Prostatic carcinoma producing syndrome of inappropriate secretion of antidiuretic hormone

PROSTATIC CARCINOMA

PRODUCING

SYNDROME OF INAPPROPRIATE ANTIDIURETIC S. A. SACKS,

SECRETION OF

HORMONE*

M.D.

D. B. RHODES,

M.D.

D. R. MALKASIAN, A. A. ROSENBLOOM.

M.D. M.D.

From the Division of Urology, Department University of California School of Medicine, Los Angeles, California

of Surgery,

ABSTRACT - The syndrome of inappropriate secretion of antidiuretic hormone was recognized in a sixty-year-old man with a poorly diff erentiated metastatic adenocarcinoma of the prostate gland. Elevated levels of antidiuretic hormone were found in the patient’s serum and in the prostatic tumor but not in the cerebrospinal fluid, The patient’s clinical course is detailed, and the pathophysiology of this syndrome is discussed.

discovered in instances of carcinoma of the duodenum, 6 pancreas, ’ adrenal gland,8 ureter,g and has also been seen in lymphoma and Hodgkins’ disease. l”,rl The presence of the syndrome in a patient with carcinoma of the prostate gland has been previously reported. l2 Recently, we recognized SIADH in a patient with carcinoma of the prostate gland in whom we were able to document significantly elevated levels of ADH in the patient’s serum and from the prostatic tumor. Identification of the hormone was made by a specific radioimmunoassay.

The classic syndrome of inappropriate secretion of antidiuretic hormone? (SIADH)’ includes the following clinical determinations: (1) hyponatremia and hypotonicity of the extracellular fluids; (2) persistence of sodium excretion in the urine despite hyponatremia; (3) absence of the clinical and laboratory signs of dehydration; (4) unimpaired renal function; and (5) unimpaired adrenal function. The syndrome was initially recognized in 1957’ and was reviewed in detail in 1967,’ and again in 1973. 3 Since its original description, SIADH has been observed in a variety of clinical conditions which have recently been enumerated and categorized. 3 Notable among these are diseases of neoplasia in which ADH (antidiuretic hormone) or an ADH-like substance may be secreted by the neoplasm. The association of SIADH and tumors outside the central nervous system was initially recognized with bronchogenie carcinoma4,5 and has subsequently been

Case Report A sixty-year-old Caucasian male was first evaluated in June, 1973, because of constant pains in the lower back and right shoulder. Physical examination revealed an enlarged, hard, fixed prostate gland and an enlarged liver. Radiographic bone survey revealed osteoblastic lesions in the left fifth, sixth, and seventh anterior ribs, right clavicle, thoracic and lumbar spine, and bony pelvis. A technetium diphosphonate bone

*Supported in part by the University Medical Research Foundation and the Blalock Foundation. 7Arginine vasopressin [cys-tyr-phe-glu(NHz)-asp(NHz)cys-pro-arg-gly-(NHz)].

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scan revealed increased uptake of isotope in the calvarium, spine, rib cage, pelvis, and proximal femurs. Serum acid phosphatase total was 37.7 E.LU.per milliliter, with a prostatic (L-tartrate inhibited) fraction of 33.3 pU. per milliliter. Serum alkaline phosphatase was 705 pI_J., and serum lactic acid dehydrogenase 346 PU. per milliliter. Serum hemoglobin was 13.8 Gm. per 100 ml, and hematocrit 40.9, with a white blood count of 8,400. Serum electrolytes were unremarkable: sodium 137 mEq., potassium 4.2 mEq., chloride 96 mEq., and bicarbonate 27 mEq. per liter. The blood urea nitrogen was 9 mg. per 100 ml. An excretory urogram demonstrated normal upper urinary tracts, and cytoscopic evaluation revealed an enlarged, hard, fixed prostate gland with moderate urethral obstruction. The bladder was mildly trabeculated. A transperineal needle biopsy of the prostate gland revealed a poorly differentiated prostatic adenocarcinoma with perineural lymphatic invasion. The patient was initially treated with 2 mg. of diethylstilbestrol daily. His bone pain persisted, however, and there was some question regarding the regularity with which the patient took his medication. Bilateral orchiectomy was performed in August, 1973. Serum electrolytes at that time revealed: sodium 129 mEq., potassium 4.7 mEq., chloride 88 mEq., and bicarbonate 26 mEq. per liter. The blood urea nitrogen was 5 mg. and serum creatinine 0.9 mg. per 100 ml. The patient obtained moderate pain relief for two months following orchiectomy, but he presented again in November, 1973, complaining of fatigue, 40-pound weight loss, loss of appetite, and diffuse bone pain. Serum electrolyte determinations at that time revealed: sodium 122 mEq., potassium 3.9 mEq., chloride 77 mEq., and bicarbonate 25 mEq. per liter. Blood urea nitrogen was 10 mg. per 100 ml. and hematocrit 36. Initial fluid and electrolyte replacement therapy consisted of 2 L. of dextrose and 0.5 per cent normal saline administered intravenously over an eight-hour period. Following this infusion, however, the serum sodium fell to 115 mEq. and serum chloride to 73 mEq. per liter. The serum osmolality at this time was 250 mOsm. and urine osmolality 560 mOsm. per liter. The urine sodium excretion was 18 mEq. per liter. These data suggested that ADH secretion was continuing in spite of a hypo-osmolar, hyponatremic state. The syndrome of inappropriate secretion of antidiuretic hormone was recognized and was treated by limiting fluids to 1,000 CC. of water per day by mouth and by permitting an

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unrestricted sodium diet. On the eighth hospital day cerebrospinal fluid, prostatic tissue, and serum were obtained and submitted for ADH radioimmunoassay. Sequential laboratory values during this patient’s hospital course are detailed in Table I. Despite an apparent improvement of his serum electrolytes, the patient continued to lose weight and his clinical condition deteriorated rapidly. Bone pain was unremitting. The patient was treated with analgesics, systemic steroids, and intravenous diethylstilbestrol diphosphate (Stilphostrol). No improvement was noted, and the patient died one month following hospital admission. Postmortem examination revealed widespread poorly differentiated adenocarcinoma of the prostate gland with extensive metastases to bone, lymph nodes, and liver. The brain was not involved. Methods Serum and cerebrospinal fluid ADH concentrations were determined and measured using a recently described quantitative radioimmunoassay technique. 13,x4ADH in the prostatic carcinoma was extracted as described for neurohypophyseal tissue and was also quantitated using the radioimmunoassay technique. 15,16 Results The serum concentration of ADH was 10.8p.U. per milliliter, when the serum osmolality was 261 mOsm. and the urine osmolality 600 mOsm. per liter. This is an inappropriately high serum level of ADH. ADH in the cerebrospinal fluid was undetectable. ADH concentration in three separate samples of prostate tumor approximated 17.2 PU. per milligram. Comment ADH (via cyclic adenosine monophosphate) governs the extent of reabsorption of “free water” which has been generated in the ascending limb of Henle’s loop. ADH exerts its influence by increasing the permeability of cells in the distal convoluted tubule and collecting tubule to water. As “free water” continues to be reabsorbed into the circulation, plasma solute concentration decreases and urinary solute concentration increases. Osmoreceptors in the central nervous system apparently detect subtle changes in blood osmolality and appropriately adjust the secretion of ADH from the supraoptico-hypophyseal axis.

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reflexia, and Cheyne-Stokes respirations. Laboratory examination in SIADH reveals hyponatremia and hypo-osmolality of the body fluids (serum), which occur when the urine is relatively hypertonic and contains appreciable amounts of sodium. The patient demonstrates no clinical evidence of dehydration, and the blood urea nitrogen is usually low. Similarly, the serum uric acid may be decreased with a relatively high uric acid clearance. ” The patient described herein manifested many of the classic symptoms and signs of SIADH, and his clinical course is remarkably similar to the

Neoplasms (such as oat cell carcinoma of the lung) may contain large quantities of ADH. This hormone is a relatively simple polypeptide which has been shown to be produced from readily available amino acid precursors. ADH secretion from neoplasms is totally independent of normal “feedback” control mechanisms, and will not suppress with the administration of ethyl alcohol or diphenylhydantoin (Dilantin). The syndrome of inappropriate secretion of antidiuretic hormone is a complex of clinical symptoms and signs associated with progressive hemodilution. The symptoms are related pri-

TABLE I. Serial laboratory determinations (1973)

Date Sodium (mEq./L.) Potassium (mEq./L.) Chloride (mEq./L.) Carbon dioxide (mEq./L.) Creatinine (mg. per 1OOml.) Blood urea nitrogen (mg. per 100 ml.) Serum osmolality (mOsm./L.) Urine osmolality (mOsm./L.) Urine potassium (mEq./L.) Urine sodium (mEq./L.) Weight (pounds)

6/11 8/14 11/27 D/28

11/29 11/30 12/l

136

3.8

4.6

94

97

28

26

7

16

.

259

.

569

589

203

25

88

7

6

2

129

122

115

115

117

118

120

124

134

140

142

127

4.2

4.7

3.9

4.3

4.5

4.7

4.0

3.2

2.8

3.3

3.5

3.5

3.2

96

88

77

75

71

76

68

79

84

92

97

102

89

27

26

25

25

31

31

30

35

30

30

27

27

29

. .

0.9

0.8

0.9

0.9

.

0.9

1.0

.

0.8

9

5

10

18

24

24

21

18

25

250

250

260

243

.

258

260

261

,.

560

340

361

536

844

600

100

38

,.

23

33

39

1

3

3

133

134

127

.

.

12/19

133

137

.

.

a

.

. .

.

. .

.

. .

. .

.

. .

,.

,.

18

14

. .

155

. .

.

141

138

.

32

138

marily to rate of decrease in serum sodium and osmolality rather than to their absolute values. Thus, when the serum sodium and osmolality decline slowly, the only indications of SIADH may be the insidious onset of headache, fatigue, lethargy, and disorientation. When there is a rapid decline in serum sodium and osmolality, the symptoms may be more profound but equally nonspecific. There are usually anorexia, emesis, confusion, and occasionally coma and convulsions. Physical examination may reveal hypothermia, hypo-

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patient with prostatic carcinoma and SIADH previously described. l2 The initial urinary sodium excretion in our patient is perhaps not as high as might be expected in this syndrome, but is not at all inconsistent with this diagnosis. In addition, the serum and tumor levels of ADH are not as elevated as those observed in other ADH-secreting neoplasms, and it may be that the syndrome was generated not by the relatively modest tumor concentrations of ADH but by the considerable mass of the tumor.

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Los Angeles,

California 90024 (DR. SACKS)

References 1. SCHWARTZ, W. B., BENNETT, W., CURELOP, S., and BARTTER, F. C.: A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone, Am. J. Med. 23: 529 (1957). 2. BARTTER, F. C., and SCHWARTZ, W. B.: The syndrome of inappropriate secretion of antidiuretic hormone, ibid. 42: 796 (1967). 3. BARTTER, F. C.: The syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Diseasea-Month, Chicago, Year Book Medical Publishers, Inc., November, 1973. 4. THORN, N. A., and TRANSBL, I.: Hyponatremia and bronchogenic carcinoma associated with renal excretion of large amounts of antidiuretic material, Am. J. Med. 35: 257 (1963). 5. AMATRUDA, T. T., JR., MULROW, P. J., GALLAGHER, J. C., and SAWYER, W. H.: Carcinoma of the lung with inappropriate antidiuresis. Demonstration of antidiuretic-hormone-like activity in tumor extract, N. Engl. J. Med. 269: 544 (1963). 6. LEBACQ, E., and DELAERE, J.: Hyponatremie avec dilution plasmatique par secretion inadequate de vasopressine, dans un cas de tumeur duodenale, Rev. Med.Chir. mal. foie 40: 169 (1965). 7. DESOUSA, R. C., and JENNY, M.: Hyponatremie par dilution dans un cas de carcinome pancreatique, Schweiz. Med. Wochenschr. 94: 930 (1964).

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8. FALCHUK, K. R. : Inappropriate antidiuretic hormonelike syndrome associated with an adrenocortical carcinoma, Am. J. Med. Sci. 266: 393 (1973). 9. MELLINGER, R. C., PETERMANN, F. L., and JURGENSON, J. C.: Hyponatremia with low urinary aldosterone occurring in an old woman, J. Clin. Endocrinol. 34: 85 (1972). 10. SPITTLE, M. F.: Inappropriate antidiuretic hormone secretion in Hodgkins’ disease, Postgrad. Med. J. 42: 523 (1966). 11. CASSILETH, P. A., and TROTMAN, B. W.: Inappropriate antidiuretic hormone in Hodgkins’ disease, Am. J. Med. Sci. 265: 233 (1973). 12. SELLWOOD, R. A., et al. : Inappropriate secretion of antidiuretic hormone by carcinoma of the prostate, Br. J. Surg. 56: 933 (1969). 13. SKOWSKY, W. R., ROSENBLOOM, A. A., and FISHER, D. A. : Radioimmunoassay measurement of arginine vasopressin in serum: development and application, J. Clin. Endocrinol. Metab. 38: 278 (1974). 14. ROSENBLOOM, A. A., and FISHER, D. A.: Radioimmunoassay of arginine vasotocin, Endocrinology 95: 1726 (1974). 15. VORHERR, H., MASSRY, S. G., UTIGER, R. D., and principle in malignant KLEEMAN, C. R.: Antidiuretic tumor extracts from patients with inappropriate ADH syndrome, J. Clin. Endocrinol. Metab. 28: 162 (1968). 16. UTIGER, R. D.: Inappropriate antidiuresis and carcinoma of the lung: detection of arginine vasopressin in tumor extracts by immunoassay, ibid. 26: 970 (1966). 17. DORHOUT MEES, E. J., BLOM VAN ASSENDELFT, P., and NIEUWENHUIS, M. G.: Elevation of uric acid clearance caused by inappropriate antidiuretic hormone secretion, Acta Med. Stand. 189:69 (1971).

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