Pancreatic Carcinoma, Pseudohyperparathyroidism and Renal Calculi: Report of a Case

Vol. 101, Apr. Printed in U.S.A.

THE JOURNAL OF UROLOGY

Copyright© 1969 by The Williams & Wilkins Co.

PANCREATIC CARCINOMA, PSEUDOHYPERPARATHYROIDISM AND RENAL CALCULI: REPORT OF A CASE DAVID J. ALBERT, MAX MILLER, CR;ARLES A. HUBAY

AND

LESTER PERSKY

From the Clinical Research Center and the Departments of Urology and Surgery, University Hospitals of Cleveland and the Case Western Reserve School of Medicine, Cleveland, Ohio

The occurrence of hypercalcemia with carciuomatosis is a well documented finding. Hypercalcemia in the absence of bone metastases, while unusual, is being reported with increasing frequency since it first appeared in the literature in 1936. 1 Plimpton and Gellhorn reported on 10 cases with this unusual combination and postulated 3 possible mechanisms to explain the hypercalcemia :2 1) a parathyroid hormone-like substance produced by the neoplasm as originally theorized by Albright and Reifenstein,3 2) a vitamin-D-like substance elaborated by the tumor causing increased absorption of calcium through the intestine or 3) an abnormal calcium binding substance produced by the primary lesion. In 1964 Tashjian and associates identified the substance and found it to have similar immunochemical properties of parathyroid hormone, strongly suggesting the first aforementioned mechanism. 4 • 5 The calcific deposits in the kidney which may be associated with carcinomatous hypercalcemia are rarely demonstrable by radiographic techniques and are found at autopsy to be confined to Accepted for publication April 18, 1968. 1 Gutman, A. B., Tyson, T. L. and Gutman, E. B.: Serum calcium, inorganic phosphorus and phosphatase activity in hyperparathyroidism, Paget's disease, multiple myeloma and neoplastic disease of the bones. Arch. Intern. Med., 57: 379413, 1936. 2 Plimpton, C. H. and Gellhorn, A.: Hypercalcemia in malignant disease without evidence of bone destruction. Amer. J. Med., 21:750-759, 1956. 3 Albright, F. and Reifenstein, E. C., Jr.: The Parathyroid Glands and Metabolic Bone Disease: Selected Studies. Baltimore: The Williams & Wilkins Co., 1948. 4 Tashjian, A.H., Jr., Levine, L. and Munson, P. L.: Immunochemical indentification of parathyroid hormone in non-parathyroid neoplasms associated with hypercalcemia. J. Exp. Med., 119: 467-484, 1964. 5 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., 36:805-814, 1964.

the tubular cells and lumina. 6 The occurrence of metastatic carcinoma without bone involvement, but with hypercalcemia and gross urinary tract calculi presenting as ureteral colic, was first reported by Alanis and Flanagan in 1959. 7 The case records of the Massachusetts General Hospital revealed 2 cases with pseudohyperparathyroidism and gross renal calculi: one with carcinoma of the transverse colon, the other with adenocarcinoma of the kidney. 8 • 9 The only other case with this unusual combination was reported by Hodgkinson in 1964 with transitional cell carcinoma of the renal pelvis. 10 This paper will report the fifth case of metastatic carcinoma without bone invasion presenting with calculus disease in the urinary tract. This patient demonstrated many of the stigmata of primary hyperparathyroidism and the true nature of his disease was not confirmed until the secondary exploration for a parathyroid adenoma, a common series of events in the experience of other investigators. 5, 6 , 11-14 6 Lucas, P. F.: Acute hypercalcemia from carcinomatosis without bone metastasis. Brit. Med. J., 1:1330-1331, 1960. 7 Alanis, B. F. and Flanagan, J. F.: Myopathy and hypercalcemia occurring with carcinoma of the kidney. J.A.M.A., 171:2076-2080, 1959. 8 Case records of the Massachusetts General Hospital, case 43161. New Engl. J. Med., 256:750, 1957. 9 Case records of the Massachusetts General Hospital, case 80-1961. New Engl. J. Med., 265:953, 1961. 10 Hodgkinson, A.: Hyperparathyroidism and cancer. Brit. Med. J., 2:444, 1964. 11 Case records of the Massachusetts General Hospital, case 63-1963. New Engl. J. Med., 269: 801, 1963. Ml 12 Lamberg, B. A., Pelkonen, R. and Frick, M. H.: Hypercalcaemia in renal carcinoma. Acta Med. Scand., 176:187-194, 1964. 13 Schatten, W. E., Ship, A. G., Pieper, W. J. and Bartter, F. C.: Syndrome resembling hyperparathyroidism associated with squamous cell carcinoma. Ann. Surg., 148:890-894, 1958. 14 Stone, G. E., Waterhouse, C. and Terry, R.: Hypercalcemia of malignant disease: case report and a proposed mechanism of etiology. Ann. Intern. Med., 54:977-985, 1961.

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ALBERT AND ASSOCIATES

CASE REPORT

J. R., a 48-year-old Caucasian man, UH No. 813-875, was first admitted to our hospital on December 11, 1964 with a 2-year history of progressively severe diarrhea. In 1962, with the gradual onset of diarrhea, the patient had polyuria, polydipsia, polyphagia and fatigue which he endured until June 1963. At that time bright red bleeding per rectum was precipitated by the diarrhea. Fasting blood sugar was 380 mg. per cent. The man was initially treated with oral tolbutamide with poor control of glycosuria, spilling from 10 to 15 gm. per day. Diarrhea continued in a variety of patterns: periods of frank steatorrhea with rectal bleeding, 10 to 15 loose watery movements per day, color from light tan to dark brown, odorless to foul smelling and painless to severe abdominal cramping. Past medical history revealed that the patient had passed a left renal calculus in 1961. Physical examination revealed a blood pressure of 110/80; pulse, 76 (regular); temperature, 37.3 C. The only physical abnormality noted was an erythematous, scaly, papular rash involving the anus, scrotum and inner thighs. Examination of the liver by two physicians failed to demonstrate enlargement. Laboratory tests showed hematocrit, 40 per cent; white blood cells (WBC), 5,050; fasting blood sugar, 140, 150 mg. per cent; blood urea nitrogen (BUN), 15 mg. per cent; calcium, 10.3 mg. per cent; phosphorus, 2.3 mg. per cent; total protein, 5.3 mg. per cent; albumin, 3.4 gm. per cent; alkaline phosphatase, 12 KingArmstrong units; carotene, 80 mg. per cent. Urinalysis revealed 1 to 3 WBC per high power field with a few hyaline, coarsely and finely granular casts. Creatinine clearance was 95 cc per minute. All stool specimens were positive for occult blood. No stool pathogens were isolated. Upper gastrointestinal series with a small bowel follow-through was intrinsically normal but there was delayed transit. No pancreatic calcifications were noted. The patient improved somewhat with pan-

creatolipase therapy and more rigid control of glycosuria with 15 units of neutral protein Hagedorn insulin daily. He was discharged with the presumptive diagnoses of pancreatic insufficiency and diabetic enteropathy. The second admission on June 17, 1966 followed 10 days of intermittent right flank pain and gross hematuria. Pertinent laboratory data were: hematocrit, 46 per cent; WBC, 7,000; calcium, 11.4, 12.0 mg. per cent; phosphorus, 2.1, 2.2 mg. per cent; alkaline phosphatase, 23, 26 KA units; uric acid, 5.1 mg. per cent. On cystoscopy a calculus was visualized in the right ureteral orifice. A ureteral catheter passed the obstruction and was left indwelling for 5 days. At that time, the calculus was extracted cystoscopically. The patient was re-admitted to the hospital 5 days later, on June 28, with left ureteral colic. An excretory urogram revealed obstruction and delayed function with normal function re-established on the right. The next day the patient vomited 200 cc guaiac-positive material and developed tachycardia, diaphoresis and pallor. A left ureteral catheter was successfully passed as a temporizing measure and a hydronephrotic drip obtained. By the third hospital day, the hematocrit had dropped to 24 per cent and the patient was given 1,000 cc whole blood. A repeat upper gastrointestinal series failed to reveal the source of bleeding. There was a transitory drop in the serum calcium during the gastrointestinal bleeding, but once the blood loss ceased, the calcium rose again to abnormal levels. The patient's condition stabilized and the diagnosis of hyperparathyroidism was pursued by the metabolic service. The serum calcium, phosphorus, alkaline phosphatase and serum total protein are summarized in the table. Twenty-four hour calcium excretion with a dietary intake of 145 mg. calcium per day was 323 mg. and 364 mg. Twenty-four hour phosphorus excretion was 555 mg. and 622 mg. Bone survey revealed generalized demineralization in excess for the June

Calcium (mg.%) Phosphorus (mg,%) Alkaline phosphatase (KA units) Serum total protein (gm.%)

July

20

23

24

29

11.4 2.1 23

12.0 2.2 26

9.8 2.1

8.1 1.8 22

6

30

8.2 1. 7

9.0 2.1 23 I

11

10.3 11. 7 10.7 11.2 1.8 2.3 2.4 2.2 28 4.6 4.9 4.9 5.4

PANCREATIC CARCINOMA, PSEUDOHYPERPARATHYROIDISM AND RENAL CALCULI

patient's age with no evidence of metastases. There was loss of the dental lamina dura. No subperiosteal bone resorption could be demonstrated in the hands. With these data, a diagnosis of hyperparathyroidism was made and the patient

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was transferred to the surgical service. When the ureteral catheter was removed, an infusion pyelogram revealed normal bilateral function without obstruction. Exploration of the neck was performed on July 19. All 4 parathyroid glands were

FIG. 1. Normal parathyroid obtained at initial neck exploration. X450

FIG. 2. Liver biopsy shows metastatic adenocarcinoma in lower right; section of adjacent normalJiver in upper left. X180.

FIG. 3. Autopsy specimen, pancreatic carcinoma. Lymphatic invasion is seen in lower middle portion. X45.

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ALBERT AND ASSOCIATES

FIG. 4. Liver with extensive metastatic carcinoma

identified and 3 were removed for histological diagnosis. No adenomas were found grossly or microscopically (fig. 1). Convalescence was uneventful and the patient was discharged from the hospital on July 24. Three days later the patient was re-admitted to the hospital with left ureteral colic. An excretory urogram confirmed recurrent left ureteral obstruction and attempted manipulation cystoscopically was unsuccessful. A ureteral catheter was left indwelling. The hematocrit had fallen to 27 per cent and was 36 per cent after transfusion of 1000 cc whole blood. Stools were guaiac positive. After removal of the ureteral catheter, the patient was afebrile and asymptomatic. He was discharged on August 10. No calculus was recovered. The patient's final admission to the hospital was on September 19, again for left ureteral colic. The patient was pale and lethargic. Laboratory tests revealed hematocrit, 39 per cent; WBC, 8,400; calcium, 16.8 mg. per cent; phosphorus, 4.5 mg. per cent; alkaline phosphatase, 37 KA units; BUN, 26 mg. per cent. With adequate hydration and intravenous dexamethasone (4 mg. every 8 hours for 48 hours) the calcium fell to 13.1 mg. per cent, but the BUN rose to 45 mg. per cent. An excretory urogram was not entirely satisfactory because of overlying feces, but the right kidney was seen to function normally. Mediastinal exploration for an occult parathyroid adenoma was performed on September 23. Careful exploration revealed no parathyroid tissue.

Fw. 5. Obstructing calculus in lower right ureter. Proximal hydroureter and hydronephrosis.

Palpation of the liver through the thoracotomy incision revealed diffuse nodularity. The mediastinotomy was extended and a liver biopsy revealed metastatic adenocarcinoma (fig. 2). The patient did well until 4 days postoperatively when he became tachypneic and disoriented. A chest film demonstrated bilateral lower lobe atelectasis.

PANCREATIC CARCINOMA, PSEUDOI-IYPERPARATHYROIDISM AND RENAL CALCULI

The patient's condition deteriorated through the night and he died the following morning. Autopsy revealed adenocarcinoma of the pal'tcreas with metastases to the liver and parapancreatic lymph nodes (figs. 3 and 4). The liver weighed 2,000 gm. There was bilateral hydronephrosis with an obstructing calculus in the right lower ureter (fig. 5). Microscopic examination of the kidneys demonstrated a diffuse nephrocalc.:inosis with mild chronic pyelonephritis" Sections of the vertebral bodies failed to demonstrate metastatic disease. There was osteoporosis and fatty infiltration of the bone marrow. Death was attributed to bilateral acute bronchopneu-monia with fibrinous pleuritis. No parathyroid adenoma was found. DISCUSSION

Lafferty has indicated that the occurrence of renal calculi with pseudohyperparathyroidism is an unusual finding and may be of value in differentiating this entity from true hyperparathyroidism. More than half of his patients with para-thyroid adenoma gave a history of renal calculi, while only 4 of 50 cases of malignancy presented such a history.1 5 Our patient had a history of urinary tract calculi 5 years prior to his death making it difficult to attribute the calculi later in his course solely to the carcinomatous hypercalcemia. The grave threat of hypercalcemia crisis is mentioned by Lucas iu the first report of a patient with pancreatic carcinoma and pseudohyperparathyroidism.6 On his final admission, our patient presented with the classical signs and symptoms of hypercalcemia, dehydration, somnolence, vomiting and a rising BUN and inorganic phosphorus. The admission serum calcium of 16.8 mg. per cent confirrnecl the diagnosis and vigorous fluid and steroid therapy brought a gratifying response. V\Tith the long history of re15 Lafferty, F. vV.: Pseudohyperparnthyroidism. Medicine, 45:247-260, 1966.

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nal calculi, the absence of earlier elevation of the alkaline phosphatase and the entirely negative search for an occult ··--r···-· the diagnosis of primary seemed reasonable and the secondary for a parathyroid adenoma justified. When a thorough neck exploration fails to reveal a parathyroid adenoma, the search for an occult carcinoma must be intensified. The sign~ of pancreatic insufficiency in this patient may have given a. significant clue as to the location of the primary neoplasm, but as with most carcinomas, the symptoms were so protean as to obscure the true nature of the disease. The rise the alkaline phosphatase from 12 KA units in December 1964 to 24 units in June 1966 in the absence of radiographic bone changes of parathyroidisn1 is most consistent with hyperparathyroidism rather than primary parathyroidism. No abdominal mass was palpable, even in the final postoperative and exhaustive x-ray and laboratory studies did not elucidate the primary site. The dramatic fall of the serum calcium from 16.8 to 12.4 mg. pet cent following corticosteroid therapy was a further clue to the proper diagnosis, since this response is rare with hypercalcernia ·""''jw,u,,,,., to parathyroid adenoma. 15 The gastrointestinal bleeding was probably not the result of the ps,n-creatic carcinoma but from the chronic tis with ulceration demonstrated at autopsy. SUJ\1"MARY

A case of pancreatic carcinoma calcemia and no bone metastasis is The combination of pseudohyperparathyroidism of malignancy and gross renal calculi is unusuaL The confusing differential diagnosis of trne parathyroidism and that of carcinomatous calcemia was encountered ancl the definitive diagnosis was not secured until a exploration for an occult parathyroid a.clenoma was performed.