The Rationale against Routine Subtotal Parathyroidectomy for Primary Hyperparathyroidism Joseph N. Attie, MD, New Hyde Park, New York Leslie Wise, MD, New Hyde Park, New York Rabia Mir, MD, New Hyde Park, New York Lauren V. Ackerman,
MD, New Hyde Park, New York
The traditional concept that most cases of hyperparathyroidism are due to hypersecretion of parathormone from a solitary adenoma, the surgical extirpation of which will result in cure, has been challenged in recent years. Some authors [I,21 have reported a high incidence of hyperplasia of all four glands and a significant rate of recurrence of hyperparathyroidism when only the abnormally enlarged parathyroid gland was removed. Because of the “high” incidence of recurrent hypercalcemia and the difficulty in differentiating hyperplasia from adenoma by conventional microscopy, they advocated routine removal of three and a half glands in all patients with primary hyperparat,hyroidism. Our approach parathyroid
has been glands,
to resect only grossly as it was our impression
enlarged that the
long-term results were just as satisfactory. Because of the controversy concerning the optimal treatment, I&: believed it important to review our experience. Material
and Methods
Of 319 patients surf$cally treated for hyperparathyroidism from January 1953 through March 1978,292 had primary hyperparathyroidism. Of these, 101 consecutive patients operated on for primary hyperparathyroidism f’rc‘rn .July 1965 through June 1974 were reviewed. Of the 10 Lpatients, 91 per cent were examined and only 9 per cent were lost to follow-up. Seventy-four patients (73.3 per cent) From the Departments of Surgery and Pathology, Long Island Jewish-Hillside Medical Center, New Hyde Park, and The State University of New York at Stow Brook. Stow Brook. New York Reprint requests should be addressed to Leslie Wise, MD, Long Island Jewish-Hillside Medical Center, New Hyde Park, New York 11040. Presentadat the Joint Meeting of the American Society for Head and Neck Surgery and the Society of Head and Neck Surgeons, Toronto, Ontario, Canada, May 29-31, 1978.
Volume 136, October
1978
were evaluated by personal interview and their serum calcium, phosphorus, alkaline phosphat,ase, and albumin levels were determined in our laboratories; the serum parathormone levels were determined at the University of Miami Medical School in the Special Laboratory Services under Dr. Eric Reiss and Janet M. Canterbury [Y]. An additional ten patients (9.9 per cent) were questioned by telephone for symptoms, and up-to-date biochemical results were obtained from their local physicians. Another eight patients (7.9 per cent) had died, but in none of them was the cause of death due to a complication of hyperparathyroidism. The remaining nine patients (8.9 per cent) were lost to follow-up despite exhaust,ive efforts to locat,e them. Sex and Age. Of the 101 patients, thirty-seven (37 per cent) were male and sixty-four (63 per cent) were female. The youngest patient was sixteen years old and t.he oldest seventy-four years old (mean age, 51.0 i 14.8 years). Diagnosis. The presenting symptoms of the 101 patients are summarized in Table I. The diagnosis of primary hyperparathyroidism was based generally on persistently elevated serum calcium levels of more than 1 I .O mg/lOO ml (normal in our laboratories, 9.0 to 10.5 mg:/lOO ml) with or without. depressed phosphorus concentrations after the exclusion of other causes of hypercalcemia. ‘l’he mean preoperative serum calcium level was 12.4 f I .:i mg/lOO ml. whereas the mean serum phosphorus level was 2.6 f 0.7 mg/lOO ml (normal in our laboratories. Z1.0to 4.5 ml/100 ml). Although some patients had elevated alkaline phosphatase and/or elevated parathormone levels, these were not considered essential for the diagnosis. ‘I’hns, all the patients operated on had serum calcium levels of more than 11.0 mg/lOO ml, except for those five in whom a parathyroid adenoma was discovered incidentally during thyroid exploration. It is our practice to expose and identify if possible all four or, rarely, five parathyroid glands. If all of them are en-
437
Attie et al
TABLE I
Presenting Features in 101 Patients
Renal calculi Asymptomatic hypercalcemia Gastrointestinal complications (peptic ulcer, pancreatitis) Incidental finding during thyroid explorations Coma Minimal symptoms (fatigue, polyuria) Skeletal manifestations Psychotic manifestations MEA-l presenting as insulinoma Total
41 40 6 5 4 2 1 1 1 101
larged, all but half of one gland are removed; otherwise, only the enlarged gland (or glands) is removed. Those glands that appear normal on gross inspection are left in situ. Pathologic Findings. All the pathologic material on the 101patients was restudied by us. In ninety-five patients, a single enlarged parathyroid gland was removed (1 of these was eventually found to have multiple endocrine, adenopathy-I[MEA-I]). A biopsy was taken also from one’normal parathyroid gland in one of the ninety-five patients, and the remaining three normal-appearing parathyroid glands were biopsied in another. The apparently normal parathyroid glands in the other ninety-three patients were not biopsied or removed. In five patients two enlarged parathyroid glands were found and resected, and in one of these an additional grossly normal parathyroid gland was removed. (Figure 1.) In one patient three enlarged parathyroid glands were removed. Microscopically, a total of 109 totally resected parathyroid glands were examined. The size of the glands that were considered diseased varied from 0.8 to 11.0 cm in diameter (mean size, 2.3 * 1.4 cm). A well developed capsule was identified in forty-three glands, whereas the rest had a rather delicate capsule. All showed increased cellularity and replacement of stromal fat. Sixty-two were composed entirely of chief cells, four of oxyphil cells (Figure 2), and only one of water-clear cells. The remaining forty-two glands were composed of chief, oxyphil, and water-clear cells, the chief cell being predominant. One parathyroid gland showed features of lipoadenoma; it weighed 14 gm, measured 8.0 by 2.5 by 2.0 cm, and contained more fat than parathyroid chief cells. (Figure 3.) Cases of parathyroid carcinoma were excluded from this study. Results
The patients operated on during this nine year period were followed for a minimum of three years and a maximum of twelve years (mean follow-up, 5.8 f 2.4 years). Recurrences. Of the ninety-two patients who were followed, there were only two (2.2 per cent) in whom reoperation was necessary. The first was operated on initially in June 1972. This patient was noted to have asymptomatic hypercalcemia on routine biochemical profile, and at operation an enlarged left inferior
438
Figure 7. Three parathyroid glands removed from the same patient. The two grossly enlarged glands measured 1.5 and 0.8 cm in diameter and were hyperceliuiar, with less than JO per cent stromai fat. The gross/y normal parathyroid gland (0.3 cm in diameter) was also partial/y hyperceiiuiar. (Hematoxyiin and eosfn stain; magnification X15, reduced 33 per cent.)
parathyroid gland was found and removed. The serum calcium level returned to within normal limits and remained there for t.hree years, at which time an increase again was observed. In February 1976 she was again operated on for asymptomatic hypercalcemia, and this time an enlarged right superior parathyroid gland was removed. At present her serum calcium and parathormone levels are within normal limits, and she remains asymptomatic. The second reoperation was on a patient with MEA-I, who required three operations before a cure was effected. In August 1971 this patient underwent distal pancreatectomy for an insulinoma; during hospitalization she was found to be hypercalcemic. In September 1971 an enlarged left inferior parathyroid gland was excised; the other three parathyroid glands appeared macroscopically normal. Postoperatively, the serum calcium level returned to within normal limits. After an interval, recurrence
The American Journal of Surgery
Treatment of Primary Hyperparathyroidism
Figure 2. Functioning oxyphil ceils with densely packed mitochondria. (Lead citrate and uranyt acetate stain; magnification X6000, reduced 35 per cent. )
Figure 3. Hyperfunctioning lipoadenoma of parathyroid gland, There is more fat than parathyroid chief Cells. (Hematoxylin and eosin stain; magnification X400, reduced 32 per cent. )
of -the hypercalcemia developed, and in January 1975 the patient. was again reexplored, and an enlarged right superior parathyroid gland was removed. Once again, the remaining two parathyroid glands appeared grossly unremarkable. The serum calcium level temporarily returned to within normal limits, but after a few months the hypercalcemia recurred, and at a third operative procedure the left superior parathyroid gland and half the right inferior parathyroid gland, both of which were now enlarged, were resected. At present, the serum calcium level is within normal limits and the patient is asymptomatic, but
Volume 136, October 1976
it. is interest,ing that the serum parat hormone level is still elevated. The postoperative biochemical results in our patients are summarized in Table II. ‘l’he serum calcium levels varied from 8.7 to I 1.O n&l00 ml; the value of’ 11.0 mg/lOO ml, however. occurred in only one 01‘ three determinations in one patient, the other two values being within the normal range. ‘I’he postoperative parathormone levels ranged from 10 to XC) ~lEq/ml. The mean serum parathyroid hormone level was 62.7 f 45.2 ~IHq/ml. Of’ the seventy-four parathormone samples tested, eleven were
439
Attie et al
TABLE II
Biochemical Data of the 74 Patients Reevaluated Biochemically Postoperatively in Our Laboratories
Serum Calcium (mg/lOO ml) Phosphorus (mg/lOO ml) Albumin (gm/iOO ml) Alkaline phosphatase (NJ)
Mean f SD 9.8 3.1 4.2 58.4
f 0.4 f 0.5 f 0.2 f 20.4
Range 8.7-i 1 .o 1.9-4.5 3.5-5.5 24-138
considered elevated, assuming that the normal range is 10 to 75 /*lEq/ml. It should be noted, however, that values from 75 to 100 plEq/ml fall into a grey zone which is difficult to interpret, and a number of conditions other than hyperparathyroidism may give rise to these modest elevations. In the Special Laboratory Services at the University of Miami Medical School the lowest serum parathormone level in patients with proven primary hyperparathyroidism was 100 JEq/ml [4]. In only one -of our, seventy-four patients was there an elevated serum calcium level to 11 mg/lOO ml (in 1 of 3 determinations); this patient also had an elevated parathyroid hormone level. Marginally elevated serum parathormone levels in the presence of normal serum calcium values do not necessarily indicate hyperparathyroidism. No patient in this series demonstrated any evidence of permanent hypoparathyroidism postoperatively. Comments
Recently, the classic approach of resection of only grossly enlarged parathyroid glands in cases of primary hyperparathyroidism has been challenged [1,2,5]. Paloyan and co-workers [1,5] and Haff and Ballinger [2] advocated routine subtotal (3.5 glands) parathyroidectomy in all patients with primary hyperparathyroidism even in the absence of diffuse enlargement of all parathyroid glands. They claimed that limited resections resulted in high recurrence rates and that even normal-looking glands were found to be hyperplastic histologically. Purnell, Schalz, and Beahrs [6], however, reported only a 1 per cent recurrence in 198 patients operated on for primary hyperparathyroidism in whom only enlarged glands were removed. Clark, Way, and Hunt [7] collected all the reports in the English literature and found that in a total of 3,204 patients treated by selective parathyroidectomy, the recurrence rate was only 0.7 per cent. In Clark’s own series only one patient of 242 without MEA or familial hyperparathyroidism had recurrent hyperparathyroidism after removal of only enlarged glands. In our series of primary hyperparathyroidism, we had two proven
440
recurrences, one in a patient with MEA-I and the other with no known cause. We believe that with proper experience, normal-looking parathyroid glands can be identified; in our series such glands were not removed and usually not biopsied. We agree with Clark, Way, and Hunt [7] that the biopsy of normal-looking glands is unnecessary and of little value except to assure that a particular anatomic structure is a parathyroid gland [8]. The amount of functioning parathyroid tissue required for calcium homeostasis has not been clearly established. The 2 per cent incidence of permanent hypoparathyroidism after routine subtotal parathyroidectomy reported by Paloyan, Paloyan, and Pickleman [5] and the 5 per cent reported by Haff and Ballinger [2] are certainly higher than the incidence reported by surgeons who advocate selective parathyroidectomy. It is surprising that the preservation of only half a gland did not result in a higher rate of hypoparathyroidism in these series. Bruining [9] reported a 27 per cent incidence of severe hypoparathyroidism after subtotal resection of parathyroid glands; he then reverted to selective resection and reduced this incidence to 1.2 per cent. One explanation for the relatively low incidence of hypoparathyroidism after subtotal parathyroidectomy may be that some patients in these series possessed more than four glands and, therefore, may have retained one and a half glands postoperatively. Heinbath [IO], in a study of twenty-five human cadavers, found that two patients had five glands and another two had six. In 428 human dissections, Gilmour [I 1] found five parathyroid glands in twenty-five subjects and six glands in another three subjects. Wang [12] performed 160 autopsies and found five parathyroid glands in three patients and six glands in one. Thus, in a total of 613 autopsies, thirty-six patients (6.0 per cent) had more than four parathyroid glands. There are several arguments against the hypothesis that a large percentage of patients with primary hyperparathyroidism may indeed have diffuse functional hyperplasia, even though one large and three normal-looking parathyroid glands may be found. In nearly all patients, the removal of the one or, less frequently, two enlarged parathyroid glands results in a prompt return of the calcium levels to within normal limits. Furthermore, in patients with long-standing severe hypercalcemia, especially with bone damage, the removal of only the one large parathyroid gland results in precipitous and often prolonged decreases in calcium to below normal levels, indicating that the three remaining glands are not functionally hyperactive. In those patients in whom recurrence of hyperparathyroidism does take
The American Journal Of Surgery
Treatment
it usually does so after an interval of normocalcemia, sometimes lasting several years. It would seem that in these cases, the normal-looking glands preserved at the original operation were not hyperfunctioning at the time, but that one or more of them subsequently became hyperfunctioning and produced a state of hyperparathyroidism de novo. Since 1953 we have operated on 319 patients with hyperparathyroidism (Table III), and our philosophy of surgical management has remained unchanged. By meticulous dissection in a dry field, an attempt is made to identify all four parathyroid glands. The size, color, location, consistency, and amount of surrounding fat is noted for each gland before any tissue is removed. Care is taken not to divide branches of the thyroid arteries, as one of these may be needed subsequently to search for an ectopically located parathyroid. Gross macroscopic evaluation of -rhe parathyroid glands is probably the most accurate single method of differentiating a normal from an abnormal gland; the ability to identify the glands is learned by observation during thyroid operatio 2s. We believe that in cases of primary hyperparathyroidism, only grossly abnormal parathyroid tissue shculd be removed except in cases of MEA or familial hyperparathyroidism (when subtotal parathyroidectomy is indicated). In most other cases, only one parathyroid gland is enlarged while the other three appear normal; less frequently two or, very rarely, three large parathyroid glands are found. In the past these cases were labeled as single, double, or triple adenomas. If all four glands were enlarged, it was called hyperplasia. In our series of 101 patients with hyyjerparathyroidism, ninety-five had one enlarged gla:ld, five had two enlarged glands, and one had three enlarged glands. Castleman, Schantz, and Roth [IS] found hyperplasia of all four glands to be the cause of primary hyperparathyroidism in 85 of 557 patients (15.3 per cent). In two extensive reviews of the literature [ 7, 141, the incidence of diffuse hyperplasia ranged from zero to 20 per cent. It seems that under certain rare conditions there is a stimulus present that will cause hyperplasia of all the parathyroid glands, and in such cases subtotal parathyroidectomy is probably indicated; the only stimulus known at the present time is hypocalcemia. This is best illust,rated in patients with secondary pamthyroid hyperplasia due to renal failure. In patients with MEA, especially those with medullary thyroid carcinoma, the excessive secretion of calcitonin tends to produce hypocalcemia with constant stimulation of the parathyroid glands; uniform parathyroid hyperplasia, therefore, is a common place.
Volume
136,
October
1976
TABLE III
of Primary
Hyperparathyroidism
Presenting Features of 319 Patients Operated on for Hyperparathyroidism (1953-1978)
Asymptomatic hypercalcemia Renal calculi Secondary hyperparathyroidism Incidental during thyroid explorations Skeletal manifestations Gastrointestinal complications (peptic ulcer, pancreatitis) Neurologic or psychotic manifestations Coma Minimal symptoms (fatigue, polyuria, etc.) Tertiary hyperparathyroidism MEA-I (insulinoma, Zollinger-Ellison syndrome) MEA-II (associated with medullary carcinoma)
128 96 24 17 13 12 8 8 3 2
finding in these patients. It has also been shown [15] that gastrin can produce hypocalcemia and cause hyperplasia of the parathyroid glands. Paloyan et al [16] reported stimulation of the parathyroid glands by hypersecretion of glucagon in patients with chronic pancreatitis. In the majority of cases, however, the cause of primary hyperparathyroidism is unknown. Since there are an overwhelming number of cases from different series that have not recurred after the removal of a single enlarged gland, it is probable that this gland is autonomous and not the result of a specific stimulus. Certainly, if there is a stimulus in these patients creating a tendency toward hyperparathyroidism, it seems to act extremely slowly, causing only a very small number of recurrences during the lifetime of most patients. Most explorations today are performed on patients with asymptomatic hypercalcemia. Even the slightest possibility of postoperative hypoparathyroidism must be avoided, for how tragic it would be to convert a totally asymptomatic patient into a permanent “cripple.” Routine subtotal parathyroidectomy in this group of patients would expose a significant number of them to grave complications. It is true that usually the treatment of hypoparathyroidism is not too complicated, especially with dietary calcium supplements and purified analogues of vitamin D. In some instances, however, the condition is very difficult to control. The margin between controlling doses and intoxicating doses of vitamin D may be small [I 71, and there is a potential risk of nephrocalcinosis, nephrolithiasis, and renal failure [18]; serum calcium studies must continue for years, and the patient’s requirements may change. Untreated long-term hypocalcemia may result in cataracts, convulsions, and other complications. It is precisely in the patients with asymptomatic hypercalcemia (who constitute 60 to 70 per cent of patients operated on today) that the decisions at surgery are most difficult to make. The abnormal
441
Attie et al
Figure 4. Hypercelkdar parathyroid gland divided into lobules by fibrous bands of connective tissue. (Hematoxytin and eosin stain; magnification X400, reduced 32 per cent.)
glands in these patients are often only minimally enlarged. Use of magnifying loupes and meticulous dissection is essential for the proper gross evaluation of the parathyroid glands. It is also in this group that the pathologist has the greatest difficulty in differentiating adenoma, hyperplasia, and normal parathyroid glands. If renal function is normal and carcinoma is excluded, the differential diagnosis is between adenoma and hyperplasia, and there is no definite way to make this distinction. It has been stated that if a parathyroid gland has a capsule, this is an indication that it is an adenoma; but this is a false assumption, for tissue outside the so-called capsule also may be hyperfunctioning. Furthermore, fibrous bands of connective tissue may divide the parathyroid into lobules. (Figure 4.) Many parathyroid glands removed as single adenomas had capsules which varied considerably from thick fibrous structures to delicate coverings. In the past it was thought that fat did not appear within a hyperfunctioning parathyroid lesion, but in fact, this finding is not infrequent. (Figure 5.) In one of our patients, a lipoadenoma weighing 14 gm was made up of functioning parathyroid cells separated by large amounts of fat. (Figure 3.) The traditional histologic appearance of an adenoma is an encapsulated tumor composed of cords, sheets, and a follicular arrangement of chief cells with a rim of normal or atrophic parathyroid tissue outside the capsule. It is now recognized that a rim of normal parathyroid tissue may be found adjacent to a nodular proliferation of chief cells in hyperplasia as well. Furthermore, in many so-called adenomas, a normal
442
rim of parathyroid tissue is not found. It has also been claimed that knowledge of the tissue structure of the remaining parathyroid glands can produce an accurate diagnosis, but this again does not seem to be true because the histologic examination of biopsy specimens from the other glands measuring 0.1 to 0.2 cm may not be diagnostic except for identification purposes. Furthermore, an entire spectrum of pathologic diagn,oses may be made in the same patient and even in the same gland [4]. The identification of three or four enlarged glands is presumptive evidence of primary hyperplasia. However, cases ‘of chief cell hyperplasia have been seen in which only a portion of one or more glands was involved (occult hyperplasia) [ 191. To add to the confusion, instances of adenoma in association with slight hyperplasia of the other glands have also been reported [20,21]. If a surgeon removes a single large gland, it is often impossible to differentiate histologically whether it is an adenoma or hyperplasia. If the surgeon then removes a second gland which is of normal size, it might also show focal hyperplasia, and if he removes a third and fourth gland, similar changes could be present. These findings are thought by some to indicate that the patient has chief cell hyperplasia. Why is it, then, that when an enlarged parathyroid gland is removed, the other glands (some of which may show variable degrees of hyperplasia) almost never cause any future trouble to the patient? In one of our patients, two enlarged glands were removed and two normal-appearing glands biopsied; all glands showed a variable degree of hyperplasia, and yet the patient has had no postoperative recurrence. There
The American Journal of Surgery
Treatment
of Primary
Hyperparathyroidism
Figure 5, Accumulation of stromal fat in a hypercellular parathyroid gland. (Hematoxylin and eosin stain; magnification X400, reduced 32 per cent.)
must be a fair number of similar cases in our study which have not been identified, since not all glands were routinely biopsied. In those reported series where three and a half glands are routinely removed, the pathologic reports are bound to show a high incidence of hyperplasia (at Washington University [2] it tias 48 per cent and in the series by Paloyan, I,awrence, and Straus [22] it was 77 per cent). Although many of our patients had histologic evidence of nyperplasia in the normal-appearing glands that were biopsied at surgery, such findings apparently do not have clinical significance, since clinical evidence of recurrent hyperparathyroidism developed in only one patient in our series. \Ne do not know what happens to the remaining parathyroid glands when a dominant large gland is removed nor do we know why the original large gland bec.ame autonomous. It would seem that the hyperplasia frequently present in the remaining parathyroid glands is not sufficient to cause any symptoms of hyperparathyroidism or t.o elevate the serum calcium or the circulat.ing parathyroid hormone levels in the majority of cases. II’ a single enlarged parathyroid gland is removed and the patient is rendered euparathyroid, it does not necessarily mean that the patient did not have hyperplasia. It is of interest to speculate on the possibility that the removal of a single enlarged gland in cases of primary hyperplasia may (by a yet unknown mel:hanism) interrupt the stimulus to cell proliferation. This hypothesis probably does not apply to patients with multiple endocrine abnormalities, in whom genetic factors probably include chronic
Volume
136,
October
1976
stimuli that will predispose them to recurrent hyperparathyroidism, even though some of the glands appear grossly normal at the initial surgical explorat ion. Summary
Our therapeutic approach to the treat,ment of primary hyperparathyroidism has been the resection of only the abnormally enlarged parathyroid gland, the normal-appearing parathyroids being left intact. During the past twenty-five years we have operated on 292 patients with primary hyperparathyroidism. In all cases the serum calcium levels returned to within normal limits during the immediate postoperative period, and there were no instances of permanent hypoparathyroidism. To determine the long-term efficacy of this therapeutic approach, a retrospective study of 101 pat.ients operated on for primary hyperparathyroidism during a nine year period from
MD, New Hyde Park, New York
The traditional concept that most cases of hyperparathyroidism are due to hypersecretion of parathormone from a solitary adenoma, the surgical extirpation of which will result in cure, has been challenged in recent years. Some authors [I,21 have reported a high incidence of hyperplasia of all four glands and a significant rate of recurrence of hyperparathyroidism when only the abnormally enlarged parathyroid gland was removed. Because of the “high” incidence of recurrent hypercalcemia and the difficulty in differentiating hyperplasia from adenoma by conventional microscopy, they advocated routine removal of three and a half glands in all patients with primary hyperparat,hyroidism. Our approach parathyroid
has been glands,
to resect only grossly as it was our impression
enlarged that the
long-term results were just as satisfactory. Because of the controversy concerning the optimal treatment, I&: believed it important to review our experience. Material
and Methods
Of 319 patients surf$cally treated for hyperparathyroidism from January 1953 through March 1978,292 had primary hyperparathyroidism. Of these, 101 consecutive patients operated on for primary hyperparathyroidism f’rc‘rn .July 1965 through June 1974 were reviewed. Of the 10 Lpatients, 91 per cent were examined and only 9 per cent were lost to follow-up. Seventy-four patients (73.3 per cent) From the Departments of Surgery and Pathology, Long Island Jewish-Hillside Medical Center, New Hyde Park, and The State University of New York at Stow Brook. Stow Brook. New York Reprint requests should be addressed to Leslie Wise, MD, Long Island Jewish-Hillside Medical Center, New Hyde Park, New York 11040. Presentadat the Joint Meeting of the American Society for Head and Neck Surgery and the Society of Head and Neck Surgeons, Toronto, Ontario, Canada, May 29-31, 1978.
Volume 136, October
1978
were evaluated by personal interview and their serum calcium, phosphorus, alkaline phosphat,ase, and albumin levels were determined in our laboratories; the serum parathormone levels were determined at the University of Miami Medical School in the Special Laboratory Services under Dr. Eric Reiss and Janet M. Canterbury [Y]. An additional ten patients (9.9 per cent) were questioned by telephone for symptoms, and up-to-date biochemical results were obtained from their local physicians. Another eight patients (7.9 per cent) had died, but in none of them was the cause of death due to a complication of hyperparathyroidism. The remaining nine patients (8.9 per cent) were lost to follow-up despite exhaust,ive efforts to locat,e them. Sex and Age. Of the 101 patients, thirty-seven (37 per cent) were male and sixty-four (63 per cent) were female. The youngest patient was sixteen years old and t.he oldest seventy-four years old (mean age, 51.0 i 14.8 years). Diagnosis. The presenting symptoms of the 101 patients are summarized in Table I. The diagnosis of primary hyperparathyroidism was based generally on persistently elevated serum calcium levels of more than 1 I .O mg/lOO ml (normal in our laboratories, 9.0 to 10.5 mg:/lOO ml) with or without. depressed phosphorus concentrations after the exclusion of other causes of hypercalcemia. ‘l’he mean preoperative serum calcium level was 12.4 f I .:i mg/lOO ml. whereas the mean serum phosphorus level was 2.6 f 0.7 mg/lOO ml (normal in our laboratories. Z1.0to 4.5 ml/100 ml). Although some patients had elevated alkaline phosphatase and/or elevated parathormone levels, these were not considered essential for the diagnosis. ‘I’hns, all the patients operated on had serum calcium levels of more than 11.0 mg/lOO ml, except for those five in whom a parathyroid adenoma was discovered incidentally during thyroid exploration. It is our practice to expose and identify if possible all four or, rarely, five parathyroid glands. If all of them are en-
437
Attie et al
TABLE I
Presenting Features in 101 Patients
Renal calculi Asymptomatic hypercalcemia Gastrointestinal complications (peptic ulcer, pancreatitis) Incidental finding during thyroid explorations Coma Minimal symptoms (fatigue, polyuria) Skeletal manifestations Psychotic manifestations MEA-l presenting as insulinoma Total
41 40 6 5 4 2 1 1 1 101
larged, all but half of one gland are removed; otherwise, only the enlarged gland (or glands) is removed. Those glands that appear normal on gross inspection are left in situ. Pathologic Findings. All the pathologic material on the 101patients was restudied by us. In ninety-five patients, a single enlarged parathyroid gland was removed (1 of these was eventually found to have multiple endocrine, adenopathy-I[MEA-I]). A biopsy was taken also from one’normal parathyroid gland in one of the ninety-five patients, and the remaining three normal-appearing parathyroid glands were biopsied in another. The apparently normal parathyroid glands in the other ninety-three patients were not biopsied or removed. In five patients two enlarged parathyroid glands were found and resected, and in one of these an additional grossly normal parathyroid gland was removed. (Figure 1.) In one patient three enlarged parathyroid glands were removed. Microscopically, a total of 109 totally resected parathyroid glands were examined. The size of the glands that were considered diseased varied from 0.8 to 11.0 cm in diameter (mean size, 2.3 * 1.4 cm). A well developed capsule was identified in forty-three glands, whereas the rest had a rather delicate capsule. All showed increased cellularity and replacement of stromal fat. Sixty-two were composed entirely of chief cells, four of oxyphil cells (Figure 2), and only one of water-clear cells. The remaining forty-two glands were composed of chief, oxyphil, and water-clear cells, the chief cell being predominant. One parathyroid gland showed features of lipoadenoma; it weighed 14 gm, measured 8.0 by 2.5 by 2.0 cm, and contained more fat than parathyroid chief cells. (Figure 3.) Cases of parathyroid carcinoma were excluded from this study. Results
The patients operated on during this nine year period were followed for a minimum of three years and a maximum of twelve years (mean follow-up, 5.8 f 2.4 years). Recurrences. Of the ninety-two patients who were followed, there were only two (2.2 per cent) in whom reoperation was necessary. The first was operated on initially in June 1972. This patient was noted to have asymptomatic hypercalcemia on routine biochemical profile, and at operation an enlarged left inferior
438
Figure 7. Three parathyroid glands removed from the same patient. The two grossly enlarged glands measured 1.5 and 0.8 cm in diameter and were hyperceliuiar, with less than JO per cent stromai fat. The gross/y normal parathyroid gland (0.3 cm in diameter) was also partial/y hyperceiiuiar. (Hematoxyiin and eosfn stain; magnification X15, reduced 33 per cent.)
parathyroid gland was found and removed. The serum calcium level returned to within normal limits and remained there for t.hree years, at which time an increase again was observed. In February 1976 she was again operated on for asymptomatic hypercalcemia, and this time an enlarged right superior parathyroid gland was removed. At present her serum calcium and parathormone levels are within normal limits, and she remains asymptomatic. The second reoperation was on a patient with MEA-I, who required three operations before a cure was effected. In August 1971 this patient underwent distal pancreatectomy for an insulinoma; during hospitalization she was found to be hypercalcemic. In September 1971 an enlarged left inferior parathyroid gland was excised; the other three parathyroid glands appeared macroscopically normal. Postoperatively, the serum calcium level returned to within normal limits. After an interval, recurrence
The American Journal of Surgery
Treatment of Primary Hyperparathyroidism
Figure 2. Functioning oxyphil ceils with densely packed mitochondria. (Lead citrate and uranyt acetate stain; magnification X6000, reduced 35 per cent. )
Figure 3. Hyperfunctioning lipoadenoma of parathyroid gland, There is more fat than parathyroid chief Cells. (Hematoxylin and eosin stain; magnification X400, reduced 32 per cent. )
of -the hypercalcemia developed, and in January 1975 the patient. was again reexplored, and an enlarged right superior parathyroid gland was removed. Once again, the remaining two parathyroid glands appeared grossly unremarkable. The serum calcium level temporarily returned to within normal limits, but after a few months the hypercalcemia recurred, and at a third operative procedure the left superior parathyroid gland and half the right inferior parathyroid gland, both of which were now enlarged, were resected. At present, the serum calcium level is within normal limits and the patient is asymptomatic, but
Volume 136, October 1976
it. is interest,ing that the serum parat hormone level is still elevated. The postoperative biochemical results in our patients are summarized in Table II. ‘l’he serum calcium levels varied from 8.7 to I 1.O n&l00 ml; the value of’ 11.0 mg/lOO ml, however. occurred in only one 01‘ three determinations in one patient, the other two values being within the normal range. ‘I’he postoperative parathormone levels ranged from 10 to XC) ~lEq/ml. The mean serum parathyroid hormone level was 62.7 f 45.2 ~IHq/ml. Of’ the seventy-four parathormone samples tested, eleven were
439
Attie et al
TABLE II
Biochemical Data of the 74 Patients Reevaluated Biochemically Postoperatively in Our Laboratories
Serum Calcium (mg/lOO ml) Phosphorus (mg/lOO ml) Albumin (gm/iOO ml) Alkaline phosphatase (NJ)
Mean f SD 9.8 3.1 4.2 58.4
f 0.4 f 0.5 f 0.2 f 20.4
Range 8.7-i 1 .o 1.9-4.5 3.5-5.5 24-138
considered elevated, assuming that the normal range is 10 to 75 /*lEq/ml. It should be noted, however, that values from 75 to 100 plEq/ml fall into a grey zone which is difficult to interpret, and a number of conditions other than hyperparathyroidism may give rise to these modest elevations. In the Special Laboratory Services at the University of Miami Medical School the lowest serum parathormone level in patients with proven primary hyperparathyroidism was 100 JEq/ml [4]. In only one -of our, seventy-four patients was there an elevated serum calcium level to 11 mg/lOO ml (in 1 of 3 determinations); this patient also had an elevated parathyroid hormone level. Marginally elevated serum parathormone levels in the presence of normal serum calcium values do not necessarily indicate hyperparathyroidism. No patient in this series demonstrated any evidence of permanent hypoparathyroidism postoperatively. Comments
Recently, the classic approach of resection of only grossly enlarged parathyroid glands in cases of primary hyperparathyroidism has been challenged [1,2,5]. Paloyan and co-workers [1,5] and Haff and Ballinger [2] advocated routine subtotal (3.5 glands) parathyroidectomy in all patients with primary hyperparathyroidism even in the absence of diffuse enlargement of all parathyroid glands. They claimed that limited resections resulted in high recurrence rates and that even normal-looking glands were found to be hyperplastic histologically. Purnell, Schalz, and Beahrs [6], however, reported only a 1 per cent recurrence in 198 patients operated on for primary hyperparathyroidism in whom only enlarged glands were removed. Clark, Way, and Hunt [7] collected all the reports in the English literature and found that in a total of 3,204 patients treated by selective parathyroidectomy, the recurrence rate was only 0.7 per cent. In Clark’s own series only one patient of 242 without MEA or familial hyperparathyroidism had recurrent hyperparathyroidism after removal of only enlarged glands. In our series of primary hyperparathyroidism, we had two proven
440
recurrences, one in a patient with MEA-I and the other with no known cause. We believe that with proper experience, normal-looking parathyroid glands can be identified; in our series such glands were not removed and usually not biopsied. We agree with Clark, Way, and Hunt [7] that the biopsy of normal-looking glands is unnecessary and of little value except to assure that a particular anatomic structure is a parathyroid gland [8]. The amount of functioning parathyroid tissue required for calcium homeostasis has not been clearly established. The 2 per cent incidence of permanent hypoparathyroidism after routine subtotal parathyroidectomy reported by Paloyan, Paloyan, and Pickleman [5] and the 5 per cent reported by Haff and Ballinger [2] are certainly higher than the incidence reported by surgeons who advocate selective parathyroidectomy. It is surprising that the preservation of only half a gland did not result in a higher rate of hypoparathyroidism in these series. Bruining [9] reported a 27 per cent incidence of severe hypoparathyroidism after subtotal resection of parathyroid glands; he then reverted to selective resection and reduced this incidence to 1.2 per cent. One explanation for the relatively low incidence of hypoparathyroidism after subtotal parathyroidectomy may be that some patients in these series possessed more than four glands and, therefore, may have retained one and a half glands postoperatively. Heinbath [IO], in a study of twenty-five human cadavers, found that two patients had five glands and another two had six. In 428 human dissections, Gilmour [I 1] found five parathyroid glands in twenty-five subjects and six glands in another three subjects. Wang [12] performed 160 autopsies and found five parathyroid glands in three patients and six glands in one. Thus, in a total of 613 autopsies, thirty-six patients (6.0 per cent) had more than four parathyroid glands. There are several arguments against the hypothesis that a large percentage of patients with primary hyperparathyroidism may indeed have diffuse functional hyperplasia, even though one large and three normal-looking parathyroid glands may be found. In nearly all patients, the removal of the one or, less frequently, two enlarged parathyroid glands results in a prompt return of the calcium levels to within normal limits. Furthermore, in patients with long-standing severe hypercalcemia, especially with bone damage, the removal of only the one large parathyroid gland results in precipitous and often prolonged decreases in calcium to below normal levels, indicating that the three remaining glands are not functionally hyperactive. In those patients in whom recurrence of hyperparathyroidism does take
The American Journal Of Surgery
Treatment
it usually does so after an interval of normocalcemia, sometimes lasting several years. It would seem that in these cases, the normal-looking glands preserved at the original operation were not hyperfunctioning at the time, but that one or more of them subsequently became hyperfunctioning and produced a state of hyperparathyroidism de novo. Since 1953 we have operated on 319 patients with hyperparathyroidism (Table III), and our philosophy of surgical management has remained unchanged. By meticulous dissection in a dry field, an attempt is made to identify all four parathyroid glands. The size, color, location, consistency, and amount of surrounding fat is noted for each gland before any tissue is removed. Care is taken not to divide branches of the thyroid arteries, as one of these may be needed subsequently to search for an ectopically located parathyroid. Gross macroscopic evaluation of -rhe parathyroid glands is probably the most accurate single method of differentiating a normal from an abnormal gland; the ability to identify the glands is learned by observation during thyroid operatio 2s. We believe that in cases of primary hyperparathyroidism, only grossly abnormal parathyroid tissue shculd be removed except in cases of MEA or familial hyperparathyroidism (when subtotal parathyroidectomy is indicated). In most other cases, only one parathyroid gland is enlarged while the other three appear normal; less frequently two or, very rarely, three large parathyroid glands are found. In the past these cases were labeled as single, double, or triple adenomas. If all four glands were enlarged, it was called hyperplasia. In our series of 101 patients with hyyjerparathyroidism, ninety-five had one enlarged gla:ld, five had two enlarged glands, and one had three enlarged glands. Castleman, Schantz, and Roth [IS] found hyperplasia of all four glands to be the cause of primary hyperparathyroidism in 85 of 557 patients (15.3 per cent). In two extensive reviews of the literature [ 7, 141, the incidence of diffuse hyperplasia ranged from zero to 20 per cent. It seems that under certain rare conditions there is a stimulus present that will cause hyperplasia of all the parathyroid glands, and in such cases subtotal parathyroidectomy is probably indicated; the only stimulus known at the present time is hypocalcemia. This is best illust,rated in patients with secondary pamthyroid hyperplasia due to renal failure. In patients with MEA, especially those with medullary thyroid carcinoma, the excessive secretion of calcitonin tends to produce hypocalcemia with constant stimulation of the parathyroid glands; uniform parathyroid hyperplasia, therefore, is a common place.
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TABLE III
of Primary
Hyperparathyroidism
Presenting Features of 319 Patients Operated on for Hyperparathyroidism (1953-1978)
Asymptomatic hypercalcemia Renal calculi Secondary hyperparathyroidism Incidental during thyroid explorations Skeletal manifestations Gastrointestinal complications (peptic ulcer, pancreatitis) Neurologic or psychotic manifestations Coma Minimal symptoms (fatigue, polyuria, etc.) Tertiary hyperparathyroidism MEA-I (insulinoma, Zollinger-Ellison syndrome) MEA-II (associated with medullary carcinoma)
128 96 24 17 13 12 8 8 3 2
finding in these patients. It has also been shown [15] that gastrin can produce hypocalcemia and cause hyperplasia of the parathyroid glands. Paloyan et al [16] reported stimulation of the parathyroid glands by hypersecretion of glucagon in patients with chronic pancreatitis. In the majority of cases, however, the cause of primary hyperparathyroidism is unknown. Since there are an overwhelming number of cases from different series that have not recurred after the removal of a single enlarged gland, it is probable that this gland is autonomous and not the result of a specific stimulus. Certainly, if there is a stimulus in these patients creating a tendency toward hyperparathyroidism, it seems to act extremely slowly, causing only a very small number of recurrences during the lifetime of most patients. Most explorations today are performed on patients with asymptomatic hypercalcemia. Even the slightest possibility of postoperative hypoparathyroidism must be avoided, for how tragic it would be to convert a totally asymptomatic patient into a permanent “cripple.” Routine subtotal parathyroidectomy in this group of patients would expose a significant number of them to grave complications. It is true that usually the treatment of hypoparathyroidism is not too complicated, especially with dietary calcium supplements and purified analogues of vitamin D. In some instances, however, the condition is very difficult to control. The margin between controlling doses and intoxicating doses of vitamin D may be small [I 71, and there is a potential risk of nephrocalcinosis, nephrolithiasis, and renal failure [18]; serum calcium studies must continue for years, and the patient’s requirements may change. Untreated long-term hypocalcemia may result in cataracts, convulsions, and other complications. It is precisely in the patients with asymptomatic hypercalcemia (who constitute 60 to 70 per cent of patients operated on today) that the decisions at surgery are most difficult to make. The abnormal
441
Attie et al
Figure 4. Hypercelkdar parathyroid gland divided into lobules by fibrous bands of connective tissue. (Hematoxytin and eosin stain; magnification X400, reduced 32 per cent.)
glands in these patients are often only minimally enlarged. Use of magnifying loupes and meticulous dissection is essential for the proper gross evaluation of the parathyroid glands. It is also in this group that the pathologist has the greatest difficulty in differentiating adenoma, hyperplasia, and normal parathyroid glands. If renal function is normal and carcinoma is excluded, the differential diagnosis is between adenoma and hyperplasia, and there is no definite way to make this distinction. It has been stated that if a parathyroid gland has a capsule, this is an indication that it is an adenoma; but this is a false assumption, for tissue outside the so-called capsule also may be hyperfunctioning. Furthermore, fibrous bands of connective tissue may divide the parathyroid into lobules. (Figure 4.) Many parathyroid glands removed as single adenomas had capsules which varied considerably from thick fibrous structures to delicate coverings. In the past it was thought that fat did not appear within a hyperfunctioning parathyroid lesion, but in fact, this finding is not infrequent. (Figure 5.) In one of our patients, a lipoadenoma weighing 14 gm was made up of functioning parathyroid cells separated by large amounts of fat. (Figure 3.) The traditional histologic appearance of an adenoma is an encapsulated tumor composed of cords, sheets, and a follicular arrangement of chief cells with a rim of normal or atrophic parathyroid tissue outside the capsule. It is now recognized that a rim of normal parathyroid tissue may be found adjacent to a nodular proliferation of chief cells in hyperplasia as well. Furthermore, in many so-called adenomas, a normal
442
rim of parathyroid tissue is not found. It has also been claimed that knowledge of the tissue structure of the remaining parathyroid glands can produce an accurate diagnosis, but this again does not seem to be true because the histologic examination of biopsy specimens from the other glands measuring 0.1 to 0.2 cm may not be diagnostic except for identification purposes. Furthermore, an entire spectrum of pathologic diagn,oses may be made in the same patient and even in the same gland [4]. The identification of three or four enlarged glands is presumptive evidence of primary hyperplasia. However, cases ‘of chief cell hyperplasia have been seen in which only a portion of one or more glands was involved (occult hyperplasia) [ 191. To add to the confusion, instances of adenoma in association with slight hyperplasia of the other glands have also been reported [20,21]. If a surgeon removes a single large gland, it is often impossible to differentiate histologically whether it is an adenoma or hyperplasia. If the surgeon then removes a second gland which is of normal size, it might also show focal hyperplasia, and if he removes a third and fourth gland, similar changes could be present. These findings are thought by some to indicate that the patient has chief cell hyperplasia. Why is it, then, that when an enlarged parathyroid gland is removed, the other glands (some of which may show variable degrees of hyperplasia) almost never cause any future trouble to the patient? In one of our patients, two enlarged glands were removed and two normal-appearing glands biopsied; all glands showed a variable degree of hyperplasia, and yet the patient has had no postoperative recurrence. There
The American Journal of Surgery
Treatment
of Primary
Hyperparathyroidism
Figure 5, Accumulation of stromal fat in a hypercellular parathyroid gland. (Hematoxylin and eosin stain; magnification X400, reduced 32 per cent.)
must be a fair number of similar cases in our study which have not been identified, since not all glands were routinely biopsied. In those reported series where three and a half glands are routinely removed, the pathologic reports are bound to show a high incidence of hyperplasia (at Washington University [2] it tias 48 per cent and in the series by Paloyan, I,awrence, and Straus [22] it was 77 per cent). Although many of our patients had histologic evidence of nyperplasia in the normal-appearing glands that were biopsied at surgery, such findings apparently do not have clinical significance, since clinical evidence of recurrent hyperparathyroidism developed in only one patient in our series. \Ne do not know what happens to the remaining parathyroid glands when a dominant large gland is removed nor do we know why the original large gland bec.ame autonomous. It would seem that the hyperplasia frequently present in the remaining parathyroid glands is not sufficient to cause any symptoms of hyperparathyroidism or t.o elevate the serum calcium or the circulat.ing parathyroid hormone levels in the majority of cases. II’ a single enlarged parathyroid gland is removed and the patient is rendered euparathyroid, it does not necessarily mean that the patient did not have hyperplasia. It is of interest to speculate on the possibility that the removal of a single enlarged gland in cases of primary hyperplasia may (by a yet unknown mel:hanism) interrupt the stimulus to cell proliferation. This hypothesis probably does not apply to patients with multiple endocrine abnormalities, in whom genetic factors probably include chronic
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1976
stimuli that will predispose them to recurrent hyperparathyroidism, even though some of the glands appear grossly normal at the initial surgical explorat ion. Summary
Our therapeutic approach to the treat,ment of primary hyperparathyroidism has been the resection of only the abnormally enlarged parathyroid gland, the normal-appearing parathyroids being left intact. During the past twenty-five years we have operated on 292 patients with primary hyperparathyroidism. In all cases the serum calcium levels returned to within normal limits during the immediate postoperative period, and there were no instances of permanent hypoparathyroidism. To determine the long-term efficacy of this therapeutic approach, a retrospective study of 101 pat.ients operated on for primary hyperparathyroidism during a nine year period from
