
BOXER AND ASSOCIATES
highly significant (p < 0.0005). If anemia, fever, weight loss and fatigue were viewed as a tetrad 3 (43 per cent) of the patients with hepatic dysfunction displayed the complex compared to 5 per cent of the other patients (p = 0.015). None of the patients with hepatic dysfunction had flank pain, whereas that symptom was noted in 30 per cent of those without hepatic dysfunction (p < 0.10). None of the 5 patients with hepatic dysfunction associated with the triad of fever, fatigue and weight loss had evidence of metastases, although 6 patients with the triad but without hepatic dysfunction had metastases at the time of presentation. There were no differences between the 7 patients with hepatic dysfunction and the 76 patients who had normal liver function in regard to tumor size, location, weight, diameter cut surface or gross venous invasion. There were no statistical differences in evidence of glomerulonephritis, pyelonephritis or ischemia; cortical adenomas; arterial disease, and venous, capsular, hilar or pelvic invasion. There were no differences in cell type (granular, clear or fusiform), the presence or absence of foam or giant cells, or the over-all or nuclear grade. Finally, neither group was different in the incidence of adrenal and lymph node metastases. All patients with hepatic dysfunction had a solid pattern in more than 90 per cent of the tumor and this observation was statistically significant compared to patients without hepatic dysfunction (p < 0.05). The hepatic dysfunction in the 7 patients was staged according to the method described by Robson. 30 Three patients had stage I disease, 2 had stage II, 1 was lost to followup and 1 is alive after 2 years with metastatic disease that developed 1 year postoperatively. The patients with stage IV disease died within 8 months ofnephrectomy. These figures compared to an over-all survival of 62 per cent at 5 years for those patients with stages I, II and III disease without hepatic dysfunction and 1.5 years in patients with metastatic disease and no hepatic dysfunction. DISCUSSION
The association of hepatic dysfunction with renal carcinoma but without hepatic metastases is now a well recognized clinical syndrome and has been recorded in 102 patients, including the 7 reported herein. The clinical triad of fever, fatigue and weight loss associated with abnormal liver function studies should alert the clinician to the possible presence of renal carcinoma, although considerable delay usually occurs from clinical presentation to detection of the underlying renal malignancy, a probable factor in the poor long-term prognosis of many patients with renal carcinoma. The etiology of hepatic dysfunction as well as the cause of the associated symptoms of fever, fatigue and weight loss are unknown, although Utz and associates have suggested a humoral factor. 10, 28 To date, such a substance has not been isolated nor have experimental animal models for renal carcinoma revealed any humoral abnormality. The actual incidence of hepatic dysfunction associated with renal carcinoma is probably greater than currently recognized. Utz and associates reported, since 1961, a 40 per cent incidence of abnormal liver function studies obtained routinely in all patients with renal carcinoma at the Mayo Clinic. The prognostic significance of abnormal liver function tests remains unclear. Although 1 of our patients survived 10 years most of those with the syndrome are dead of metastatic disease within 5 years unless liver function returns to normal after nephrectomy and constitutional symptoms disappear. Earlier recognition of the underlying renal tumor producing hepatic dysfunction may result in prompt treatment, thereby improving survival. The clinician must be aware of the various systemic signs and symptoms that make the diagnosis of renal carcinoma often difficult and delayed.
Ms. Barbara Kahn assisted in the preparation of this manuscript, and Ms. Dolores Adams and Dr. Alan Forsythe provided computer and statistical analysis. REFERENCES
1. Skinner, D. G., Colvin, R. B., Vermillion, C. D., Pfister, R. C. and Leadbetter, W. F.: Diagnosis and management of renal cell carcinoma. A clinical and pathologic study of 309 cases. Cancer, 28: 1165, 1971. 2. Berger, L. and Sinkoff, M. W.: Systemic manifestations of hypernephroma: a review of 273 cases. Amer. J. Med., 22: 791, 1957. 3. Hempstead, R. H. and Priestley, J. T.: Fever as a predominant symptom of hypernephroma, report of two cases. Proc. Mayo Clin. Staff Meet., 27: 67, 1952. 4. Kiely, J.M.: Hypernephroma-the internist's tumor. Med. Clin. N. Amer., 50: 1067, 1966. 5. Clarke, B. G. and Goade, W. J., Jr.: Fever and anemia in renal cancer. New Engl. J. Med., 254: 107, 1956. 6. Rosenbach, L. M. and Xefteris, E. D.: Erythrocytosis associated with carcinoma of the kidney. J.A.M.A., 176: 136, 1961. 7. Goldberg, M. F., Tashjian, A.H., Jr., Order, S. E. and Dammin, G. J.: Renal adenocarcinoma containing a parathyroid hormone-like substance and associated with marked hypercalcemia. Amer. J. Med., 36: 805, 1964. 8. Creevy, C. D.: Confusing clinical manifestations of malignant renal neoplasms. Arch. Intern. Med., 55: 895, 1935. 9. Stauffer, M. H.: Nephrogenic hepatosplenomegaly (abstract). Gastroenterology, 40: 694, 1961. 10. Utz, D. C., Warren, M. M., Gregg, J. A., Ludwig, J. and Kelalis, P. P.: Reversible hepatic dysfunction associated with hypernephroma. Mayo Clin. Proc., 45: 161, 1970. 11. Walsh, P. N. and Kissane, J.M.: Nonmetastatic hypernephroma with reversible hepatic dysfunction. Arch. Intern. Med., 122: 214, 1968. 12. Ramos, C. V. and Taylor, H. B.: Hepatic dysfunction associated with renal carcinoma. Cancer, 29: 1287, 1972. 13. Durocher, J. R.: Alkaline phosphatase and hypernephroma (letter). New Engl. J. Med., 281: 1369, 1969. 14. Lemmon, W. T., Jr., Holland, P. V. and Holland, J. M.: The hepatopathy of hypernephroma. Amer. J. Surg., 110: 487, 1965. 15. Shipman, K. H., Downing, S. W. and Bradford, H. A.: Hypernephroma presenting as fever of unknown origin associated with elevated serum alkaline phosphatase levels. J. Urol., 89: 160, 1963. 16. Tartaglia, A. P., Wolfe, S. and Propp, S.: Hepatic dysfunction and fever associated with hypernephroma. N. Y. State J. Med., 70: 2231, 1970. 17. Mohamed, S. D.: Reversible non-metastatic liver-cell dysfunction and thrombocytosis from hypernephroma. Lancet, 2: 621, 1965. 18. Case Records of the Massachusetts General Hospital. Case 801961. New Engl. J. Med., 265: 953, 1961. 19. Lackner, L. H. and Cordonnier, J. J.: Unusual manifestations ofhypernephroma. Arch. Surg., 93: 675, 1966. 20. Cronin, R. E., Kaehny, W. D., Miller, P. D., Stables, D. P., Gabow, P. A., Ostroy, P. R. and Schrier, R. W.: Renal cell carcinoma: unusual systemic manifestations. Medicine, 55: 291, 1976. 21. Mena, E., Bull, F. E., Bookstein, J. J., Goldstein, H. M., Neiman, H. L., Thornberry, J. R. and Lim, C. G.: Angiography of the nephrogenic hepatic dysfunction syndrome. Radiology, 111: 65, 1974. 22. Bowman, H. S. and Martinez, E. J.: Fever, anemia, and hyperhaptoglobinemia: an extrarenal triad ofhypernephroma. Ann. Intern. Med., 68: 613, 1968. 23. Summerskill, W. H. and Shorter, R. G.: Progressive hepatic failure. Its association with undifferentiated renal tumor. Arch. Intern. Med., 120: 81, 1967. 24. Warren, M. M., Kelalis, P. P. and Utz, D. C.: The changing concept ofhypernephroma. J. Urol., 104: 376, 1970. 25. Vermillion, S. E., Morlock, C. G., Bartholomew, L. H. and Kelalis, P. P.: Nephrogenic hepatic dysfunction: secondary to
NON-METASTATIC HEPATIC DYSFUNCTION ASSOCIATED WITH RENAL CARCINOMA
turnefactive xanthogranulomatous pyelonephritis. Ann. Surg., 171: 130, 1970. .26. Abels, J. C., Rekers, P. E., Binkley, G. E., Pack, G. T. and Rhoads, C. P.: Metabolic studies in patients with cancer of the gastrointestinal tract. II. Hepatic dysfunction. Ann. Intern. Med., Hi: 221, 1942. 27. C., Suwansirikul, S. and Penzer, P.: Renal cell carcinoma with extra-renal manifestations in a 10-month-old child. Amer. J. Dis. Child., 121: 528, 1971.
28. Hanash, K. A., Utz, D. C., Ludwig, J., Wakim, K. G., Ellefson, R. D. and Kelalis, P. P.: Syndrome of reversible dysfunction associated with hypernephroma: an experimental study. Invest. Urol., 8: 399, 1971. 29. Gehan, E. A.: Statistical methods for survival time studies. Cancer Therapy: Prognostic Factors and Criteria of Response. Edited by M. J. Staquet. New York: Raven Press, 1975. 30. R'Obson, C. J.: Radical nephrectomy for renal cell carcinoma. J. Urol., 89: 37, 1963.
THE JOURNAL OF UROWGY
Copyright © 1978 by The Williams & Wilkins Co.
NON-METASTATIC HEPATIC DYSFUNCTION ASSOCIATED WITH RENAL CARCINOMA RICHARD J. BOXER,* JERRY WAISMAN, MICHAEL M. LIEBER, FRANCISCO M. MAMPASO AND DONALD G. SKINNER From the Division of Urology, Department of Surgery, and Department of Pathology, University of California, Los Angeles, California
ABSTRACT
A retrospective computer analysis of 102 patients treated for renal tubular carcinoma revealed 7 patients who presented with non-metastatic hepatic dysfunction. Of these 7 patients 5 also had the triad of fever, weight loss and fatigue. Only 1 patient survived more than 10 years after nephrectomy. A review of the literature on non-metastatic hepatic dysfunction revealed a significant interval between onset of symptoms and detection of the underlying renal malignancy, as well as a poor over-all survival rate if the syndrome persisted after nephrectomy. Renal tubular carcinoma or renal cell carcinoma, henceforth referred to as renal carcinoma, may present with a wide variety of symptoms and signs, ranging from the classic triad of hematuria, flank pain and palpable abdominal mass occurring in 10 per cent of the cases 1 to common but more obtuse signs, such as fever, 2• 3 fatigue, weight loss, weakness and anemia. 4 • 5 These neoplasms also may secrete parathormone, thus causing symptoms and signs of hyperparathyroidism, erythropoietin causing erythrocytosis or renin-producing hypertension. 6 • 7 Because of the wide range of unusual and nonspecific presenting features the detection of a renal carcinoma often is difficult and delayed. In 1935 Creevy described 3 patients with renal carcinoma who presented with a clinical picture simulating hepatic cirrhosis. 8 However, it was not until 1961 that Stauffer reported the syndrome of reversible hepatic dysfunction associated with renal carcinoma. 9 None of his 5 patients had liver metastases at the time of nephrectomy but preoperative liver function studies included retention of bromsulphthalein, an elevated serum alkaline phosphatase level, an increased prothrombin time, an elevated a-2-globulin fraction of the blood proteins and an abnormal thymol turbidity test. These abnormal liver function studies reverted to normal after nephrectomy but long-term surveillance of these patients was not reported. This syndrome of reversible hepatic dysfunction associated with renal carcinoma subsequently has been noted by others and to date 95 cases have been reported. 10-2 :1 Long-term observation has been recorded in 39 patients and only 17 of them have survived 2 years. Warren and associates reported on 13 patients in whom the syndrome persisted postoperatively and only 4 were alive at 2 years. 24 Of 13 patients whose liver function tests returned to normal postoperatively 11 survived 2 years. 24 The syndrome also has been reported in patients with xanthogranulomatous pyelonephritis stimulating renal carcinoma25 and localized cancer of the gastrointestinal tract, 26 as well as in a 10-month-old infant with renal carcinoma. 27 A humoral etiology has been suggested but not proved by isolation of an active substance or by experimental models. 28 During a 20-year period 7 patients with hepatic dysfunction Accepted for publication May 13, 1977. Read at annual meeting of Western Section, American Urological Association, San Francisco, California, March 13-17, 1977. Supported in part by the Blalock Foundation, University of California, Los Angeles, California. *Requests for reprints: c/o Editor's Office, Department of Surgery, University of California at Los Angeles, Los Angeles, California 90024.
associated with renal carcinoma were treated at our hospital. Herein we relate the clinical, radiographic and survival data, and describe the features of the renal specimens from these patients compared to similar patients with renal carcinoma but without hepatic dysfunction. MATERIALS AND METHODS
The clinical reports and operative specimens of 102 patients who underwent nephrectomy for renal carcinoma at our hospital were reviewed and coded for analysis by computer. Thirty-five symptoms, 20 physical and radiological signs, 35 features of the kidneys and the neoplasms, and 12 therapeutic modalities were annotated for each patient. The tumor specimens were reviewed independently by 2 pathologists (J. W. and F. M. M.) without knowledge of the clinical data, and 17 gross and 18 microscopic characteristics of each specimen were obtained. Analysis of the data was performed by computer and each feature was related to survival data by the Fisher exact test and the chi-square test. Survival data were computed by the life table analysis method. 29 In this study hepatic dysfunction was determined by an elevation of blood alkaline phosphatase level, retention of bromsulphthalein, albumin:globulin ratio of less than 1, elevated serum haptoglobin (a-2-globulin) level and increased serum prothrombin time. Of the 102 patients 76 had 2 or more of the enumerated tests of hepatic dysfunction. The 7 patients described herein had abnormal results of at least 3 of the aforementioned tests, indicating liver dysfunction. CASE REPORT
A 44-year-old white man was in excellent health until March 1965 when he noticed the sudden onset of fever (contant at lOOF), malaise, weight loss and fatigue. A heterophil test and blood culture were normal and, after 3 months of symptoms, the man was hospitalized. History included an abdominal perineal resection for carcinoma of the rectum. Physical examination revealed an enlarged firm liver but a barium enema, upper gastrointestinal series, cholecystogram and hepatic scan were within normal limits. Laboratory data indicated liver dysfunction (table 1), while a needle biopsy of the liver showed normal histology. The patient was transferred to our hospital for further laboratory tests. A bone marrow aspirate, repeat hepatic scan and isotope scan of the brain were normal, as well as other tests of urine and serum chemistry studies. The urinary sediment showed 4 red blood cells per high power field and an excretory urogram revealed a mass in the upper pole of the right kidney. Subsequently, a radical nephrectomy and liver biopsy were performed.
468
NON-METASTATIC HEPATIC DYSFUNCTION ASSOCIATED WITH RENAL CARCINOMA TABLE
Date
BromsulDhthalein at 45 Minutes (% retention)
Alkaline Phosphatase Level (King-Armstrong units; normal 1-4)
16.6 17.9
9.9* 21
6/22/65 8/22/65
1. Laboratory data from the case report
Prothrombin Time (sec.)
SerumGluAlbumin: a-2-Globulin tamic OxaloaRatio (% serum protein, cetic Transami- Globulin (gm.) normal 7-11) nase (units)
16 (control = 12.5) 18.5 (control = 13.5)
24 29
3.0:4.1 3.0:4.2
16% (1.1 gm.) 17.5% (1.3 gm.)
SedimentationRate (mm./hr.)
Liver Biopsy
Normal
32
Slight periportal fibrosis
8/30/65t 9/22/65 10/20/65 7/25/66
0.1
5.6 4.9 6.9
12 32
13 (control = 13)
5.0:2.5
10% (0. 75 gm.)
23 18
* Bodansky units, normal 1-4. t Rt. radical nephrectomy.
A, renal carcinoma with sheets of cells separated by delicate vascular stroma. H & E, reduced from x250. H, neoplastic cells have granular cytoplasm. Reduced from x675. TABLE
2. Significant features of renal carcinoma compared in
patients with and without hepatic dysfunction* Feature Flank pain Gross hematuria Fever Weight loss Fatigue No symptoms Anemia Splenomegaly Solid (>90%) patternt Tubular ( <5%) patternt Triad (fever, fatigue, weight loss)
Hepatic Dysfunction (%) No= 7 0 0 71
86 86 0 71
17 100 86 72
No Hepatic Dysfunction(%) No= 69 30 31 10 26 25 30 20 0
56 52 9
p Value <0.10 <0.10 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 <0.05 <0.10 <0.0005
* Two or more tests of hepatic function available. t The over-all microscopic appearance of the tumors was grouped into solid, cystic, tubular and papillary patterns.
A renal carcinoma was present with the characteristic gross appearance. The renal tumor contained 90 per cent granular cells, 10 per cent clear cells and 10 per cent fusiform (spindleshaped) cells (see figure). There were no giant or foam cells. Ninety per cent of the tumor showed a solid pattern and 10 per cent was cystic. The over-all grade of the carcinoma was 3 (poorly differentiated), while the nuclear grade1 was 2 (inter-
mediate). There was microscopic invasion of the veins and hilus but not of the main renal vein, capsule, pelvis or regional lymph nodes, thus indicating a stage I tumor. The liver biopsy showed slight periportal fibrosis and inflammation. Convalescence was uneventful and the patient was discharged from the hospital 7 days postoperatively. Subsequent liver function studies reverted to normal and in July 1975, 10 years after nephrectomy, the patient was well without evidence of residual recurrent disease. RESULTS
The average age of the 7 patients with hepatic dysfunction was 55. 7 years, exactly the same as the group without the syndrome. There were 3 men (43 per cent) and 4 women (57 per cent) with this syndrome, whereas the general population with renal carcinoma contained 31 per cent women and 69 per cent men. None of the patients with the syndrome had evidence of liver metastases by clinical or radiologic tests. The significant variables are listed in table 2. Fever, fatigue, weight loss and anemia were statistically more common in patients with hepatic dysfunction than in those without this syndrome (p < 0.01). Of the 7 patients 5 (71 per cent) with hepatic dysfunction had the symptom complex of fever, fatigue and weight loss, whereas 5 (7.2 per cent) of69 patients without hepatic dysfunction had the triad. This difference is
470
BOXER AND ASSOCIATES
highly significant (p < 0.0005). If anemia, fever, weight loss and fatigue were viewed as a tetrad 3 (43 per cent) of the patients with hepatic dysfunction displayed the complex compared to 5 per cent of the other patients (p = 0.015). None of the patients with hepatic dysfunction had flank pain, whereas that symptom was noted in 30 per cent of those without hepatic dysfunction (p < 0.10). None of the 5 patients with hepatic dysfunction associated with the triad of fever, fatigue and weight loss had evidence of metastases, although 6 patients with the triad but without hepatic dysfunction had metastases at the time of presentation. There were no differences between the 7 patients with hepatic dysfunction and the 76 patients who had normal liver function in regard to tumor size, location, weight, diameter cut surface or gross venous invasion. There were no statistical differences in evidence of glomerulonephritis, pyelonephritis or ischemia; cortical adenomas; arterial disease, and venous, capsular, hilar or pelvic invasion. There were no differences in cell type (granular, clear or fusiform), the presence or absence of foam or giant cells, or the over-all or nuclear grade. Finally, neither group was different in the incidence of adrenal and lymph node metastases. All patients with hepatic dysfunction had a solid pattern in more than 90 per cent of the tumor and this observation was statistically significant compared to patients without hepatic dysfunction (p < 0.05). The hepatic dysfunction in the 7 patients was staged according to the method described by Robson. 30 Three patients had stage I disease, 2 had stage II, 1 was lost to followup and 1 is alive after 2 years with metastatic disease that developed 1 year postoperatively. The patients with stage IV disease died within 8 months ofnephrectomy. These figures compared to an over-all survival of 62 per cent at 5 years for those patients with stages I, II and III disease without hepatic dysfunction and 1.5 years in patients with metastatic disease and no hepatic dysfunction. DISCUSSION
The association of hepatic dysfunction with renal carcinoma but without hepatic metastases is now a well recognized clinical syndrome and has been recorded in 102 patients, including the 7 reported herein. The clinical triad of fever, fatigue and weight loss associated with abnormal liver function studies should alert the clinician to the possible presence of renal carcinoma, although considerable delay usually occurs from clinical presentation to detection of the underlying renal malignancy, a probable factor in the poor long-term prognosis of many patients with renal carcinoma. The etiology of hepatic dysfunction as well as the cause of the associated symptoms of fever, fatigue and weight loss are unknown, although Utz and associates have suggested a humoral factor. 10, 28 To date, such a substance has not been isolated nor have experimental animal models for renal carcinoma revealed any humoral abnormality. The actual incidence of hepatic dysfunction associated with renal carcinoma is probably greater than currently recognized. Utz and associates reported, since 1961, a 40 per cent incidence of abnormal liver function studies obtained routinely in all patients with renal carcinoma at the Mayo Clinic. The prognostic significance of abnormal liver function tests remains unclear. Although 1 of our patients survived 10 years most of those with the syndrome are dead of metastatic disease within 5 years unless liver function returns to normal after nephrectomy and constitutional symptoms disappear. Earlier recognition of the underlying renal tumor producing hepatic dysfunction may result in prompt treatment, thereby improving survival. The clinician must be aware of the various systemic signs and symptoms that make the diagnosis of renal carcinoma often difficult and delayed.
Ms. Barbara Kahn assisted in the preparation of this manuscript, and Ms. Dolores Adams and Dr. Alan Forsythe provided computer and statistical analysis. REFERENCES
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