- Email: [email protected]
Surgical management of persistence or recurrence after subtotal parathyroidectomy for primary hyperparathyroidism
Surgical Management of Persistence or Recurrence After Subtotal Parathyroidectomy for Primary Hyperparathyroidism Melvin A. Block, MD, Detroit, Michigan Boy Frame, MD, Detroit, Michigan Michael Kleerekoper, MD, Detroit, Michigan Dhanwade S. Rao, MB, BS, Detroit, Michigan
Accumulated experience has demonstrated that primary hyperparathyroidism is associated with a broad spectrum of pathologic involvement of the parathyroid glands [1,2]. Therefore it is incumbent upon the surgeon at the time of operation to determine the pathologic abnormalities on the basis of gross enlargement and a darker than normal color of the parathyroids. The surgeon must be a gross pathologist, and rely on the microscopist primarily to ensure identification of tissue as parathyroid [2]. A consensus is developing that diversity in reports of the frequency of multiple gland involvement has been due, to a great extent, to interpretation by microscopists of hyperplasia in multiple parathyroid glands to a degree not supported by clinical evidence [3]. The incidence of multiple parathyroid gland involvement in primary hyperparathyroidism appears to be established at 15 to 20 per cent, including in patients with multiple endocrine neoplasia (MEN) syndromes and hereditary hyperparathyroidism [2,4]. The operation of choice for patients with multiple gland involvement has been subtotal parathyroidectomy, although the alternative of immediate total parathyroidectomy with autotransplantation has also been advocated [5]. We have followed a policy of selective subtotal parathyroidectomy for multiple gland involvement, with a failure to control hypercalcemia in 14 per cent of cases [2,6]. This rate of persistence and recurrence of hypercalcemia was supported recently in a report by Edis and van Heerden [ 71. The question arises as to the optimal management for patients who have persistent or recurrent hypercalcemia after subtotal From the Departments of Surgery and Medicine, Henry Ford Hospital, Detroit, Michigan. Presented at the Twenty-Fifth Annual Meeting of The Society of Head and Neck Surgeons, Pittsburgh, Pennsylvania, April 1-4, 1979. Reprint requests should be addressed to Melvin A. Block, MD, Henry Ford Hospital, Detroit, Michigan 49202.
Volume 138, October 1979
parathyroidectomy for multiple gland involvement producing primary hyperparathyroidism. Our review of this experience, reported herein, indicates that treatment for subtotal parathyroidectomy failure should be individualized also. The decision for or against reoperation is related to the severity of hypercalcemia and its complications. The operative procedure is determined by factors including whether persistence or recurrence is the problem, a knowledge of the adequacy of the prior operation, the degree of enlargement of the remnant of parathyroid tissue, the presence of supernumerary parathyroid glands, other factors concerning the location and anatomic status of the remaining parathyroid glands, and the significance of stimulating factors such as chronic renal insufficiency resulting from hyperparathyroidism. Material
During the period 1960 through 19’77,267 patients with primary hyperparathyroidism were treated at our institution by operation. Of these patients, 44 (16 per cent) were found to have multiple gland involvement and were treated by subtotal parathyroidectomy. In 25 patients at least. four parathyroid glands were grossly enlarged; in 19 patients three parathyroid glands were enlarged and the fourth appeared normal in size or only slightly enlarged and in most cases was preserved except for removal of a biopsy specimen. The follow-up periods for these 44 patients varied from 1 to 19 years (average 4.9). Each patient has been evaluated for evidence of persistence or recurrence of hypercalcemia. When subtotal parathyroidectomy was performed, an estimated 30 mg of parathyroid tissue was preserved if four or more glands were enlarged. An estimated maximum of 50 mg of parathyroid tissue of a fourth normal-sized gland was preserved in patients in whom three enlarged glands were removed and only a biopsy was performed for the fourth. A search was always made for supernumerary
561
Block et al
TABLE I
Patient No.
Persistent Hypercalcemia After Subtotal Parathyroidectomy for Primary Hyperparathyroidism Due to Multiple Parathyroid Gland Involvement Weight of Parathyroids Removed by Subtotal Parathvroidectomv
1
2.47 1.84 1.06 0.90”
2
0.90 0.16 0.10 Biopsy 0.17 0.16 0.14 0.07’
3
Treatment for Persistence
Associated Factors
(a)
Chronic renal insufficiency attributed to primary hyperparathyroidism (BUN 55, S Cr 5.2 mg/ 100 ml) None recognized
Outcome of Treatment for Persistence Hypoparathyroidism postop; Rx with vitamin 0 and Ca supplements for 5 yr, then not needed. On chronic renal dialysis Lost to follow-up
Removal of remnant to complete total parathyroidectomy 3 yr later; weight of remnant then 0.97 g (see Figure 1) Not treated (S. calcium 10.6-11.1 mg/lOO ml)
fourth* Evidence of pituitary adenoma, S prolactin normal; probable MEN
Recurrent hypercalcemia at 8 months after 2nd operation (S Ca 10.0-11.4 mg/lOO ml)
Removal 5th parathyroid and l/2 remnant, each weighing 50 mg
* Approximately 30 to 50 mg of parathyroid tissue was preserved from these fourth parathyroid glands. BUN = blood urea nitrogen: Ca = calcium; Cr = creatinine; MEN = multiple endocrine neoplasia; postop = postoperatively; Rx = treatment; S = serum.
TABLE II
Patient No. 4
5
6
Recurrent Hypercalcemia After Subtotal Parathyroidectomy for Primary Hyperparathyroidism Due to Multiple Parathyroid Gland Involvement Weight of Parathyroids Removed by Subtotal Parathyroidectomy
(g)
Dimensions of 3 enlarged parathyroids: 2.3 X 0.8 X 0.8 cm, 1.5 X 1.5 X 0.8 cm, 0.8 X 0.4 X 0.1 cm; the fourth, grossly normal 3.4 1.1 0.2 Biopsy fourth
3.06 1.0 0.15 Biopsy fourth
Interval From Operation to Recurrence (yr) 3
18
7
Associated Factors
Treatment for Recurrence
None recognized; SCato9mg/lOO ml postop
Removal of remnant (1.1 g) to complete total parathyroidectomy, immediate autotransplantation
Requires Rx to date for hypoparathyroidism
MEN-l syndrome; moderate renal insufficiency evident 18 yr postop (BUN 32-36 mg/ 100 ml). Evidence of pituitary tumor 18 yr postop; S prolactin elevated Temporary hypocalcemia postop, S Ca down to 6.5 mg/ 100 ml. Evidence of pituitary tumor after 7 yr, S prolactin elevated, probable MEN
Not treated yet
Under further evaluation; is now diabetic
Hypercalcemia mild, intermittent (S Ca 8.6-l 1.7 mg/lOO ml)
Still under evaluation; is now diabetic; S glucagon at upper limits of normal
BUN = blood urea nitrogen; Ca = calcium; MEN = multiple endocrine neoplasia; postop = postoperatively;
562
Outcome of Treatment for Recurrence
Rx = prescription; S = serum.
The American Journal of Surgery
Unsuccessful Subtotal Parathyroidectomy
parathyroid glands. In preserving a remnant of parathyroid tissue in cases with enlargement of all parathyroid glands, the smallest gland was selected first for transection to maximize the likelihood of a viable remnant. Persistence of hypercalcemia has been defined as the finding of more than one elevated serum calcium level within 6 months of the parathyroid operation. Recurrence has been considered present when, after a normocalcemic interval, two or more serum calcium elevations are found 6 months or more after subtotal parathyroidectomy. Cases with enlargement of less than three parathyroid glands were excluded from this study. Such cases do occur as part of the spectrum of parathyroid gland enlargement. Our experience indicates that subtotal parathyroidectomy, performed routinely for such cases, is even more successful than when used for enlargement of four or more parathy-
roid glands. Rarely, only two parathyroid glands are greatly enlarged. Results
Of the 44 patients treated by subtotal parathyroidectomy for enlargement of three or more parathyroid glands producing primary hyperparathyroidism, persistence of hypercalcemia was evident in three patients and recurrence in three. Thus, the overall failure rate to date for this procedure is 14 per cent. In the three patients with persistent hypercalcemia, associated factors and treatment are outlined in Table I (see also Figure 1). Similar information is outlined in Table II for the three patients with recurrent hypercalcemia after subtotal parathyroidectomy for multiple gland involvement causing primary hyperparathyroidism. In all patients except patient 4, subtotal parathyroidectomy was the initial operation performed at our institution. It is of interest that a supernumerary parathyroid gland appeared to be a factor in persistent hypercalcemia in only one of our patients, and in this patient evidence of hypercalcemia developed again 8 months after reoperation. Other factors evident in our patients that may be of etiologic significance include chronic renal insufficiency on the basis of primary hyperparathyroidism in three patients (evident at time of first operation in one patient and later in one patient) and multiple endocrine neoplasia (MEN 1) with pituitary tumors in three patients. Both factors were present in one patient. Subtotal parathyroidectomy has controlled hypercalcemia in three additional patients with the MEN 1 syndrome and in three patients with renal insufficiency attributed to primary hyperparathyroidism. Two illustrative cases of persistent and recurrent hypercalcemia are presented.
Volume 138, October 1979
Figure 1. Top, section cross of parathyroid glands removed at initial subtotal parathyroidectomy for primary hyperparathyrodism due multiple to gland involvement. Bottom, hyperplastic remnant removed 3 years later to complete total parathyrotdectomy because of persistent hypercalcemia.
Case 3: A 30 year old woman presented with mental depression, easy fatigability, and headaches. Evaluation showed persistent hypercalcemia with serum calcium levels in the range of 11.2 to 11.6 mg/lOO ml. The diagnosis of primary hyperparathyroidism was made. At operation, all four parathyroid glands were grossly enlarged and all glands were removed except for an estimated 30 mg at the right upper position (see weights of the parathyroid glands excised in Table I). Postoperatively, the patient’s serum calcium returned to normal levels except for one isolated determination of 12.3 mg/lOO ml. After 2 months, the patient suspected a recurrence of hypercalcemia because of a recurrence of her emotional symptoms. Persistent hypercalcemia was confirmed with serum calcium levels of 11.0 to 11.4 mg/lOO ml. Selective venous catheterization studies failed to show definite localization of hyperfunctioning parathyroid tissue. Reoperation was advised and performed 3 l/2 years after the initial procedure. At this procedure a fifth parathyroid gland found caudad to the left thyroid lobe was removed. The gland weighed 50 mg. The preserved remnant of the upper right parathyroid gland had enlarged. Approximately one half of this remnant was removed and found to weigh 50 mg. Subsequently the patient was asymptomatic for 8 months when she again
563
Block et al
suspected recurrent hypercalcemia on the basis of a return of mental depression. Again, intermittent elevated serum calcium levels of up to 11.4 mg/lOO ml have appeared. Further studies have also disclosed x-ray evidence of a pituitary adenoma without elevated blood levels of trophic hormones. The patient continues under evaluation and reoperation is planned. No other evidence of a multiple endocrine neoplasia syndrome or familial disease has been found. Case 4: A 33 year old man developed symptomatic renal calculi. Serum calcium levels varied from 11.4 to 12.3 mg/lOO ml and a diagnosis of primary hyperparathyroidism was made. A subtotal parathyroidectomy was performed; the dimensions of the parathyroid glands removed are shown in Table II. Postoperatively, serum calcium levels decreased to 9.0 to 9.3 mg/lOO ml. He remained asymptomatic with periodic normal rechecks of serum calcium. After 4 years, recurrent symptoms from new renal calculi appeared, and increased levels of serum calcium were recognized at 10.6 to 11.9 mg/lOO ml. A plasma immunoreactive parathyroid hormone level was increased at 112 ng/dl (normal less than 80). A diagnosis of recurrent primary hyperparathyroidism was made. Computerized tomography of the neck and mediastinum was not helpful in localizing a parathyroid tumor. Reoperation was advised and the remaining remnant of parathyroid gland, which weighed 1.1 g, was found and removed. After the gland was totally removed, a portion was cut into thin slices and placed in muscle of the left forearm. Postoperatively, severe hypocalcemia developed as evidence of hypoparathyroidism. The patient remains normocalcemic on vitamin D and oral calcium therapy with periodic reevaluations. One of the three patients reoperated on was studied by selective venous catheterization with determination of serum parathyroid hormone levels. This study was not helpful. Arteriography has not been used. Computerized tomography has not been helpful in delineating cervical parathyroid tumors but has been valuable in identifying mediastinal parathyroid tumors in other patients. Plasma immunoreactive parathyroid hormone levels were increased in the three patients in whom this hormone was measured. Comments
A persistence and recurrence rate of 14 per cent after subtotal parathyroidectomy for primary hyperparathyroidism due to multiple gland involvement is not considered at this time to necessitate a more aggressive policy in either removing more parathyroid tissue during the procedure or in performing a routine total parathyroidectomy with immediate autotransplantation of tissue. Further surveillance is, of course, needed. Chronic renal insufficiency of a moderate or greater severity, even
564
though a result of primary hyperparathyroidism, does appear to justify but does not mandate immediate total parathyroidectomy with autotransplantation. The stimulus, whatever it may be, for the original development of primary hyperparathyroidism added to the additional stimulus from chronic renal insufficiency appears to make patients particularly susceptible to persistence or recurrence after subtotal parathyroidectomy. Total parathyroidectomy with autotransplantation might be considered for patients with the MEN-l syndrome since three of the six such patients in whom we performed subtotal parathyroidectomy have shown persistence or eventual recurrence of hypercalcemia. However, in these patients the persistent or recurrent hypercalcemia has been mild in two cases and appeared after intervals of 7 and 18 years. In the latter patient who developed evidence of recurrence after 18 years, the onset of chronic renal insufficiency may also have been an etiologic factor. Continued evaluation is necessary. Hyperparathyroidism in the MEN-2a syndrome appears to be milder than in patients with the MEN-l syndrome [B]. Total parathyroidectomy with autotransplantation does entail a variable period of months of hypoparathyroidism. In addition, ultimate success of the transplant is not ensured and the precise overall success rate has not yet been established. It is advisable to freeze parathyroid tissue, in addition to immediate autotransplantation, in the event of fail-
ure of the initial transplant procedure to correct hypoparathyroidism. Edis and van Heerden [7] emphasize the need for a diligent search for supernumerary parathyroid glands in performing subtotal parathyroidectomy since these glands have been the major cause of persistence after subtotal parathyroidectomy; in their experience, recurrence has not developed. Certainly, supernumerary parathyroids, particularly in the mediastinum or high in the neck, are a potential cause of failure of subtotal parathyroidectomy, although this was documented in only one of our six cases. This report may be criticized for the inclusion of patients with chronic renal insufficiency. However, in each case evidence indicated that the renal insufficiency was a complication of primary hyperparathyroidism, occurring after problems with renal calculi or even late after the initial subtotal parathyroidectomy and in association with recurrent hypercalcemic hyperparathyroidism. It is evident that whenever primary hyperparathyroidism is due to hyperplasia of all parathyroid glands, if the underlying stimulus persists, whether it is renal in-
The American Journal of Surgery
Unsuccessful Subtotal Parathyroidectomy
sufficiency or that associated with MEN syndromes, the potential for further hyperplasia of parathyroid remnants must also be great. In exploring parathyroid glands for primary hyperparathyroidism, the surgeon must be a surgical pathologist, first in identifying all parathyroid glands, then in determining which are enlarged, and finally in deciding which should be totally removed, which should be biopsied, or which require subtotal parathyroidectomy. Errors can be made in either excessive or inadequate removal, Evidence of multiple gland involvement requires subtotal parathyroidectomy, a search for supernumerary parathyroid glands, and consideration of total parathyroidectomy with autotransplantation for selected patients, as discussed earlier. The identification of three or four normal glands should direct a search for a missing tumor in the thyroid, high in the neck, in the mediastinum, or in other inconspicuous locations for parathyroid tumors. In these cases, an effort should be made to preserve the normal parathyroid glands to avoid permanent hypoparathyroidism once the single enlarged gland is found and removed. Reoperation in the neck is associated with technical difficulties, an increased morbidity, and an increased potential for permanent hypoparathyroidism [9]. Our experience indicates an approximately equal chance for late recurrence or persistence after subtotal parathyroidectomy for multiple gland involvement. Logic suggests that persistence is more likely to arise from the preservation of too much parathyroid tissue or the failure to remove all hyperplastic parathyroid glands, particularly supernumerary glands. However, our experience does not clearly distinguish different causes for these two types of failure in controlling hypercalcemia. Before reoperation for persistence or recurrence, the surgeon should have maximal information available for localization of remaining hyperplastic parathyroid tissue. Noninvasive studies are the safest. Ultrasonography appears to be of greatest value in studies of the neck but has not been helpful in evaluating the mediastinum. Echograms are particularly useful in detecting the rare enlarged parathyroid gland located high in the neck. Since metal clips may produce distortion in ultrasonograms or computerized tomograms, it appears preferable that colored sutures be used at the time of operation to mark parathyroid tissue in the neck. Computerized tomography appears to be reliable in detecting parathyroid tumors in the mediastinum, but our experience indicates that it is less helpful than ultrasonography for studies of the neck. Improvements in resolution capabilities are steadily increasing the
Volume 139, Oclober 1979
value of both ultrasonography and computerized tomography [lO,ll]. Invasive studies in our hands are less valuable and are associated with greater morbidity and expense than ultrasonography and computerized tomography. Selective vein catheterization studies and arteriography may be of value for the patient in whom the noninvasive studies are not definitive and the patient who had an extensive neck exploration at the time of previous surgery [12]. Catheterization of small thyroid veins requires considerable technical skill, and previous surgery frequently limits this possibility. Policies for the extent of reoperation should be individualized. General guidelines are outlined as follows: (1) If the patient has mild or borderline hypercalcemia, perform no operation but follow up with periodic reevaluation of serum calcium levels and for complications of hypercalcemia, especially renal insufficiency. (2) Search for enlarged supernumerary parathyroid glands, especially in cases of persistent hypercalcemia. If such a gland is found, remove and evaluate the remnant for further partial excision if it is enlarged. (3) If the patient has chronic renal insufficiency, perform total parathyroidectomy with autotransplantation (and freezing of additional parathyroid tissue for future use, if needed). (4) If only a single enlarged remnant of parathyroid gland is present, perform total parathyroidectomy and autotransplantation (with freezing of additional parathyroid tissue for future use, if needed). This is particularly indicated for recurrent hypercalcemia. Total parathyroidectomy with autotransplantation does not, of course, ensure against recurrent hypercalcemia from hyperplasia of the transplanted parathyroid tissue [23]. The primary advantage of autotransplantation is the relative ease with which additional parathyroid tissue can be removed from the forearm in contrast to the increased risk and complexity of reoperation on the neck. This discussion has been based on the premise that a subtotal parathyroidectomy was actually performed at the initial procedure. Of course, if at least four glands were not identified at the previous operation, persistence or recurrence may be caused by overlooked third or fourth hyperplastic glands. In such cases, reoperation is directed to finding the missing enlarged parathyroid glands, including a search for supernumerary glands, after preoperative localization studies. If again the missing hyperplastic glands are not identified, additional measuressuch as partial thyroidectomy, dissection high in the neck, exploration of the mediastinum, and intraoperative sampling of veins for assay of parathyroid hormone
565
Block et al
levels to aid future operative approaches should be considered. These experiences again emphasize the need for continued periodic reevaluation of patients after operation for hyperparathyroidism, particularly in cases of multiple gland involvement.
tion, especially subtotal parathyroidectomy, for primary hyperparathyroidism due to multiple gland involvement. If mild or borderline hypercalcemia persists or recurs, close follow-up study is indicated. References
Summary
(1) In an experience with 44 patients requiring subtotal parathyroidectomy for primary hyperparathyroidism due to multiple gland involvement, persistence was identified in 3 patients and recurrence in 3, resulting in a failure rate of 14 per cent. (2) The development of chronic renal insufficiency secondary to hyperparathyroidism appears to be an aggravating factor in the failure of subtotal parathyroidectomy to control hypercalcemia in such cases. An associated MEN-l syndrome may possibly also be a predisposing factor. (3) Overlooked supernumerary hyperfunctioning parathyroid glands may be the cause of persistent hypercalcemia. (4) If reoperation is performed, ultrasonography of the neck and computerized tomography of the mediastinum are justified preoperatively for localization studies. (5) If hyperplasia of the preserved remnant of parathyroid is the only explanation for failure of subtotal parathyroidectomy, its removal is justified with autotransplantation of parathyroid tissue and freezing of additional tissue for possible future use. (6) The presence of moderate or severe chronic renal insufficiency, related to primary hyperparathyroidism, appears to justify total parathyroidectomy with autotransplantation for primary hyperparathyroidism due to multiple gland involvement. (7) Periodic reevaluation is indicated for all patients after opera-
566
1. Block MA, Greenawald KA, Horn RC Jr, Frame B: Involvement of multiple parathyroids in hyperparathyroidism. Am J Surg 114: 530, 1967. 2. Block MA, Frame B, Jackson CE: The extent of operation for primary hyperparathyroidism. Arch Surg 109: 798, 1974. 3. Edis AJ, Beahrs OH, van Heerden JA, Akwari OE: “Conservative” versus “liberal” approach to parathyroid neck exploration. Surgery 82: 468, 1977. 4. Clark OH, Way LW, Hunt TK: Recurrent hyperparathyroidism. Ann Surg 184: 391, 1978. 5. Wells SA Jr, Ellis GJ, Gunnells JC, Schneider AB, Sherwood IM: Parathyroid autotransplantation in primary parathyroid hyperplasia. N Engl J Med 295: 57, 1976. 6. Block MA, Frame B, Jackson CE: The efficacy of subtotal parathyroidectomy for primary hyperparathyroidism due to multiple gland involvement. Surg Gynecol O&et 147: 1, 1978. 7. Edis AJ, van Heerden JA: Results of subtotal parathyroidectomy for primary chief cell hyperplasia. Surgery, in press. 8. Block MA, Jackson CE, Tashjian AH Jr: Management of parathyroid glands in surgery for medullary thyroid carcinoma. Arch Surg 110: 617, 1975. 9. Brennan MF, Doppman JL, Marx SJ, Spiegel AM, Brown EM. Aurbach GD: Reoperative parathyroid surgery for persistent hyperparathyroidism. Surgery 63: 669, 1978. 10. Doppman JL, Brennan MF, Koehler JO, Marx SJ: Computed tomography for parathyroid localization. J Comput Assist Tomogr 1: 30, 1977. 11. Cracker EF, Jellins J, Freund J: Parathyroid lesions localized by radionuclide subtraction and ultrasound. Radiology 130: 215, 1979. 12. Edis AJ, Sheedy PF II, Beahrs OH, van Heerden JA: Results of reoperation for hyperparathyroidism with evaluation of preoperative localization studies. Surgery 84: 384, 1978. 13. Brennan MF, Brown EM, Marx SJ, Spiegel AM, Broachs AE, Doppman JL, Webber B, Aurbach GD: Recurrent hyperparathyroidism from an autotransplanted parathyroid adenoma. N Engl J Med 299: 1057, 1978.
The American Journal of Surgery
Accumulated experience has demonstrated that primary hyperparathyroidism is associated with a broad spectrum of pathologic involvement of the parathyroid glands [1,2]. Therefore it is incumbent upon the surgeon at the time of operation to determine the pathologic abnormalities on the basis of gross enlargement and a darker than normal color of the parathyroids. The surgeon must be a gross pathologist, and rely on the microscopist primarily to ensure identification of tissue as parathyroid [2]. A consensus is developing that diversity in reports of the frequency of multiple gland involvement has been due, to a great extent, to interpretation by microscopists of hyperplasia in multiple parathyroid glands to a degree not supported by clinical evidence [3]. The incidence of multiple parathyroid gland involvement in primary hyperparathyroidism appears to be established at 15 to 20 per cent, including in patients with multiple endocrine neoplasia (MEN) syndromes and hereditary hyperparathyroidism [2,4]. The operation of choice for patients with multiple gland involvement has been subtotal parathyroidectomy, although the alternative of immediate total parathyroidectomy with autotransplantation has also been advocated [5]. We have followed a policy of selective subtotal parathyroidectomy for multiple gland involvement, with a failure to control hypercalcemia in 14 per cent of cases [2,6]. This rate of persistence and recurrence of hypercalcemia was supported recently in a report by Edis and van Heerden [ 71. The question arises as to the optimal management for patients who have persistent or recurrent hypercalcemia after subtotal From the Departments of Surgery and Medicine, Henry Ford Hospital, Detroit, Michigan. Presented at the Twenty-Fifth Annual Meeting of The Society of Head and Neck Surgeons, Pittsburgh, Pennsylvania, April 1-4, 1979. Reprint requests should be addressed to Melvin A. Block, MD, Henry Ford Hospital, Detroit, Michigan 49202.
Volume 138, October 1979
parathyroidectomy for multiple gland involvement producing primary hyperparathyroidism. Our review of this experience, reported herein, indicates that treatment for subtotal parathyroidectomy failure should be individualized also. The decision for or against reoperation is related to the severity of hypercalcemia and its complications. The operative procedure is determined by factors including whether persistence or recurrence is the problem, a knowledge of the adequacy of the prior operation, the degree of enlargement of the remnant of parathyroid tissue, the presence of supernumerary parathyroid glands, other factors concerning the location and anatomic status of the remaining parathyroid glands, and the significance of stimulating factors such as chronic renal insufficiency resulting from hyperparathyroidism. Material
During the period 1960 through 19’77,267 patients with primary hyperparathyroidism were treated at our institution by operation. Of these patients, 44 (16 per cent) were found to have multiple gland involvement and were treated by subtotal parathyroidectomy. In 25 patients at least. four parathyroid glands were grossly enlarged; in 19 patients three parathyroid glands were enlarged and the fourth appeared normal in size or only slightly enlarged and in most cases was preserved except for removal of a biopsy specimen. The follow-up periods for these 44 patients varied from 1 to 19 years (average 4.9). Each patient has been evaluated for evidence of persistence or recurrence of hypercalcemia. When subtotal parathyroidectomy was performed, an estimated 30 mg of parathyroid tissue was preserved if four or more glands were enlarged. An estimated maximum of 50 mg of parathyroid tissue of a fourth normal-sized gland was preserved in patients in whom three enlarged glands were removed and only a biopsy was performed for the fourth. A search was always made for supernumerary
561
Block et al
TABLE I
Patient No.
Persistent Hypercalcemia After Subtotal Parathyroidectomy for Primary Hyperparathyroidism Due to Multiple Parathyroid Gland Involvement Weight of Parathyroids Removed by Subtotal Parathvroidectomv
1
2.47 1.84 1.06 0.90”
2
0.90 0.16 0.10 Biopsy 0.17 0.16 0.14 0.07’
3
Treatment for Persistence
Associated Factors
(a)
Chronic renal insufficiency attributed to primary hyperparathyroidism (BUN 55, S Cr 5.2 mg/ 100 ml) None recognized
Outcome of Treatment for Persistence Hypoparathyroidism postop; Rx with vitamin 0 and Ca supplements for 5 yr, then not needed. On chronic renal dialysis Lost to follow-up
Removal of remnant to complete total parathyroidectomy 3 yr later; weight of remnant then 0.97 g (see Figure 1) Not treated (S. calcium 10.6-11.1 mg/lOO ml)
fourth* Evidence of pituitary adenoma, S prolactin normal; probable MEN
Recurrent hypercalcemia at 8 months after 2nd operation (S Ca 10.0-11.4 mg/lOO ml)
Removal 5th parathyroid and l/2 remnant, each weighing 50 mg
* Approximately 30 to 50 mg of parathyroid tissue was preserved from these fourth parathyroid glands. BUN = blood urea nitrogen: Ca = calcium; Cr = creatinine; MEN = multiple endocrine neoplasia; postop = postoperatively; Rx = treatment; S = serum.
TABLE II
Patient No. 4
5
6
Recurrent Hypercalcemia After Subtotal Parathyroidectomy for Primary Hyperparathyroidism Due to Multiple Parathyroid Gland Involvement Weight of Parathyroids Removed by Subtotal Parathyroidectomy
(g)
Dimensions of 3 enlarged parathyroids: 2.3 X 0.8 X 0.8 cm, 1.5 X 1.5 X 0.8 cm, 0.8 X 0.4 X 0.1 cm; the fourth, grossly normal 3.4 1.1 0.2 Biopsy fourth
3.06 1.0 0.15 Biopsy fourth
Interval From Operation to Recurrence (yr) 3
18
7
Associated Factors
Treatment for Recurrence
None recognized; SCato9mg/lOO ml postop
Removal of remnant (1.1 g) to complete total parathyroidectomy, immediate autotransplantation
Requires Rx to date for hypoparathyroidism
MEN-l syndrome; moderate renal insufficiency evident 18 yr postop (BUN 32-36 mg/ 100 ml). Evidence of pituitary tumor 18 yr postop; S prolactin elevated Temporary hypocalcemia postop, S Ca down to 6.5 mg/ 100 ml. Evidence of pituitary tumor after 7 yr, S prolactin elevated, probable MEN
Not treated yet
Under further evaluation; is now diabetic
Hypercalcemia mild, intermittent (S Ca 8.6-l 1.7 mg/lOO ml)
Still under evaluation; is now diabetic; S glucagon at upper limits of normal
BUN = blood urea nitrogen; Ca = calcium; MEN = multiple endocrine neoplasia; postop = postoperatively;
562
Outcome of Treatment for Recurrence
Rx = prescription; S = serum.
The American Journal of Surgery
Unsuccessful Subtotal Parathyroidectomy
parathyroid glands. In preserving a remnant of parathyroid tissue in cases with enlargement of all parathyroid glands, the smallest gland was selected first for transection to maximize the likelihood of a viable remnant. Persistence of hypercalcemia has been defined as the finding of more than one elevated serum calcium level within 6 months of the parathyroid operation. Recurrence has been considered present when, after a normocalcemic interval, two or more serum calcium elevations are found 6 months or more after subtotal parathyroidectomy. Cases with enlargement of less than three parathyroid glands were excluded from this study. Such cases do occur as part of the spectrum of parathyroid gland enlargement. Our experience indicates that subtotal parathyroidectomy, performed routinely for such cases, is even more successful than when used for enlargement of four or more parathy-
roid glands. Rarely, only two parathyroid glands are greatly enlarged. Results
Of the 44 patients treated by subtotal parathyroidectomy for enlargement of three or more parathyroid glands producing primary hyperparathyroidism, persistence of hypercalcemia was evident in three patients and recurrence in three. Thus, the overall failure rate to date for this procedure is 14 per cent. In the three patients with persistent hypercalcemia, associated factors and treatment are outlined in Table I (see also Figure 1). Similar information is outlined in Table II for the three patients with recurrent hypercalcemia after subtotal parathyroidectomy for multiple gland involvement causing primary hyperparathyroidism. In all patients except patient 4, subtotal parathyroidectomy was the initial operation performed at our institution. It is of interest that a supernumerary parathyroid gland appeared to be a factor in persistent hypercalcemia in only one of our patients, and in this patient evidence of hypercalcemia developed again 8 months after reoperation. Other factors evident in our patients that may be of etiologic significance include chronic renal insufficiency on the basis of primary hyperparathyroidism in three patients (evident at time of first operation in one patient and later in one patient) and multiple endocrine neoplasia (MEN 1) with pituitary tumors in three patients. Both factors were present in one patient. Subtotal parathyroidectomy has controlled hypercalcemia in three additional patients with the MEN 1 syndrome and in three patients with renal insufficiency attributed to primary hyperparathyroidism. Two illustrative cases of persistent and recurrent hypercalcemia are presented.
Volume 138, October 1979
Figure 1. Top, section cross of parathyroid glands removed at initial subtotal parathyroidectomy for primary hyperparathyrodism due multiple to gland involvement. Bottom, hyperplastic remnant removed 3 years later to complete total parathyrotdectomy because of persistent hypercalcemia.
Case 3: A 30 year old woman presented with mental depression, easy fatigability, and headaches. Evaluation showed persistent hypercalcemia with serum calcium levels in the range of 11.2 to 11.6 mg/lOO ml. The diagnosis of primary hyperparathyroidism was made. At operation, all four parathyroid glands were grossly enlarged and all glands were removed except for an estimated 30 mg at the right upper position (see weights of the parathyroid glands excised in Table I). Postoperatively, the patient’s serum calcium returned to normal levels except for one isolated determination of 12.3 mg/lOO ml. After 2 months, the patient suspected a recurrence of hypercalcemia because of a recurrence of her emotional symptoms. Persistent hypercalcemia was confirmed with serum calcium levels of 11.0 to 11.4 mg/lOO ml. Selective venous catheterization studies failed to show definite localization of hyperfunctioning parathyroid tissue. Reoperation was advised and performed 3 l/2 years after the initial procedure. At this procedure a fifth parathyroid gland found caudad to the left thyroid lobe was removed. The gland weighed 50 mg. The preserved remnant of the upper right parathyroid gland had enlarged. Approximately one half of this remnant was removed and found to weigh 50 mg. Subsequently the patient was asymptomatic for 8 months when she again
563
Block et al
suspected recurrent hypercalcemia on the basis of a return of mental depression. Again, intermittent elevated serum calcium levels of up to 11.4 mg/lOO ml have appeared. Further studies have also disclosed x-ray evidence of a pituitary adenoma without elevated blood levels of trophic hormones. The patient continues under evaluation and reoperation is planned. No other evidence of a multiple endocrine neoplasia syndrome or familial disease has been found. Case 4: A 33 year old man developed symptomatic renal calculi. Serum calcium levels varied from 11.4 to 12.3 mg/lOO ml and a diagnosis of primary hyperparathyroidism was made. A subtotal parathyroidectomy was performed; the dimensions of the parathyroid glands removed are shown in Table II. Postoperatively, serum calcium levels decreased to 9.0 to 9.3 mg/lOO ml. He remained asymptomatic with periodic normal rechecks of serum calcium. After 4 years, recurrent symptoms from new renal calculi appeared, and increased levels of serum calcium were recognized at 10.6 to 11.9 mg/lOO ml. A plasma immunoreactive parathyroid hormone level was increased at 112 ng/dl (normal less than 80). A diagnosis of recurrent primary hyperparathyroidism was made. Computerized tomography of the neck and mediastinum was not helpful in localizing a parathyroid tumor. Reoperation was advised and the remaining remnant of parathyroid gland, which weighed 1.1 g, was found and removed. After the gland was totally removed, a portion was cut into thin slices and placed in muscle of the left forearm. Postoperatively, severe hypocalcemia developed as evidence of hypoparathyroidism. The patient remains normocalcemic on vitamin D and oral calcium therapy with periodic reevaluations. One of the three patients reoperated on was studied by selective venous catheterization with determination of serum parathyroid hormone levels. This study was not helpful. Arteriography has not been used. Computerized tomography has not been helpful in delineating cervical parathyroid tumors but has been valuable in identifying mediastinal parathyroid tumors in other patients. Plasma immunoreactive parathyroid hormone levels were increased in the three patients in whom this hormone was measured. Comments
A persistence and recurrence rate of 14 per cent after subtotal parathyroidectomy for primary hyperparathyroidism due to multiple gland involvement is not considered at this time to necessitate a more aggressive policy in either removing more parathyroid tissue during the procedure or in performing a routine total parathyroidectomy with immediate autotransplantation of tissue. Further surveillance is, of course, needed. Chronic renal insufficiency of a moderate or greater severity, even
564
though a result of primary hyperparathyroidism, does appear to justify but does not mandate immediate total parathyroidectomy with autotransplantation. The stimulus, whatever it may be, for the original development of primary hyperparathyroidism added to the additional stimulus from chronic renal insufficiency appears to make patients particularly susceptible to persistence or recurrence after subtotal parathyroidectomy. Total parathyroidectomy with autotransplantation might be considered for patients with the MEN-l syndrome since three of the six such patients in whom we performed subtotal parathyroidectomy have shown persistence or eventual recurrence of hypercalcemia. However, in these patients the persistent or recurrent hypercalcemia has been mild in two cases and appeared after intervals of 7 and 18 years. In the latter patient who developed evidence of recurrence after 18 years, the onset of chronic renal insufficiency may also have been an etiologic factor. Continued evaluation is necessary. Hyperparathyroidism in the MEN-2a syndrome appears to be milder than in patients with the MEN-l syndrome [B]. Total parathyroidectomy with autotransplantation does entail a variable period of months of hypoparathyroidism. In addition, ultimate success of the transplant is not ensured and the precise overall success rate has not yet been established. It is advisable to freeze parathyroid tissue, in addition to immediate autotransplantation, in the event of fail-
ure of the initial transplant procedure to correct hypoparathyroidism. Edis and van Heerden [7] emphasize the need for a diligent search for supernumerary parathyroid glands in performing subtotal parathyroidectomy since these glands have been the major cause of persistence after subtotal parathyroidectomy; in their experience, recurrence has not developed. Certainly, supernumerary parathyroids, particularly in the mediastinum or high in the neck, are a potential cause of failure of subtotal parathyroidectomy, although this was documented in only one of our six cases. This report may be criticized for the inclusion of patients with chronic renal insufficiency. However, in each case evidence indicated that the renal insufficiency was a complication of primary hyperparathyroidism, occurring after problems with renal calculi or even late after the initial subtotal parathyroidectomy and in association with recurrent hypercalcemic hyperparathyroidism. It is evident that whenever primary hyperparathyroidism is due to hyperplasia of all parathyroid glands, if the underlying stimulus persists, whether it is renal in-
The American Journal of Surgery
Unsuccessful Subtotal Parathyroidectomy
sufficiency or that associated with MEN syndromes, the potential for further hyperplasia of parathyroid remnants must also be great. In exploring parathyroid glands for primary hyperparathyroidism, the surgeon must be a surgical pathologist, first in identifying all parathyroid glands, then in determining which are enlarged, and finally in deciding which should be totally removed, which should be biopsied, or which require subtotal parathyroidectomy. Errors can be made in either excessive or inadequate removal, Evidence of multiple gland involvement requires subtotal parathyroidectomy, a search for supernumerary parathyroid glands, and consideration of total parathyroidectomy with autotransplantation for selected patients, as discussed earlier. The identification of three or four normal glands should direct a search for a missing tumor in the thyroid, high in the neck, in the mediastinum, or in other inconspicuous locations for parathyroid tumors. In these cases, an effort should be made to preserve the normal parathyroid glands to avoid permanent hypoparathyroidism once the single enlarged gland is found and removed. Reoperation in the neck is associated with technical difficulties, an increased morbidity, and an increased potential for permanent hypoparathyroidism [9]. Our experience indicates an approximately equal chance for late recurrence or persistence after subtotal parathyroidectomy for multiple gland involvement. Logic suggests that persistence is more likely to arise from the preservation of too much parathyroid tissue or the failure to remove all hyperplastic parathyroid glands, particularly supernumerary glands. However, our experience does not clearly distinguish different causes for these two types of failure in controlling hypercalcemia. Before reoperation for persistence or recurrence, the surgeon should have maximal information available for localization of remaining hyperplastic parathyroid tissue. Noninvasive studies are the safest. Ultrasonography appears to be of greatest value in studies of the neck but has not been helpful in evaluating the mediastinum. Echograms are particularly useful in detecting the rare enlarged parathyroid gland located high in the neck. Since metal clips may produce distortion in ultrasonograms or computerized tomograms, it appears preferable that colored sutures be used at the time of operation to mark parathyroid tissue in the neck. Computerized tomography appears to be reliable in detecting parathyroid tumors in the mediastinum, but our experience indicates that it is less helpful than ultrasonography for studies of the neck. Improvements in resolution capabilities are steadily increasing the
Volume 139, Oclober 1979
value of both ultrasonography and computerized tomography [lO,ll]. Invasive studies in our hands are less valuable and are associated with greater morbidity and expense than ultrasonography and computerized tomography. Selective vein catheterization studies and arteriography may be of value for the patient in whom the noninvasive studies are not definitive and the patient who had an extensive neck exploration at the time of previous surgery [12]. Catheterization of small thyroid veins requires considerable technical skill, and previous surgery frequently limits this possibility. Policies for the extent of reoperation should be individualized. General guidelines are outlined as follows: (1) If the patient has mild or borderline hypercalcemia, perform no operation but follow up with periodic reevaluation of serum calcium levels and for complications of hypercalcemia, especially renal insufficiency. (2) Search for enlarged supernumerary parathyroid glands, especially in cases of persistent hypercalcemia. If such a gland is found, remove and evaluate the remnant for further partial excision if it is enlarged. (3) If the patient has chronic renal insufficiency, perform total parathyroidectomy with autotransplantation (and freezing of additional parathyroid tissue for future use, if needed). (4) If only a single enlarged remnant of parathyroid gland is present, perform total parathyroidectomy and autotransplantation (with freezing of additional parathyroid tissue for future use, if needed). This is particularly indicated for recurrent hypercalcemia. Total parathyroidectomy with autotransplantation does not, of course, ensure against recurrent hypercalcemia from hyperplasia of the transplanted parathyroid tissue [23]. The primary advantage of autotransplantation is the relative ease with which additional parathyroid tissue can be removed from the forearm in contrast to the increased risk and complexity of reoperation on the neck. This discussion has been based on the premise that a subtotal parathyroidectomy was actually performed at the initial procedure. Of course, if at least four glands were not identified at the previous operation, persistence or recurrence may be caused by overlooked third or fourth hyperplastic glands. In such cases, reoperation is directed to finding the missing enlarged parathyroid glands, including a search for supernumerary glands, after preoperative localization studies. If again the missing hyperplastic glands are not identified, additional measuressuch as partial thyroidectomy, dissection high in the neck, exploration of the mediastinum, and intraoperative sampling of veins for assay of parathyroid hormone
565
Block et al
levels to aid future operative approaches should be considered. These experiences again emphasize the need for continued periodic reevaluation of patients after operation for hyperparathyroidism, particularly in cases of multiple gland involvement.
tion, especially subtotal parathyroidectomy, for primary hyperparathyroidism due to multiple gland involvement. If mild or borderline hypercalcemia persists or recurs, close follow-up study is indicated. References
Summary
(1) In an experience with 44 patients requiring subtotal parathyroidectomy for primary hyperparathyroidism due to multiple gland involvement, persistence was identified in 3 patients and recurrence in 3, resulting in a failure rate of 14 per cent. (2) The development of chronic renal insufficiency secondary to hyperparathyroidism appears to be an aggravating factor in the failure of subtotal parathyroidectomy to control hypercalcemia in such cases. An associated MEN-l syndrome may possibly also be a predisposing factor. (3) Overlooked supernumerary hyperfunctioning parathyroid glands may be the cause of persistent hypercalcemia. (4) If reoperation is performed, ultrasonography of the neck and computerized tomography of the mediastinum are justified preoperatively for localization studies. (5) If hyperplasia of the preserved remnant of parathyroid is the only explanation for failure of subtotal parathyroidectomy, its removal is justified with autotransplantation of parathyroid tissue and freezing of additional tissue for possible future use. (6) The presence of moderate or severe chronic renal insufficiency, related to primary hyperparathyroidism, appears to justify total parathyroidectomy with autotransplantation for primary hyperparathyroidism due to multiple gland involvement. (7) Periodic reevaluation is indicated for all patients after opera-
566
1. Block MA, Greenawald KA, Horn RC Jr, Frame B: Involvement of multiple parathyroids in hyperparathyroidism. Am J Surg 114: 530, 1967. 2. Block MA, Frame B, Jackson CE: The extent of operation for primary hyperparathyroidism. Arch Surg 109: 798, 1974. 3. Edis AJ, Beahrs OH, van Heerden JA, Akwari OE: “Conservative” versus “liberal” approach to parathyroid neck exploration. Surgery 82: 468, 1977. 4. Clark OH, Way LW, Hunt TK: Recurrent hyperparathyroidism. Ann Surg 184: 391, 1978. 5. Wells SA Jr, Ellis GJ, Gunnells JC, Schneider AB, Sherwood IM: Parathyroid autotransplantation in primary parathyroid hyperplasia. N Engl J Med 295: 57, 1976. 6. Block MA, Frame B, Jackson CE: The efficacy of subtotal parathyroidectomy for primary hyperparathyroidism due to multiple gland involvement. Surg Gynecol O&et 147: 1, 1978. 7. Edis AJ, van Heerden JA: Results of subtotal parathyroidectomy for primary chief cell hyperplasia. Surgery, in press. 8. Block MA, Jackson CE, Tashjian AH Jr: Management of parathyroid glands in surgery for medullary thyroid carcinoma. Arch Surg 110: 617, 1975. 9. Brennan MF, Doppman JL, Marx SJ, Spiegel AM, Brown EM. Aurbach GD: Reoperative parathyroid surgery for persistent hyperparathyroidism. Surgery 63: 669, 1978. 10. Doppman JL, Brennan MF, Koehler JO, Marx SJ: Computed tomography for parathyroid localization. J Comput Assist Tomogr 1: 30, 1977. 11. Cracker EF, Jellins J, Freund J: Parathyroid lesions localized by radionuclide subtraction and ultrasound. Radiology 130: 215, 1979. 12. Edis AJ, Sheedy PF II, Beahrs OH, van Heerden JA: Results of reoperation for hyperparathyroidism with evaluation of preoperative localization studies. Surgery 84: 384, 1978. 13. Brennan MF, Brown EM, Marx SJ, Spiegel AM, Broachs AE, Doppman JL, Webber B, Aurbach GD: Recurrent hyperparathyroidism from an autotransplanted parathyroid adenoma. N Engl J Med 299: 1057, 1978.
The American Journal of Surgery