SCIENTIFIC PAPERS
Initial Failure of Surgical Exploration in Patients with Primary Hyperparathyroidism Louis-Joseph Auguste, MD, Joseph N. Attie, MD, David Schnaap, MD, NewHydePark, NewYork To determine the causes of failures of cervical exploration for primary hyperparathyroidism, we reviewed 892 patients operated on by one surgeon from 1953 to 1990. Twenty-seven patients (3%) remained hypercalcemic or developed hypercalcemia within 6 months of surgery. Of these, five patients had one adenoma removed initially; at reoperation, three patients had a second adenoma that was successfully removed, whereas the other
two patients had hyperplasia and required subtotal parathyroidectomies. No enlarged parathyroid glands were identified in 2 2 patients. Eventually, six patients became normocalcemic spontaneously, seven patients underwent re-exploration with a suecessful outcome in all but one ease, two patients had ectopic hyperparathyroidism associated with carcinoma elsewhere, and seven patients refused reoperation and remain hypercalcemic. The failure rate of surgical exploration for primary hyperparathyroidism can be reduced by systematically exploring all four parathyroid glands. All abnormal parathyroids should be removed with histologic verification. When no abnormal glands are found, localization studies should be performed before reexploration.
hypercalcemia following failed initial surgp ersistent ical exploration for primary hyperparathyroidism has been reported in 3% to 8% of cases (Table I). Reexploration in such cases is extremely difficult, can be associated with a significant incidence of complications, and has a lower success rate than that of initial exploration. The purposes of this study were to determine the causes for these failures, review the subsequent course in this group of patients, and discuss possible measures to be undertaken to minimize future failed parathyroid explorations. From the Long Island Jewish Medical Center, Long Island Campus for the Albert Einstein College of Medicine, Division of Head and Neck Surgery, New Hyde Park, New York. Requests for reprints should be addressed to Louis-Joseph Auguste, MD, Long Island Jewish Medical Center, Department of Surgery, New Hyde Park, New York 11042. Presented at the 36th Annual Meeting of the Society of Head and Neck Surgeons, Washington, DC, May 19-22, 1990.
PATIENTS AND METHODS Between July 1953 and February 1990, 892 parathyroid explorations were performed for hyperparathyroidism by one surgeon (JNA). In 865 patients, long-term normocalcomia was achieved by the removal of 1 or more parathyroid adenomas, or in the case of hyperplasia, by subtotal parathyroidectomy (3 89glands). However, in 27 patients (3%), the initial exploration was unsuccessful: either no abnormal parathyroid glands were found, the removal of enlarged parathyroids did not result in normocalcemia, or the hypercalcemia recurred within 6 months following operation. These patients form the basis of this study. Data on their mode of presentation were obtained from hospital and office records. Follow-up data were gathered from hospital charts, office records, the patients themselves, referring physicians, and next of kin. When possible, the patients were recalled for re-examination and their blood studied for serum calcium levels. RESULTS There were 27 failed initial explorations for primary hyperparathyroidism (Table II) in 12 men and 15 women ranging in age from 21 to 79 years (mean: 52 years). In 5 of the 27 patients, enlarged parathyroid glands were found and removed, but the patients remained hypercalcemic. In three of these patients who were re-explored, a second enlarged parathyroid (adenoma) was found and excised with resulting normocaleemia in each. In one of the three patients, reoperation was performed 2 days postoperatively; the other two had successful preoperative localization, one by intravenous differential radioimmune assay of parathyroid hormone and arteriography and the other by ultrasound and magnetic resonance imaging (MRI). One of the five patients not improved by removal of the enlarged parathyroid gland proved to have diffuse hyperplasia and was cured by subtotal parathyroidectomy (389glands). The fifth patient in this group was found to have multiple endocrine neoplasia type I and remains mildly hypercalcemic despite subtotal parathyroidectomy (389 glands). No enlarged parathyroid glands were identified in 22 patients at the initial operation. Six of these patients were re-explored (four by us and two by other surgeons); one adenoma was removed in each case and normocalcemia ensued. Three patients had suec~ssful preoperative localization studies (one by computed tomography scan and two by intravenous differential radioimmunoassay of parathyroid hormone and arteriography) prior to reoperation. There were no complications and no persistent hypocalcemia in any patient undergoing rcoperation. A spontaneous return of serum calcium to normal levels occurred after an interval of several months to 5 years in six patients who were not re-explored. In four patients, only three normal parathyroid glands were iden-
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TABLEI
Failed Initial Parathyroid Explorations Failed Author
No. of Patients
Exploration (% )
Successful Reoperations
Persistent Hypercalcemia
Spontaneous Eucalcemia
Silver et al [ 1] McGarity et al [2] Wang [3] Martin et al [4] Present study
102 193 712 500 892
8 (8) 12 (6.2) 37 (5.2) 25 (5) 27 (3)
1 5 33 5 11
2 5 4 17 7
2 2 O 3 6
TABLE
II
Initially Failed Parathyroid ExploraUona in 27 Patients from 1953-1990 No. of Patients
ReoperatiOn Single aden0ma removed Second adenoma removed Subtotal parathyroidectomy
12 6 3 2
completed for hyperplasia No adenoma at reoperation
1
persistent hypercalcemta No reoperation
Ectopic hyperparathyrodism Spontaneous normocalcemia
Infarcted by injection of dye Persistent hypercalcemia
15 2 6 1 6
tiffed at operation, whereas in two patients, four normal parathyroids were observed. Biopsies were done on the normal-appearing parathyroids, but no parathyroid glands were removed in any of these cases. One patient had three normal parathyroids found at exploration. The fourth gland (right superior) was identified by arteriography as an adenoma and was intentionally infarcted by dye injected during a second arteriogram. This patient has been normocalcemic for 11 years, Two patients with hypercalcemia, hypophosphatemia, and elevated serum parathyroid hormone levels proved to have ectopic hyperparathyroidism due to carcinoma of the lung and carcinoma of the liver, respectively. Both patients had four normal parathyroids identified, and no parathyroid tissue was removed. Seven patients who had negative exploratioris did not undergo reoperation and remain hypercalcemic at 1 to 13 years postoperatively. In five of these patients, three normal and no enlarged parathyroids were found at operation. In the other two patients, one enlarged parathyroid gland was resected with no improvement. Of this group, one patient died 2 years postoperatively with a serum calcium level of 1 t.4 mg/mL at the time of last examination, and one patient was lost to follow-up. The remaining five patients have been followed for I to 12 years. Recent serum calcium levels varied from 10.7 to 12.6 mg/mL. None of these patients has had any symptoms or complications related to their hyperparathyroidism. In two of these patients, attempts to localize their adenomas by 334
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noninvasive modalities (ultrasound, MRI, and thalliumtechnetium subtraction [TTS]) were unsuccessful. In one patient, an enlarged parathyroid was suggested by preoperative ultrasound and MRI. At reoperation, no adenoma was found, and this patient remains hypercalcemic. COMMENTS This series reaffirms the high success rate of cervical exploration for primary hyperparathyroidtsm (97%). The first requirement for success is proper diagnosis, based on elevation of serum calcium levels associated with high or normal parathormone levels, often with elevated serum chloride and decreased serum phosphate levels. If all of these parameters are not present, other causes of hypercalcemia must be considered [5]. Ectopic hyperparathyroidism may mimic primary hyperparathyroidism; in a recent study, a parathyroid hormone-related protein (detected by radioimmune assay) was demonstrated in the case of a malignancy-producing hypercalcemia [6]. The presence of other endocrine syndromes or a family history suggests multiple endocrine neoplasm or familial hyperparathyroidism. In familial hypocalciuric hypercalcemia, serum calcium and parathormone levels ate elevated but urinary calcium is low. Patients with this disease have normal parathyroid glands and do not benefit from surgical intervention. Hypercalcemia can also be caused by bone metastases from other malignancies, but the parathormone levels in these cases are low or normal. The initial exploration must be thorough. An attempt should be made to identify all four parathyroid glands, and meticulous attention should be paid to the thyroid gland and to the regional lymph nodes. Primary hyperparathyroidism may be associated with thyroid disease. In our series of 892 patients, 17 (19%) had nodular goiter and 19 (2%) had incidental papillary thyroid carcinoma. In one of our patients, biopsy Of an abnormal lymph node revealed sarcoidosis as the cause of hyperealcemia, and in another patient, the presence of metastatic thyroid cancer in a paratracheal lymph node alerted us to the diagnosis of carcinoma of the thyroid. A knowledge of the normal anatomy and appearance of the parathyroid glands is of paramount importance to the operating surgeon. The normal parathyroids are soft, tan, and surrounded by a variable amount of fat that increases with age. They measure 2 to 12 mm and weigh 30 to 70 rag. In contrast, adenomas are firm, reddishbrown, and rarely surrounded by fat. They measure 5
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mm to 10 cm in greatest diameter and weigh 70 mg to 10 g. The superior parathyroids are more constant in position and are usually located along the posterior surface of the thyroid, near the upper pole. The inferior glands are usually closer to the lower pole of the thyroid and may be anterior, lateral, or posterior in position. The normal inferior gland is often at a distance from the thyroid gland and may be attached to the thymus within the anterior mediastinum [7]. If the exploration reveals more than one and less than four enlarged parathyroid glands in the absence of familial hyperparathyroidism and concurrently with one or more normal-appearing glands, the diagnosis of multiple adenoma is established, and only the enlarged parathyroids should be excised. Ectopic locations are frequent causes of failed parathyroid explorations. The superior parathyroid gland may lie very high in position behind the upper pole of the thyroid gland. At times the superior thyroid vessels must be ligated and divided and the upper pole of the thyroid mobilized to expose these glands. Two of our missed adenomas were located very high in the upper pole region; in one patient, the lesion was localized by selective venous catheterization and arteriography and resected by another surgeon, while in the other patient, the lesion was demonstrated by selective arteriography and destroyed by infarction intentionally induced by overinflation of the gland during a second arteriogram. When a superior parathyroid gland is large, it may descend due to gravity into the posterior mediastinum along the esophagus for a variable distance. Such a location should be suspected when there is a bulge and loss of the concavity of the tracheeesophageal groove, or if the inferior thyroid artery is pushed anteriorly and becomes convex over the adenoma. This displacement of the artery over a low-lying superior adenoma has been demonstrated in some of our patients by MRI. The inferior parathyroid gland can descend into the anterior mediastinum along the thymic remnant when it enlarges. In some instances, the inferior parathyroid gland is within the thymus at birth and may be the source of an intrathymic parathyroid adenoma. Ectopic inferior parathyroids have been reported in the vicinity of the aortic arch, near the hilum of the lung, and even within the pericardium. One of our patients required a sternotomy at another hospital to resect an adenoma in the vicinity of the aortic arch. Parathyroid adenomas have been found within the carotid sheath. On rare occasions, the inferior parathyroid glands occur high near the upper border of the larynx in an undescended thymic remnant
[8]. in rare instances, parathyroid tumors occur within the thyroid gland. We encountered this situation in two of our patients. Intrathyroid parathyroid adenomas are said to occur in 1% of cases [9]. Most often, it is the inferior rather than the superior gland that is intrathyroidal. If all four glands appear normal, a fifth gland should be sought since a supernumerary parathyroid is present in about 5% of patients, although no such instance was encountered in our series. These glands are most often associated with
TABLE III Success Rate of Reoperatlons
Author
No. of Patients
Brennan et al [ 15] wang [3] Grant et al [ 16] Cheung et al [ 17] Granberg et al [ 18] Present study
95 112 157 83 47 12
Successful Reoperations ( % ) 91 102 139 71 39 10
(96) (91) (89) (85) (83) (83)
the thyroid remnant, indicating a common derivation from the third pharyngeal pouch [10]. Some investigators believe that biopsy of normal-appearing glands should be done to confirm the normal histology. In some instances, a small biopsy specimen will be interpreted as microscopic hyperplasia and lead the surgeon to resect more tissue [11]. The finding of microscopic hyperplasia in normal-appearing glands is probably of no clinical significance, as shown by Harrison et al [12], and the removal of such glands is unnecessary. Furthermore, multiple biopsies of normal parathyroid glands may lead to hypocalcemia [13]. In patients with persistent hypercalcemia, reoperation is not always indicated. In six of our patients, the serum calcium level returned to normal spontaneously. This has been reported by other surgeons [14]. The return to normocalcemia may be due to the destruction of the blood supply to the adenoma during exploration. Reoperations may be extremely difficult because of scarring and altered anatomy. The success rate of reoperations is lower than in primary operations and varies from 83% to 96% (Table III). Of 12 of our patients who underwent reoperation, 2 remain hypercalcemic, 1 due to failure to find the adenoma at the second operation. The other patient, who was diagnosed as having multiple endocrine neoplasia type I, is mildly hypercalcemic despite three explorations and the completion of subtotal parathyroidectomy (389 glands). Preoperative localization should be performed prior to re-exploration. If any of the noninvasive preoperative localization modalities (ultrasound, TTS, or MRI) were not employed prior to the first exploration, such tests should be utilized before reoperating. During the past 3 years, we have used 1 or more of the localization techniques in 160 patients. The accuracy rate was over 90% [19]. These tests are especially useful in reoperated cases [20]. They often pinpoint the location of the adenoma and allow the surgeon to avoid long and difficult dissection in scarred areas that need not be explored. If the noninvasive methods are unsuccessful, selective venous sampling and arteriography can be used with great success. In three of the six patients re-explored successfully for a missed solitary adenoma, and in two of the three patients with a second adenoma missed at the primary operation, preoperative localization was used and successfully located the tumor. Our approach in reoperation for persistent hypercal-
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cemia is similar to that suggested by Cohn and Silen [14]. The previous cervical incision is used, and the flaps are raised in the usual manner. To avoid the scarring from previous surgery, a lateral approach is used. The fascia along the sternomastoid muscle is incised and the muscle is retracted laterally. The carotid sheath is retracted laterally and the strap muscles medially to expose the lateral aspect of the thyroid gland. The lateral surface of the thyroid and the tracheoesophageal groove are readily dissected, bringing the region of the parathyroid glands into view. Care must be taken to expose and identify the recurrent and the external laryngeal nerves to avoid damage to these structures. If the adenoma is not found in the usual areas and a normal superior parathyroid gland is identified, the anterior mediastinum is dissected; if no tumor is seen, the thymus is removed because of the possibility of an intrathymic tumor. If a normal inferior gland is identified, a search is made for a superior parathyroid adenoma in the posterior mediastinum along the esophagus. If the cervical exploration is unsuccessful, and especially if localization studies have detected the adenoma within the chest, mediastinotomy is performed, usually after an interval of 1 to 2 weeks. In conclusion, cervical exploration for primary hyperparathyroidism is successful in over 95% of cases. The failure rate may be further reduced by establishing an accurate diagnosis, reviewing the patient's family history, performing noninvasive localization tests, and examining all four glands at the time of operation. All enlarged parathyroids should be removed when dealing with single or multiple adenomas; subtotal parathyroidectomy (31A glands) should be performed in patients with hyperplasia or multiple endocrine neoplasia. Frozen section should be performed to confirm all excised parathyroid tissue. If exploration is unsuccessful, ectopic locations such as the thymus, the anterior and posterior mediastinum, and the carotid sheath should be explored; when no adenoma is found, partial thyroidectomy in the area of the missing parathyroid should be performed.
REFERENCES 1. Silver CE, Schoenbach SF, Barzel US. Surgical treatment of primary hyperparathyroidism. NY State J Med 1977; 77: 732-5. 2. McGarity WC. Matthews WH, Fulenwider JT. Isaacs JW, Miller DA. The surgical management of primary hyperparathy-
336
roidism: a personal series. Surg Gynecol Obstet 1980; 151: 764-8. 3. Wang CA. Parathyroid re-exploration. Ann Surg 1977; 186: 140-5. 4. Martin JK, Von Heerden JA, Edis A J, Dahlin DC. Persistent postoperative hyperparathyroidism. Surg Gynecol Obstet 1980; 151: 764-8. 5. Clark OH, Siperstein AE. The hypercalcemia syndrome: Hyperparathyroidism. In: Friesen S, Thompson N. eds. Surgical endocrinology. Philadelphia: JB Lippincott, 1990:311-37. 6. Burtis W J, Brady TG, Orloff J J, et al. Immuno-chemical characterization of circulating parathyroid hormone-related protein in patients with humeral hypercalcemia or cancer. N Engl J Med 1990; 322:1106-12. 7. Wang CA. The anatomic basis of parathyroid surgery, Ann Surg 1976; 183: 271-5. 8. Edis AJ, Purnell DC, van Heerdan JA. The undescended parathymus: an occasional cause of failed neck exploration for hyperparathyroidism. Ann Surg 1979; 190: 64-8. 9. Davies DR. The surgery of primary hyperparathyroidism. J Clin Endocrinol Metab 1974; 3: 253-65. 10. Palmer JA, Sutton FR. Importance of a fifth parathyroid gland in the surgical treatment of hyperparathyroidism. Can J Surg 1978; 21: 350-1. 11. Cusamano R J, Mahadevia P, Silver CE. Intraoperative histologic evaluation in exploration of the parathyroid glands. Surg Gynecol Obstet 1989; 169: 506-10. 12. Harrison TS, Duarte B, Reitz R, et al. Primary hyperparathyroidism: 4- to 8-year postoperative follow-up demonstrating persistent functional insignificance of microscopic parathyroid hyperplasia and decreased autonomy of parathyroid hormone release. Ann Surg 1981; 194: 429-37. 13. Kaplan EL. Bartlett S. Sugimoto J, Fredland A. Relation of postoperative hypocalcemia to operative techniques: deleterious effect of excessive use of parathyroid biopsy. Surgery 1982; 92: 82734. 14. Cohn H, Silen W. Lessons of parathyroid reoperations. Am J Surg 1982; 144: 511-7. 15. Brennan MF, Doppman JL, Marx SJ. Spiegel AM, Brown EM, Auerbach GD. Reoperative parathyroid surgery for persistent hyperparathyroidism. Surgery 1978; 83: 669-76. 16. Grant CS, van Heerden JA, Charboneau JW. James ME, Reading CC. Clinical management of persistent and/or recurrent primary hyperparathyroidism. World J Surg 1986; 10: 555-65. 17. Cheung PSY, Borgstrom A, Thompson NW. Strategy in reoperative surgery for hyperparathyroidism. Arch Surg 1989: 124: 676-80. 18. Granberg PO, Johansson G, Lindvall N. et al. Reoperation for primary hyperparathyroidism. Am J Surg 1982; 143: 296-300. 19. Attie JN, Khan A, Rumancik WM. Moskowitz GW, Hirsch MA, Herman PG. Preoperative localization of parathyroid adenomas. Am J Surg 1988; 156: 323-6. 20. Levin KE, Gooding GA. Okerlund M. et al. Localizing studies in patients with persistent or recurrent hyperparathyroidism. Surgery 1987; 102: 917-25.
THE AMERICAN JOURNAL OF SURGERY VOLUME 160 OCTOBER 1990
Initial Failure of Surgical Exploration in Patients with Primary Hyperparathyroidism Louis-Joseph Auguste, MD, Joseph N. Attie, MD, David Schnaap, MD, NewHydePark, NewYork To determine the causes of failures of cervical exploration for primary hyperparathyroidism, we reviewed 892 patients operated on by one surgeon from 1953 to 1990. Twenty-seven patients (3%) remained hypercalcemic or developed hypercalcemia within 6 months of surgery. Of these, five patients had one adenoma removed initially; at reoperation, three patients had a second adenoma that was successfully removed, whereas the other
two patients had hyperplasia and required subtotal parathyroidectomies. No enlarged parathyroid glands were identified in 2 2 patients. Eventually, six patients became normocalcemic spontaneously, seven patients underwent re-exploration with a suecessful outcome in all but one ease, two patients had ectopic hyperparathyroidism associated with carcinoma elsewhere, and seven patients refused reoperation and remain hypercalcemic. The failure rate of surgical exploration for primary hyperparathyroidism can be reduced by systematically exploring all four parathyroid glands. All abnormal parathyroids should be removed with histologic verification. When no abnormal glands are found, localization studies should be performed before reexploration.
hypercalcemia following failed initial surgp ersistent ical exploration for primary hyperparathyroidism has been reported in 3% to 8% of cases (Table I). Reexploration in such cases is extremely difficult, can be associated with a significant incidence of complications, and has a lower success rate than that of initial exploration. The purposes of this study were to determine the causes for these failures, review the subsequent course in this group of patients, and discuss possible measures to be undertaken to minimize future failed parathyroid explorations. From the Long Island Jewish Medical Center, Long Island Campus for the Albert Einstein College of Medicine, Division of Head and Neck Surgery, New Hyde Park, New York. Requests for reprints should be addressed to Louis-Joseph Auguste, MD, Long Island Jewish Medical Center, Department of Surgery, New Hyde Park, New York 11042. Presented at the 36th Annual Meeting of the Society of Head and Neck Surgeons, Washington, DC, May 19-22, 1990.
PATIENTS AND METHODS Between July 1953 and February 1990, 892 parathyroid explorations were performed for hyperparathyroidism by one surgeon (JNA). In 865 patients, long-term normocalcomia was achieved by the removal of 1 or more parathyroid adenomas, or in the case of hyperplasia, by subtotal parathyroidectomy (3 89glands). However, in 27 patients (3%), the initial exploration was unsuccessful: either no abnormal parathyroid glands were found, the removal of enlarged parathyroids did not result in normocalcemia, or the hypercalcemia recurred within 6 months following operation. These patients form the basis of this study. Data on their mode of presentation were obtained from hospital and office records. Follow-up data were gathered from hospital charts, office records, the patients themselves, referring physicians, and next of kin. When possible, the patients were recalled for re-examination and their blood studied for serum calcium levels. RESULTS There were 27 failed initial explorations for primary hyperparathyroidism (Table II) in 12 men and 15 women ranging in age from 21 to 79 years (mean: 52 years). In 5 of the 27 patients, enlarged parathyroid glands were found and removed, but the patients remained hypercalcemic. In three of these patients who were re-explored, a second enlarged parathyroid (adenoma) was found and excised with resulting normocaleemia in each. In one of the three patients, reoperation was performed 2 days postoperatively; the other two had successful preoperative localization, one by intravenous differential radioimmune assay of parathyroid hormone and arteriography and the other by ultrasound and magnetic resonance imaging (MRI). One of the five patients not improved by removal of the enlarged parathyroid gland proved to have diffuse hyperplasia and was cured by subtotal parathyroidectomy (389glands). The fifth patient in this group was found to have multiple endocrine neoplasia type I and remains mildly hypercalcemic despite subtotal parathyroidectomy (389 glands). No enlarged parathyroid glands were identified in 22 patients at the initial operation. Six of these patients were re-explored (four by us and two by other surgeons); one adenoma was removed in each case and normocalcemia ensued. Three patients had suec~ssful preoperative localization studies (one by computed tomography scan and two by intravenous differential radioimmunoassay of parathyroid hormone and arteriography) prior to reoperation. There were no complications and no persistent hypocalcemia in any patient undergoing rcoperation. A spontaneous return of serum calcium to normal levels occurred after an interval of several months to 5 years in six patients who were not re-explored. In four patients, only three normal parathyroid glands were iden-
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AUGUSTE ET AL
TABLEI
Failed Initial Parathyroid Explorations Failed Author
No. of Patients
Exploration (% )
Successful Reoperations
Persistent Hypercalcemia
Spontaneous Eucalcemia
Silver et al [ 1] McGarity et al [2] Wang [3] Martin et al [4] Present study
102 193 712 500 892
8 (8) 12 (6.2) 37 (5.2) 25 (5) 27 (3)
1 5 33 5 11
2 5 4 17 7
2 2 O 3 6
TABLE
II
Initially Failed Parathyroid ExploraUona in 27 Patients from 1953-1990 No. of Patients
ReoperatiOn Single aden0ma removed Second adenoma removed Subtotal parathyroidectomy
12 6 3 2
completed for hyperplasia No adenoma at reoperation
1
persistent hypercalcemta No reoperation
Ectopic hyperparathyrodism Spontaneous normocalcemia
Infarcted by injection of dye Persistent hypercalcemia
15 2 6 1 6
tiffed at operation, whereas in two patients, four normal parathyroids were observed. Biopsies were done on the normal-appearing parathyroids, but no parathyroid glands were removed in any of these cases. One patient had three normal parathyroids found at exploration. The fourth gland (right superior) was identified by arteriography as an adenoma and was intentionally infarcted by dye injected during a second arteriogram. This patient has been normocalcemic for 11 years, Two patients with hypercalcemia, hypophosphatemia, and elevated serum parathyroid hormone levels proved to have ectopic hyperparathyroidism due to carcinoma of the lung and carcinoma of the liver, respectively. Both patients had four normal parathyroids identified, and no parathyroid tissue was removed. Seven patients who had negative exploratioris did not undergo reoperation and remain hypercalcemic at 1 to 13 years postoperatively. In five of these patients, three normal and no enlarged parathyroids were found at operation. In the other two patients, one enlarged parathyroid gland was resected with no improvement. Of this group, one patient died 2 years postoperatively with a serum calcium level of 1 t.4 mg/mL at the time of last examination, and one patient was lost to follow-up. The remaining five patients have been followed for I to 12 years. Recent serum calcium levels varied from 10.7 to 12.6 mg/mL. None of these patients has had any symptoms or complications related to their hyperparathyroidism. In two of these patients, attempts to localize their adenomas by 334
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noninvasive modalities (ultrasound, MRI, and thalliumtechnetium subtraction [TTS]) were unsuccessful. In one patient, an enlarged parathyroid was suggested by preoperative ultrasound and MRI. At reoperation, no adenoma was found, and this patient remains hypercalcemic. COMMENTS This series reaffirms the high success rate of cervical exploration for primary hyperparathyroidtsm (97%). The first requirement for success is proper diagnosis, based on elevation of serum calcium levels associated with high or normal parathormone levels, often with elevated serum chloride and decreased serum phosphate levels. If all of these parameters are not present, other causes of hypercalcemia must be considered [5]. Ectopic hyperparathyroidism may mimic primary hyperparathyroidism; in a recent study, a parathyroid hormone-related protein (detected by radioimmune assay) was demonstrated in the case of a malignancy-producing hypercalcemia [6]. The presence of other endocrine syndromes or a family history suggests multiple endocrine neoplasm or familial hyperparathyroidism. In familial hypocalciuric hypercalcemia, serum calcium and parathormone levels ate elevated but urinary calcium is low. Patients with this disease have normal parathyroid glands and do not benefit from surgical intervention. Hypercalcemia can also be caused by bone metastases from other malignancies, but the parathormone levels in these cases are low or normal. The initial exploration must be thorough. An attempt should be made to identify all four parathyroid glands, and meticulous attention should be paid to the thyroid gland and to the regional lymph nodes. Primary hyperparathyroidism may be associated with thyroid disease. In our series of 892 patients, 17 (19%) had nodular goiter and 19 (2%) had incidental papillary thyroid carcinoma. In one of our patients, biopsy Of an abnormal lymph node revealed sarcoidosis as the cause of hyperealcemia, and in another patient, the presence of metastatic thyroid cancer in a paratracheal lymph node alerted us to the diagnosis of carcinoma of the thyroid. A knowledge of the normal anatomy and appearance of the parathyroid glands is of paramount importance to the operating surgeon. The normal parathyroids are soft, tan, and surrounded by a variable amount of fat that increases with age. They measure 2 to 12 mm and weigh 30 to 70 rag. In contrast, adenomas are firm, reddishbrown, and rarely surrounded by fat. They measure 5
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FAILED PARATHYROID EXPLORATION
mm to 10 cm in greatest diameter and weigh 70 mg to 10 g. The superior parathyroids are more constant in position and are usually located along the posterior surface of the thyroid, near the upper pole. The inferior glands are usually closer to the lower pole of the thyroid and may be anterior, lateral, or posterior in position. The normal inferior gland is often at a distance from the thyroid gland and may be attached to the thymus within the anterior mediastinum [7]. If the exploration reveals more than one and less than four enlarged parathyroid glands in the absence of familial hyperparathyroidism and concurrently with one or more normal-appearing glands, the diagnosis of multiple adenoma is established, and only the enlarged parathyroids should be excised. Ectopic locations are frequent causes of failed parathyroid explorations. The superior parathyroid gland may lie very high in position behind the upper pole of the thyroid gland. At times the superior thyroid vessels must be ligated and divided and the upper pole of the thyroid mobilized to expose these glands. Two of our missed adenomas were located very high in the upper pole region; in one patient, the lesion was localized by selective venous catheterization and arteriography and resected by another surgeon, while in the other patient, the lesion was demonstrated by selective arteriography and destroyed by infarction intentionally induced by overinflation of the gland during a second arteriogram. When a superior parathyroid gland is large, it may descend due to gravity into the posterior mediastinum along the esophagus for a variable distance. Such a location should be suspected when there is a bulge and loss of the concavity of the tracheeesophageal groove, or if the inferior thyroid artery is pushed anteriorly and becomes convex over the adenoma. This displacement of the artery over a low-lying superior adenoma has been demonstrated in some of our patients by MRI. The inferior parathyroid gland can descend into the anterior mediastinum along the thymic remnant when it enlarges. In some instances, the inferior parathyroid gland is within the thymus at birth and may be the source of an intrathymic parathyroid adenoma. Ectopic inferior parathyroids have been reported in the vicinity of the aortic arch, near the hilum of the lung, and even within the pericardium. One of our patients required a sternotomy at another hospital to resect an adenoma in the vicinity of the aortic arch. Parathyroid adenomas have been found within the carotid sheath. On rare occasions, the inferior parathyroid glands occur high near the upper border of the larynx in an undescended thymic remnant
[8]. in rare instances, parathyroid tumors occur within the thyroid gland. We encountered this situation in two of our patients. Intrathyroid parathyroid adenomas are said to occur in 1% of cases [9]. Most often, it is the inferior rather than the superior gland that is intrathyroidal. If all four glands appear normal, a fifth gland should be sought since a supernumerary parathyroid is present in about 5% of patients, although no such instance was encountered in our series. These glands are most often associated with
TABLE III Success Rate of Reoperatlons
Author
No. of Patients
Brennan et al [ 15] wang [3] Grant et al [ 16] Cheung et al [ 17] Granberg et al [ 18] Present study
95 112 157 83 47 12
Successful Reoperations ( % ) 91 102 139 71 39 10
(96) (91) (89) (85) (83) (83)
the thyroid remnant, indicating a common derivation from the third pharyngeal pouch [10]. Some investigators believe that biopsy of normal-appearing glands should be done to confirm the normal histology. In some instances, a small biopsy specimen will be interpreted as microscopic hyperplasia and lead the surgeon to resect more tissue [11]. The finding of microscopic hyperplasia in normal-appearing glands is probably of no clinical significance, as shown by Harrison et al [12], and the removal of such glands is unnecessary. Furthermore, multiple biopsies of normal parathyroid glands may lead to hypocalcemia [13]. In patients with persistent hypercalcemia, reoperation is not always indicated. In six of our patients, the serum calcium level returned to normal spontaneously. This has been reported by other surgeons [14]. The return to normocalcemia may be due to the destruction of the blood supply to the adenoma during exploration. Reoperations may be extremely difficult because of scarring and altered anatomy. The success rate of reoperations is lower than in primary operations and varies from 83% to 96% (Table III). Of 12 of our patients who underwent reoperation, 2 remain hypercalcemic, 1 due to failure to find the adenoma at the second operation. The other patient, who was diagnosed as having multiple endocrine neoplasia type I, is mildly hypercalcemic despite three explorations and the completion of subtotal parathyroidectomy (389 glands). Preoperative localization should be performed prior to re-exploration. If any of the noninvasive preoperative localization modalities (ultrasound, TTS, or MRI) were not employed prior to the first exploration, such tests should be utilized before reoperating. During the past 3 years, we have used 1 or more of the localization techniques in 160 patients. The accuracy rate was over 90% [19]. These tests are especially useful in reoperated cases [20]. They often pinpoint the location of the adenoma and allow the surgeon to avoid long and difficult dissection in scarred areas that need not be explored. If the noninvasive methods are unsuccessful, selective venous sampling and arteriography can be used with great success. In three of the six patients re-explored successfully for a missed solitary adenoma, and in two of the three patients with a second adenoma missed at the primary operation, preoperative localization was used and successfully located the tumor. Our approach in reoperation for persistent hypercal-
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cemia is similar to that suggested by Cohn and Silen [14]. The previous cervical incision is used, and the flaps are raised in the usual manner. To avoid the scarring from previous surgery, a lateral approach is used. The fascia along the sternomastoid muscle is incised and the muscle is retracted laterally. The carotid sheath is retracted laterally and the strap muscles medially to expose the lateral aspect of the thyroid gland. The lateral surface of the thyroid and the tracheoesophageal groove are readily dissected, bringing the region of the parathyroid glands into view. Care must be taken to expose and identify the recurrent and the external laryngeal nerves to avoid damage to these structures. If the adenoma is not found in the usual areas and a normal superior parathyroid gland is identified, the anterior mediastinum is dissected; if no tumor is seen, the thymus is removed because of the possibility of an intrathymic tumor. If a normal inferior gland is identified, a search is made for a superior parathyroid adenoma in the posterior mediastinum along the esophagus. If the cervical exploration is unsuccessful, and especially if localization studies have detected the adenoma within the chest, mediastinotomy is performed, usually after an interval of 1 to 2 weeks. In conclusion, cervical exploration for primary hyperparathyroidism is successful in over 95% of cases. The failure rate may be further reduced by establishing an accurate diagnosis, reviewing the patient's family history, performing noninvasive localization tests, and examining all four glands at the time of operation. All enlarged parathyroids should be removed when dealing with single or multiple adenomas; subtotal parathyroidectomy (31A glands) should be performed in patients with hyperplasia or multiple endocrine neoplasia. Frozen section should be performed to confirm all excised parathyroid tissue. If exploration is unsuccessful, ectopic locations such as the thymus, the anterior and posterior mediastinum, and the carotid sheath should be explored; when no adenoma is found, partial thyroidectomy in the area of the missing parathyroid should be performed.
REFERENCES 1. Silver CE, Schoenbach SF, Barzel US. Surgical treatment of primary hyperparathyroidism. NY State J Med 1977; 77: 732-5. 2. McGarity WC. Matthews WH, Fulenwider JT. Isaacs JW, Miller DA. The surgical management of primary hyperparathy-
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