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10.1245/ASO.2006.12.009
Annals of Surgical Oncology 13:103-109 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type 1: Individualized Management With Low Recurrence Rates

Chen-Hsen Lee, MD, FACS1,4, Ling-Ming Tseng, MD1,4, Jui-Yu Chen, MD1,4, Hsin-Yun Hsiao, MD2,4 and An-Hang Yang, MD, PhD3,4

1 Department of Surgery, Taipei-Veterans General Hospital, 201, Sec. 2, Shih-Pai Rd, Taipei, Taiwan
2 Department of Insternal Medicine, Taipei-Veterans General Hospital, 201, Sec. 2, Shih-Pai Rd, Taipei, Taiwan
3 Department of Pathology, Taipei-Veterans General Hospital, 201, Sec. 2, Shih-Pai Rd, Taipei, Taiwan
4 School of Medicine, National Yang-Ming Univeristy, 155, Li-Nong Street, Sec. 2, Taipei, Taiwan

Correspondence: Address correspondence and reprint requests to: Chen-Hsen Lee, MD, FACS; E-mail: chlee{at}vghtpe.gov.tw


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: To evaluate the outcomes in different surgical modalities for primary hyperparathyroidism in multiple endocrine neoplasia type 1 (MEN1) patients, intraoperative findings from a single surgeon were studied to investigate a potentially improved modality of parathyroidectomy (PTx).

Methods: All 22 patients had PTx by a single surgeon in the past 21 years. Three modalities of PTx were used, depending on the operative findings, after all parathyroids and the thymus were identified. If fewer than three glands were enlarged, selective removal of the enlarged glands with or without biopsy of a normal-appearing gland was performed (selective PTx); if all glands were enlarged, either a subtotal PTx leaving a 50-mg remnant in situ or a total PTx with autotransplantation (TPTx + AT) was performed.

Results: There were 7 men and 15 women, aged 22 to 67 years (average, 43 years). Sixteen had familial and six had sporadic MEN1. They underwent 23 operations, including 11 selective PTx, 6 subtotal PTx, and 6 TPTx + AT. On follow-up for 1 to 19 years, only one patient (4.6%) had recurrent hyperparathyroidism 5.5 years after subtotal PTx. Others had either normocalcemia (n = 14; 63.6%) or hypocalcemia (n = 7; 31.8%). Those who had either a subtotal PTx or TPTx + AT had a significantly higher rate of postoperative hypocalcemia than those who had a selective PTx (9.9% vs. 54.5%; P = .032; Fisher’s exact test).

Conclusions: Primary hyperparathyroidism in our MEN1 patients was less aggressive than that reported in the literature. Selective PTx according to the intraoperative findings achieved optimal outcomes.

Key Words: Multiple endocrine neoplasia type 1 • Parathyroidectomy • Recurrence • Hypocalcemia


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Primary hyperparathyroidism (HPT) is the most common endocrinopathy in multiple endocrine neoplasia type 1 (MEN1). However, MEN1 is rare, representing only 2% to 4% of all cases of primary HPT.1 Patients with MEN1 generally have asymmetric tumors in three or all four parathyroid glands.1,2 Controversies remain in its surgical treatment. Subtotal parathyroidectomy (PTx) leaving approximately a 50-mg remnant in situ is the most common operation in the treatment of MEN1 HPT. In the literature, rates of recurrent hypercalcemia and postoperative persistent hypocalcemia range from 0% to 88% and 12% to 33%,3–8 respectively; these rates are much higher than those from sporadic cases, thus indicating a lack of optimal management. Meanwhile, no data have been reported for the treatment of MEN1 in Chinese patients. In this article, data are presented on the individualized management of HPT in MEN1 patients with a low recurrence rate.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Population
In the past 21 years (1982–2002), 22 cases with HPT associated with MEN1 were diagnosed and treated at the Taipei Veterans General Hospital. The diagnosis of a MEN1 HPT was based on increased serum calcium and parathyroid hormone (PTH) levels, as well as (1) coexisting endocrine neoplastic disease in the pancreas, pituitary gland, and/or adrenal cortex or (2) at least one first-degree relative with MEN1. The medical records of these patients were reviewed retrospectively. All 22 patients were operated on by a single surgeon (C.-H.L.). One patient with pituitary adenoma and parathyroid carcinoma and another patient with invasive pituitary tumor and sudden hypoparathyroidism after hypophysectomy were not included in this series.

Operative Strategy
Of the 22 patients, 11 (group 1), who had only 1 to 3 enlarged parathyroid glands, were treated by selective removal of the enlarged parathyroids with or without biopsy of one of the normal parathyroids (selective PTx). For the other 11 patients, in whom all glands identified were enlarged, 6 (group 2) were treated by a subtotal PTx (removal of all parathyroid glands leaving 50 mg of parathyroid in situ; subtotal PTx), and 5 (group 3) were treated by a total PTx (TPTx) with autotransplantation of approximately 70 to 100 mg of parathyroid chips into the muscle pockets in the forearm. During the operations, both thymus tips were removed, and all parathyroids were identified before PTx was attempted in each patient. Normal parathyroids and the remnants were marked with hemoclips. Symptomatic postoperative hypocalcemia was managed by calcium replacement and supplemented with calcitriol if needed. Coexisting neoplastic endocrine diseases were diagnosed by clinical symptoms with appropriately increased serum levels of hormones or positive provocative tests, image studies, and pathologic analysis, if they were resected.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Among the 22 patients, 7 were men, and 15 were women. They were aged 22 to 67 years (average, 43 years) at the time of PTx. Sixteen of the 22 were familial and 6 were sporadic cases (Table 1Go). The patients underwent 23 parathyroid operations and were followed up for .5 to 19.5 years (average, 7.2 years). Five patients died, either from unrelated causes or from associated malignancies. Only one patient had recurrent HPT, and seven were hypocalcemic. In group 1 patients, four had one enlarged gland, two had two enlarged glands, and five had three enlarged glands; two patients had a biopsy-proven second normal gland. They were normocalcemic or mildly hypocalcemic without the need for calcium replacement after a follow-up of 6 months to 19.5 years (average, 7.0 years). Serum intact PTH levels were normal except in one patient (patient 8), who had low PTH and was in a hypocalcemic state. Pathologically, the enlarged glands were diagnosed as adenomas (n = 3) and hyperplasia (n = 8). In group 2, one patient (patient 12) had six enlarged glands and was treated by 51/2 PTx; the others had 31/2 PTx. Three of the six patients were hypocalcemic and needed calcium replacement. One (patient 15) had recurrent HPT 5.5 years after subtotal PTx and became normocalcemic after reoperation by a TPTx with autotransplantation (TPTx + AT). The follow-up was 1.5 to 15.5 years (average, 6.9 years). The pathologic diagnosis showed hyperplasia in all patients except one (patient 12), who had two hyperplastic glands and four supranumerary parathyroid cysts. In group 3, two of the six patients underwent completion TPTx: one was the only patient with recurrent HPT from group 2, and the other patient had persistent HPT after operation in another hospital. Three of the six patients were hypocalcemic and needed calcium replacement after a follow-up of 2 to 11.5 years (average, 7.7 years). The pathologic diagnosis showed that one patient had one adenoma and three normal glands, and all others had hyperplasia (Table 2Go).


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  		TABLE 1. General data, operative findings, modalities, pathologic characteristics, and outcomes of 22 MEN1 patients with primary hyperparathyroidism treated by 23 parathyroidectomies
 

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  		TABLE 2. The outcomes and weight of parathyroids removed in three groups of patients who underwent different surgical modalities of parathyroidectomy
 
When the pathologic diagnosis was compared with the operative findings, all cases with a diagnosis of adenoma had only one enlarged gland found at operation, whereas those diagnosed as hyperplasia had one to four enlarged glands (Fig. 1Go). The total weight of the removed glands ranged from .3 to 12.5 g (average, 3.1 g).


Figure 1
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  		FIG. 1. Operative findings, pathologic diagnoses, and outcomes of the 22 patients with hyperparathyroidism in multiple endocrine neoplasia type 1.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
MEN1 is an autosomal dominant disease typified by parathyroid, gastroenteropancreas, and pituitary involvements. Primary HPT is the most prevalent abnormality in MEN1, occurring in >90% of affected patients.9 The optimal modality of PTx for MEN1 HPT remains controversial.

Previous studies have shown the efficacy of sub-total PTx, resection of 31/2 parathyroid glands, with a long-term recurrence rate of <20%.10–12 However, successful resolution of HPT after selective removal of one or two enlarged glands has also been described.13 Others have reported high recurrence rates after subtotal PTx.14 These results indicate possible different disease aggressiveness in different patients. Although a mitogenic growth factor has been reported in the serum of MEN1 patients,15 it has not been reported to stimulate human parathyroids. This growth factor is found in fewer than half of MEN1 patients16 and should not be used to justify a routine aggressive modality of PTx in all patients.

We individualized the extent of parathyroid resection according to the operative findings. Only one patient, who had a subtotal PTx, had recurrent HPT that was treated successfully by TPTx + AT. It may be debated that our follow-up period is insufficient, because the disease can recur after more than 10 years of postoperative normocalcemia.12 Burgess et al.8 reported that early recurrence of HPT was less likely to develop in patients in whom ionized calcium levels of ≤4.0 mg/dL were achieved during the perioperative period, although hypocalcemia is the major stimulator of growth and secretion of the parathyroid.17 Because symptomatic hypocalcemia adversely affects the quality of life, one can debate the wisdom of prophylactic extensive resection of the parathyroids to prevent an unlikely late recurrence at the expense of long-term hypocalcemia. The same scenario was also reported in tertiary HPT, in which a surgical strategy of resection was limited to the enlarged gland so that postoperative complications could be minimized.18 In our only patient with recurrent HPT (patient 15), it was not difficult to find the clipped remnant, which had grown from 50 mg to 2.1 g in 5.5 years after initial 31/2 PTx. In the hands of experienced endocrine surgeons, the complication rate of re-PTx for recurrent HPT is not high.19

In Table 3Go, 7 (31.8%) of 22 patients had hypocalcemia at follow-up. This result is comparable with those reported in the literature.3,5,8 Most of these hypocalcemic patients (six of seven) belonged to groups 2 and 3. Those who had an extensive PTx (subtotal PTx or TPTx + AT) had a significantly higher rate of postoperative hypocalcemia than those who had a selective PTx (9.9% vs. 54.5%; P = .032; Fisher’s exact test). Among the 16 patients with familial MEN1 HPT, 8 were treated by selective PTx and 8 by extensive PTx. Twelve patients (75%) were normocalcemic, and four (25%) were hypocalcemic. All four had extensive PTx. Three (50%) of the six patients with sporadic disease were normocalcemic, and three (50%) were hypocalcemic, one after selective and two after extensive PTx. The risk of postoperative hypocalcemia in our sporadic MEN1 patients (3 in 6) was similar to that in the familial MEN1 patients (4 in 16; P = .354), with a similar period of follow-up (7.4 vs. 6.6 years). Patients who undergo selective PTx have a significantly lower rate of postoperative hypocalcemia than those with an extensive PTx. This result supports the use of selective PTx in both familial and sporadic MEN1 patients (Table 3Go).


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  		TABLE 3. The incidence of hypocalcemia and PTx modalities between familial and sporadic MEN1 HPT patients (incidence of hypocalcemia between familial and sporadic MEN1 HPT patients receiving selective or extensive PTx)
 
Four (patients 3, 9, 13, and 19) of these 22 patients were treated surgically for their HPT when the serum total calcium levels were only near the high-normal limit. Two of them had increased levels of ionized serum calcium and low serum albumin because of repeated upper gastrointestinal bleeding (cases 9 and 19). All four patients had at least one enlarged parathyroid shown on image studies before operations. Pathologic examinations reported hyperplasia in three patients and adenoma in one patient. No patient had recurrent HPT, but two had long-term hypocalcemia that necessitated calcium replacement. Whether these patients benefited from aggressive early intervention, indicated by increased serum intact PTH and positive imaging study results, remains to be seen.

Pathologically, diffuse hyperplasia with involvement of all four glands has been reported in most of the major series of MEN1 HPT. This led to strong advice for extensive PTx, subtotal PTx, or TPTx + AT to prevent recurrent disease. The Uppsala group14 reported an expected recurrence rate of 69% within 4 years if less than a subtotal PTx was performed. In this series, however, the seven patients who had selective PTx and were followed up for >5 years showed no evidence of recurrence. Recent extensive studies have found the genetics of MEN1 to be heterogenous. More than 100 varieties of germline mutations have been reported.20–23 Further studies may find our patients, who are ethnically Chinese, to be genetically different from other reported cases. Similar patients, however, with only one or two abnormal glands and a low recurrence rate, have also been reported by others.24,25 We do not argue about the efficacy of an extensive PTx for MEN1 patients with disease affecting all parathyroid glands, but we emphasize the existence of clinically variant forms. Some patients with phenotypical presentations of MEN1 may not be gene carriers, as Teh26 et al. have reported. In these patients, HPT may be less aggressive and may be treated less aggressively. Further studies may make possible a selective PTx guided by germline analysis in the management of MEN1 HPT. An international collaborative study will help to see whether a genotype/phenotype correlation exists.

In our five patients who had only a single parathyroid gland enlargement, four had a pathologic diagnosis of adenomas, and one had hyperplasia. The differential diagnosis of an adenoma from a hyperplasia is sometimes difficult even by experienced pathologists.24 The basic pathologic criteria for chief cell hyperplasia are that hyperplastic glands lack definitely complete circumscription and usually show lobular arrangement, whereas those for adenoma are that the tumors are distinctly circumscribed and lack a lobular pattern. A rim of normal-appearing or atrophic parathyroid tissue located immediately outside the adenomatous lesion is also counted as one of the basic pathologic criteria of adenomas. However, we did not use the pathologic diagnosis in our decision making for a selective or an extensive PTx, because multiple-gland disease has been reported in MEN1 patients with either pathologic diagnosis.25 Intraoperative monitoring of PTH in the diagnosis of multiglandular involvement is controversial.27–30 Most cases of multiglandular disease are characterized by a stepwise decline of intraoperative PTH, but a drastic decrease (adenoma-like) of the PTH level just a few minutes after excision of only one abnormal gland, despite another abnormal parathyroid remaining in the neck, has been reported.27,30 Proye et al.30 observed that 50% of patients who presented with multiglandular disease had "adenoma-like" kinetics of intraoperative PTH. Preoperative diagnosis of the MEN1 syndrome is important, and all parathyroid glands and the thymus need to be explored and evaluated.12 Intraoperative biopsy of a second normal gland may guarantee long-term postoperative normocalcemia. However, those with normal parathyroid glands left in situ need careful long-term follow-up. Metachronous pathologic change of the parathyroid has been studied in MEN2a patients but not in MEN1 patients.31

It is also interesting to find that both adenomas and hyperplasia can be observed in the same patient, as well as in different members of the same family. This indicates the possibility of a polyclonal germline mutation in our patients and may account for different disease behaviors (Table 4Go).


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  		TABLE 4. Pathologic findings, operative findings, modalities, and outcomes of the 16 patients with familial MEN1 hyperparathyroidism
 
In conclusion, the HPT in our MEN1 patients seems less aggressive than those reported in other series. Their management can be individualized. Selective PTx, identification of all parathyroids, biopsy of a second normal gland, and removal of only the diseased gland can be performed with a low rate of recurrent hypercalcemia and with a smaller risk of hypoparathyroidism.

Received for publication December 10, 2004. Accepted for publication August 2, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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