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Ectopic hyperparathyroidism
Ectopic Hyperparathyroidism
T. .I. Foley, MD, Milwaukee, Wisconsin
Ectopic hyperparathyroidism, also called pseudohyperparathyroidism, is a clinical syndrome defined as a nonparathyroid tumor associated with hypercalcemia and hypophosphatemia [I]. Menguy [Z] adds to this definition the absence of skeletal metastasis, the disappearance of clinical and laboratory manifestations of hyperparathyroidism after removal of the tumor, the presence of a substance immunologically resembling parathyroid hormone in the tumor removed at surgery or at postmortem examination, and the recurrence of manifestations of hyperparathyroidism with recurrence of tumor. The incidence of ectopic hyperparathyroidism was first suggested by Albright in 1941 [3]. In the 1950’s and more frequently in the 1960’s more cases were reported. Lafferty [4] reports ectopic hyperparathyroidism as the third most common cause of hypercalcemia at University Hospitals of Cleveland. The confusion of ectopic hyperparathyroidism with primary hyperparathyroidism still occurs. Knowledge of the incidence and differential diagnosis of ectopic hyperparathyroidism is essential to surgeons treating patients with hypercalcemia, who represent between 2 and 3 per cent of our hospitalized patients. Of 48,000 calcium determinations at St. Joseph’s Hospital in Milwaukee in the last twentyfive months, 2.1 per cent were above 10.5 mg per 100 ml. From the Department of Surgery, St. Joseph’s Hospital, Milwaukee, Wisconsin. Reprint requests shouti be addressed to Dr Foley, 2457 North Mayfair Road, Mwaukee. Wisconsin 53226.
106
Case Report The patient, a thirty-five year old woman, consulted her gynecologist because of a mass in the left epigastrium that had been present for five months and had enlarged during the past three months. During the past ten days she had had increasing, vague, ulcer type pains associated with eructations, gas, and diarrhea. She also complained of sparse hair and brittle nails. All of these symptoms dramatically disappeared after removal of the tumor. (Figure 1.) She was known to have had a heart murmur since childhood. Diabetes developed in her mother at age sixty-five. There was no history of renal calculi. During the patient’s second pregnancy nine years ago she had had significant hypertension. Physical examination revealed a well developed woman in no distress. Palpation indicated a normal thyrr,id and no neck masses were felt. A grade 4 systolic murmur was heard loudest at the second left interspace in the parasternal region. There was a firm, solid, slightly movable mass, 10 cm in diameter, in the abdomen. A loud systolic bruit separate from the heart murmur was heard over the mass. Pertinent laboratory studies revealed serum calcium levels of 13,13.1,13.7 mg per 100 ml. Serum phosphorus values were 1.7, 2.5, and 2 mg per 100 ml. (Figure 2.) The blood sugar and glucose tolerance tests revealed slightly elevated levels, indicating mild diabetes mellitus. Urinary calcium was 235 mg per twenty-four hours and the urinary phosphorus was 700 mg per twenty-four hours. X-ray examination of the chest revealed a prominence of the pulmonary arteries compatible with left to right intra-atria1 septal defect. Intravenous pyelogram and upper and lower gastrointestinal barium studies revealed no abnormalities other than a mass, 9 cm in size, in the area of the distal pancreas. (Figure 3.) X-ray study of the hands, skull, and teeth revealed no abnormalities. The electrocardiogram revealed an incomplete
The American Journal ol Surgery
Ectopic Hyperparathyroidism
bundle branch block. The hematocrit was 33 per cent and the hemoglobin was 10 gm per 100 ml. The patient was given 1 unit of cell mass preoperatively. Laparotomy was performed through a transverse incision. A 9 cm, rounded vascular tumor was removed from the retroperitoneal area below, but not attached to, a normal pancreas. There was no evidence of spread of tumor. During the postoperative period the serum calcium level dropped rapidly. TWO hours postoperatively the calcium level was 9.0 mg per 100 ml. On the third postoperative day she began to exhibit clinical hypocalcemia with twitching, irritability, and Chvostek’s sign, all of which responded immediately to calcium therapy. At this time daily calcium levels were 7, 7.3, 8.6, 8.9, 9.0, 8.4, 8.3,8.4, 9.0,9.1, and 9.3 mg per 100 ml. (Figure 2.) Grossly, the tumor was solid, weighed 636 gm, and measured 12 cm in diameter. The mass was encapsulated with a grayish pink cut surface. (Figure 4.) Microscopically, the lesion consisted of closely packed cells, for the most part having vesicular nuclei with irregularly clumped chromatin surrounded by various amounts of pale acidophilic-staining cytoplasm. The majority of the nuclei were round or oval. Some appeared to contain nucleoli. Generally the cells were arranged in trabecular formations that in many areas tended to form into distinct gland-like structures. Numerous capillary vessels were seen coursing through the lesion. Mitotic figures were also observed, averaging one per five high powered fields viewed. The lesion was thought to be an adenomatous neoplasm most likely of pancreatic origin.
Figure 1. Drawing showing the tumor in the abdomen separate from the pancreas.
CALCIUM-Normal
6
Ranpa
i
4
Comments Today the human parathyroid hormone has been identified, and the active radical (the amino terminal) has been synthesized. The life cycle of the parathyroid hormone is at least partially molecule known. It begins as a huge manufactured
of 12,500 molecular weight, is stored as a 9,500 molecular weight molecule, and is secreted in the
l 0
I -I
512345 PR-OP.
I
6
7 Port-op.
6
9
10
II
12
13
14 IS
Days
Figure 2. Graph showing the abnormally h&h calcium and iow phosphorus levels preoperatively and the immediate shitT postoperatively.
Figure 3. X-ray fibn alYer barium swallow showing the tumor pushing the stomach forward and medially.
Volume
128, July 1974
109
Foley
Figure 4. Photograph showing the erterlorand cut ~e&on of the &we tumor.
blood as a 7,000 molecular weight molecule [5]. A peptidase enzyme system that accounts for the critical balance of calcium and parathyroid hormone has been identified [6]. The clinician has a new tool, the parathyroid hormone immunoassay. In principle this test is simple. It is based on the antibody parathyroid hormone competing with iodine-131-labeled parathyroid hormone for a known antigen. In practice the test is complicated. It is performed in only a few laboratories and the serum must be shipped frozen. Parathyroid hormone immunoassay has, however, been proved to be clinically reliable, particularly when negative balance between parathyroid hormone and calcium is considered (when the calcium level is low for any reason the parathyroid hormone level will be high). In general parathyroid hormone levels in primary hyperparathyroidism can be differentiated from those of ectopic hyper[ 71. parathyroidism Summary
A considerable body of evidence now strongly suggests that certain tumors actually metabolize and secrete hormone-like substances. Present technology has been able to identify, measure, and even partially synthesize some of these materials. Specific quantitation of tumor-secreted material is a very exciting possibility if indeed such secretion occurs more than we now know.
110
A case of ectopic hyperparathyroidism is presented in which a large retroperitoneal tumor produced preoperative findings of hyperparathyroidism and in which a temporary hypoparathyroid state occurred immediately postoperatively. The diagnosis, treatment, and significance are discussed briefly. Acknowledgment: I would like to thank Mr Ted Conde for the medical illustrations and photographs and Miss Frances McManiman, our librarian. References 1. Scholz DA. Riggs BL, Purell DC, Goldsmith RS, Arnaud CD: Ectopic hyperparathyrofdism with renal calculi and subperiostial bone reabsorption. Mayo C/in Proc 46: 124, 1973. 2. Menguy R: Pseudohyperparathyrotdism due to malignant melanoma. Surg Clin North Am49: 49, 1969. 3. Case Records of the Massachusetts General Hospital. N Engl J&f&255: 798, 1941. 4. Lafferty FW. Pseudohyperparathyroidism. Medicine 45: 247, 1966. 5. Brewer HB Jr, Fairwell T, Ronan R. Sizemore GW, Arnaud CD: Human parathyroid hormone: amino-acid sequence of the amino-terminal residues l-34. Proc Nat/ Acad Sci USA 69: 3585, 1972. 6. Fischer JA, Oldham SB, Sizemore GW, Arnaud CD: Calciumregulated parathyroid hormone peptidase. Proc Nail Acad SciUSA69: 2341, 1972. 7. Riggs BL, Arnaud CD, Reynolds JC, Smith LH: Immunologic differentiation of primary hyperparathyroidism from hyperparathyroidism due to nonparathyroid cancer. J C/in /west 50: 2079.1971.
The American Journalof Surgery
T. .I. Foley, MD, Milwaukee, Wisconsin
Ectopic hyperparathyroidism, also called pseudohyperparathyroidism, is a clinical syndrome defined as a nonparathyroid tumor associated with hypercalcemia and hypophosphatemia [I]. Menguy [Z] adds to this definition the absence of skeletal metastasis, the disappearance of clinical and laboratory manifestations of hyperparathyroidism after removal of the tumor, the presence of a substance immunologically resembling parathyroid hormone in the tumor removed at surgery or at postmortem examination, and the recurrence of manifestations of hyperparathyroidism with recurrence of tumor. The incidence of ectopic hyperparathyroidism was first suggested by Albright in 1941 [3]. In the 1950’s and more frequently in the 1960’s more cases were reported. Lafferty [4] reports ectopic hyperparathyroidism as the third most common cause of hypercalcemia at University Hospitals of Cleveland. The confusion of ectopic hyperparathyroidism with primary hyperparathyroidism still occurs. Knowledge of the incidence and differential diagnosis of ectopic hyperparathyroidism is essential to surgeons treating patients with hypercalcemia, who represent between 2 and 3 per cent of our hospitalized patients. Of 48,000 calcium determinations at St. Joseph’s Hospital in Milwaukee in the last twentyfive months, 2.1 per cent were above 10.5 mg per 100 ml. From the Department of Surgery, St. Joseph’s Hospital, Milwaukee, Wisconsin. Reprint requests shouti be addressed to Dr Foley, 2457 North Mayfair Road, Mwaukee. Wisconsin 53226.
106
Case Report The patient, a thirty-five year old woman, consulted her gynecologist because of a mass in the left epigastrium that had been present for five months and had enlarged during the past three months. During the past ten days she had had increasing, vague, ulcer type pains associated with eructations, gas, and diarrhea. She also complained of sparse hair and brittle nails. All of these symptoms dramatically disappeared after removal of the tumor. (Figure 1.) She was known to have had a heart murmur since childhood. Diabetes developed in her mother at age sixty-five. There was no history of renal calculi. During the patient’s second pregnancy nine years ago she had had significant hypertension. Physical examination revealed a well developed woman in no distress. Palpation indicated a normal thyrr,id and no neck masses were felt. A grade 4 systolic murmur was heard loudest at the second left interspace in the parasternal region. There was a firm, solid, slightly movable mass, 10 cm in diameter, in the abdomen. A loud systolic bruit separate from the heart murmur was heard over the mass. Pertinent laboratory studies revealed serum calcium levels of 13,13.1,13.7 mg per 100 ml. Serum phosphorus values were 1.7, 2.5, and 2 mg per 100 ml. (Figure 2.) The blood sugar and glucose tolerance tests revealed slightly elevated levels, indicating mild diabetes mellitus. Urinary calcium was 235 mg per twenty-four hours and the urinary phosphorus was 700 mg per twenty-four hours. X-ray examination of the chest revealed a prominence of the pulmonary arteries compatible with left to right intra-atria1 septal defect. Intravenous pyelogram and upper and lower gastrointestinal barium studies revealed no abnormalities other than a mass, 9 cm in size, in the area of the distal pancreas. (Figure 3.) X-ray study of the hands, skull, and teeth revealed no abnormalities. The electrocardiogram revealed an incomplete
The American Journal ol Surgery
Ectopic Hyperparathyroidism
bundle branch block. The hematocrit was 33 per cent and the hemoglobin was 10 gm per 100 ml. The patient was given 1 unit of cell mass preoperatively. Laparotomy was performed through a transverse incision. A 9 cm, rounded vascular tumor was removed from the retroperitoneal area below, but not attached to, a normal pancreas. There was no evidence of spread of tumor. During the postoperative period the serum calcium level dropped rapidly. TWO hours postoperatively the calcium level was 9.0 mg per 100 ml. On the third postoperative day she began to exhibit clinical hypocalcemia with twitching, irritability, and Chvostek’s sign, all of which responded immediately to calcium therapy. At this time daily calcium levels were 7, 7.3, 8.6, 8.9, 9.0, 8.4, 8.3,8.4, 9.0,9.1, and 9.3 mg per 100 ml. (Figure 2.) Grossly, the tumor was solid, weighed 636 gm, and measured 12 cm in diameter. The mass was encapsulated with a grayish pink cut surface. (Figure 4.) Microscopically, the lesion consisted of closely packed cells, for the most part having vesicular nuclei with irregularly clumped chromatin surrounded by various amounts of pale acidophilic-staining cytoplasm. The majority of the nuclei were round or oval. Some appeared to contain nucleoli. Generally the cells were arranged in trabecular formations that in many areas tended to form into distinct gland-like structures. Numerous capillary vessels were seen coursing through the lesion. Mitotic figures were also observed, averaging one per five high powered fields viewed. The lesion was thought to be an adenomatous neoplasm most likely of pancreatic origin.
Figure 1. Drawing showing the tumor in the abdomen separate from the pancreas.
CALCIUM-Normal
6
Ranpa
i
4
Comments Today the human parathyroid hormone has been identified, and the active radical (the amino terminal) has been synthesized. The life cycle of the parathyroid hormone is at least partially molecule known. It begins as a huge manufactured
of 12,500 molecular weight, is stored as a 9,500 molecular weight molecule, and is secreted in the
l 0
I -I
512345 PR-OP.
I
6
7 Port-op.
6
9
10
II
12
13
14 IS
Days
Figure 2. Graph showing the abnormally h&h calcium and iow phosphorus levels preoperatively and the immediate shitT postoperatively.
Figure 3. X-ray fibn alYer barium swallow showing the tumor pushing the stomach forward and medially.
Volume
128, July 1974
109
Foley
Figure 4. Photograph showing the erterlorand cut ~e&on of the &we tumor.
blood as a 7,000 molecular weight molecule [5]. A peptidase enzyme system that accounts for the critical balance of calcium and parathyroid hormone has been identified [6]. The clinician has a new tool, the parathyroid hormone immunoassay. In principle this test is simple. It is based on the antibody parathyroid hormone competing with iodine-131-labeled parathyroid hormone for a known antigen. In practice the test is complicated. It is performed in only a few laboratories and the serum must be shipped frozen. Parathyroid hormone immunoassay has, however, been proved to be clinically reliable, particularly when negative balance between parathyroid hormone and calcium is considered (when the calcium level is low for any reason the parathyroid hormone level will be high). In general parathyroid hormone levels in primary hyperparathyroidism can be differentiated from those of ectopic hyper[ 71. parathyroidism Summary
A considerable body of evidence now strongly suggests that certain tumors actually metabolize and secrete hormone-like substances. Present technology has been able to identify, measure, and even partially synthesize some of these materials. Specific quantitation of tumor-secreted material is a very exciting possibility if indeed such secretion occurs more than we now know.
110
A case of ectopic hyperparathyroidism is presented in which a large retroperitoneal tumor produced preoperative findings of hyperparathyroidism and in which a temporary hypoparathyroid state occurred immediately postoperatively. The diagnosis, treatment, and significance are discussed briefly. Acknowledgment: I would like to thank Mr Ted Conde for the medical illustrations and photographs and Miss Frances McManiman, our librarian. References 1. Scholz DA. Riggs BL, Purell DC, Goldsmith RS, Arnaud CD: Ectopic hyperparathyrofdism with renal calculi and subperiostial bone reabsorption. Mayo C/in Proc 46: 124, 1973. 2. Menguy R: Pseudohyperparathyrotdism due to malignant melanoma. Surg Clin North Am49: 49, 1969. 3. Case Records of the Massachusetts General Hospital. N Engl J&f&255: 798, 1941. 4. Lafferty FW. Pseudohyperparathyroidism. Medicine 45: 247, 1966. 5. Brewer HB Jr, Fairwell T, Ronan R. Sizemore GW, Arnaud CD: Human parathyroid hormone: amino-acid sequence of the amino-terminal residues l-34. Proc Nat/ Acad Sci USA 69: 3585, 1972. 6. Fischer JA, Oldham SB, Sizemore GW, Arnaud CD: Calciumregulated parathyroid hormone peptidase. Proc Nail Acad SciUSA69: 2341, 1972. 7. Riggs BL, Arnaud CD, Reynolds JC, Smith LH: Immunologic differentiation of primary hyperparathyroidism from hyperparathyroidism due to nonparathyroid cancer. J C/in /west 50: 2079.1971.
The American Journalof Surgery