Manifestations of renal cell carcinom

MANIFESTATIONS

ROBERT JAMES ROY

P. GIBBONS, E.

MONTIE,

J. CORREA,

J. TATE

MASON,

OF RENAL

CELL CARCINO\~t -i

M.D. M.D.

JR.,

M.D.

M.D.

From the Division of Urology, The Virginia Medical Center, Seattle, Washington

Mason

ABSTRACT - Patients with renal cell carcinoma often have no speci$c localizing symptoms or signs, and their presentation will often involve many organ systems, Since 40 per cent of these patients do not have genitourinary symptoms, care must be taken to avoid being misled by normal findings on urinalysis. More than 50 per cent of patients with renal cell carcinoma have vague symptoms suggesting a gastrointestinal origin; thus if primary gastrointestinal studies do not disclose a cause fw these symptoms, excretory urography must be included as a screening procedure. -

The early diagnosis of renal cell carcinoma (hypernephroma) can be a difficult and an intriguing problem for the physician who may be challenged with the initial presentation of this tumor. To aid in recognizing the often subtle manifestations of renal cell carcinoma, we have reviewed the recent literature and the experience of The Virginia Mason Medical Center consisting of 110 patients with a tissue diagnosis of renal cell carcinoma seen between 1947 and 1971. Symptoms, signs, and abnormal laboratory findings will be detailed according to the organ system involved. Genitourinary The classic triad of flank pain, renal mass, and gross hematuria is of little value in the early diagnosis of renal cell carcinoma. l-6 In our series, 35 per cent of the patients had none of of the triad of symptoms (Table I). The absence of either gross or microscopic hematuria, which was the circumstance in 63 per cent of our patients, has no value in the individual case when considering the possible diagnosis of renal cell carcinoma. In other words, the urinalysis is not a reliable screen test for this malignancy. Pinals and Krane7 have stressed that “failure to show positive urinary findings even after other manifestations have long been present is not

uncommon and constitutes perhaps the most important diagnostic stumbling block.” The presence of pain or an abdominal mass is likewise infrequent. Varicoceles have been reported in from 0.6 to 11 per cent of patients with renal cell carcinoma.’ It should be considered significant when they are acute, on the left side, and do not empty with recumbency - symptoms which are most likely due to obstruction of the left testicular vein with tumor. Metastases to the vagina, penis, epididymis, and testis occasionally are seen secondary to the potential vascular communication by reversal of flow from the left renal vein to the lower genitourinary tract.7’8 These metastases may be manifested as vaginal TABLE I. Renal cell carcinoma: incidence of genitourinary manifestations at time of diagnosis ~____ Per Cent Genitourinary Manifestations Hematuria Abdominal pain Mass None of triad Normal urinalysis

OVER-ALL

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37 27

21 35 38

68

In Literature

18 to 60 35 to 50 17 to 63 . 55 to 70

TABLE II. Renal cell car-cinema: incidence of gastrointestinal manifestations at time of diagnosis Gastrointestinal Manifestations Weight loss Abdominal pain Mass Anorexia Other (nausea and flatulence and/or change in bowel habits) OVER-ALL

Incidence This Institution 30 27 21 12

6 61

bleeding, priapism, epididymitis, or a testicular mass. 9*10 The presence of a calcified renal mass may be a more difficult problem for the urologist and radiologist. Recently Daniel et al. l1 found that 4.1 per cent of all renal masses were calcified; of the calcified renal masses, 58 per cent proved to be renal carcinomas. Ten per cent of all renal cell carcinomas were calcified, and the renal mass which was diffusely calcified had a 90-per cent incidence of malignancy. Gastrointestinal A significant number of patients with renal cell carcinoma have nonspecific abdominal or gastrointestinal related complaints. In our series 61 per cent of the patients had complaints suggesting abdominal or gastrointestinal origin (Table II). Hepatomegaly and splenomegaly is seen occasionally. l2 Many of these symptoms are thought to be reflex in origin, secondary to retroperitoneal irritation by the tumor. The lack of characteristic renal pain or flank mass may be the precise reason why the diagnosis is delayed. Is13 Excretory urography should be considered as a screening procedure in patients with nonspecific gastrointestinal complaints if an adequate explanation has not been obtained with initial barium studies. Renal -cell carcinoma presenting with an acute condition within the abdomen is generally due to spontaneous rupture of the tumor with secondary bleeding and can easily be misdiagnosed.‘4*‘5 The Budd-Chiari syndrome may be noted secondary to obstruction of the hepatic veins by tumor. Symptoms secondary to metastases to the gallbladder, pancreas, and jejunum have also been reported. 16-lg Abnormal liver function tests associated with renal cell carcinoma without metastases were first described as a syndrome in 1961, and in-

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cluded an elevated sulfobromophtalein, prothrombin time, alpha-2 globulin, bilirubin, and alkaline phosphatase. l2 The incidence in patients with renal cell carcinoma is unclear and depends. somewhat on the criteria used for hepatic dysfunction. Utz et ~1.~~ at the Mayo Clinic reported 40 per cent of 148 patients with sufficient liver function test studies had at least 3 of these abnormalities. Other observers report a lo- to 19per cent incidence.21,22 The failure of liver function to return to normal after excision of the tumor implies a significantly worse prognosis. 20-27The etiology is unknown, and attempts to reproduce the syndrome in mice by injecting serum or tumor extracts from patients with hepatic dysfunction have been unsuccessful.2s An isolated elevated alkaline phosphatase without other abnormal liver function tests or bone lesions has been described, although the incidence is unclear.29 This elevated alkaline phosphatase may be due to production of a placental isoenzyme, as has been documented in lung and other carcinomas.30-3e There is a large amount of interest in the production of fetal enzymes or proteins by malignancies and renal tumors are no exception.33

Hematologic The most frequent hematologic abnormality associated with this neoplasm is anemia. It is found in approximately 30 per cent of patients and is usually not secondary to blood loss by hematuria, to hemolysis, or to bone marrow replacement. 29134The anemia is generally a hypoproliferative type with a low serum iron and low total iron-binding capacity, and it is thought to be secondary to bone marrow depression by the tumor as seen with many other malignancies.35-36 Erythrocytosis (hematocrit greater than 55 per cent) has a documented instance of 1 to 5 per cent. 29 The primary differential diagnosis is with polycythemia Vera. 37p38 Approximately 4 per cent of patients with erythrocytosis have renal cell carcinoma, and up to 33 per cent of those patients with erythrocytosis and hematuria have renal cell carcinoma. 39 The erythrocytosis usually regresses after excision or palliation of the tumor; likewise, the persistence or return of erythrocytosis suggests metastatic disease.40 Erythropoietic activity in tumor extracts and in fluid obtained from tissue culture cell lines has been documented.41,42

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An elevated erythrocyte sedimentation rate (ESR) is a common finding in renal malignancy, although certainly not specific for renal cell however, to carcinoma. 7*2g It is important, remember that the elevation frequently is only minimal, and a normal ESR does not rule out a renal cell carcinoma. 1,43 An elevated serum haptoglobin has been noted with many malignancies and is generally believed to indicate metastatic disease. 44 However, renal cell carcinoma may be unusual in that the serum haptoglobin may be elevated without metastases and may be curable at that stage.34 The elevated haptoglobin may even appear as a monoclonal spike and can be associated with anemia, fever, decreased serum iron, weakness, and weight 10~s.~~

Endocrinologic In 5 to I5 per cent of patients with renal cell carcinoma hypercalcemia develops usually secondary to metastases.7 Warren, Utz, and Kelalis46 believe that hypercalcemia without metastases may be more common than previously appreciated. In their series, 13 per cent had elevated calcium levels with only 2 of these having small bony metastases. In many cases hypercalcemia and hypophosphatemia have been documented by immunologic and biologic methods to be secondary to the production of either an ectopic parathyroid hormone-like substance or immunoreactive fragments of parathyroid hormone (PTH).46M55 Carcinoma of the lung and renal cell carcinoma are divided about evenly as the most frequent source of ectopic PTH synthesis. 37,56 The ratio of the immunoassay of PTH to serum calcium may be elevated to a lesser degree in patients with ectopic PTH than those with primary hyperthyroidism. 53,57 Recent studies have described patients with renal cell carcinoma and hypercalcemia without metastases in whom undetectable levels of PTH were found. 58 Excessive quantities of circulating prostaglandins have been implicated as a possible cause for this hypercalcemia.58,‘g Ectopic ACTH production from renal cell carcinoma has been reported, but is more frequently observed with bronchogenic carcinoma, thymomas, and pancreatic carcinoma. 6031 There have been 2 patients with renal cell carcinoma associated with gynecomastia, decreased libido, and a positive pregnancy test secondary to production of an ectopic human

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chorionic gonadotropin-like substance.33*62 In another report the tumor was believed to be secreting enteroglucagon, and there were symptoms and signs similar to those comparable of other glucagon-secreting neoplasms including constipation, skin rash, hemolytic anemia, and edema.63,64 It is also noteworthy that renal cell carcinoma is one of the most frequent causes of metastases to the thyroid glands7 Pulmonary

and Cardiovascular

The lung is the most common site of metastases for renal cell carcinoma.35 Solitary and multiple pulmonary nodules are frequent and obviously may simulate a primary lung carcinoma. Several reports have emphasized the potential to endobronchial metastases which may be diagnosed with bronchoscopy or sputum cytology. 7+65 However, the possibility of an asymptomatic solitary pulmonary nodule being a metastasis from a hypernephroma is less than 1 per cent.66 Cardiovascular manifestations generally are secondary to significant arteriovenous shunting within the tumor and are potentially reversible.7,67-71 This results in a high output cardiac failure, accompanied by cardiomegaly, congestive heart failure, systolic hypertension, and high-pitch continuous abdominal bruit. There has been some difference of opinion regarding the association of hypertension and renal cell carcinoma. “,” There is no documented evidence that the tumor itself secretes a pressor substance, although a production of renin has been postulated. 1,7,35 Neurologic Approximately 5 to 10 per cent of all patients with renal cell carcinoma have metastases to the brain, and these are generally vascular on arteriography. 73 Neurologic symptoms secondary to renal cell carcinoma are most commonly due to metastases. The histologic appearance may be somewhat confusing with primary central nervous system neoplasms. Weigens2 cases of metastases to the berg74 reported cervical spinal cord which were initially interpreted as a primary nonchromaffin paraganglioma. 74 In our experience one known metastasis was initially diagnosed as a meningioma. Nonmetastatic presentations with polyneuritis or a peripheral mononeuropathy are rare and

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certainly not as frequent as with lung, breast, stomach, pancreatic, or ovarian carcinoma.2g*75-77 Lindau-von Hippel disease is frequently associated with renal cysts, renal cell carcinoma, or both. 7*,7g Musculoskeletal Solitary metastasis to bone is more frequent with renal cell carcinoma than with any other tumor.*’ Metastases to the vertebral column are the most frequent, and metastases to the long bones, especially to the humerus and femur, are also very common. Pulsatile bone tumors are distinctive in that they are usually due to metastases from either renal or thyroid carcinoma, or less commonly primary hemangioepithelioma of bone. ” Pulsatile sternal metastases have been confused with thoracic aortic aneurysms. So Systemic Symptoms Fever associated with renal cell carcinoma was first described in 1887.8 The incidence at initial presentation is reported at 10 to 20 per cent and is the sole presenting symptom in 2 to 4 per cent. 82-84The fever may respond to continuous corticosteroid therapy but returns to previous levels with their cessation. An endogenous pyrogen, formed either by the tumor itself or from leukocytes within the tumor, has been demonstrated in febrile patients.85,86 Secondary amyloidosis is associated with a malignancy in approximately 15 per cent of patients. 87 Renal cell carcinoma accounts for one quarter to one third of all carcinomas responsible for secondary amyloidosis, and the incidence in patients with renal cell carcinoma The clinical presentation is 1 to 3 per cent. 12,87-8g will be one of rapid deterioration of renal function with uremia, with or without hepatosplenomegaly, usually with a moderate amount of albuminuria. Metastases may not be present and renal failure secondary to the amyloidosis may be the cause of death. Resolution of the amyloidosis after the removal of the carcinoma has not been documented. 1100Ninth Avenue Seattle,

Washington 98101 (DR. GIBBONS)

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71. CURTISS, E. I., SHAVER, J. A., and BOEHNKE, A. M.: Left to right shunt due to arteriovenous fistula formation in a renal cell carcinoma, Arch. Intern. Med. 134: 951 (1974). 72. HALE, N., and BURKLAND, C.: Unrecognized renal tumors: a study of 54 cases in 6,577 autopsies and personal cases, J. Ural. 49: 426 (1943). Silent adenocarcinoma of kidney 73. RUSCHE, C. F.: with solitary metastases occurring in brothers, ibid. 70: 146 (1953). renal carcinoma: 74. WEICENSBERC, I. J.: Metastatic unusual and deceptive presenting features, South. Med. J. 65: 611 (1972). 75. GREENBERG, E., DIVERTIE, M. B., and WOOLNER, L. B.: A review of unusual systemic manifestations associated with carcinoma, Am. J. Med. 36: 166 (1964). 76. HOLT, G.: Nervous system and occult cancer: idiopathic neuronal dysfunction and multiple system syndromes, Am. J. Med. Sci. 250: 120 (1965). IgM paraproteinemia, 77. THRUST, D. C.: Neuropathy, and antibodies in hypernephroma, Br. Med. J. 4: 474 (1970).

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