World J. Surg. 1,721-730, 1977
9 1977 by the Soci&~ Internationale de Chirurgie
Surgical Treatment of Hyperparathyroidism FREDERICO AWN, M.D. and RICHARD H. EGDAHL, M.D., PH.D. Department of Surgery, Boston University School of Medicine, Boston, Massachusetts, U.S.A.
However, the most important milestone was probably the widespread implementation of multichannel biochemical screening and its consequences. Among these, the discove12r of large numbers of hypercalcemic patients led to a magnification of the problem presented by asymptomatic patients, as well as by cases with previously unsuspected neuropsychiatric or ill-defined manifestations. Hyperparathyroidism is still, in spite of improvements in the medical management of hypercalcemia, an almost exclusively surgical condition. Multiple problems still challenge endocrine surgeons, and many aspects of its operative treatment are controversial. Our objectives in this review are to discuss the indications for surgery and possible strategies in the various forms of hyperparathyroidism as well as a brief examination of complications and results of parathyroid exploration.
A dramatic rise in the number of diagnosed cases of hyperparathyroidism has been accompanied by significant progress in diagnostic and management techniques. Indications for parathyroid surgical exploration have been established for cases presenting with hypercalcemia and any of several clinical syndromes. Asymptomatic or mildly symptomatic patients with the disease can be followed for longer intervals prior to surgery, but surgical treatment is recommended. Normoc',dcemic hyperparathyroidism with repeated renal stones exists as a disease entity and further investigation is needed to determine guidelines for operative treatment. Surgery is reserved for medically intractable cases in secondary hyperparathyroidism. The surgical strategy should be based on the identification of all glands and, with few exceptions, only abnormal tissue should be resected. Mediastinal explorations are rarely needed and should always be preceded by careful localization studies. Surgical results are generally good, with low recurrence rates if definitive surgery is possible. Mortality and morbidity rates are also very low and, while the most common postoperative complication is temporary hypocalcemia, vocal cord paralysis is a rare but debilitating one.
Indications for N e c k E x p l o r a t i o n
We consider that parathyroid surgery is almost always indicated in patients who have multiple episodes of nephrolithiasis, hypercalcemia, hypophosphatemia, hypercalciuria, and no evidence of malignancy or other causes of elevated calcium levels. In such "classic" cases, the measurement of parathyroid hormone levels may not be necessary in the preoperative investigation. A yet unresolved problem is presented by patients with a single episode of stone formation. In these mildly symptomatic patients, as well as in subjects with asymptomatic hypercalcemia, careful medical follow-up can be conducted for extended periods of time because little is known about the natural history
In recent years a great deal of development and refinement of methods and treatment of hyperparathyroidism has been achieved. Examples of such advances include selective venous catheterization and angiography techniques, measurement of plasma PTH and urinary cAMP levels, changes in the concept of pathological classification, and preservation and transplantation of parathyroids.
Reprint requests: Richard H. Egdahl, M.D., Department of Surgery, Boston University Medical Center, 720 Harrison Avenue, Boston, Massachusetts 02118, U.S.A.
721
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of the disease. A variable proportion of such patients who refused surgery or had important contraindications for the operation have lived for many years without evidence of progression of the disease. A 5year study [1] showed, however, that 34% of patients with asymptomatic hypercalcemia who were being followed up medically had to be operated on due to development of bone, renal, or psychological problems or to increase in serum calcium concentrations. Also, 20% of the initial group of patients under control dropped out of the study, making medical follow-up unreliable. For these reasons, we and many other authors [1, 2] advocate early surgical exploration of these patients. Surgery is uniformly indicated whenever the diagnosis of hyperparathyroidism is substantiated in patients presenting manifestations of bone disease, neuromuscular involvement, psychiatric and ectodermal manifestations, gastrointestinal symptomatology, hypertension, or arthritis [3, 4]. Exceptions to this rule include rare patients with serious cardiovascular or metabolic contraindications. Patients who present with mild degrees of hypercalcemia (10.5-11.5 mg/100 ml) can be observed for prolonged periods of time [1, 4], but operation should not be excessively delayed so that bone damage can be minimized and reversed. Care should be taken about the appropriate timing of the surgical exploration since hypercalcemic crisis can be triggered by surgical procedures performed for coexisting diseases, such as peptic ulcer, impacted ureteral stone, and cholecystitis, and can even occur during hospitalization for other diseases, such as pneumonia or pyelitis. Cervical exploration should be undertaken prior to any other surgical procedure [3, 5]. In severe (> 14 mg/100 ml) or moderate (11.5-14 rag/100 ml) hypercalcemia, early exploration is indicated to avoid kidney and bone damage or the risk of life-threatening hypercalcemic crisis. However, the presence of acute hypercalcemic crisis with clinical manifestations of neuromuscular compromise, dehydration, and cardiovascular abnormalities poses additional anesthetic and surgical risks. This situation should by all means be reversed prior to surgery, whenever possible. The immediate goals of therapy include correction of fluid and electrolyte disturbances and vigorous diuresis with isotonic saline and furosemide or mannitol to encourage urinary excretion of calcium. Intravenous administration of phosphate solutions dramatically lowers serum calcium, but carries with it the risk of renal parenchymal precipitation of calcium phosphate salts with kidney damage [6]. Although mithramycin therapy is often effective in relieving hypercalcemia [7], the drug has significant toxicity which includes a rare hemorrhag-
World J. Surg. Vol. 1, No. 6, November, 1977
ic syndrome. In most instances, however, with the minimal number of doses of mithramycin that are required, these complications are unlikely to occur. Relatively favorable results have been obtained with the administration of calcitonin as a physiological antagonist of PTH [8]. When renal function is seriously impaired, and excess calcium cannot be washed out by renal excretion, peritoneal or hemodialysis may become necessary to normalize serum calcium levels. Normocalcemic hyperparathyroidism with repeated kidney stone formation requires a more extensive diagnostic work-up in order to sort out patients with only intermittent hypercalcemia. Repeated determinations of serum Calcium concentrations, PTH levels, and ionized calcium concentrations may be helpful in the diagnosis of these patients. Shieber et al. [9] found grossly normal, but microscopically abnormal, parathyroid glands in patients with normocalcemia and recurrent renal calculi, and obtained good clinical and biochemical results with subtotal parathyroid resection. More recently, a large group of normocalcemic stone formers who underwent surgery was reported by Johansson et al. [10] from Uppsala. The percentage of abnormal parathyroids found in these patients was remarkably high (almost 70%). We believe that refined selection procedures must be developed to further increase the accuracy of the indications and the quality of the results. In secondary hyperparathyroidism, surgery is reserved for intractable pruritus, soft tissue calcium deposition, or skeletal signs and symptoms not relieved by regulating the dialysate composition, vitamin D administration, or dietary manipulations [3, 11]. Tertiary hyperparathyroidism, induced by autonomous hyperactivity of the parathyroids after successful renal transplantation, is not uncommon, but the condition is usually transient; it is only when hypercalcemia persists for months or tends to increase despite medical treatment that subtotal parathyroidectomy is indicated [12].
Diagnostic Procedures to Localize the Tumor
Identifying the parathyroid glands is the first problem that faces the surgeon. Since the number and position of the parathyroid glands are variable and the operative search for these glands can be a difficult and time-consuming surgical procedure, it can be advantageous to localize the hypersecreting gland or glands before the exploration. Palpation is rarely helpful in the localization of an abnormal parathyroid gland. The alternative instrumental techniques presently available are frequently complex, invasive,
F. Aun and R. H. Egdahh Surgery for Hyperparathyroidism
costly, and not free of inaccuracies or morbidity; therefore, they should only be undertaken in patients who are to be reexplored. Radioimmunoassay of PTH in samples obtained by selective catheterization of small veins of the neck and mediastinum [13, 14], although technically difficult, provides the basis for ascertaining hormone gradients between parathyroid venous effluent and peripheral blood. As a result, differentiation between single gland and multiple gland disease in primary hyperparathyroidism is greatly enhanced, since patients with an adenoma have unilateral elevations in the levels of PTH, whereas hyperplastic glands present bilaterally elevated levels. Venous sampling alone is not as helpful in patients with mediastinal tumors, since the venous branches of these lesions frequently ascend to the neck. Selective arteriograms of thyroid and internal mammary vessels can sometimes directly demonstrate cervical and mediastinal tumors. Cervical masses often displace or distort the normal loop of the inferior thyroid artery, but the relationship of parathyroid to thyroid tissue in the neck is an important cause of false-positive results. Other experimental and less invasive procedures, such as thyroid lymphography [15] and thermography [16], still deserve more extensive trials.
The Surgical Strategy
During surgical exploration for hyperparathyroidism, numerous combinations of findings can occur and the surgeon must have clearly in mind the plan for each eventuality. The strategy for the operation is related to the pathologic condition that is found during exploration. The recent reevaluation of parathyroid pathology and the reported dramatic increase in the incidence of chief cell hyperplasia [17, 18] has further complicated the surgical approach. A basic principle is that all 4 glands should always be identified before a decision to resect any tissue is made, and few surgeons nowadays would feel comfortable after the simple resection of an enlarged gland if the others were not visualized and inspected. In the "routine" case the parathyroids are not immediately evident and a careful exploration of both sides of the neck must be carried out; in these instances, it is desirable to identify the recurrent laryngeal nerves as a first step to avoid their accidental damage. The dissection includes the tracheoesophageal groove and the carotid sheath if the tumor is not readily found. In vivo intraoperative staining of parathyroid glands with toluidine blue has shown lack of specificity for parathyroids, and the occur-
723
rence of cardiac arrhythmias attributable to the dye has resulted in a decrease in the use of this method. More recently, the infusion of methylene blue has been tried in an attempt to correlate the uptake of the blue dye by the parathyroid gland with its size and histology [ 19, 20]. Reports of small series of patients show promising results with a relatively selective discoloration of adenomas and hyperplastic glands in 87% of the patients, in contrast to staining of only 25% of the normal glands. No adverse effects attributable to the dye were observed [19]. When all glands have been identified, we advise the removal of only obviously or suspiciously pathologic glands. We and some other surgeons only biopsy one of the grossly normal glands [3, 2l], whereas others [4, 22] biopsy all the remaining glands. Frozen section examinations of the biopsies should be obtained. The introduction of special intracellular fat staining methods that reveal the presence of numerous prominent intracellular sudanophilic bodies in the chief cells of suppressed "normal" parathyroid glands, and their absence in adenoma cells and in chief cell hyperplasia [23], may obviate the need for multigland biopsy. Biopsies are taken from the portion of the gland that is farthest away from the blood supply to avoid ischemia and eventual necrosis of the remnant. When enlargement of all glands is found, resection of 31/2 to 33/4 glands is performed. Subtotal parathyroidectomy is also indicated for the occasional patient in whom all 4 glands are of normal size, there is no evidence of a fifth gland, and the diagnosis is convincing. The presence of MEA syndromes, familial hyperparathyroidism, and chronic renal failure are also reasons for subtotal resection of the glands. In such patients, it is crucial to leave a well-vascularized remnant and the surgeon should partially resect each gland until he is pleased with one of the remnants before resecting the remaining glands, because the observance of this sequence offers 4 possibilities for an ideal remnant. An alternative policy is to resect 31/2 or 33/4 glands whenever the diagnosis of primary hyperparathyroidism is made, regardless of whether none, one, or all of the glands are enlarged, and regardless of their gross and light microscopic appearance [17, 24]. A potential risk of recurrence is present when glands with normal characteristics are left intact, but subtotal resection does not offer a guarantee against recurrent hyperparathyroidism and obviously increases the risk of postoperative hypoparathyroidism. When 3 or 4 normal glands are found in a patient with proven hyperparathyroidism, or when 3 obviously enlarged glands have been located and a thorough exploration of the neck has not disclosed
724 the missing adenoma or hyperplastic gland, it must be remembered that a relatively high percentage of adenomas are found in the mediastinum. Blunt dissection behind the manubrium of the sternum and exposure of the thymus often allows the excision of mediastinal tumors. The possibility of intrathyroidal parathyroids must also be considered, since they are present in 8% of the cases [25]. A hemithyroidectomy on the side of the missing parathyroid gland is sometimes indicated. At this stage it is better to end the exploration than to open the patient's chest to carry on a thorough mediastinal exploration. If hypercalcemia persists or recurs in the postoperative period, a second exploration of the neck area must be preceded by careful localization studies as described above, performed when the patient has fully recovered from the initial operation. A special approach must be taken in patients with suspected carcinoma of the parathyroid glands, which accounts for about 4% of the cases of primary hyperparathyroidism. The diagnosis is then based primarily on the degree of invasiveness and the gross appearance; preliminary biopsy is contraindicated because of the possibility of spreading the tumor locally. Adequate radical surgical treatment includes resection of the ipsilateral thyroid lobe and recurrent laryngeal nerve, if involved. Some workers advocate only careful excision of the tumor with a wide margin of normal tissue, since regional lymphatics are seldom involved [26].
Complications of Parathyroid Surgery The most important postoperative complications are hypocalcemia and vocal cord paralysis. The latter has a highly variable incidence, ranging between 0.5% [27] and 10% [5]. Careful and patient dissection with early identification of the recurrent laryngeal nerve generally prevents this complication. When the dysfunction is due to traumatic edema only, complete recovery is the rule, but this sometimes requires several weeks. Severe bone-hunger tetany is seldom seen today because of the mild degrees of bone involvement observed in the majority of patients, and postoperative hypocalcemia is generally due to slow return of function of the parathyroid remnant. When the vitality of the remnant is severely compromised, hypoparathyroidism is permanent. This complication is more frequently reported in series of patients subjected to subtotal parathyroidectomy, and this higher incidence is a strong argument against removing more than 1 normal gland or biopsying all 4 glands. The
World J. Surg. Vol. 1, No. 6, November, 1977 medical management of these patients is complex and delicate. Appropriate doses of calcium and vitamin D have to be titrated on an individual basis. The mild degrees of hypocalcemia that are often observed postoperatively in the "routine" case need not be treated, but the diagnosis of impending tetany should be made by monitoring serum calcium concentrations, before the development of Trousseau's sign. When serum calcium levels return to the norreal range, calciferol can be tapered over a period of weeks and ultimately calcium therapy can also be stopped. The stimulus to gastric secretion and gastrin release by hypercalcemia and the added stress of surgery suggests that patients with hyperparathyroidism should be good candidates for postoperative peptic ulceration. However, this complication is rare [28]. Acute pancreatitis due to elevated glucagon levels [29], or to acute posterior penetrating duodenal ulcers [30] may occur in the postoperative period but is rare. Similarly, wound problems and depressive reactions are infrequent following parathyroid surgery.
Results of Parathyroid Surgery Resection of a parathyroid adenoma almost always leads to complete reversal of the deleterious effects of excessive PTH. PTH levels rapidly return to normal along with the serum calcium, urinary cyclic AMP, and serum gastrin levels. Clinically, most patients with either hyperplasia or adenoma show postoperative improvement in renal and neuropsychiatric problems [31]. However, in patients with severe and longstanding cardiovascular or renal complications, an unchanged course of the primary disease accounts for the less favorable results, although further progression of the pathological process may be arrested. Mortality rates for parathyroid exploration are close to zero in several large series of cases [28], which is remarkable in view of the fact that a high percentage of patients are in the sixth and seventh decades, and they present a wide range of associated pathological processes and metabolic problems. Although the percentage of successful neck explorations is high, the surgical findings vary greatly among different authors. The incidence of adenoma ranges from 100% [32] to 40% [33], reflecting, among other things, a disagreement among pathologists. Hyperparathyroidism is associated with a wide spectrum of clinical abnormalities in which 4 pathologic entities (primary and secondary hyperplasia, adeno-
F. Aun and R. H. Egdahl: Surgery for Hyperparathyroidism
ma, and carcinoma) can each account for any of the syndromes. Although the incidence of persistent hypercalcemia ranges between 1 and 12% [34] and is similar in series of patients operated upon by either the "radical" or the "selective" approaches, subtotal parathyroidectomies have had a zero recurrence rate [28], whereas selective resections have been followed by a 1-3% recurrence rate [35, 36]. In patients with multiple endocrine adenomatosis recurrence rates are reported to be as high as 33% [35].
R6sum6 Ces derni6res annEes ont Et6 marqudes simultandment par un accroissement considerable du nombre de diagnostics d'hyperparathyroidie, et par de remarquables progr6s dans le diagnostic et le traitement de la maladie. Les indications de l'exploration chirurgicale ont 6t6 prdcisEes pour les cas prdsentant une hypercalcdmie avec des tableaux cliniques divers. Pour les patients asymptomatiques ou n ' a y a n t que peu de symptomes, l'operation peut-6tre retardee, mais il faut nEanmoins r e c o m m a n d e r un traitement chirurgical. L'hyperparathyroidie normocalcdmique avec lithiase rEnale r6cidivante est une entit6 clinique reconnue, mais dont les indications operatoires sont encore mal prEcisEes, faute de documents suffisants. Dans l'hyperparathyroidie secondaire, il ne faut op6rer que les cas resistant au traitement medical. Le principe de toute intervention doit 6tre l'identification des 4 glandes et, h de rares exceptions pr6s, il faut rEsEquer tout tissu anormal. I1 est rare de devoir explorer le mEdiastin et ceci devrait toujours 6tre prEcEdE d'dtudes soigneuses de localisation. Les rEsultats de la chirurgie sont, en gEnEral, bons avec peu de rEcidives si les conditions op6ratoires permettent une cure chirurgicale d'emblEe compl6te. L a mortalit6 et la morbiditE sont faibles. L a complication la plus frEquente est l'hypocalc6mie transitoire; la plus g~nante, mais elle est rare, est la paralysie des cordes vocales.
References
I. Purnell, D.C., Smith, L.H., Scholz, D.A. Elveback, L.R., Arnaud, C.D.: Primary hyperparathyroidism: a prospective clinical study. Am. J. Med. 50:670, 1971 2. Attie, J.N., Khafif, R.A.: Surgical exploration in asymptomatic hypercalcemia. Am. J. Surg. 132:449, 1976 3. Edis, A.J., Ayala, L.A., Egdahl, R.H.: Manual of
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Endocrine Surgery. Berlin-Heidelberg-New York, Springer-Verlag, 1975 4. Mason, E.E., Hoines, J., Freeman, J.B.: Hyperparathyroidism: evaluation of four decades of parathyroid surgery. Can. J. Surg. /8:422, 1975 5. Romanus, R., Heimann, P., Nilsson, O., Hansson, G.: Surgical treatment of hyperparathyroidism. Prog. Surg. /2:22, 1973 6. Breuer, E.I., Lebauer, J.: Caution in the use of phosphates in the treatment of severe hypercalcemia. J. Clin. Endocrinol. 27:695, 1967 7. Perlia, C.P., Gubisch, N.J., Wolter, J., Edelberg, D., Dederick, M.M., Taylor, S.G.: Mithramycin in the treatment of hypercalcemia. Cancer 25:389, 1970 8. Bergqvist, E., Sj6berg, H.E., Hjem, B., Hallberg, D., Carlstr6m, A.: Calcitonin in the treatment of hypercalcemic crisis. Acta Med. Scand. I92:385, 1972 9. Shieber, W., Birge, S.J., Avioli, L.V., Teitelbaum, S.L.: Normocalcemic hyperparathyroidism with normal parathyroid glands. Arch. Surg. 103:299, 1971 10. Johansson, H., Thordn, L., Wemer, I., Grimelius, L.: Normocalcemic hyperparathyroidism, kidney stones and idiopathic hypercalciuria. Surgery 77:791, 1975 11. Savoy, G.M., Yium, J.J., Jordan, P.H., Jr., Guinn, G. A.: Hyperparathyroidism in patients on chronic hemodialysis. Am. J. Surg. 126:755, 1973 12. Geis, W.P., Popovtzer, M.M., Corman, J.L., Halgrimson, C.G., Groth, C.G., Starzl, T.E.: The diagnosis and treatment of hyperparathyroidism after renal homotrmasplantation. Surg. Gynecol. Obstet. 137:997, 1973 13. Reitz, R.E., Pollard, J.J., Wang, C.A., Fleischle, D.J, Cope, O., Hernay, T.M., Deftos, L.J., Potts, J.T.: Localization of parathyroid adenomas by selective venous catheterization and radioimmunoassay. N. Engl. J. Med. 281:348, 1969 14. Monchik, J.M., Doppman, J.L., Earll, J.M., Aurbach, G.D.: Localization of hyperfunctioning parathyroid tissue. Am. J. Surg. 120:413, 1975 15. Kato, T., Hattori, T., Miura, K., Sato, M.: Application of thyroid lymphography to preoperative localization of hyperfunctioning parathyroid adenomas. Ann. Surg. 179:378, 1974 16. Young, G.B.: Thermography, Proc. R. Soc. Med. 6l :264, 1968 17. Haft, R.C., Armstrong, R.G.: Trends in the current management of primary hyperparathyroidism. Surgery 75:715, 1974 18. Esselstyn, C.B., Levin, H.S., Eversmann, J.J.: Reappraisal of parathyroid pathology in hyperparathyroidism. Surg. Clin. North Am. 54:443, 1974 19. Gordon, D.L., Airan, M.C., Thomas, W., Seidman, L.H.: Parathyroid identification by methylene blue infusion. Br. J. Surg. 62:747, 1975 20. Dudley, N.E.: Methylene blue for rapid identification of the parathyroids. Br. Med. J. 2:680, 1971 21. Seyfer, A.E., Sigdestad, J.B., Hirata, R.M.: Surgical considerations in hyperparathyroidism: reappraisal of the need for multigland biopsy. Am. J. Surg. 132:338, 1976 22. Block, M.A., Frame, B., Jackson, C.E., Parfitt, A.M., Horn, R.C., Jr.: Primary diffuse microscopical hyperplasia of the parathyroid glands. Arch. Surg. 111:348, 1976 23. Roth, S.I., Gallagher, M.J.: The rapid identification of
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24. 25.
26. 27. 28. 29.
World J. Surg. Vol. 1, No. 6, November, 1977
normal parathyroid glands by the presence of intracellular fat. Am. J. Pathol. 84:521, 1976 Ballinger, W.F., Haft, R.C.: Hyperparathyroidism: increased frequency of diagnosis. South. Med. J. 63:571, 1970 Spiegel, A.M., Marx, S.J., Doppman, J.L., Beazley, R.M., Ketcham, A.S., Kasten, B., Aurbach, G.D.: Intrathyroidal parathyroid adenoma or hyperplasia. J.A.M.A. 234:1029, 1975 Schantz, A., Castleman, B.: Parathyroid carcinoma. Cancer 3l :600, 1973 Bruining, H.A.: Surgical Treatment of Hyperparathyroidism. Assen, The Netherlands, Royal Vangorcum, 1971 Paloyan, E., Lawrence, A.M., Straus, F.H.: Hyperparathyroidism. New York, Grune and Stratton, 1973 Paloyan, E., Lawrence, A.M., Straus, F.H., Paloyan, D., Harper, P.V., Cummings, D.: Alpha-cell hyperpla-
INVITED COMMENTARY EDWARD PALOYAN, M.D.
Loyola University Medical Center, Maywood, Illinois, U.S.A.
As I am in basic agreement with the concepts and approach so elegantly presented by Aun and Egdahl, my remarks are limited to two aspects of this subject, namely, the role of head and neck irradiation in the etiology of hyperparathyroidism, and the extent and technique of parathyroidectomy. The apparent incidence of primary hyperparathyroidism in America, Western Europe, and Australia has increased from 1 patient per 1,000 population in 1965 to 2.5 patients per 1,000 in 1971, a 150% increase in case findings. Since 1971, it is believed that this increase has been even more striking [1-4]. Projection of the 1965-74 figures indicates that hyperparathyroidism now afflicts almost 1% of our population. This disease masquerades as many clinical syndromes and may well represent a common metabolic expression of several diverse conditions. The etiology of primary hyperparathyroidism is unknown. There are a number of suggestions that external factors may contribute to the development of primary hyperparathyroidism. Such causally impli-
30. 31. 32. 33. 34. 35. 36.
sia in calcific pancreatitis associated with hyperparathyroidism. J.A.M.A. 200:97, 1967 Mixter, C.G., Keynes, W.M., Cope, O.: Further experience with pancreatitis as a diagnostic clue to hyperparathyroidism. N. Engl. J. Med. 266:265, 1962 Myers, R.T.: Follow-up study of surgically-treated primary hyperparathyroidism. Ann. Surg. 179:729, 1974 Blalock, J.B.: The surgical treatment of hyperparathyroidism. Surg. Gynecol. Obstet. 133:627, 1971 Haft, R.C., Black, W.C., Ballinger, W.F.: Primary hyperparathyroidism changing clinical, surgical and pathologic aspects. Ann. Surg. 171:85, 1970 Paloyan, E., Paloyan, D., Pickelman, J.: Hyperparathyroidism today. Surg. Clin. North Am. 53:211, 1973 Clark, O.H., Way, L.W., Hunt, T.K.: Recurrent hyperparathyroidism. Ann. Surg. 184:391, 1976 Muller, H.: True recurrence of hyperparathyroidism: proposed criteria of recurrence. Br. J. Surg. 62:556, 1975
cated factors are thiazide diuretics [5-7], glucocorticolds [8], thiouracil [9], and alcohol abuse [10]. More recently, we and others have been impressed by the association of prior radiation of the head and neck and the subsequent development of primary hyperparathyroidism, parathyroid hyperplasia, or parathyroid adenoma [ 11-16]. Similar phenomen.a have been recorded in animals [17-20]. Our interest in radiation-associated thyroid tumors led us to the observation that a number of patients with such tumors also had hyperparathyroidism. In a combined retrospective and prospective study of 89 patients with hyperparathyroidism proven by operation in whom an accurate positive or negative history of radiation treatment was obtained, 27 (30%) had a prior history of radiation exposure. Four (15%) of the 27 patients had associated thyroid cancers [12]. The hypothesis that radiation is an etiologic factor in the development of parathyroid tumors and hyperparathyroidism is currently being tested. Regarding the extent and technique of parathyroidectomy, recent polemics on the extent of parathyroid resection have been engendered by (a) reports of high recurrence rates following resection of an " a d e n o m a " ; (b) difficulties in distinguishing hyperplastic from normal parathyroid parenchyma at the time of operation (especially in the early stages of the disease and in patients with renal stones); and (c) the absence of uniform criteria for the correction of
9 1977 by the Soci&~ Internationale de Chirurgie
Surgical Treatment of Hyperparathyroidism FREDERICO AWN, M.D. and RICHARD H. EGDAHL, M.D., PH.D. Department of Surgery, Boston University School of Medicine, Boston, Massachusetts, U.S.A.
However, the most important milestone was probably the widespread implementation of multichannel biochemical screening and its consequences. Among these, the discove12r of large numbers of hypercalcemic patients led to a magnification of the problem presented by asymptomatic patients, as well as by cases with previously unsuspected neuropsychiatric or ill-defined manifestations. Hyperparathyroidism is still, in spite of improvements in the medical management of hypercalcemia, an almost exclusively surgical condition. Multiple problems still challenge endocrine surgeons, and many aspects of its operative treatment are controversial. Our objectives in this review are to discuss the indications for surgery and possible strategies in the various forms of hyperparathyroidism as well as a brief examination of complications and results of parathyroid exploration.
A dramatic rise in the number of diagnosed cases of hyperparathyroidism has been accompanied by significant progress in diagnostic and management techniques. Indications for parathyroid surgical exploration have been established for cases presenting with hypercalcemia and any of several clinical syndromes. Asymptomatic or mildly symptomatic patients with the disease can be followed for longer intervals prior to surgery, but surgical treatment is recommended. Normoc',dcemic hyperparathyroidism with repeated renal stones exists as a disease entity and further investigation is needed to determine guidelines for operative treatment. Surgery is reserved for medically intractable cases in secondary hyperparathyroidism. The surgical strategy should be based on the identification of all glands and, with few exceptions, only abnormal tissue should be resected. Mediastinal explorations are rarely needed and should always be preceded by careful localization studies. Surgical results are generally good, with low recurrence rates if definitive surgery is possible. Mortality and morbidity rates are also very low and, while the most common postoperative complication is temporary hypocalcemia, vocal cord paralysis is a rare but debilitating one.
Indications for N e c k E x p l o r a t i o n
We consider that parathyroid surgery is almost always indicated in patients who have multiple episodes of nephrolithiasis, hypercalcemia, hypophosphatemia, hypercalciuria, and no evidence of malignancy or other causes of elevated calcium levels. In such "classic" cases, the measurement of parathyroid hormone levels may not be necessary in the preoperative investigation. A yet unresolved problem is presented by patients with a single episode of stone formation. In these mildly symptomatic patients, as well as in subjects with asymptomatic hypercalcemia, careful medical follow-up can be conducted for extended periods of time because little is known about the natural history
In recent years a great deal of development and refinement of methods and treatment of hyperparathyroidism has been achieved. Examples of such advances include selective venous catheterization and angiography techniques, measurement of plasma PTH and urinary cAMP levels, changes in the concept of pathological classification, and preservation and transplantation of parathyroids.
Reprint requests: Richard H. Egdahl, M.D., Department of Surgery, Boston University Medical Center, 720 Harrison Avenue, Boston, Massachusetts 02118, U.S.A.
721
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of the disease. A variable proportion of such patients who refused surgery or had important contraindications for the operation have lived for many years without evidence of progression of the disease. A 5year study [1] showed, however, that 34% of patients with asymptomatic hypercalcemia who were being followed up medically had to be operated on due to development of bone, renal, or psychological problems or to increase in serum calcium concentrations. Also, 20% of the initial group of patients under control dropped out of the study, making medical follow-up unreliable. For these reasons, we and many other authors [1, 2] advocate early surgical exploration of these patients. Surgery is uniformly indicated whenever the diagnosis of hyperparathyroidism is substantiated in patients presenting manifestations of bone disease, neuromuscular involvement, psychiatric and ectodermal manifestations, gastrointestinal symptomatology, hypertension, or arthritis [3, 4]. Exceptions to this rule include rare patients with serious cardiovascular or metabolic contraindications. Patients who present with mild degrees of hypercalcemia (10.5-11.5 mg/100 ml) can be observed for prolonged periods of time [1, 4], but operation should not be excessively delayed so that bone damage can be minimized and reversed. Care should be taken about the appropriate timing of the surgical exploration since hypercalcemic crisis can be triggered by surgical procedures performed for coexisting diseases, such as peptic ulcer, impacted ureteral stone, and cholecystitis, and can even occur during hospitalization for other diseases, such as pneumonia or pyelitis. Cervical exploration should be undertaken prior to any other surgical procedure [3, 5]. In severe (> 14 mg/100 ml) or moderate (11.5-14 rag/100 ml) hypercalcemia, early exploration is indicated to avoid kidney and bone damage or the risk of life-threatening hypercalcemic crisis. However, the presence of acute hypercalcemic crisis with clinical manifestations of neuromuscular compromise, dehydration, and cardiovascular abnormalities poses additional anesthetic and surgical risks. This situation should by all means be reversed prior to surgery, whenever possible. The immediate goals of therapy include correction of fluid and electrolyte disturbances and vigorous diuresis with isotonic saline and furosemide or mannitol to encourage urinary excretion of calcium. Intravenous administration of phosphate solutions dramatically lowers serum calcium, but carries with it the risk of renal parenchymal precipitation of calcium phosphate salts with kidney damage [6]. Although mithramycin therapy is often effective in relieving hypercalcemia [7], the drug has significant toxicity which includes a rare hemorrhag-
World J. Surg. Vol. 1, No. 6, November, 1977
ic syndrome. In most instances, however, with the minimal number of doses of mithramycin that are required, these complications are unlikely to occur. Relatively favorable results have been obtained with the administration of calcitonin as a physiological antagonist of PTH [8]. When renal function is seriously impaired, and excess calcium cannot be washed out by renal excretion, peritoneal or hemodialysis may become necessary to normalize serum calcium levels. Normocalcemic hyperparathyroidism with repeated kidney stone formation requires a more extensive diagnostic work-up in order to sort out patients with only intermittent hypercalcemia. Repeated determinations of serum Calcium concentrations, PTH levels, and ionized calcium concentrations may be helpful in the diagnosis of these patients. Shieber et al. [9] found grossly normal, but microscopically abnormal, parathyroid glands in patients with normocalcemia and recurrent renal calculi, and obtained good clinical and biochemical results with subtotal parathyroid resection. More recently, a large group of normocalcemic stone formers who underwent surgery was reported by Johansson et al. [10] from Uppsala. The percentage of abnormal parathyroids found in these patients was remarkably high (almost 70%). We believe that refined selection procedures must be developed to further increase the accuracy of the indications and the quality of the results. In secondary hyperparathyroidism, surgery is reserved for intractable pruritus, soft tissue calcium deposition, or skeletal signs and symptoms not relieved by regulating the dialysate composition, vitamin D administration, or dietary manipulations [3, 11]. Tertiary hyperparathyroidism, induced by autonomous hyperactivity of the parathyroids after successful renal transplantation, is not uncommon, but the condition is usually transient; it is only when hypercalcemia persists for months or tends to increase despite medical treatment that subtotal parathyroidectomy is indicated [12].
Diagnostic Procedures to Localize the Tumor
Identifying the parathyroid glands is the first problem that faces the surgeon. Since the number and position of the parathyroid glands are variable and the operative search for these glands can be a difficult and time-consuming surgical procedure, it can be advantageous to localize the hypersecreting gland or glands before the exploration. Palpation is rarely helpful in the localization of an abnormal parathyroid gland. The alternative instrumental techniques presently available are frequently complex, invasive,
F. Aun and R. H. Egdahh Surgery for Hyperparathyroidism
costly, and not free of inaccuracies or morbidity; therefore, they should only be undertaken in patients who are to be reexplored. Radioimmunoassay of PTH in samples obtained by selective catheterization of small veins of the neck and mediastinum [13, 14], although technically difficult, provides the basis for ascertaining hormone gradients between parathyroid venous effluent and peripheral blood. As a result, differentiation between single gland and multiple gland disease in primary hyperparathyroidism is greatly enhanced, since patients with an adenoma have unilateral elevations in the levels of PTH, whereas hyperplastic glands present bilaterally elevated levels. Venous sampling alone is not as helpful in patients with mediastinal tumors, since the venous branches of these lesions frequently ascend to the neck. Selective arteriograms of thyroid and internal mammary vessels can sometimes directly demonstrate cervical and mediastinal tumors. Cervical masses often displace or distort the normal loop of the inferior thyroid artery, but the relationship of parathyroid to thyroid tissue in the neck is an important cause of false-positive results. Other experimental and less invasive procedures, such as thyroid lymphography [15] and thermography [16], still deserve more extensive trials.
The Surgical Strategy
During surgical exploration for hyperparathyroidism, numerous combinations of findings can occur and the surgeon must have clearly in mind the plan for each eventuality. The strategy for the operation is related to the pathologic condition that is found during exploration. The recent reevaluation of parathyroid pathology and the reported dramatic increase in the incidence of chief cell hyperplasia [17, 18] has further complicated the surgical approach. A basic principle is that all 4 glands should always be identified before a decision to resect any tissue is made, and few surgeons nowadays would feel comfortable after the simple resection of an enlarged gland if the others were not visualized and inspected. In the "routine" case the parathyroids are not immediately evident and a careful exploration of both sides of the neck must be carried out; in these instances, it is desirable to identify the recurrent laryngeal nerves as a first step to avoid their accidental damage. The dissection includes the tracheoesophageal groove and the carotid sheath if the tumor is not readily found. In vivo intraoperative staining of parathyroid glands with toluidine blue has shown lack of specificity for parathyroids, and the occur-
723
rence of cardiac arrhythmias attributable to the dye has resulted in a decrease in the use of this method. More recently, the infusion of methylene blue has been tried in an attempt to correlate the uptake of the blue dye by the parathyroid gland with its size and histology [ 19, 20]. Reports of small series of patients show promising results with a relatively selective discoloration of adenomas and hyperplastic glands in 87% of the patients, in contrast to staining of only 25% of the normal glands. No adverse effects attributable to the dye were observed [19]. When all glands have been identified, we advise the removal of only obviously or suspiciously pathologic glands. We and some other surgeons only biopsy one of the grossly normal glands [3, 2l], whereas others [4, 22] biopsy all the remaining glands. Frozen section examinations of the biopsies should be obtained. The introduction of special intracellular fat staining methods that reveal the presence of numerous prominent intracellular sudanophilic bodies in the chief cells of suppressed "normal" parathyroid glands, and their absence in adenoma cells and in chief cell hyperplasia [23], may obviate the need for multigland biopsy. Biopsies are taken from the portion of the gland that is farthest away from the blood supply to avoid ischemia and eventual necrosis of the remnant. When enlargement of all glands is found, resection of 31/2 to 33/4 glands is performed. Subtotal parathyroidectomy is also indicated for the occasional patient in whom all 4 glands are of normal size, there is no evidence of a fifth gland, and the diagnosis is convincing. The presence of MEA syndromes, familial hyperparathyroidism, and chronic renal failure are also reasons for subtotal resection of the glands. In such patients, it is crucial to leave a well-vascularized remnant and the surgeon should partially resect each gland until he is pleased with one of the remnants before resecting the remaining glands, because the observance of this sequence offers 4 possibilities for an ideal remnant. An alternative policy is to resect 31/2 or 33/4 glands whenever the diagnosis of primary hyperparathyroidism is made, regardless of whether none, one, or all of the glands are enlarged, and regardless of their gross and light microscopic appearance [17, 24]. A potential risk of recurrence is present when glands with normal characteristics are left intact, but subtotal resection does not offer a guarantee against recurrent hyperparathyroidism and obviously increases the risk of postoperative hypoparathyroidism. When 3 or 4 normal glands are found in a patient with proven hyperparathyroidism, or when 3 obviously enlarged glands have been located and a thorough exploration of the neck has not disclosed
724 the missing adenoma or hyperplastic gland, it must be remembered that a relatively high percentage of adenomas are found in the mediastinum. Blunt dissection behind the manubrium of the sternum and exposure of the thymus often allows the excision of mediastinal tumors. The possibility of intrathyroidal parathyroids must also be considered, since they are present in 8% of the cases [25]. A hemithyroidectomy on the side of the missing parathyroid gland is sometimes indicated. At this stage it is better to end the exploration than to open the patient's chest to carry on a thorough mediastinal exploration. If hypercalcemia persists or recurs in the postoperative period, a second exploration of the neck area must be preceded by careful localization studies as described above, performed when the patient has fully recovered from the initial operation. A special approach must be taken in patients with suspected carcinoma of the parathyroid glands, which accounts for about 4% of the cases of primary hyperparathyroidism. The diagnosis is then based primarily on the degree of invasiveness and the gross appearance; preliminary biopsy is contraindicated because of the possibility of spreading the tumor locally. Adequate radical surgical treatment includes resection of the ipsilateral thyroid lobe and recurrent laryngeal nerve, if involved. Some workers advocate only careful excision of the tumor with a wide margin of normal tissue, since regional lymphatics are seldom involved [26].
Complications of Parathyroid Surgery The most important postoperative complications are hypocalcemia and vocal cord paralysis. The latter has a highly variable incidence, ranging between 0.5% [27] and 10% [5]. Careful and patient dissection with early identification of the recurrent laryngeal nerve generally prevents this complication. When the dysfunction is due to traumatic edema only, complete recovery is the rule, but this sometimes requires several weeks. Severe bone-hunger tetany is seldom seen today because of the mild degrees of bone involvement observed in the majority of patients, and postoperative hypocalcemia is generally due to slow return of function of the parathyroid remnant. When the vitality of the remnant is severely compromised, hypoparathyroidism is permanent. This complication is more frequently reported in series of patients subjected to subtotal parathyroidectomy, and this higher incidence is a strong argument against removing more than 1 normal gland or biopsying all 4 glands. The
World J. Surg. Vol. 1, No. 6, November, 1977 medical management of these patients is complex and delicate. Appropriate doses of calcium and vitamin D have to be titrated on an individual basis. The mild degrees of hypocalcemia that are often observed postoperatively in the "routine" case need not be treated, but the diagnosis of impending tetany should be made by monitoring serum calcium concentrations, before the development of Trousseau's sign. When serum calcium levels return to the norreal range, calciferol can be tapered over a period of weeks and ultimately calcium therapy can also be stopped. The stimulus to gastric secretion and gastrin release by hypercalcemia and the added stress of surgery suggests that patients with hyperparathyroidism should be good candidates for postoperative peptic ulceration. However, this complication is rare [28]. Acute pancreatitis due to elevated glucagon levels [29], or to acute posterior penetrating duodenal ulcers [30] may occur in the postoperative period but is rare. Similarly, wound problems and depressive reactions are infrequent following parathyroid surgery.
Results of Parathyroid Surgery Resection of a parathyroid adenoma almost always leads to complete reversal of the deleterious effects of excessive PTH. PTH levels rapidly return to normal along with the serum calcium, urinary cyclic AMP, and serum gastrin levels. Clinically, most patients with either hyperplasia or adenoma show postoperative improvement in renal and neuropsychiatric problems [31]. However, in patients with severe and longstanding cardiovascular or renal complications, an unchanged course of the primary disease accounts for the less favorable results, although further progression of the pathological process may be arrested. Mortality rates for parathyroid exploration are close to zero in several large series of cases [28], which is remarkable in view of the fact that a high percentage of patients are in the sixth and seventh decades, and they present a wide range of associated pathological processes and metabolic problems. Although the percentage of successful neck explorations is high, the surgical findings vary greatly among different authors. The incidence of adenoma ranges from 100% [32] to 40% [33], reflecting, among other things, a disagreement among pathologists. Hyperparathyroidism is associated with a wide spectrum of clinical abnormalities in which 4 pathologic entities (primary and secondary hyperplasia, adeno-
F. Aun and R. H. Egdahl: Surgery for Hyperparathyroidism
ma, and carcinoma) can each account for any of the syndromes. Although the incidence of persistent hypercalcemia ranges between 1 and 12% [34] and is similar in series of patients operated upon by either the "radical" or the "selective" approaches, subtotal parathyroidectomies have had a zero recurrence rate [28], whereas selective resections have been followed by a 1-3% recurrence rate [35, 36]. In patients with multiple endocrine adenomatosis recurrence rates are reported to be as high as 33% [35].
R6sum6 Ces derni6res annEes ont Et6 marqudes simultandment par un accroissement considerable du nombre de diagnostics d'hyperparathyroidie, et par de remarquables progr6s dans le diagnostic et le traitement de la maladie. Les indications de l'exploration chirurgicale ont 6t6 prdcisEes pour les cas prdsentant une hypercalcdmie avec des tableaux cliniques divers. Pour les patients asymptomatiques ou n ' a y a n t que peu de symptomes, l'operation peut-6tre retardee, mais il faut nEanmoins r e c o m m a n d e r un traitement chirurgical. L'hyperparathyroidie normocalcdmique avec lithiase rEnale r6cidivante est une entit6 clinique reconnue, mais dont les indications operatoires sont encore mal prEcisEes, faute de documents suffisants. Dans l'hyperparathyroidie secondaire, il ne faut op6rer que les cas resistant au traitement medical. Le principe de toute intervention doit 6tre l'identification des 4 glandes et, h de rares exceptions pr6s, il faut rEsEquer tout tissu anormal. I1 est rare de devoir explorer le mEdiastin et ceci devrait toujours 6tre prEcEdE d'dtudes soigneuses de localisation. Les rEsultats de la chirurgie sont, en gEnEral, bons avec peu de rEcidives si les conditions op6ratoires permettent une cure chirurgicale d'emblEe compl6te. L a mortalit6 et la morbiditE sont faibles. L a complication la plus frEquente est l'hypocalc6mie transitoire; la plus g~nante, mais elle est rare, est la paralysie des cordes vocales.
References
I. Purnell, D.C., Smith, L.H., Scholz, D.A. Elveback, L.R., Arnaud, C.D.: Primary hyperparathyroidism: a prospective clinical study. Am. J. Med. 50:670, 1971 2. Attie, J.N., Khafif, R.A.: Surgical exploration in asymptomatic hypercalcemia. Am. J. Surg. 132:449, 1976 3. Edis, A.J., Ayala, L.A., Egdahl, R.H.: Manual of
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Endocrine Surgery. Berlin-Heidelberg-New York, Springer-Verlag, 1975 4. Mason, E.E., Hoines, J., Freeman, J.B.: Hyperparathyroidism: evaluation of four decades of parathyroid surgery. Can. J. Surg. /8:422, 1975 5. Romanus, R., Heimann, P., Nilsson, O., Hansson, G.: Surgical treatment of hyperparathyroidism. Prog. Surg. /2:22, 1973 6. Breuer, E.I., Lebauer, J.: Caution in the use of phosphates in the treatment of severe hypercalcemia. J. Clin. Endocrinol. 27:695, 1967 7. Perlia, C.P., Gubisch, N.J., Wolter, J., Edelberg, D., Dederick, M.M., Taylor, S.G.: Mithramycin in the treatment of hypercalcemia. Cancer 25:389, 1970 8. Bergqvist, E., Sj6berg, H.E., Hjem, B., Hallberg, D., Carlstr6m, A.: Calcitonin in the treatment of hypercalcemic crisis. Acta Med. Scand. I92:385, 1972 9. Shieber, W., Birge, S.J., Avioli, L.V., Teitelbaum, S.L.: Normocalcemic hyperparathyroidism with normal parathyroid glands. Arch. Surg. 103:299, 1971 10. Johansson, H., Thordn, L., Wemer, I., Grimelius, L.: Normocalcemic hyperparathyroidism, kidney stones and idiopathic hypercalciuria. Surgery 77:791, 1975 11. Savoy, G.M., Yium, J.J., Jordan, P.H., Jr., Guinn, G. A.: Hyperparathyroidism in patients on chronic hemodialysis. Am. J. Surg. 126:755, 1973 12. Geis, W.P., Popovtzer, M.M., Corman, J.L., Halgrimson, C.G., Groth, C.G., Starzl, T.E.: The diagnosis and treatment of hyperparathyroidism after renal homotrmasplantation. Surg. Gynecol. Obstet. 137:997, 1973 13. Reitz, R.E., Pollard, J.J., Wang, C.A., Fleischle, D.J, Cope, O., Hernay, T.M., Deftos, L.J., Potts, J.T.: Localization of parathyroid adenomas by selective venous catheterization and radioimmunoassay. N. Engl. J. Med. 281:348, 1969 14. Monchik, J.M., Doppman, J.L., Earll, J.M., Aurbach, G.D.: Localization of hyperfunctioning parathyroid tissue. Am. J. Surg. 120:413, 1975 15. Kato, T., Hattori, T., Miura, K., Sato, M.: Application of thyroid lymphography to preoperative localization of hyperfunctioning parathyroid adenomas. Ann. Surg. 179:378, 1974 16. Young, G.B.: Thermography, Proc. R. Soc. Med. 6l :264, 1968 17. Haft, R.C., Armstrong, R.G.: Trends in the current management of primary hyperparathyroidism. Surgery 75:715, 1974 18. Esselstyn, C.B., Levin, H.S., Eversmann, J.J.: Reappraisal of parathyroid pathology in hyperparathyroidism. Surg. Clin. North Am. 54:443, 1974 19. Gordon, D.L., Airan, M.C., Thomas, W., Seidman, L.H.: Parathyroid identification by methylene blue infusion. Br. J. Surg. 62:747, 1975 20. Dudley, N.E.: Methylene blue for rapid identification of the parathyroids. Br. Med. J. 2:680, 1971 21. Seyfer, A.E., Sigdestad, J.B., Hirata, R.M.: Surgical considerations in hyperparathyroidism: reappraisal of the need for multigland biopsy. Am. J. Surg. 132:338, 1976 22. Block, M.A., Frame, B., Jackson, C.E., Parfitt, A.M., Horn, R.C., Jr.: Primary diffuse microscopical hyperplasia of the parathyroid glands. Arch. Surg. 111:348, 1976 23. Roth, S.I., Gallagher, M.J.: The rapid identification of
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World J. Surg. Vol. 1, No. 6, November, 1977
normal parathyroid glands by the presence of intracellular fat. Am. J. Pathol. 84:521, 1976 Ballinger, W.F., Haft, R.C.: Hyperparathyroidism: increased frequency of diagnosis. South. Med. J. 63:571, 1970 Spiegel, A.M., Marx, S.J., Doppman, J.L., Beazley, R.M., Ketcham, A.S., Kasten, B., Aurbach, G.D.: Intrathyroidal parathyroid adenoma or hyperplasia. J.A.M.A. 234:1029, 1975 Schantz, A., Castleman, B.: Parathyroid carcinoma. Cancer 3l :600, 1973 Bruining, H.A.: Surgical Treatment of Hyperparathyroidism. Assen, The Netherlands, Royal Vangorcum, 1971 Paloyan, E., Lawrence, A.M., Straus, F.H.: Hyperparathyroidism. New York, Grune and Stratton, 1973 Paloyan, E., Lawrence, A.M., Straus, F.H., Paloyan, D., Harper, P.V., Cummings, D.: Alpha-cell hyperpla-
INVITED COMMENTARY EDWARD PALOYAN, M.D.
Loyola University Medical Center, Maywood, Illinois, U.S.A.
As I am in basic agreement with the concepts and approach so elegantly presented by Aun and Egdahl, my remarks are limited to two aspects of this subject, namely, the role of head and neck irradiation in the etiology of hyperparathyroidism, and the extent and technique of parathyroidectomy. The apparent incidence of primary hyperparathyroidism in America, Western Europe, and Australia has increased from 1 patient per 1,000 population in 1965 to 2.5 patients per 1,000 in 1971, a 150% increase in case findings. Since 1971, it is believed that this increase has been even more striking [1-4]. Projection of the 1965-74 figures indicates that hyperparathyroidism now afflicts almost 1% of our population. This disease masquerades as many clinical syndromes and may well represent a common metabolic expression of several diverse conditions. The etiology of primary hyperparathyroidism is unknown. There are a number of suggestions that external factors may contribute to the development of primary hyperparathyroidism. Such causally impli-
30. 31. 32. 33. 34. 35. 36.
sia in calcific pancreatitis associated with hyperparathyroidism. J.A.M.A. 200:97, 1967 Mixter, C.G., Keynes, W.M., Cope, O.: Further experience with pancreatitis as a diagnostic clue to hyperparathyroidism. N. Engl. J. Med. 266:265, 1962 Myers, R.T.: Follow-up study of surgically-treated primary hyperparathyroidism. Ann. Surg. 179:729, 1974 Blalock, J.B.: The surgical treatment of hyperparathyroidism. Surg. Gynecol. Obstet. 133:627, 1971 Haft, R.C., Black, W.C., Ballinger, W.F.: Primary hyperparathyroidism changing clinical, surgical and pathologic aspects. Ann. Surg. 171:85, 1970 Paloyan, E., Paloyan, D., Pickelman, J.: Hyperparathyroidism today. Surg. Clin. North Am. 53:211, 1973 Clark, O.H., Way, L.W., Hunt, T.K.: Recurrent hyperparathyroidism. Ann. Surg. 184:391, 1976 Muller, H.: True recurrence of hyperparathyroidism: proposed criteria of recurrence. Br. J. Surg. 62:556, 1975
cated factors are thiazide diuretics [5-7], glucocorticolds [8], thiouracil [9], and alcohol abuse [10]. More recently, we and others have been impressed by the association of prior radiation of the head and neck and the subsequent development of primary hyperparathyroidism, parathyroid hyperplasia, or parathyroid adenoma [ 11-16]. Similar phenomen.a have been recorded in animals [17-20]. Our interest in radiation-associated thyroid tumors led us to the observation that a number of patients with such tumors also had hyperparathyroidism. In a combined retrospective and prospective study of 89 patients with hyperparathyroidism proven by operation in whom an accurate positive or negative history of radiation treatment was obtained, 27 (30%) had a prior history of radiation exposure. Four (15%) of the 27 patients had associated thyroid cancers [12]. The hypothesis that radiation is an etiologic factor in the development of parathyroid tumors and hyperparathyroidism is currently being tested. Regarding the extent and technique of parathyroidectomy, recent polemics on the extent of parathyroid resection have been engendered by (a) reports of high recurrence rates following resection of an " a d e n o m a " ; (b) difficulties in distinguishing hyperplastic from normal parathyroid parenchyma at the time of operation (especially in the early stages of the disease and in patients with renal stones); and (c) the absence of uniform criteria for the correction of
