Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A

Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A Klaus K.-F. Herfarth, MD, Detlef Bartsch, MD, Gerard M. Doherty, MD, Samuel A. Wells, Jr., MD, and Terry C. Lairmore, MD, St. Louis, Mo.

Background. The surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A (MEN 2A) is controversial. We report the long-term follow-up, mutational analysis, and surgical outcome in a large group of patients with MEN 2A and hype,parathywidism. Methods. Clinical and genetic data for MEN 2A patients with biochemically and pathologically confirmed hyperparathyroidism and a minimum of 5 years of follow-up were analyzed retrospectively, and outcomes after surgical management were compared. Results. Thirty-five (29%) of 119 patients from 14 MEN 2A kindreds had biochemical and pathologic evidence of hyperparathyroidism, with a mean Jbllow-up of 14. 7 years. The phenotypic expression of hyperparathyroidism was associated with germline mutations of the RET protooncogene at codons 634 and 618. At initial operation, 21 (62%) patients had a selective resection, eight (24%) had a subtotal resection, five (14 %) had total parathyroidectomy with autotransplantation, and one had an inadvertent total parathyroidectomy. Twenty-seven (77%) patients were cured by the first operation. Persistent hype,parathyroidism occurred in three (8. 6 %) patients; and recurrent hyperparathyroidism occurred in five (14.3%) patients; both occurred only in patients treated with selective or subtotal resection. Permanent postoperatiT)e hypoparathyroidism occurred in six (21%) of 29 patients after selective or subtotal resection, in the one patient with inadvertent total parathyroidectomy, and in one (20 %) of 5 patients treated with total parathyroidectomy and autotransplantation. Conclusions. Recurrent or persistent hyperparathyroidism occurs after selective or subtotal parathyroidectomy, as a result of either missed glands or interval development of neoplasia in previously normal parathyroid glands left in situ. Therefore we advocate total parathyroidectomy and heterotopic autot'ransplantation for patients with hyperparathyroidism and MEN 2A. (Surgery 1996;120:966-74.) From the Department of SurgeU, Washington University School oatMedicine, St. Louis, Mo., and the Department of Surgery, Philipps-UniversityMarburg, Germany

MULTIPLE ENDOCRINENEOPLASIATYPE2A (MEN 2A) was first described by Steiner et al. 1 in 1968. In its full expression this autosomal d o m i n a n t familial cancer disorder is characterized by the development of medullary thyroid carcinoma (MTC), pheochromocytomas, a n d hyperparathyroidism. MEN 2A syndrome has recently b e e n shown to be associated with germline mutations in the RET p r o t o o n c o g e n e 2' 3 on chromosome 10q11.2, which encodes a t r a n s m e m b r a n e receptor ty-

Supported in part by the Deutsche Forschungsgemeinschaft(DFG) (I{-K.-F.H.:He 2499/1-2 and D.B.: BA 1467/1-2). Presented at the SeventeenthAnnual Meeting of the AmericanAssociation of Endocrine Surgeons,Napa, Calif.,April 21-23, 1996. Reprint requests: Terry C. Lairmore, MD, Department of Surgery, WashingtonUniversitySchool of Medicine,Box 8109, CSRB3346, 660 S. Euclid,St. Louis, MO 63110. Copyright 9 1996 by Moshy-YearBook, Inc. 0039-6060/96/$5.00 + 0 11/6/76606 966

SURGERY

rosine kinase. 4, 5 The RET mutations in patients with MEN 2A are missense mutations that result in the substitution of a novel a m i n o acid for one of five highly conserved cysteine residues in the extracellular ligandb i n d i n g domain of the RET receptor tyrosine kinase protein. 6 The MEN 2A phenotype has a high p e n e t r a n c e b u t variable expressivity. Virtually all affected individuals who inherit a RET protooncogene mutation have multiple foci of MTC both thyroid lobes. Overall, approximately 42% of patients with MEN 2A have pheochromocytomas that are often bilateral, but the prevalence of adrenal medullary disease varies greatly between different MEN 2A kindreds. 7 The most variable compon e n t of MEN 2A syndrome is hyperparathyroidism, which occurs in approximately 35% of all such individuals.7 Although the basic parathyroid histopathology in patients with familial forms of hyperparathyroidism is usually considered to be multigland disease or

Surgery Volume 120, Number 6 hyperplasia, the frequent finding of asymmetrical parathyroid enlargement and an apparent increased incidence of ectopic or supernumerary glands have been described in previous studies. 8-11 In addition, some authors have suggested that the hypercalcemia in patients with hyperparathyroidism and MEN 2A is generally mild and that these patients are less frequently symptomatic than patients with primary sporadic hyperparathyroidism.11, 12 The optimal surgical management of hyperparathyroidism in patients with MEN 2A remains controT~ersial. Because of the infi-equency of parathyroid disease in patients with MEN 2A, most previous studies have included relatively few patients with MEN 2A and hyperparathyroidism, those patients have undergone a broad spectrum of surgical procedures at several institutions, and in some instances the results have been analyzed along with those of patients with MEN 1 or primary parathyroid hyperplasia. Selective parathyroidectomy (excision of only those glands judged by the operating smgeon to be enlarged) and subtotal parathyroidectomy (3~glands) are advocated by many surgeons for the treatment of patients with hyperparathyroidism and MEN 2AJ ~ Our group has previously recommended total parathyroidectomy with heterotopic autotransplantation in patients with familial forms of hyperparathyroidism. 14 Thus far no studies have addressed the long-term outcome of different operative procedures in a large number of patients specifically with MEN 2A and hyperparathyroidism. We sought to determine the optimal surgical management of these patients by analyzing retrospectively the outcome of 35 patients with MEN 2A and biochemically and histologically proven hyperparathyroidism at a minimum follow-up of 5 years after primary operation. We also investigated the relationship between mutations in the RET protooncogene and the phenotypic expression of hyperparathyroidism in MEN 2A.

PATIENTS AND METHODS Kindreds with MEN 2A. Clinical, genetic, and pathologic data for all patients with familial endocrine disorders who were cared for or monitored by our group are maintained in a database as part of the Multiple Endocrine Neoplasia Program at Washington University in St. Louis. This database includes the clinical data, laboratory values, genotype data, operative reports, and pathology reports for most of the patients. Data for 119 patients from 14 MEN 2A kindreds were analyzed retrospectively for the occurrence of hyperparathyroidism, surgical procedure, and postoperative outcome.

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fined as a preoperative serum calcium level equal to or greater than 10.5 mg/dt combined with a histopathologic diagnosis of parathyroid hyperplasia or adenoma (increased gland weight, hypercellularity, or both). Only patients with a minimum tbllow-up of 5 years after the initial parathyroid operation were included in the study. Forty-eight patients had histopathologic diagnose of parathyroid neoplasia with a minimum follow-up of 5 years. Six of these patients were excluded from the study because they lacked preoperative serum calcium level measurements. An additional seven patients with preoperative serum calcium levels below 10.5 mg/dl were also excluded. Therefore a total of 35 patients with biochemical and histopathologic evidence of HPT were included in the analysis. Genetic analysis. Genetic testing for mutations in the RETprotooncogene was performed by using direct mutation analysis as described previously. 3' 15 Operative procedure. The primary operation was performed in 17 different hospitals between 1963 and 1989. Depending on the surgeon or clinical circumstances, a selective resection (excision of two or less glands), subtotal resection (excision of 3 or 3~ glands), or total parathyroidectomy was performed. In patients undergoing planned total parathyroidectomy, heterotopic autotransplantations were performed at the time of the initial operation. For some patients undergoing reoperative neck surgery after a thyroidectomy for MTC or for recurrent or persistent hyperparathyroidism, cryopreserved parathyroid tissue was transplanted in a second step after it had been determined the patient was rendered aparathyroid. The operative strategy for patients treated by our group in the current era includes a bilateral neck exploration and identification of all four parathyroid glands including a search for ectopic or supernumerary glands. A total parathyroidectomy and transcervical excision of the cranial portion of the thymus are performed with heterotopic autotransplantation of approximately 30 to 50 mg parathyroid tissue from a normal-sized gland into the nondominant forearm. Most patients with MEN 2A undergoing thyroidectomy are now operated on in the first 2 or 3 decades of life on the basis of direct mutational analysis. 15 These patients are managed with a total thyroidectomy and central lymph node dissection, and heterotopic grafting of parathyroid tissue is performed to prevent postoperative hypocalcemia, regardless of whether there is evidence of hyperparathyroidism:

Patients with MEN 2A and hyperparathyroidism.

Technique of parathyroid transplantation and cryopreservation. A freshly removed parathyroid gland is

Because of the variable and sometimes equivocal presence of parathyroid disease in patients with MEN 2A, the presence of hyperparathyroidism was strictly de-

bivalved, cut into 30 to 50 pieces approximately 1 x 3 mm in size each, and placed in sterile iced saline solution. An incision is made in the nondominant forearm,

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Table I. Location of ectopic parathyroid glands Location

n

Anterior mediastinum In or adjacent to thymus Unknown relation to thymus Intrathyroidal Posterior mediastinum Total

17 13 4 1 1 19

and separate intramuscular pockets are created by spreading the fibers of the brachioradialis muscle with a fine forceps. Approximately four to five tissue pieces are placed in each site; a total of 15 to 25 pieces of parathyroid tissue are transplanted. The separate beds are closed with a fine silk suture to prevent extrusion of the fragments and to mark the site of the transplanted tissue. Cryopreservation of the remaining pieces is performed by stepwise viable freezing of the tissue in vials containing 10% dimethyl sulfoxide, 10% autologous serum, and 80% cell culture medium. Method o f follow-up. The follow-up data were extracted from the database or obtained by retrospective chart review. For some patients the most recent laboratory values were obtained directly from each patient's primary physician. After total thyroidectomy and parathyroid transplantation, patients managed by our group are placed on replacement L-thyroxine (2 p g / k g or an average dose of 100 to 150 pg/day), 1,25 dihydroxyvitamin D~ (1 pg/day), and calcium carbonate (1000 to 2000 mg/day). Serum calcium levels are determined at 6 weeks after operation. In most patients the calcium and vitamin D supplements are discontinued at 8 weeks after operation. The serum calcium concentration and serum parathyroid h o r m o n e concentrations are measured in each antecubital vein 2 weeks later. Persistent hyperparathyroidism is defined as persistence of hypercalcemia or a return of hypercalcemia within 6 months of the primary operation, Recurrent hyperparathyroidism is defined as a return to a hypercalcemic state after a m i n i m u m 6-month period of normocalcemia. Postoperative hypoparathyroidism was defined as dependence on vitamin D or calcium supplementation to maintain normocalcemia for longer than 12 months after operation.

RESULTS Clinical characteristics. The mean age at the time of diagnosis of hyperparathyroidism for patients with MEN 2A was 29.9 + 15.0 years (range, 7 to 64 years). Of the 35 MEN 2A patients with biochemical and histopathologic evidence of hyperparathyroidism, 23 were female and 12 were male (female to male ratio, 1.92:1). The

difference in the gender distribution was not statistically significant (p = 0.1573, Fisher's exact test). The mean preoperative serum calcium level was 11.39 _+ 0.91 m g / d l (range, 10.5 to 13.6 m g / d l ) . Data regarding preoperative symptoms were available for 26 (74%) of the 35 patients with hyperparathyroidism. Eleven (42%) of these patients were symptomatic. Signs or symptoms of hyperparathyroidism included nephrolithiasis (3 of 11, 27%), bone pain (4 of 11, 36%), and neuromuscular symptoms such as fatigue, weakness, or lethargy (6 of 11, 55%). One patient presented with a hypercalcemic crisis consisting of severe headache, syncope, nausea, vomiting, and an initial serum calcium concentration of 13.2 mg/dl. The diagnosis of hyperparathyroidism was made synchronously with the diagnosis of MTC in 30 (86%) patients. The diagnosis of hyperparathyroidism was made after the diagnosis of MTC in four (11%) patients. In one patient, diagnosis ofhyperparathyroidism was made 10 years before the diagnosis of MTC. Parathyroid gland enlargement. Pathologic evidence of diffuse chief cell hyperplasia was described in 17 (48.5%) of the patients. In three (8.6%) patients, parathyroid hyperplasia and asymmetric enlargement (or "adenomas") of one or more glands were described. In 14 (40%) of the patients a gross operative or histopathologic diagnosis of parathyroid adenoma(s) was recorded, including 10 (28.5%) patients with a single enlarged gland, three (8.6%) patients with two enlarged glands, and 1 (2.9%) patientwith three enlarged glands. In one patient only normal parathyroid tissue was described in the pathology report from the initial operation. This patient had persistent hypercalcemia after operation and a missed parathyroid adenoma was subsequently removed at reoperation.

Ectopic and supernumerary parathyroid glands. Fifteen (43%) patients with MEN 2A and confirmed hyperparathyroidism were noted to have parathyroid glands in ectopic locations. More than one ectopic gland was identified in four patients. Overall, there were 19 (1517%) ectopically located glands out o f 121 total parathyroid glands identifiecl (Table I). Thirteen of the 19 ectopic glands were located in or adjacent to the thymus. Four glands were in the anterior mediastinum with an unknown relation to the thymus. One gland was found inside the thyroid capsule, and one was found in the posterior mediastinum. Supernumerary (fifth) glands were identified in three (8.6%) patients. Genetic analysis. Hyperparathyroidism occurred in some affected patients from 7 of the 14 MEN 2A kindreds studied. In the remaining 7 kindreds no patient had confirmed hyperparathyroidism. The phenotypic expression of hyperparathyroidism within a kindred was associated with specific mutations at c o d o n

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Table II. Number of patients with MEN 2A in the studied kindreds, associated mutation in the RET protooncogene, and phenotypic expression of hyperparathyroidism

Altered codon of RET 634 634 618 618 618 620 620 611 609 Total

Amino acid change

No. of kindreds

No. of patients

No. of patients with HUll (%)

Cys to Arg Cys to Tyr Cys to Ser Cys to Arg Cys to Gly Cys to Arg Cys to Phe Cys to Tyr Cys to Tyr

4 2 1 2 1 1 1 1 1 14

63 14 17 9 6 5 1 2 2 119

29 (46) 3 (21) 2 (12) 1 (11) 0000-035 (29)

HPT, Hyperparathyroidism.

634 (Cys to Arg, three kindreds; Cys to Tyr, two kindreds) and codon 618 (Cys to Arg, one kindred; Cys to Ser, one kindred) of the RETprotooncogene. No hyperparathyroidism was seen in families with mutations at codons 609, 611, and 620 (Table II). Comparison of all patients with MEN 2A and any mutation at codon 634 with all patients with a mutation at any other codon showed a statistically significant correlation between the expression of hyperparathyroidism and any mutation at codon 634 (p < 0.0001, Fisher's exact test). The prevalence of hyperparathyroidism in affected members of a kindred was highest (46%) in families with the codon 634 (Cys to Arg) mutation. No specific mutation showed a relationship to the more severe symptomatic form of hyperparathyroidism. Operative procedure. Thirty-one patients underwent a total or completion thyroidectomy for MTC concomitant with the operation for hyperparathyroidism. Surge@ was performed for hyperparathyroidism only in four patients. The number of parathyroid glands identified was conservatively estimated by including only those glands specifically detailed by the surgeon in the operative note or those glands confirmed by frozen section biopsy or final pathologic examination, or both. At the time of initial operation four parathyroid glands were described in 18 (51.4%) patients, three glands were described in 8 (22.9%) patients, and two or fewer glands were described in 9 (25.7%) of the patients. A selective resection (removal of two or fewer parathyroid glands including only those that are judged enlarged) was performed in 21 (62%) patients. Eight (24%) patients had a subtotal resection (3 or 3~ gland parathyroidectomy) and five (14%) patients had a total parathyroidectomy with autotransplantation. Parathyroid tissue was transplanted into the forearm muscle in four patients and into the stemocleidomastoid muscle

in one patient. One patient had an inadvertent total parathyroidectomy without autotransplantation. Follow-up. The mean follow-up period from the initial operation was 14.7 _+ 5.6 years (range, 5.0 to 28.9 years). Twenty-seven (77%) patients were cured after the first operation without persistent or recurrent hyperparathyroidism. Persistence or recurrence occurred in eight (23%) of the patients. Overall, eight (23%) patients had permanent postoperative hypocalcemia. Seven of these patients became hypoparathyroid after the initial operation. Surgical outcomes after initial operation are summarized in Table III. Persistent hyperparathyroidism. Hypercalcemia persisted after primary operation in three (8.6%) patients, all of whom had been treated with selective resection of one enlarged parathyroid gland at initial operation. Three glands were identified in one patient, and only one gland was identified in another patient. Four glands were identified by the surgeon in the third patient, but only two were histologically confirmed. The first two of these patients each underwent a second operation for persistent hyperparathyroidism, caused by an enlarged parathyroid gland missed during each patient's primary operation. In one of the two only a single additional parathyroid gland could be identified; this patient underwent heterotopic parathyroid transplantation after resection of the enlarged gland. In the second patient two hypercellular and two adenomatous parathyroid glands were resected after tile removal of one gland at initial operation, resulting in an inadvertent total parathyroidectomy. This patient was aparathyroid until she died of metastatic MTC. The third patient has been hypercalcemic for the last 7 years with a serum calcium concentration of approximately 12.0 mg/dl. He is asymptomafic and refuses reoperation. Recurrent hyperparathyroidism. Hyperparathyroidism recurred in 5 (14.3%) patients overall. The mean

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T a b l e I I L Surgical outcome after first operation for hyperparathyroidism

Initial operation Selective resection Subtotal resection Total PTX with AT Total PTX without AT Total

No. of patients

Persistence(%)

Recurrence(%)

3 (14.3) 0 (0) 0 (0) 0 (0) 3 (8.6)

3 (14.3) 2 (25) 0 (0) 0 (0) 5 (14.3)

21 8 5 1 35

Hypoparathyroid(%) 4 1 1 1 8*

(19) (12.5) (20) (100) (23)

PTX, Parathyr0idectomy; AT, autotransplantation, *One additional patient became hypoparathyroid after second operation for persistent hyperparathyroidism,

interval between initial operation and recurrence was 11.4 _+ 8.7 years (range, 4.4 to 27.6 years). All patients with recurrent hyperparathyroidism had either selective or subtotal resection as the primary procedure. All five patients with recurrent hyperparathyroidism underwent reoperation, and three patients were subsequently cured. The reasons for the development of recurrent hyperparathyroidism in this group of patients included missed glands, ectopic or supernumerary glands not identified at the first operation, and documented interval develo p m e n t of neoplasia in a previously biopsied gland left in situ. One patient had an enlarged parathyroid gland that was not identified at the initial operation. Another patient had an enlargement of a parathyroid gland that was biopsied and reported as normal at the time of initial operation. The third patient had a supernumerary gland located in the mediastiunm. Two patients were not cured by the reoperation. In one of these patients three glands were identified and resected at the initial operation. A fourth gland was resected at the second operation, but the patient remained hypercalcemic. This patient died of the effects of a stroke she suffered during a diagnostic arteriogram. A supernumerary gland was identified within the mediastinum at autopsy. In the other patient two glands were described and resected at the initial operation. Another parathyroid gland was resected during a first reoperation. No further parathyroid tissue could be found in a third operation that included extensive mediastinal exploration. This patient remains hypercalcemic with an elevated parathyroid h o r m o n e (PTH) level. Postoperative hypoparathyroidism. Overall, permanent postoperative hypocalcemia occurred in eight (23%) of the patients (Table III). Four patients underwent selective resection as the initial procedure. One patient had a subtotal parathyroidectomy of all three glands that had been visualized. Another patient had an inadvertent total parathyroidectomy, and one patient became hypoparathyroid after reoperation for persistent hypercalcemia and the removal of five glands in total. In one patient only two parathyroids were identified after an earlier total thyroidectomy; both were resected with cryopreservation of parathyroid tissue. After it was

apparent that the patient was rendered aparathyroid after operation, cryopreserved parathyroid tissue was transplanted at a subsequent procedure. This patient remained hypoparathyroid despite delayed parathyroid transplantation.

DISCUSSION The surgical m a n a g e m e n t of hyperparathyroidism in the setting of the familial endocrine neoplasia syndromes is complicated by a genetic predisposition to multiglandular disease, hyperparathyroidism caused by supernumerary and ectopically located parathyroid glands, and a higher incidence of persistent or recurrent hyperparathyroidism after any surgical procedure as compared with its incidence in patients undergoing operation for sporadic primary hyperparathyroidism. Because of the rarity and variable definition of hyperparathyroidism specifically in patients with MEN 2A syndrome, it has been difficult for a single group to study a large e n o u g h cohort of patients to draw firm conclusions regarding the optimal surgical management. Previous reports have included relatively few patents with MEN 2A and have analyzed the results in conjunction with patients with MEN 1 ~~ is, 14 or have been associated with a shorter follow-up period 1~ (Table IV). We have analyzed retrospectively the longterm outcome of different operative procedures in 35 MEN 2A patients with biochemically and histopathologically proven hyperparathyroidism treated at 17 different institutions during a 25-year period. Forty-two percent of the patients for w h o m data regarding preoperative signs and symptoms were available exhibited sequelae of hypercalcemia. Our results suggest that patients with MEN 2A and rigorously defined hyperparathyroidism are more frequently symptomatic than previously reported. 11,12 Although the incidence of renal calculi in our patients (11%; 3 of 26) is somewhat lower than in previous studies, TM 12 we report a patient with MEN 2A and hyperparathyroidism who presented with a hypercalcemic crisis. Previous authors have suggested that patients with layperparathyroidism and MEN 2A tend to have mild hypercalcemia and are less often symptomatic. TM 12, 16 In our series of 35 patients the female to male ratio

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T a b l e IV. Results of o p e r a t i o n for hyperparathyroidism in patients with MEN 2A

Author

No. of MEN 2A Year patients

van Heerden et al.

1983

Kraimps et al. O'Riordian et al.

1992 1993

Raue et al.

1995

Herfarth et al. (present study)

1996

Type of resection

Persistent or reatrrent hyperparathyroidism(%)

Permanent hypo Cure-calcemia initial/ (%) follow-up

Follow-up (yr)

9 4 18 67 49 11 35

Subtotal/selective* Selective Overall Overall Selective/subtotal Total PTX/AT Overall

13" 0 0 15 16 18 23

13" 25 22 13 16 9 23

93/87* 100/100 100/100 97/85 96/84 100/82 91/77

3.6 8.0 5.8 8.0

(mean)* (median)t (median) (median)

14.7 (mean)

29 5

Selective/subtotal Total PTX/AT

28 0

17 20

72 100/100

14.4 (mean) 16.3 (mean)

PTX, Parathyroidectomy; A~/, autotransplantation. *Thirty-six MEN 1 mad 9 MEN 2A combined. tFollow-up combined with 38 MEN 1 patients.

o f MEN 2A patients with hyperparathyroidism was 1.92:1. A l t h o u g h this difference in g e n d e r distribution was n o t statistically significant, several previous reports have also described a p r e p o n d e r a n c e o f female MEN 2A patients with hyperparathyroidism. These include a female to male ratio of 2.6:1 in a series of 18 patients n a n d a female to male ratio of 1.58;1 in a series of 67 patients, a2 Just as sporadic primary hyperparathyroidism is most c o m m o n in postmenopausal females, this observation suggests the possibility that o t h e r genetic o r h o r m o n a l factors present in the female milieu contribute to the expression o f hyperparathyroidism in addition to the inheritance o f a m u t a n t RET allele. Previous authors have stressed the i m p o r t a n c e of distinguishing between parathyroid a d e n o m a and hyperplasia in patients with familial forms of hyperparathyroidism, a n d have suggested different surgical strategies for the t r e a t m e n t of each condition. 1~ 13 It is possible that these m o r p h o l o g i c descriptions reflect extremes o f a spectrum o f asymmetric versus multiple gland enlargement. In patients with MEN 2A it appears likely that an inherited germline mutation confers a predisposition to multiglandular disease, whether the parathyroid neoplasms arise synchronously o r metachronously. It is difficult to rationalize a subtotal or selective therapeutic a p p r o a c h if one accepts that a basic multiglandular pathophysiology exists in patients with familial forms ofhyperparathyroidism. O n e patient in our series h a d d o c u m e n t e d recurrence o f hyperparathyroidism caused by the interval d e v e l o p m e n t of a parathyroid neoplasm in a gland that h a d b e e n identified, biopsied, a n d believed to be morphologically and histopathologically n o r m a l at the initial operation 4.4 years earlier. Sixty-nine p e r c e n t o f our MEN 2A patients with hyperparathyroidism h a d multiglandular disease identified at the time of the initial operation. If the findings

at the time of r e o p e r a t i o n for persistent or r e c u r r e n t disease are included, the percentage of patients with eventual multiple gland involvement rises to 77%. Previous reports have also n o t e d a high frequency o f multiglandular disease, u,17 although Raue et al. 12 described single a d e n o m a s in 54% o f their patients. T h r e e (8.6%) patients in this series h a d supernumerary glands; in two patients a s u p e r n u m e r a r y gland was responsible for the d e v e l o p m e n t o f r e c u r r e n t hyperparathyroidism. T h e incidence of s u p e r n u m e r a r y glands in n o r m a l individuals varies between 3% a n d 14%. 182~ However, hyperparathyroidism caused by a hyperfunctioning supernumerary g l a n d is rare and has b e e n estim a t e d to account for only 0.7% o f all patients with hyperparathyroidism. 21 The h i g h e r rate of involvement o f a fifth gland in the d e v e l o p m e n t o f hyperparathyroidism in patients with MEN 2A also reflects the mulfiglandular nature of the parathyroid disease in this disorder. Mulligan et al. 22 e x a m i n e d the relationship between specific RET mutations a n d p h e n o t y p e in families with MEN 2A and suggested an association between any mutation at c o d o n 634 a n d the d e v e l o p m e n t o f parathyroid disease. Furthermore, a m o n g families with a mutation at c o d o n 634, these investigators f o u n d a strong correlation between the d e v e l o p m e n t o f hyperparathyroidism a n d the specific mutation TGC to CGC (Cys634Arg). T h e relationship of hyperparathyroidism to this specific mutation could n o t be c o n f i r m e d by Schuffenecker et al. 23 However, both groups f o u n d a correlation between the presence o f any m u t a t i o n at c o d o n 634 a n d the dev e l o p m e n t o f hyperparathyroidism in patients with MEN 2A. O u r results support these previous observations in part. Thirty-two (91%) o f o u r patients with confirmed hyperparathyroidism have mutations at c o d o n 634, whereas three patients (9%) have mutations at c o d o n 618. Comparison o f all patients with MEN 2A and

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any mutation at codon 634 with all patients with mutations at any other codon showed a statistically significant correlation between the expression of hyperparathyroidism and any mutation at codon 634 (p < 0.0001, Fisher's exact test). Furthermore, the percentage of patients expressing parathyroid disease was greatest in families with a codon 634 Cys to Arg mutation (Table II). However, we do not currently advocate modifying the surgical strategy for management of parathyroids in patients with MEN 2A on the basis of genotype analysis. O u r data confirm that the surgical treatment of hyperparathyroidism in patients with MEN 2A is associated with a lower cure rate and increased incidence of persistent and recurrent hyperparathyroidism compared with the treatment of patients with sporadic primary hyperparathyroidism. Although this series ind u d e s patients treated at 17 different hospitals and not only in specialized centers, only 27 (77%) patients were cured by the first operation. Persistent hyperparathyroidism occurred in three (8.6%) patients, and recurrent hyperparathyroidism occurred in five (14.3%) patients; both occurred only in patients treated with less than a four-gland resection (either selective or subtotal parathyroidectomy with parathyroid tissue left in the neck). These results are in contrast to previous reports that suggest that hyperparathyroidism in MEN 2A is readily curable regardless of the operative procedure, and that a selective or minimal surgical strategy is generally warranted. 1~ In our series recurrent hyperparathyroidism occurred after a mean of 11.4 years (median, 7.2 years) after the initial operative procedure; in one patient hyperparathyroidism recurred after 28.9 years. These results confirm the findings of Raue et al., 12 who reported a recurrence rate of 12% a median 8 years after the initial operation. Therefore recurrence of hyperparathyroidism in MEN 2A may occur some time after the initial operation, and a long follow-up time is essential to evaluate the outcome of different surgical procedures. Our mean follow-up time was 14.7 years (median, 15.6 years). It is possible that previous studies with shorter median follow-ups of 5.8 years aI or 8 years 1~ may have underestimated the incidence of recurrent hyperparathyroidism. O'Riordain et al. n do not r e c o m m e n d routine transcervical thymectomy in MEN 2A patients with hyperparathyroidism. In our series, ectopic inferior parathyroid glands were identified in or adjacent to the thymus in nine (25%) patients. Four glands were not identified in the initial operation of all three patients with persistent hyperparathyroidism after operation. It should be noted that for purposes of this retrospective study, we considered a parathyroid gland identified only if the surgeon detailed it explicitly in the operative note, or if the gland was histologically proven. Potentials for error in this analysis include failure of the surgeon to docu-

Surgery December 1996 m e n t a gland that was identified or the incorrect identification of glands not proven by biopsy. We are in agreement with previous authors that identification of all four parathyroid glands and a search for ectopic or supernumerary glands together constitute a cornerstone in the surgical management of familial forms of hyperparathyroidism.l~ The principal arguments against total parathyroidectomy and heterotopic autotransplantation include the contention that cure rates for patients with MEN 2A and hyperparathyroidism are excellent with lesser procedures and that there is an unacceptable rate of perman e n t postoperative hypoparathyroidism associated with this procedure. ]~ However, the occurrence of postoperative hypoparathyroidism in patients with hyperparathyroidism and MEN 2A treated with selective or subtotal resections was 25% 1~, 22% 11, 16% 12, and 23% (MEN 1 and MEN 2A combined) 13 in previous reports. Only five patients underwent total parathyroidectomies with autotransplantation in our series. One patient (20%) had permanent postoperative hypoparathyroidism. This patient was operated on very early in our experience, in 1977, and underwent transplantation with cryopreserved tissue 3 days after parathyroidectomy. The graft failure in this patient is likely related to a technical error in freezing of the cryopreserved tissue. In a recent prospective experience with total parathyroidectomy and transplantation in 13 patients undergoing early thyroidectomy for MTC on the basis of the results of direct genetic testing, all 13 patients (100%) now have discontinued calcium and vitamin D supplementation and have serum calcium concentrations in the normal range with a parathormone gradient between the grafted and nongrafted arms. 15 The clear establishment of the optimal operative approach to the m a n a g e m e n t of patients with familial forms of hyperparathyroidism awaits a prospective randomized surgical trial. On the basis of our experience we advocate total parathyroidectomy with heterotopic autotransplantation in patients with MEN 2A. It is important to note that kindred members who are identiffed as affected are currently undergoing early thyroidectomy for MTC on the basis of the results of mutational analysis in the first or second decade of life. 15 The performance of radical total thyroidectomy, central lymph node dissection, and cervical thymectomy with the intent to cure in these patients carries a significant risk of devascularization of parathyroid tissue left in situ. In addition, MEN 2A patients are not likely to be hypercalcemic or manifest parathyroid enlargement at this age, and a selective approach would be impractical and would also leave the patient with a lifetime of risk for subsequent enlargement of parathyroid tissue requiring reoperative neck surgery with its attendant increased morbidity.

Surgery Volume 120, Number 6

CONCLUSIONS H y p e r p a r a t h y r o i d i s m in p a t i e n t s w i t h M E N 2A is ass o c i a t e d w i t h m u t a t i o n i n c o d o n s 634 a n d 618 o f t h e R E T p r o t o o n c o g e n e . T h e disease is m o r e f r e q u e n t l y a n d m o r e severely s y m p t o m a t i c t h a n p r e v i o u s l y rep o r t e d . I n m o s t p a t i e n t s w i t h M E N 2A a n d h y p e r p a r a t h y r o i d i s m t h e r e is e v i d e n c e o f m u l t i g l a n d u l a r disease. Recurrent or persistent hyperparathyroidism occurs in s o m e p a t i e n t s a f t e r selective o r s u b t o t a l p a r a t h y r o i d e c tomy, as a r e s u l t o f m i s s e d g l a n d s , s u p e r n u m e r a r y g l a n d s , o r interval d e v e l o p m e n t o f n e o p l a s i a in previously n o r m a l p a r a t h y r o i d g l a n d s left i n situ. P o s t o p e r a tive h y p o p a r a t h y r o i d i s m is also c o m m o n . W e t h e r e f o r e a d v o c a t e total p a r a t h y r o i d e c t o m y a n d h e t e r o t o p i c aut o t r a n s p l a n t a t i o n for p a t i e n t s w i t h h y p e r p a r a t h y r o i d i s m a n d M E N 2A. We t h a n k Mary K. DeBenedetti, RN, and Margaret M. Frisella, RN, for their support in organizing and collecting the data.

REFERENCES 1. Steiner AL, Goodman AD, Powers SR. Study of a kindred with pheoehromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing's disease: multiple endocrine neoplasia type 2. Medicine 1968;47:371-409. 2. Mulligan LM, KwokJBJ, Healey CS, et aI. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia ~pe 2A. Nature 1993;363:458-60. 3. Donis-Keller H, Dou S, Chi D, et at. Mutations in the RET protooncogene are associated with MEN 2A and FMTC. Hum Mol Genet 1993;2:851-6. 4. Takahashi M, Ri~J, Cooper GM. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 1985; 42:581-8. 5. Takahashi M, Cooper GM. Ret transforming gene encodes a fusion protein homologous to tyrosine kinases. Mol Cell Biol 1987;7:1378-85. 6. Mulligan LM, Ponder BAJ. Genetic basis of endocrine disease: muhiple endocrine neoplasia type 2. J Clin Endocrinol Metab 1995;80:1989-95. 7. Howe JR, Norton JA, Wells SAJr. Prevalence of pheoehromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2A: results of long-term follow-up. Surgery 1993;114:1070-7. 8. Minx sJ, Menczel J, Campbell S, Anerbach GD, Spiegel AM, Norton JA. Heterogeneous size of the parathyroid glands in familial multiple endocrine neoplasia type 1. Clin Endocrinol (Oxt) 1991;35:521-6. 9. Hellrnan P, Skogseid B,Juhlin C, Akerstrtm G, RastadJ. Findings and long term results of parathyroid surgery in multiple endocrine neoplasia type 1. WorldJ Surg 1992;16:718-23. 10. Kraimps JL, Duh Q-'L Demeure M, Clark OH. Hyperparathyroidism in multiple endocrine neoplasia syndrome. Surgery 1992;112:1080-8. 11. O'Riordain DS, O'Brien T, Grant CS, Weaver A, Gharib H, van HeerdenJA. Surgical management of primal7 hyperparathyroidism in multiple endocrine neoplasia types 1 and 2. Surgery 1993;114:1031-9. 12. Raue F, KraimpsJL, Dralle H, et at. Primary hyperparathyroidism in multiple endocrine neoplasia type 2A. J Intern Med 1995; 238:369-73. 13. van HeerdenJA, Kent RB, Sizemore GW, Grant CS, ReMine WH.

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Primary hyperparathyroidism in patients with multiple endocrine neoplasia syndromes. Arch Surg 1983;118:533-6. 14. Wells SAJr, Farndon JR, Dale JK, Leight GS, Dilley WG. Long term evaluation of patients with primary parathyroid hyperplasia managed by total parathyroidectomy and heterotopic autotransplantation. Ann Surg 1980;192:451-8. 15. Wells SAJr, Chi D, Toshima K, et at. Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A. Ann Surg 1994;220:237-50. 16. Block MA, Jackson CE, Greenawald KA, Yott JB, Tashijan AH. Clinical characteristics distinguishing hereditary from sporadic medullary thyroid carcinoma. Arch Surg 1980;115:142-8. 17. Cance WG, Wells SAJ. Multiple endocrine neoplasia type 2A. Curr Probl Surg 1985;22:1-56. 18. BoydJD. Development of the thyroid and parathyroid glands and the thymus. Ann R Coll Surg Engt 1950;7:455-71. 19. Gilmour JR. The gross anatomy of the parathyroid glands. J Pathol Bacteriol 1938;46:133-49. 20. Wang CA. The anatomic basis of parathyroid surgery. Ann Surg 1976;183:271-5. 21. Russell CF, Grant CS, van HeerdenJA. Hyperthnctioning supernumerary parathyroid glands: an occasional cause of hyperparathyroidism. Mayo Clin Proc 1982;57:121-4. 22. Mulligan LM, Eng C, Healey CS, et al. Specific mutations of the RETproto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nature Genetics 1994;6:70-4. 23. Schuffenecker I, Billaud M, Calendar A, et at. RET proto-oncogene mutations in French MEN 2A and FMTC families. Hum Mol Genet 1994;3:1939-43.

DISCUSSION Dr. Jean Louis Krahnps (Poitiers, France). We h a d a similar experience in a French multicentric study including 56 cases with the same results but a different analysis. We had a high rate of hypoparathyroidism (22%). Reasons were a too aggressive approach by total or subtotal parathyroidectomy and probably synchronous total thyroidectomy and lymph node clearance in the central neck compartment. We had 11% persistent disease (six cases), hut in one case after total parathyroidectomy with autotransplantation because of a fifth missed gland. So the most important part of surgical exploration in MEN 2A-related hyperparathyroidism is to identify all the parathyroid glands to avoid missed enlarged glands and to preserve normal glands during thyroidectomy a n d bilateral lymph node clearance. In your study was the parathyroid operation synchronous with thyroidectomy for MTC and bilateral lymph node clearance? Dr. Herfarth. Thirty-one of the 35 patients h a d a total or rest thyroidectomy concomitant with the operation for hyperparathyroidism, and I agree that all glands should be identified during the operation. In this study the operations were performed at 17 different hospitals and four glands were identified in only half the patients. A higher percentage of four-gland identification could be achieved in previous studies from other authors. However, the incidence of postoperative hypoparathyroidism also ranged between 13% and 25% after selective or subtotal parathyroid resection. I think total parathyroidectomy with heterotopic autotransplantation is a good m e t h o d to treat these patients. Dr. Ashok R. Shaha (New York, NY). Can you summarize your current results of antotransplantation of the parathyroid?

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In other words, how long do you n e e d to put them o n calcium? If you clyopreserve, at what time do you retrieve it and use it again and in what percentage of the patients do you need to use it again? Dr. Herfarth. To date, we operate on MEN 2A family members on the basis of mutation analysis. Individuals with a disease causing PET mutation receive a total thyroidectomy with central lymph node resection a n d a total parathyroidectomy with heterotopic autotransplantation. So far we have operated o n 51 MEN 2A kindred members. Forty of them have a positive PTH gradient, and calcium or vitamin D supplementation h a d been stopped. Eight patients have a pending PTH gradie n t with a postoperative period of less than 8 weeks. Two of them have discontinued their supplementation because of lack of compliance. However, neither shows hypocalcemic symptoms. One patient died; cause of death was not related to the disease. Only two patients are past 8 weeks after operation u n d e r calcium or vitamin D supplementation. Both have a positive PTH gradient, and we will discontinue the substitution in one of them in the next few days. In summary, only 2% to 4% of the patients remain u n d e r calcium or vitamin D substitution. Dr. Gary B. Talpos (Detroit, MI). We have not performed total or subtotal parathyroidectomy in MEN 2 patients at Henry Ford Hospital since 1974, when Dr. Melvin Block showed that removing only the abnormal glands was sufficient. Removing multiple normal glands invariably resulted in longterm calcium and vitamin D dependence. What surprises me, however, is your 35 % incidence of parathyroid disease in MEN 2 patients. We d o n ' t see that. We rarely see hypercalcemia in these patients after a curative thyroidectomy on the basis of normal calcitonin determinations after operation. Do you have any data regarding the calcitonin levels in your patients? Dr. Herfarth. Most of the patients in this study were historic

Surgery December 1996 patients. They were operated on between 1963 and 1989. Therefore we do not have calcitonin measurements of most of the patients. However, all these patients are MEN 2A family members a n d had a histopathologically proven MTC. O u r definition of hyperparathyroidisnl was also very strict: only patients with a preoperative serum calcium level equal to or greater than 10.5 m g / d l and histopathologically proven parathyroid disease were included in the study. Therefore all of these patients are patients with MEN 2A who had hyperparathyroidism. I was surprised to find so many symptomatic hyperparathyroidism patients with MEN 2A. Dr. N o r m a n W. T h o m p s o n (Ann Arbor, MI), It is interesting that Dr. Talpos just discussed this, because historically his predecessor at Henry Ford Hospital, Mel Block, was the first to point out that MEN 2 disease did not behave like MEN 1 parathyroid disease. He wrote a paper in 1974 pointing out that a standard subtotal parathyroidectomy led to an extremely high incidence of p e r m a n e n t hypoparathyroidism in MEN 2 patients. He r e c o m m e n d e d then that you only remove enlarged glands in this particular mnltigland disease. We had reached the same conclusions about that time and have followed that policy ever since because we h a d the same experience. Leaving even 50 mg of viable parathyroid tissue led to p e r m a n e n t hypoparathyroidism, suggesting that the stimulus for continued or recurrent disease was far less than in MEN I. We just reviewed 34 patients with MEN 2 parathyroid disease who have b e e n operated on since 1974 a n d n o n e had a recurrence a n d n o n e were made hypoparathyroid. No patient had more than two enlarged glands removed. This is in contrast to that which was just presented. I suggest a little caution because of the possibility that not everybody will have as good results with total parathyroidectomy and transplantation as you have.

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