DOCUMENTED HYPERPARATHYROIDISM OF THIRTY-SIX YEARS’ DURATION

THOMAS J. FAHEY, JR, MD,* A N D W. P. LAIRD MYERS, YD+

The fascinating history of the first Memorial Hospital patient who was diag- nosed as having hyperparathyroidism is reviewed. The illness presented as a cystic mass in a femur in 1929, which was treated with radiation. When the pa- tient was first seen at Memorial Hospital in 1931, the diagnosis of osteitis fibrosa cyetica was made; serum calcium was 14 mg/100 ml. In 1932, 6 years after Mandl performed the first parathyroidectomy ever for osteitis fibrosa cystica, this patient’s neck was explored, and a right hemithyroidectomy was done, with removal of two normal parathyroid glands. The parathyroid tumor was finally located and partially removed in 1937 after a second failure at neck explora- tion in 1936. Correspondence between Dr. Edward D. Churchill at the Massachusetts General Hospital and Dr. Bradley Coley at Memorial Hospital indicated the concern at that time about uncontrollable tetany, which had been fatal i n some contemporary cases and which had led to the practice of only par- tially removing the tumor. Following this, the patient was observed with docu- mented hypercalcemia and chemical evidence of hyperparathyrodism until age 79. The physical and chemical abnormalities over the years up to and includ- ing her last exam are presented. The case is important not only from the his- torical viewpoint, but because it lends a perspective to long-term parathyroid disease, which is becoming less appreciated in this day of the routine serum cal- cium by SMA-12 screening. The question of partial parathyroidectomy for adenoma or hyperplasia is reviewed, and the question of observation of pa- tients with mild hypercalcemia who probably have parathyroid tumors is dis- cussed.

35:803-807, 1975.

HIS CASE IS REPORTED NOT ONLY TO DOCU- T ment long-term hypercalcemia secondary to an incompletely excised parathyroid ade- noma, but also in the context of historical per- spective. The patient was the first case of hyperparathyroidism recognized at Memorial Hospital for Cancer and Allied Diseases, hav- ing initially been referred with a “tumor” of the femur in 1931. The clinical presentation of osteitis fibrosa cystica was not uncommon in that era.’

Presented at the 27th Annual Meeting of The James Ewing Society, Maui, HI, April 8-13, 1974.

From the Departments of Medicine, .Memorial Sloan- Kcttering Cancer Center and Cornell University Medical College, New York, NY.

Attending Physician, Memorial Hospital; Clinical As- sociate Professor of Medicine, Cornell University Medical College .

’ Chairman, Department of Medicine, Memorial Hos- pital; Professor of Medicine, Cornell University Medical College.

Address for reprints: Thomas J. Fahey, Jr., .MD, Memorial Hospital for Cancer and Allied Diseases, 1275 York Avenue, New York, h’Y 10021.

Received for publication June 11, 1974.

The syndrome which we now recognize as hyperparathyroidism was not appreciated until about the turn of this century, and even then only in limited scope. It is generally accepted that no one was cured of this disease, until Mandl reported the successful operative removal of a parathyroid adenoma in 1926, less than 50 years ago and only 5 years prior to this patient’s admission to Memorial Hospital.‘

CASE REPORT

E.S. was a 45-year-old single white woman housekeeper when she was referred to Dr. Bradley L. Coley’s Bone ‘Tumor Clinic at Memorial Hospital for Cancer and Allied Dis- eases in June, 1931 because of pain and a cystic mass in the mid left femur. She had first noted an ache in the left thigh in February, 1929, which progressed to pain on weight bearing so that finally she was unable to work. Prior to re- ferral she had been given “ 15 x-ray treatments” to the thigh elsewhere. O n June 17, 1931 she was taken to the operating room at the old Memorial Hospital on Central Park West, where a “six-cm long and 1.5 cm. wide window

803

804 CANCER March 1975 VOl. 35

was cut in the lateral aspect of the cortex of the femur with a hammer and chisel. An oily colored serous fluid escaped in considerable quantity . . . A cavity lined by smooth, glisten- ing membrane was rongured out and the cavity scrubbed with zinc chloride.” Bone chips were placed in the cavity and a plaster spica was ap- plied. Dr. Fred Stewart, pathologist, reported the pathology consisted of a “fibrous cyst wall, rare bone spicules, and crystalline deposits.”

O n June 19, 1931, 2 days postoperative, a blood calcium was found to be 14.7 mg/100 ml. Dr. Coley noted on July 1, 1931 that the patient had a palpable thyroid swelling and that she “refused thyroid exploration but these findings are of considerable interest.” Phlebitis, ir- rational spells, pulmonary infections, and a sacral bed sore complicated her postoperative period. The patient was finally discharged from the hospital 3 !h months later, in October, 1931, on crutches.

The record reveals that Dr. Coley finally in- duced her to re-enter the hospital in April, 1932 for thyroid exploration. On April 27, 1932, a right hemithyroidectomy was done. “TWO round pieces of tissue which lay posteriorly in position of parathyroids” were removed in addi- tion to the majority of the right thyroid lobe, but Dr. Stewart only found “colloid thyroid adenoma with regeneration hyperplasia” under the microscope. However, on May 2, 1932 her blood calcium was found to be 11.6 and 12 mg/100 ml. O n May 6, 1932 she was found to have a right vocal cord paralysis, which per- sisted. In October of 1932 it was indicated that her femur was in excellent condition. Sub- sequent blood calciums performed by Dr. Helen Woodard continued to be 12 mg/100 ml and higher.

The left leg began to swell again in 1934, and in February, 1935 an enlargement of the right lobe of her thyroid was again noted. Laboratory findings were felt to point to “active osteitis fibrosa cystica.” Finally in March, 1936 she was readmitted for further exploration of her neck. O n March 25, 1936 “at the posterior aspect of the middle and lower portion of the left thyroid gland, two nodular swellings, each about 12 mm. in diameter, spherical in form, dark brown- ish-purplish color, well encapsulated,’’ were shelled out easily. However, Dr. Stewart again found only thyroid adenomas and no para- thyroid tissue under the microsco e. The pa-

Following the second unsuccessful attempt to remove her parathyroid tumor, in October, 1936, Dr. Lloyd Craver began treatment to her neck with a total of 1600 rads via 200-kV x rays in eight split treatments with no effect on the serum calcium level.

In April, 1937, Dr. Coley wrote Dr. Edward Churchill at the Massachusetts General

tient’s calcium 5 days later was 16. 3 mg/ 100 ml.

Hospital about the possibility of coming to Memorial Hospital to operate on the patient for the elusive parathyroid adenoma. After review- ing the case and roentgenograms sent to him in Boston, Dr. Churchill declined the invitation, writing that “ I should not care to operate on this patient elsewhere than in Boston,” and suggested that he arrange for admission to the Massachusetts General. While attending a sur- gical meeting in New York, an appointment was made for him to examine the patient on June 5, 1937 at 10 a.m. at the reception desk at the Waldorf Astoria. She was subsequently ad- mitted to the Massachusetts General Hospital on June 19, 1937. Evaluation there revealed a calcium of 14.5 .mg/100 ml, phosphorus 2.2 mg/ 100 ml, bilateral renal stones, and bone roentgenograms consistent with hyperparathy- roidism. A letter from Dr. Churchill to Dr. Coley summarized the findings at operation:

“On July 2, [ 19371 operation was performed under gas-oxygen-ether anesthesia. Explora- tion was first carried to the ri ht side of the neck where there was a slight fu IJ lness palpable on physical examination. The right lobe of the thyroid had been removed previously and oc- cupying the position that would normally have been filled by a separate pole, a large, soft, typi- cal parathyroid adenoma was found. Because of previous operations in the course of which the integrity of the normal parathyroid glands might have been damaged, it was not deemed advisable to do a totaI resection of the tumor. Tumor tissue, measuring 4.5 X 3.2 X 2 cm. and weighing 14.2 grams, was excised. A small nodule was left at the level of the cricoid car- tilage with a good blood supply.

“Pathological examination showed a para- thyroid adenoma of glandular type. A bone biopsy was taken from the sternum at the time of operation. It showed typical osteitis fibrosa cystica. There was active proliferation of osteo- blasts but very few osteoclasts and practically no osteoid tissue in the section. Studies taken after the operations were as follows: ,July 3, 1937, calcium 11.47, phosphorus 1.90, phosphatase 21.30 units. July 12, 1937, calcium 10.17, phos- phorus 2.42, phosphatase 18.86 units.

“I am enclosing a photograph of the portion of the tumor excised, superimposed on a diagram of the thyroid gland, indicating the position [Fig. 11. I am also sending under separate cover two microscopic slides of the tumor.

“The patient’s blood findings should be fol- lowed at intervals during the next few months as it is quite possible that a mild degree of hyper- parathyroidism will reassert itself, owing to the fact that a residuum of the tumor was left be- hind. If the blood levels definitely and per- manently establish themselves at an abnormal level it may be advisable to remove more of the tumor. I should never feel safe, however, to

so. 3 T l I I n . r Y - S I X YEARS’ HYPERPARATIWROIDISM Fahcy and Myers 805

remove it all. Another reason for doing a sub- total resection in this case was the high phos- phatase value, as we have found a quite severe tetany may occur even if the other parathyroids are intact.”

Dr. Fred Stewart reviewed the slide and in- deed confirmed that it was a “parathyroid adenoma.” Figure 2 indicates the biochemical data obtained at intervals during the patient’s subsequent followup at iMemorial Hos ital. In

cellent condition; much improved over her pre- vious status, and presents no evidence of difficul- ty at this time in the neck or constitutionally.”

In October, 1949 Dr. Coley noted “It is 18 years since the patient first consulted us and she is in fine condition. Dr. Woodard has taken blood for check on her chemistry. Because the surgeons in Boston left a small piece of a para- thyroid tumor for fear of insufficient para- thyroid tissue as a result of the previous ex- ploration, she has remained in a mild state of hyperparathyroidism which has not bothered her at all.”

The patient’s last visit to the Bone Clinic at Memorial Hospital was in August, 1952, when it was noted that she had been in good health ex- cept for “arthritic pain in the left knee present during the past three years.” A roent enogram in August, 1952 revealed a “number o B intra-ab- dominal calcific densities. ” Sagittal and lateral films of the left femur revealed “a mild degree of demineralization with a segment presenting some increased density in the mid portion of the femoral diaphysis above which are small punc- tate areas also of increased density. The com-

act portion of the shaft of the femur appears to ge somewhat thicker than usually seen.”

O n March 25, 1954 a letter from the patient’s personal physician in Westchester stated: “Miss S. is unable to come to Dr. Coley’s Clinic be- cause of rather severe arthritis of both knees. As to her present condition, there would appear to be nothing related to her operations on the para- thyroids. She is moderately hypertensive and shows some signs of myocardial failure. How- ever, i t is only her arthritis which renders her unable to travel. She is being seen at the office twice weekly and receiving injections of Adenosine and B12 as well as diathermy.”

One month later, after this report had been re- viewed by Dr. Oliver Cope, who had re uested followup on the patient for the Massac 1 usetts General Parathyroid Adenoma Series, Dr. Cope wrote Dr. Coley about his concern for the per- sistent hypercalcemia in the patient. The corre- spondence is a classic in succinct exposition of the problem at that point: “I must say I am a lit- tle disturbed to see from her doctor’s letter to you that she is having arthritis, is moderately hypertensive with signs of myocardial failure. 1’0 be sure, she is 67 but these symptoms to-

1938, Dr. Coley noted “the patient fee P s in ex-

Pic;. I . Parathyroid adenorna removed in 1937 superirn- powd on diagram by Dr. Churchill.

gether with the chemical findings at your hospital of continued elevation of the blood serum calcium suggest that the whole thing means continued smoldering hyperpara- thyroidism. I am wondering whether she would not be better off with a remnant of the para- thyroid tumor removed in toto, or at least whittled down. I note that the last blood level taken in August 1952 was 13.4 mg. with a phos- phorus of 2.4. These levels suggest considerable hyperactivity and she certainly ought to be having skeletal symptoms. If she is having con- tinued hyper arathyroidism, injections of Ade-

much good. “Leaving a portion of an adenoma does not

seem to be too good an idea. Pete Churchill left a piece because of the previous operations and the fear that the undiseased parathyroids had been damaged at the previous explorations, and of course, this is a substantial reason. All the same, some of our other patients treated in this way have turned out to have further hyperpara- thyroidism and a remnant had to be removed eventually. For a time we had an idea that it would be good to leave a portion of the adenoma to minimize the post-operative tetany. This has not proved to be necessary. With better under- standing of the origins of the tetany this aspect can be controlled by proper post-operative cal- cium and phosphorus therapy.”

However, subsequent followup was only by mail communication from the patient’s per- sonal physician who continued to indicate that the patient was “doing well,” until March of 1965, when the authors made a house call on the

nosine and IY 12 and diathermy won’t do her

No. 3 ‘ r t w t w - s i x YEAKS’ H Y P E R P A R A , r ~ I Y R O I D I S M Fuhq and Myers 807

calcium screening because clinically important hyperparathyroidism will be diagnosed without i t .” They suggest that most asymptomatic pa- tients with mild hyperparathyroidism live in good symbiosis with their disease and their health is not necessarily improved by operation. However, only 3 years’ followup onjust six cases reported in this study hardly seems enough to make such assumptions.

Retrospective studies seem to indicate that renal damage and hypertension from chronic hyperparathyroidism may be significant.& Other clinical associations may also be important from the morbidity standpoint.’ O n the other hand, the Endocrine Service at Memorial Hospital has a number of patients with hypercalcemia suspected to be secondary to parathyroid adenoma, who have been followed for long periods of time without significant morbidity, and who have not come to neck exploration for a variety of reasons. O n an anecdotal basis alone this does not seem to be ap uncommon ex- perience in many centers. However, more long- term prospective studies of chronic documented hyperparathyroidism of the type the Mayo Clinic has under way are needed to assess the long-term effect of hypercalcemia on the pa- tient.’ Perhaps long-term should mean 10 to 20 years rather than 5.

With the advent of reliable radioimmunoas- says of parathormone, the numerous variations of indirect confirmatory tests of hyperparathy- roidism, none absolutely specific, usually related to renal handling of calcium and phosphorous, appear soon to be of historical curiosity only.’ More widely available parathormone assays will

make accurate prospective studies possible wherever a large population of patients is screened. Some of the problems we have previ- ously reported in diagnosing primary hyper- parathyroidism in hypercalcemic cancer pa- tients should also be greatly lessened by the availability of the radioimmunoassay of para- thormone. 4*7

Although this case report depicts the long- term survival of a patient with chronic hyper- parathyroidism, we believe it actually does not support the argument for observation of pa- tients with hypercalcemia secondary to para- thyroid adenoma. The patient’s renal and car- diovascular abnormalities, undoubtedly related to her incompletely excised parathyroid adenoma, were significant; we believe she lived into her 80s in spite of them. Experience has shown, as in this patient, that incomplete ex- cision of a parathyroid adenoma may lead to chronic hyperparathyroidism and require addi- tional surgery. Observation of borderline hyper- calcemia or borderline parathormone elevation is probably reasonable; the autoanalyser makes this easy and economically feasible and should not be condemned. Long-term prospective stud- ies of the problem are encouraged. Until more definitive information is available from long- term prospective studies, the decision to explore a patient for hyperparathyroidism should be a clinical one, based on all parameters of the pa- tient’s presentation or course and not limited to laboratory data alone.

REFERENCES

1. Arnaud, C. ll., ‘lsao, H. S., and Littledyke, T.: Radioimmunoassay or human parathyroid hormone in serum. J . Ch. Invest. 50:21-34, 1971.

2. Barr, L). P., and Bulger, I{. A: The clinical syndrome of hyperparathyroidism. A m . J . Med. Sa. 179:449-476, 1930.

3. Cope, O., Barnes, B. A., Castleman, B., .Mueller, G. C. E., and Koth, S. I . : Vicissitudes of parathyroid sur- gery-Trials of diagnosis and management in 51 patients with a variety of disorders. Ann. Surg. 154:491-508, 1961.

4. Farr, H. W., Fahey, T. J., Dash, A. G . , and Farr, C . M.: Primary hyperparathyroidism and cancer. A m . 5. Surg. 126:539-543, 1973.

5. Ilelsrrom, J., Birkc, G . , and Edval, C . A.: Hypertension and hyperparathyroidism. Br. J . Urol. 30: 13-24, 1958.

6. Mandl, F.: Hyperparathyroidism, a review of historical developments and the present state of knowledge on the sub- ject. Surgny 21:394-440, 1947.

7. Myers, W. P. la.: An analysis of medical problems in cancer. Med. Clin. Norfh A m . 45:563-583, 1961.

8. Purnell, D. C., Linwood, H. S., Scholz, D. A,, Elvebach, 1.. K., and Arnaud, C. I ) . : Primary hyperpara- thyroidism, a prospective clinical study. A m . J . Mcd. .50:670-678, 1971.

9. Rothschild, E. 0.: Personal communication, 1974.

10. Williamson, E. , and VanPeener, H. J.: Patient benefit in discovering occult hyperparathyroidism. Arch. Intern. Med. I33:430-431, 1974.