The Surgical Treatment of Primary Hyperparathyroidism: A 20 Year Experience ROBERT J. COFFEY, M.D., THOMAS C. LEE, M.D., JOHN J. CANARY, M.D.
Analysis of a series of 200 surgically treated cases of primary hyperparathyroidism was carried out in an effort to identify not only the changing clinical patterns and improved diagnostic methods but also to assess the long term results of our conventional operative methods in light of recent reports of a high incidence of diffuse hyperplasia and a high recurrence rate when surgery is restricted to removal of the adenoma. As reported by others the "chemical diagnosis" of primary hyperparathyroidism, the clinical setting in which unsuspected hypercalcemia is demonstrated on routine blood analysis, accounts for the majority of diagnoses today. Impending or actual "parathyroid crisis" has been observed with alarming frequency. The use of the thiazide challenge test provides a useful diagnostic aid in many instances. The incidence of diffuse hyperplasia was 6% in this series while an adenoma was present in 88%. No instance of recurrence was observed in either the cases of adenomas or diffuse hyperplasia. T HE SURGICAL TREATMENT of primary hyperpara-
thyroidism has become the center of considerable controversy. In 1964 we reported our earlier experiences at a meeting of the Southern Surgical Association.5 It was our belief that the responsible lesion in the great majority of the cases was a single adenoma, removal of which permanently controlled this disorder. Since then Haff,6'7 Ballinger' and Paloyan9 have advanced the thesis that approximately half of the patients with so-called adenomas have in reality a form of localized hyperplasia. They advocate removal of three to three and a half parathyroid glands in all patients with adenomas to prevent a significant rate of recurrence. In an attempt to determine which of these divergent views of surgical treatment is correct, we have reviewed 200 consecutive patients treated at Georgetown University Hospital. In each case the preoperative studies clearly favored the presence of an autonomous source of excessive parathyroid activity. Long term follow-up studies were carried out to evaluate the efficacy of treatment and the incidence of recurrence. Presented at the Annual Meeting of the Southern Surgical Association, December 5-8, 1976, Palm Beach, Florida. Submitted for publication: December 10, 1976
518
From the Departments of Surgery and The Division of Endocrinology, (Department of Medicine) Georgetown University Hospital, Washington, D.C.
Clinical Features
Recently it has been observed that there has been an explosive increase in tie frequency with which the diagnosis results from the demonstration of an elevated serum calcium level on routine sequential multiple analyzer (SMA) studies.2 This chemical presentation was present in 40 of our most recent 100 patients whereas in only five of our original 100 patients was the diagnosis suggested by such methods (Table 1). To apply the term "asymptomatic" to these patients is inaccurate. While the correct diagnosis had not been suspected on clinical grounds, a retrospective analysis of complaints such as personality changes, back ache, bone pain, lassitude, anemia, and various gastrointestinal symptoms strongly suggests that these complaints are, in fact, related to this syndrome, particularly when they are ameliorated after surgical correction of the hyperparathyroid state. Nephrolithiasis, commonly recurrent, continues as an important clinical setting in which a diagnosis of primary hyperparathyroidism is made. However, this was the salient clinical feature in only 29o of our recent patients as contrasted to 65% of the earlier series, a decline resulting from the addition of the many cases in which a chemical diagnosis was made. Peptic ulcer, pancreatitis, and bone disease continue to draw the attention of the clinician to this diagnosis in a significant number of patients. The incidence of impending or overt "acute parathyroid crisis" has been greater in our experience than is commonly reported. This acute exacerbation of chronic hyperparathyroidism is usually provoked by some incident or event that results in further elevation of the serum calcium, by means of either de-
Vol. 185 . No. 5
519
TREATMENT OF HYPERPARATHYROIDISM
creased bone formation (enforced bed rest), increased intestinal absorption (vitamin D availability) or increased mobilization from bone (phosphate deprivation). In our experience the dominant clinical feature of parathyroid crisis has been mental depression. This varies from mild lassitude, frequently with memory lapses and inattentiveness, to stupor and coma. The serum calcium is strikingly elevated, the blood urea nitrogen and creatinine are commonly high, oliguria develops, and a rapidly fatal course ensues in the untreated case. In spite of the fact that we were able to collect only 107 documented instances of this entity in a careful search of the literature in 19704 it is our conviction that many fatal cases have escaped detection since a comatose patient with an elevated blood urea nitrogen is commonly considered to have "uremic coma. " In 16 patients (8%) of this series an acute parathyroid crisis was observed. The average serum calcium level was 17.0 mg, ranging from 14.9 mg to 28.0 mg. In four of these 16 the mental dampening was relatively mild although the serum calcium was alarmingly elevated (14.9 mg, 15.0 mg, 17.9 mg, 18.2 mg). These instances of "impending crisis" differed from those of actual crisis only in the degree of depression. In the 12 cases of overt crisis a rapid and progressive deterioration of the patient ensued, making it abundantly clear that "emergency" surgical intervention is essential. In our earlier series, two patients expired while being considered for elective surgery while a recent patient died two days after a futile cervical exploration. We are convinced that the suggested treatment of these patients with phosphate or mithromycin fails to provide the immediate and definitive control obtained by surgical removal of the adenoma. The operative procedure is usually brief and technically simple, inasmuch as the parathyroid tumor is conspicuously large and easily identified in most cases, being clinically palpable in five of the 16 patients. Complete postoperative recovery usually occurs in 6-10 days. Only one serious complication, an attack of acute pancreatitis, was observed following removal of the adenoma. Improvements in Diagnosis A sustained elevation of the serum calcium level that cannot be explained on any other basis remains the keystone in the diagnosis of primary hyperparathyroidism. The radioimmunoassay of parathyroid hormone (PTH) represents an extremely valuable aid which most likely will in time become the ultimate diagnostic tool. While we currently obtain pre- and postoperative measurements of PTH levels, our indica-
TABLE 1. Clinical Features
Prior to 1970 100 Patients 62 7 9 6 5 8
Subsequent to 1970 100 Patients
Renal stones Pancreatitis Ulcer Bone changes Chemical Diagnosis Crisis
29 8 10 5 40 8
tion for surgical exploration is based largely on the aforementioned hypercalcemia. The use of arteriography and selective venous sampling with PTH assay is reserved for use in cases requiring reoperation, particularly if a mediastinal site of an adenoma is suspected. An extremely helpful diagnostic refinement has been the "thiazide test". As demonstrated by Canary10 and others,8 the oral administration of 50 mg of hydrochlorothiazide every eight hours for four days while on a high calcium diet provokes a sustained rise in the serum calcium which is not observed in the euparathyroid individual. This test has had valuable application in those cases with minimal or borderline hypercalcemia: a sustained rise in serum calcium provides the surgeron with reassuring evidence of the validity of the preoperative diagnosis. Roentgen evidence of osseous changes, particularly in the terminal phalanges of the hands and in the outer ends of clavicles, has provided useful diagnostic information in approximately lo of the cases. After the diagnosis of primary hyperparathyroidism is convincingly established, the preoperative localization of the responsible lesion is, of course, extremely desirable to the operating surgeon. However we have become convinced that in the patient who has not been previously subjected to surgical exploration of the parathyroids the use of localizing procedures, including arteriography, venous sampling, isotopic scanning, thermography, and dyes will in no way modify or alter the need for a careful and meticulous surgical exploration by an experienced surgeon. We reserve the use of these sophisticated and somewhat risky procedures for those patients in whom previous surgical intervention has failed to demonstrate appropriate parathyroid pathology with persistence of chemical evidence of hyperparathyroidism. Operative and Pathologic Findings In no other surgical enterprise is close rapport with mutual understanding and respect between the endocrinologist, the surgeon and the pathologist more essential. Concern about the time involved or the
COFFEY, LEE AND CANARY
520 TABLE 2. Pathology
Per Cent
Adenoma Hyperplasia Carcinoma Tertiary Ectopic PTH Inexplicable Negative Exploration
88.0 6.0 .5 1.0 1.0 2.0
1.5
number of biopsies has no place in parathyroid surgery. The surgeon's careful appraisal of the gross changes involving the parathyroid glands is as essential to the accuracy of the final diagnosis as the histopathologic findings by a competent and experienced pathologist. Contrary to recently published reports1 6'7'9 of a preponderance or unusually high incidence of diffuse hyperplasia, this pathologic entity was encountered in only 12 of 200 cases (6%o) (Table 2). Except in the one case of clear-cell hyperplasia all of these were of the chief cell variety. In two instances adenomatous hyperplasia was observed. On the other hand, an adenoma was found in 176 cases (88%) in four of which there were two distinct adenomas. The vast majority were of the chief cell type, the oxyphilic and clear cell variants making up less than ten percent of the group. In two cases of secondary hyperparathyroidism associated with chronic renal disease an autonomous adenoma had subsequently developed, resulting in primary hyperparathyroidism engrafted on a preexisting secondary form of the disease: or the so called "tertiary hyperparathyroidism". In two cases with typical biochemical and hormonal features of primary hyperparathyroidism, ectopic parathyroid hormone production by a myeloblastoma of the esophagus in one and carcinoma of the lung in the other, was responsible for the hyperparathyroid state. In four patients in whom a preoperative diagnosis of primary hyperparathyroidism had been firmly established, exploration has revealed normal appearing glands. The customary procedure of multiple gland biopsy plus removal of several glands in three of the cases, and appropriate thyroid resection in one, was carried out. All parathyroid tissue was judged to be normal on microscopic study by an experienced pathologist. In each of these four cases careful and repeated follow-up studies extending over a period of two to 7 years has demonstrated consistently normal calcium levels, normal PTH levels, and in three of the cases a normal response to thiazide administration. It has been suggested that these results are to be explained either on the basis
Ann. Surg. l May 1977
of unrecognized hyperplasia of the parathyroid glands because the blood supply of a hidden adenoma had been compromised. In three other patients hypercalcemia and an elevation of the PTH persists following failure to identify appropriate parathyroid pathology on cervical exploration in two and on combined cervicalmediastinal exploration in the third. After further localizing studies, reoperation is planned in these cases. As diagnostic methods improve and permit earlier recognition of primary hyperparathyroidism, the gross changes observed in the parathyroid glands will be less conspicuous and, of course, more difficult to identify. Conversely, the presence of bone changes, the occurrence of a crisis, or marked elevation of the serum calcium is usually associated with advanced and easily recognized pathology. In our experience the superior glands are involved as often as the inferior. If a superior gland adenoma is situated in an aberrent location it is most often para-or retroesophageal. In five cases the adenoma was so situated, and in one case the tumor was intimately related to an esophageal diverticulum. Inasmuch as the inferior glands are embryologically related to the thymus gland, an aberrant inferior adenoma is most often found in the upper end of the thymus, a relationship observed in two patients. In 8 cases the adenoma was found either within the substance of the thyroid gland or so intimately beneath its capsule as to be virtually indistinguishable from the thyroid.
or
Reoperation After an unsuccessful cervical exploration, persistent elevation of the serum calcium and PTH level, as well as a sustained elevation of the serum calcium after thiazide administration, is an indication for reoperation after a variable interval, usually three to 12 months. It has become our established policy in these cases to reexplore the neck as the initial phase of the operative procedure, and, if this search proves futile, to extend the incision into the mediastinum by means of splitting the sternum with "en bloc" removal of the appropriate anterior mediastinal contents. In 11 cases requiring reoperation the responsible adenoma was discovered via the neck incision in 6 cases, obviating the need for a sternal split. Division of the sternum with removal of the anterior mediastinal contents was performed in the remaining five, in four of which the adenoma was found. In a single case reexploration of the neck with removal of the mediastinal contents failed to uncover the responsible adenoma-the patient remains chemically hyperparathyroid.
Vol. 185 * No. 5
521
TREATMENT OF HYPERPARATHYROIDISM
Recurrent Hyperparathyroidism In view of the aforementioned reports of a high recurrence rate of primary hyperparathyroidism following the removal of a single adenoma in cases in which the other glands appear to be normal,1 6'7'9 a careful analysis of the long-term status of these patients was a point of major interest in this review. The follow-up studies carried out by our Division of Endocrinology included periodic clinical assessment with determination of the serum calcium, phosphorus and magnesium level, and in recent years a determination of PTH level by radioimmunoassay, as well as the thiazide challenge test. In the 176 cases of parathyroid adenoma, follow-up data over an average period of 10 years was available in 161 or 91.5%. Of these, no single instance of recurrent hyperparathyroidism has been identified. It is of interest that this group includes a number of so called "high risk" cases,3 namely, three cases of multiple endocrine adenomatosis (type 1) and three instances of familial occurence. This complete absence of recurrent disease reinforces our conviction that the adenoma in these individuals represented the total parathyroid pathology and that the adenoma was not a local manifestation of diffuse hyperplasia. Furthermore, in the 12 cases of well documented diffuse hyperplasia, removal of three parathyroid glands with preservation of a portion of the fourth resulted in permanent control of the hyperparathyroid state as evidenced by normal calcium and parathor-
mone levels on follow-up studies. These results indicate that our earlier views were correct and that the therapeutic recommendations we previously made were reasonable and continue to be effective. This report, then, is a reaffirmation of our previous data and conclusions.
DISCUSSION
operated have asymptomatic hypercalcemia discovered by multiple channel analysers. Doctor Coffey's paper substantiates the fact that most cases of hyperparathyroidism are single gland disease and can be treated as such with excellent results. His study will aid in bringing back the pendulum to the position where it belongs in the management of this disease. He also puts the proper perspective on the use of sophisticated tests to aid in location of parathyroid tissue. These tests are costly and are associated with significant morbidity especially angiography. In our experience without them, in 96% of primary cases the pathology is found and also in 75% of secondarily explored cases. This experience is similar.
DR. OLIVER H. BEAHRS (Rochester, Minnesota): Unfortunately in recent years there have been reports which have concluded that primary hyperparathyroidism in the majority of cases is due to hyperplasia or multiple gland versus single gland involvement. This has been, in our opinion, over reading of the pathology which has led to over treatment by the surgeon- this has occurred in a segment of practice in our institution. The surgeon must remember that pathology is an interpretive science not an exact one and should not ignore clinical experience. In so doing and using surgical judgment, considering all pertinent facts, his results will duplicate those reported in this paper. In a paper just presented at Western Surgical Association Meeting we reported our experiences in 198 cases of single gland resection (81% of cases during that period of time) followed for up to 7 years. In only two cases was there question of return of hypercalcemia-in one the highest level 10.2 mg/ml and 10.6 in another, both remained asymptomatic when last followed. There was no morbidity of hypocalcemia in this group of cases. In another study evaluation of cases treated more radically, 31/2 gland resections, on the assumption that underlying pathology was hyperplasia, morbidity was significant. This practice was short lived at our institution, but the philosophy persists in some quarters. This over treatment leading to hypocalcemia and other morbidity is unfortunate since today the majority of patients
References 1. Ballinger, W. F., and Haff, R. C.: Hyperparathyroidism: Increased Frequency of Diagnosis. Southern Med. J., 63:571, 1970. 2. Boonstra, E. C. and Jackson, C. E.: Hyperparathyroidism Detected by Routine Serum Calcium Analysis. Ann. Intern. Med., 63:648, 1963. 3. Clark, 0. H., Way, L. W. and Hunt, T. K.: Recurrent Hyperparathyroidism. Ann. Surg., 184:391, 1976. 4. Coffey, R. J. and Lee, T. C.: Acute Hyperparathyroidism. Am. Surg., 36:257, May 1970. 5. Coffey, R. J., Potter, J. F. and Canary, J. J.: Diagnosis and Surgical Control of Hyperparathyroidism. Ann. Surg., 165: 732, 1965. 6. Haff, R. C. and Armstrong, R. G.: Trends in the Current Management of Primary Hyperparathyroidism. Surgery, 75:715, 1974. 7. Haff, R. C. and Ballinger, W. F.: Causes of Recurrent Hypercalcemia After Parathyroidectomy for Primary Hyperparathyroidism. Ann. Surg., 173:884, 1971. 8. Lamberg, B. A. and Kuhlback, B.: The Effect of Chlorothiazide and Hydrochlorothiazide on the Excretion of Calcium in the Urine. Scand. J. Lab. Invest., 11:351, 1959. 9. Paloyan, E., Lawrence, A. M. and Straus, F. H.: Hyperparathyroidism. Med-Surg. Monographs, Grune and Stratton, N.Y., 1973. 10. Sode, J., Sabol, J., Meloni, C. and Canary, J. J.: Thiazide Challenge in Primary Hyperparathyroidism. Clin. Res., 17: 550, 1969.
DR. J. ENGLEBERT DUNPHY (San Francisco, California): A recent review of approximately 400 cases, going back for many years, largely initiated by the work of the late Leon Goldman, Drs. Orlo Clark and Thomas Hunt in our department have shown that if patients with multiple endocrine adenomatosis, familial hyperparathyroidism, or cancer are set aside as a separate group, the incidence of hyperplasia is extremely low. Our figures are almost exactly the same as Dr. Coffey's. Some 85% of cases were caused by a single adenoma, and in a long-term follow-up we have found that the recurrence rate in our hands is 0.4%. An essential part of obtaining this type of a record is technical competence, wide exposure of the neck, and identification of all parathyroid tissue. When this is done, and a single adenoma is identified, the results are highly satisfactory.
Analysis of a series of 200 surgically treated cases of primary hyperparathyroidism was carried out in an effort to identify not only the changing clinical patterns and improved diagnostic methods but also to assess the long term results of our conventional operative methods in light of recent reports of a high incidence of diffuse hyperplasia and a high recurrence rate when surgery is restricted to removal of the adenoma. As reported by others the "chemical diagnosis" of primary hyperparathyroidism, the clinical setting in which unsuspected hypercalcemia is demonstrated on routine blood analysis, accounts for the majority of diagnoses today. Impending or actual "parathyroid crisis" has been observed with alarming frequency. The use of the thiazide challenge test provides a useful diagnostic aid in many instances. The incidence of diffuse hyperplasia was 6% in this series while an adenoma was present in 88%. No instance of recurrence was observed in either the cases of adenomas or diffuse hyperplasia. T HE SURGICAL TREATMENT of primary hyperpara-
thyroidism has become the center of considerable controversy. In 1964 we reported our earlier experiences at a meeting of the Southern Surgical Association.5 It was our belief that the responsible lesion in the great majority of the cases was a single adenoma, removal of which permanently controlled this disorder. Since then Haff,6'7 Ballinger' and Paloyan9 have advanced the thesis that approximately half of the patients with so-called adenomas have in reality a form of localized hyperplasia. They advocate removal of three to three and a half parathyroid glands in all patients with adenomas to prevent a significant rate of recurrence. In an attempt to determine which of these divergent views of surgical treatment is correct, we have reviewed 200 consecutive patients treated at Georgetown University Hospital. In each case the preoperative studies clearly favored the presence of an autonomous source of excessive parathyroid activity. Long term follow-up studies were carried out to evaluate the efficacy of treatment and the incidence of recurrence. Presented at the Annual Meeting of the Southern Surgical Association, December 5-8, 1976, Palm Beach, Florida. Submitted for publication: December 10, 1976
518
From the Departments of Surgery and The Division of Endocrinology, (Department of Medicine) Georgetown University Hospital, Washington, D.C.
Clinical Features
Recently it has been observed that there has been an explosive increase in tie frequency with which the diagnosis results from the demonstration of an elevated serum calcium level on routine sequential multiple analyzer (SMA) studies.2 This chemical presentation was present in 40 of our most recent 100 patients whereas in only five of our original 100 patients was the diagnosis suggested by such methods (Table 1). To apply the term "asymptomatic" to these patients is inaccurate. While the correct diagnosis had not been suspected on clinical grounds, a retrospective analysis of complaints such as personality changes, back ache, bone pain, lassitude, anemia, and various gastrointestinal symptoms strongly suggests that these complaints are, in fact, related to this syndrome, particularly when they are ameliorated after surgical correction of the hyperparathyroid state. Nephrolithiasis, commonly recurrent, continues as an important clinical setting in which a diagnosis of primary hyperparathyroidism is made. However, this was the salient clinical feature in only 29o of our recent patients as contrasted to 65% of the earlier series, a decline resulting from the addition of the many cases in which a chemical diagnosis was made. Peptic ulcer, pancreatitis, and bone disease continue to draw the attention of the clinician to this diagnosis in a significant number of patients. The incidence of impending or overt "acute parathyroid crisis" has been greater in our experience than is commonly reported. This acute exacerbation of chronic hyperparathyroidism is usually provoked by some incident or event that results in further elevation of the serum calcium, by means of either de-
Vol. 185 . No. 5
519
TREATMENT OF HYPERPARATHYROIDISM
creased bone formation (enforced bed rest), increased intestinal absorption (vitamin D availability) or increased mobilization from bone (phosphate deprivation). In our experience the dominant clinical feature of parathyroid crisis has been mental depression. This varies from mild lassitude, frequently with memory lapses and inattentiveness, to stupor and coma. The serum calcium is strikingly elevated, the blood urea nitrogen and creatinine are commonly high, oliguria develops, and a rapidly fatal course ensues in the untreated case. In spite of the fact that we were able to collect only 107 documented instances of this entity in a careful search of the literature in 19704 it is our conviction that many fatal cases have escaped detection since a comatose patient with an elevated blood urea nitrogen is commonly considered to have "uremic coma. " In 16 patients (8%) of this series an acute parathyroid crisis was observed. The average serum calcium level was 17.0 mg, ranging from 14.9 mg to 28.0 mg. In four of these 16 the mental dampening was relatively mild although the serum calcium was alarmingly elevated (14.9 mg, 15.0 mg, 17.9 mg, 18.2 mg). These instances of "impending crisis" differed from those of actual crisis only in the degree of depression. In the 12 cases of overt crisis a rapid and progressive deterioration of the patient ensued, making it abundantly clear that "emergency" surgical intervention is essential. In our earlier series, two patients expired while being considered for elective surgery while a recent patient died two days after a futile cervical exploration. We are convinced that the suggested treatment of these patients with phosphate or mithromycin fails to provide the immediate and definitive control obtained by surgical removal of the adenoma. The operative procedure is usually brief and technically simple, inasmuch as the parathyroid tumor is conspicuously large and easily identified in most cases, being clinically palpable in five of the 16 patients. Complete postoperative recovery usually occurs in 6-10 days. Only one serious complication, an attack of acute pancreatitis, was observed following removal of the adenoma. Improvements in Diagnosis A sustained elevation of the serum calcium level that cannot be explained on any other basis remains the keystone in the diagnosis of primary hyperparathyroidism. The radioimmunoassay of parathyroid hormone (PTH) represents an extremely valuable aid which most likely will in time become the ultimate diagnostic tool. While we currently obtain pre- and postoperative measurements of PTH levels, our indica-
TABLE 1. Clinical Features
Prior to 1970 100 Patients 62 7 9 6 5 8
Subsequent to 1970 100 Patients
Renal stones Pancreatitis Ulcer Bone changes Chemical Diagnosis Crisis
29 8 10 5 40 8
tion for surgical exploration is based largely on the aforementioned hypercalcemia. The use of arteriography and selective venous sampling with PTH assay is reserved for use in cases requiring reoperation, particularly if a mediastinal site of an adenoma is suspected. An extremely helpful diagnostic refinement has been the "thiazide test". As demonstrated by Canary10 and others,8 the oral administration of 50 mg of hydrochlorothiazide every eight hours for four days while on a high calcium diet provokes a sustained rise in the serum calcium which is not observed in the euparathyroid individual. This test has had valuable application in those cases with minimal or borderline hypercalcemia: a sustained rise in serum calcium provides the surgeron with reassuring evidence of the validity of the preoperative diagnosis. Roentgen evidence of osseous changes, particularly in the terminal phalanges of the hands and in the outer ends of clavicles, has provided useful diagnostic information in approximately lo of the cases. After the diagnosis of primary hyperparathyroidism is convincingly established, the preoperative localization of the responsible lesion is, of course, extremely desirable to the operating surgeon. However we have become convinced that in the patient who has not been previously subjected to surgical exploration of the parathyroids the use of localizing procedures, including arteriography, venous sampling, isotopic scanning, thermography, and dyes will in no way modify or alter the need for a careful and meticulous surgical exploration by an experienced surgeon. We reserve the use of these sophisticated and somewhat risky procedures for those patients in whom previous surgical intervention has failed to demonstrate appropriate parathyroid pathology with persistence of chemical evidence of hyperparathyroidism. Operative and Pathologic Findings In no other surgical enterprise is close rapport with mutual understanding and respect between the endocrinologist, the surgeon and the pathologist more essential. Concern about the time involved or the
COFFEY, LEE AND CANARY
520 TABLE 2. Pathology
Per Cent
Adenoma Hyperplasia Carcinoma Tertiary Ectopic PTH Inexplicable Negative Exploration
88.0 6.0 .5 1.0 1.0 2.0
1.5
number of biopsies has no place in parathyroid surgery. The surgeon's careful appraisal of the gross changes involving the parathyroid glands is as essential to the accuracy of the final diagnosis as the histopathologic findings by a competent and experienced pathologist. Contrary to recently published reports1 6'7'9 of a preponderance or unusually high incidence of diffuse hyperplasia, this pathologic entity was encountered in only 12 of 200 cases (6%o) (Table 2). Except in the one case of clear-cell hyperplasia all of these were of the chief cell variety. In two instances adenomatous hyperplasia was observed. On the other hand, an adenoma was found in 176 cases (88%) in four of which there were two distinct adenomas. The vast majority were of the chief cell type, the oxyphilic and clear cell variants making up less than ten percent of the group. In two cases of secondary hyperparathyroidism associated with chronic renal disease an autonomous adenoma had subsequently developed, resulting in primary hyperparathyroidism engrafted on a preexisting secondary form of the disease: or the so called "tertiary hyperparathyroidism". In two cases with typical biochemical and hormonal features of primary hyperparathyroidism, ectopic parathyroid hormone production by a myeloblastoma of the esophagus in one and carcinoma of the lung in the other, was responsible for the hyperparathyroid state. In four patients in whom a preoperative diagnosis of primary hyperparathyroidism had been firmly established, exploration has revealed normal appearing glands. The customary procedure of multiple gland biopsy plus removal of several glands in three of the cases, and appropriate thyroid resection in one, was carried out. All parathyroid tissue was judged to be normal on microscopic study by an experienced pathologist. In each of these four cases careful and repeated follow-up studies extending over a period of two to 7 years has demonstrated consistently normal calcium levels, normal PTH levels, and in three of the cases a normal response to thiazide administration. It has been suggested that these results are to be explained either on the basis
Ann. Surg. l May 1977
of unrecognized hyperplasia of the parathyroid glands because the blood supply of a hidden adenoma had been compromised. In three other patients hypercalcemia and an elevation of the PTH persists following failure to identify appropriate parathyroid pathology on cervical exploration in two and on combined cervicalmediastinal exploration in the third. After further localizing studies, reoperation is planned in these cases. As diagnostic methods improve and permit earlier recognition of primary hyperparathyroidism, the gross changes observed in the parathyroid glands will be less conspicuous and, of course, more difficult to identify. Conversely, the presence of bone changes, the occurrence of a crisis, or marked elevation of the serum calcium is usually associated with advanced and easily recognized pathology. In our experience the superior glands are involved as often as the inferior. If a superior gland adenoma is situated in an aberrent location it is most often para-or retroesophageal. In five cases the adenoma was so situated, and in one case the tumor was intimately related to an esophageal diverticulum. Inasmuch as the inferior glands are embryologically related to the thymus gland, an aberrant inferior adenoma is most often found in the upper end of the thymus, a relationship observed in two patients. In 8 cases the adenoma was found either within the substance of the thyroid gland or so intimately beneath its capsule as to be virtually indistinguishable from the thyroid.
or
Reoperation After an unsuccessful cervical exploration, persistent elevation of the serum calcium and PTH level, as well as a sustained elevation of the serum calcium after thiazide administration, is an indication for reoperation after a variable interval, usually three to 12 months. It has become our established policy in these cases to reexplore the neck as the initial phase of the operative procedure, and, if this search proves futile, to extend the incision into the mediastinum by means of splitting the sternum with "en bloc" removal of the appropriate anterior mediastinal contents. In 11 cases requiring reoperation the responsible adenoma was discovered via the neck incision in 6 cases, obviating the need for a sternal split. Division of the sternum with removal of the anterior mediastinal contents was performed in the remaining five, in four of which the adenoma was found. In a single case reexploration of the neck with removal of the mediastinal contents failed to uncover the responsible adenoma-the patient remains chemically hyperparathyroid.
Vol. 185 * No. 5
521
TREATMENT OF HYPERPARATHYROIDISM
Recurrent Hyperparathyroidism In view of the aforementioned reports of a high recurrence rate of primary hyperparathyroidism following the removal of a single adenoma in cases in which the other glands appear to be normal,1 6'7'9 a careful analysis of the long-term status of these patients was a point of major interest in this review. The follow-up studies carried out by our Division of Endocrinology included periodic clinical assessment with determination of the serum calcium, phosphorus and magnesium level, and in recent years a determination of PTH level by radioimmunoassay, as well as the thiazide challenge test. In the 176 cases of parathyroid adenoma, follow-up data over an average period of 10 years was available in 161 or 91.5%. Of these, no single instance of recurrent hyperparathyroidism has been identified. It is of interest that this group includes a number of so called "high risk" cases,3 namely, three cases of multiple endocrine adenomatosis (type 1) and three instances of familial occurence. This complete absence of recurrent disease reinforces our conviction that the adenoma in these individuals represented the total parathyroid pathology and that the adenoma was not a local manifestation of diffuse hyperplasia. Furthermore, in the 12 cases of well documented diffuse hyperplasia, removal of three parathyroid glands with preservation of a portion of the fourth resulted in permanent control of the hyperparathyroid state as evidenced by normal calcium and parathor-
mone levels on follow-up studies. These results indicate that our earlier views were correct and that the therapeutic recommendations we previously made were reasonable and continue to be effective. This report, then, is a reaffirmation of our previous data and conclusions.
DISCUSSION
operated have asymptomatic hypercalcemia discovered by multiple channel analysers. Doctor Coffey's paper substantiates the fact that most cases of hyperparathyroidism are single gland disease and can be treated as such with excellent results. His study will aid in bringing back the pendulum to the position where it belongs in the management of this disease. He also puts the proper perspective on the use of sophisticated tests to aid in location of parathyroid tissue. These tests are costly and are associated with significant morbidity especially angiography. In our experience without them, in 96% of primary cases the pathology is found and also in 75% of secondarily explored cases. This experience is similar.
DR. OLIVER H. BEAHRS (Rochester, Minnesota): Unfortunately in recent years there have been reports which have concluded that primary hyperparathyroidism in the majority of cases is due to hyperplasia or multiple gland versus single gland involvement. This has been, in our opinion, over reading of the pathology which has led to over treatment by the surgeon- this has occurred in a segment of practice in our institution. The surgeon must remember that pathology is an interpretive science not an exact one and should not ignore clinical experience. In so doing and using surgical judgment, considering all pertinent facts, his results will duplicate those reported in this paper. In a paper just presented at Western Surgical Association Meeting we reported our experiences in 198 cases of single gland resection (81% of cases during that period of time) followed for up to 7 years. In only two cases was there question of return of hypercalcemia-in one the highest level 10.2 mg/ml and 10.6 in another, both remained asymptomatic when last followed. There was no morbidity of hypocalcemia in this group of cases. In another study evaluation of cases treated more radically, 31/2 gland resections, on the assumption that underlying pathology was hyperplasia, morbidity was significant. This practice was short lived at our institution, but the philosophy persists in some quarters. This over treatment leading to hypocalcemia and other morbidity is unfortunate since today the majority of patients
References 1. Ballinger, W. F., and Haff, R. C.: Hyperparathyroidism: Increased Frequency of Diagnosis. Southern Med. J., 63:571, 1970. 2. Boonstra, E. C. and Jackson, C. E.: Hyperparathyroidism Detected by Routine Serum Calcium Analysis. Ann. Intern. Med., 63:648, 1963. 3. Clark, 0. H., Way, L. W. and Hunt, T. K.: Recurrent Hyperparathyroidism. Ann. Surg., 184:391, 1976. 4. Coffey, R. J. and Lee, T. C.: Acute Hyperparathyroidism. Am. Surg., 36:257, May 1970. 5. Coffey, R. J., Potter, J. F. and Canary, J. J.: Diagnosis and Surgical Control of Hyperparathyroidism. Ann. Surg., 165: 732, 1965. 6. Haff, R. C. and Armstrong, R. G.: Trends in the Current Management of Primary Hyperparathyroidism. Surgery, 75:715, 1974. 7. Haff, R. C. and Ballinger, W. F.: Causes of Recurrent Hypercalcemia After Parathyroidectomy for Primary Hyperparathyroidism. Ann. Surg., 173:884, 1971. 8. Lamberg, B. A. and Kuhlback, B.: The Effect of Chlorothiazide and Hydrochlorothiazide on the Excretion of Calcium in the Urine. Scand. J. Lab. Invest., 11:351, 1959. 9. Paloyan, E., Lawrence, A. M. and Straus, F. H.: Hyperparathyroidism. Med-Surg. Monographs, Grune and Stratton, N.Y., 1973. 10. Sode, J., Sabol, J., Meloni, C. and Canary, J. J.: Thiazide Challenge in Primary Hyperparathyroidism. Clin. Res., 17: 550, 1969.
DR. J. ENGLEBERT DUNPHY (San Francisco, California): A recent review of approximately 400 cases, going back for many years, largely initiated by the work of the late Leon Goldman, Drs. Orlo Clark and Thomas Hunt in our department have shown that if patients with multiple endocrine adenomatosis, familial hyperparathyroidism, or cancer are set aside as a separate group, the incidence of hyperplasia is extremely low. Our figures are almost exactly the same as Dr. Coffey's. Some 85% of cases were caused by a single adenoma, and in a long-term follow-up we have found that the recurrence rate in our hands is 0.4%. An essential part of obtaining this type of a record is technical competence, wide exposure of the neck, and identification of all parathyroid tissue. When this is done, and a single adenoma is identified, the results are highly satisfactory.
