the problems encountered in the surgical management of primary hyperparathyroidism

The Problems Encountered in the Surgical Management of Primary Hyperparathyroidism

Sh inya KOBAYASHI l, Akira SUGENOVA 1, Yoshio KASUGA 1, Hiroyuki MASUDA l, Minoru FUjIMORI 1, Makoto KOMATSU 1, S h o u z o u TAKAHASHI x,

Tadahiro SHIMIZU 1, Shirou YOKOYAMA 1, Futoshi IIOA 1 and Mako to MIYAKAWA 2

ABSTRACT: The problems encountered in the diagnosis and treatment of primary hyperparathyroidism were studied in 69 cases. The accuracy of imaging for hyperplasia was less than that for adenoma or carcinoma and the major causes for multiple operations were a failure to locate the four glands and mediastinal adenoma. The intravenous administration of high doses of calcitonin could reduce the serum calcium level of patients in hypercalcemic crisis. Carcinoma required ipsilateral modified radical neck dissection because of lymph node metastases, and non-medullary thyroid carcinoma was often associated with primary hyperparathyroidism. We found removal of the parathyroid adenoma and biopsy or extirpation of only one macroscopically normal gland to be a fully satisfactory procedure after bilateral neck exploration and attempting to identify at least four glands.

KEY WORDS: thyroid carcinoma, parathyroid carcinoma, hypercalcemia, primary hyperparathyroidism, radionuclear imaging

INTRODUCTION

Since the multichannel autoanalyzer was introduced in the medical laboratory, the number of patients diagnosed with primary hyperparathyroidism has markedly in- creased. However, some problems in the diagnosis and treatment of primary hyperparathyroidism remain.

The purpose of this report is to review our experience in managing primary hyperparathyroidism giving particular attention to pre-

1The Second Department of Surgery, Shinshu Uni- versity School of Medicine, Matsumoto, Japan

2Iida City Hospital, lida, Japan Reprint requests to: Shinya Kobayashi, MD, The

Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390, Japan

operative localization, multiple operation, the crisis caused by hypercalcemia, parathyroid carcinoma, associated thyroid diseases and postoperative parathyroid function.

MATERIALS

The medical records of 69 patients with primary hyperparathyroidism who were operated on and followed up for more than 3 years in the Department of Surgery, Shinshu University School of Medicine after 1964, were reviewed. The patients consisted of 57 females and 12 males with a female to male ratio of 4.7:1, The ages of the patients ranged from 16 to 78 years with an average of 50 years.

The pathologic reports of these patients

JAPANESE JOURNAL OF SURGERY, VOL. 21, NO. 6 pp. 655-660, 1991

656 Kobayashi et al. Jpn. J. Surg. November 1991

revealed 49 patients (72 per cent) with adenoma, being single in 46 and double in 3, 15 (22 per cent) with hyperplasia, being non- MEN in 6, MEN-I in 7 and MEN-IIA in 2, 4 (6 per cent) with carcinoma and 1 with an unknown cause. The diagnosis of parathyroid carcinoma was made according to at least one of the following criteria of Schantz and Castlemanl: 1) local invasion of the contiguous structures; 2) nodal or distant metastases; and 3) capsular or vascular invasion, fibrous trabeculae, or mitosis. The surgical technique routinely used for adenoma after 1983 was tO remove the largest gland and biopsy the second largest one after looking' for four glands, whereas until 1982, only diseased parathyroid glands were removed without detecting any other glands. For hyperplasia, al! glands were removed and approximately 50 mg of gland then grafted in the forearm muscle pocket according to Wells' procedure. ~ For parathyroid carcinoma, a unilateral thyroid lobectomy with modified neck dissection was carried out. Preoperative imagings by ultrasonography (US). computed tomography (CT), 2~ ride and 99mTc-pertechnetate (TI-Tc) sub- straction scintigraphy were introduced in 1982 and carried out in 47 of the patients in this study. Details of the procedures of parathyroid imaging have been described else- where? Carboxyl-terminal parathyroid hor- mone (PTH) levels were measured by radio- immunoassay (EIKEN).

Statistical analyses were performed with the one-tailed Student's t test for unpaired observations.

RESULTS

Preoperative localization The diagnostic accuracy of the three

imaging procedures for diseased parathyroid glands are summarized in Table 1. In the parathyroid neoplasms, namely, adenoma and carcinoma, there were no significant differences among the three Procedures either in sensitivity or specificity. In hyper-

Table 1. Diagnostic Accuracy of Imagings for Parathyroid Disease

n=47

Parathyroid Disease Accuracy' & Image Procedures Sensitivity Specificity

Neoplasm T1-Tc 89 100% CT 85 97 US 83 96

Hyperplasia TI-Tc 35 66 CT 49 100 US 40 88

plasia, the sensitivities ranged from 35 to 49 per cent, and specificities from 66 to 100 per cent. Both sensitivity and specificity were highest with CT and lowest with T1-Tc subtraction scintigraphy. The results of the imaging procedures suggest that neoplasms are more easily detected than hyperplasia.

Multiple operations Of the 69 patients, 5 underwent multiple

operations because of uncontrolled hypercalcemia after their initial operation (Table 2). Two patients (#1, 2) were found at the second operation to have an adenoma aris- ing from an ectopic parathyroid gland in the thymus. The next two patients (#3, 4) were initially opera ted on for a para thyro id adenoma, but hypercalcemia persisted following the operation. Two and three hyperplastic glands, respectively, were removed in the second operation and the patients were fna l ly diagnosed as having hyperplasia. The last patient (#5) was unsuccessfully operated on in this department in the initial period. As continuous hypercalcemia persisted after the operation. Total thyroidectomy and bilateral neck dissection were carried out in the second operation and total thymectomy in the third. As hypercalcaemia persisted,~.the patient underwent irradiation of the neck and mediastinum which prodiaced a. de- crease in serum calcium.

Hypercalcemic crisis A crisis was observed in 4 patients who had

Volume 21 Number 6 Problems in parathyroid surgery 657

Table 2. Multiple Operations for Primary Hyperparathyroidism

Age and Sex Patient (Yr) Treatment Final Diagnosis

#1 54 F Two operations: (1) removal of adenoma in the cervical Multiple adenomas region

(2) sternal split and removal of adenoma in the thymus

#2 43 M Two operations: (1) removal of four parathyroid glands Adenoma in thymus (2) total thyroidectomy, sternal split

and total thymectomy

#3 53 F Two operations: (1) removal of adenoma Hyperplasia (2) removal of three hyperplastic glands

#4 53 M Two operations: (1) removal of an adenoma and a Hyperplasia normal gland. MEN type-1

(2) removal of two hyperplastic glands.

#5 25 F (1) removal of cervical lymph nodes (2) total thyroidectomy, sternal split

and total thymectomy (3) irradiation

Two operations: Pathology : unknown

Table 3. Serum Ca and PTH Levels in Crisis and Non-Crisis Patients mean_SD

No. of Patients Serum Ca (mg/dl) PTH (ng/ml) §

Crisis 6 15.8-/-1.0 3.9__+1.9 Non-crisis 63 11.9_+1.2 * 1.9=1-2.5 NS

[fffednisolone 60rag/day

(mg/dl) 20

~J 16

12

E - C T ~

I

Fig. 1. A case of hypercalcemic crisis caused by primary hyperparathyroidism was treated with high dose calcitonin. The serum calcium level was reduced by the continuous intravenous administration of calcitonin.

severe hypercalcemia with rapidly progress- ing mental deterioration. Serum calcium and PTH values are summarized in Table 3.

* p<0.01

I Serum calcium levels in the crisis patients were higher than those in the non-crisis patients but PTH levels were not. One of the 4 patients was treated with a large dose of Ele-calcitonin 120-200 uni t /day for 4 con- secutive days (Fig. 1). High dose administration of Ele-calcitonin a long with fluid and diuretics reduced the serum level o f calcium from 20 mg /d l to 13.2 m g / d l and a parathyroidectomy was per formed without any complications.

Carcinoma

Four patients with parathyroid carcinoma were included in this series. T h e serum calcium levels in these were significantly higher than in the non-cancer patients but the PTH levels were not (Table 4). Two patients who had distant metastases died from uncontrolled hypercalcemia but the remaining 2 have been well since surgery

658

Table 4.

Kobayashi et al. Jpn. J. Surg. November 1991

Serum Ca and PTH Levels in Patients with Parathyroid Carcinoma mean+SD

No. of Patients Serum Ca (mg/dl) PTH (ng/ml)

Crisis: 5 14.7+1.2 3.2-1-1.6 Non-cancer 52 12;1_+1,5 * 2.0-t-2.5 NS

* p<0.05

Table 5. Postoperative Parathyroid Function Following Operative Procedures for Hyperplasia

n--62

Normal Hypo- Hyper- Total parathyroidism parathyroisism

Adenoma 40 5 1 46 Hyperplasia 7 3 4 14 Carcinoma 2 0 0 2

Total 49 (79%) 8 (13%) 5 (8%) 62

Table 6. Postoperative Parathyroid Function n---15

Parathyroid Function Operation Procedure Normal Hyper- Hypo-

Total VFX with graft 4 0 2 Subtotal VFX 1 0 1 Ex of 1 or 2 glands 0 5 0 Total FIX without graft 0 0 2

(MEN IIA)

Total 5 5 5

PTX: parathyroidectomy, Ex: extirpation

wi thout r e c u r r e n c e for 11 a n d 6 years, respectively.

Associated thyroid diseases The thyroid diseases associated with pri-

mary hyperparathroidism were examined. Nineteen patients had simple goiter, as a follicular adenoma in 11 and an adeno- matous goiter in 8. Three patients had thyroid cancer and another 2 had chronic thyroiditis. In total, 25 of 69 (36 per cent) had associated thyroid diseases.

Postoperative parathyroid function O f the 69 parathyroid patients operated

on, 7 died and 62 were followed u p over a period ranging f rom three to 21 years. Post- operative parathyroid function is shown in Table 5. O f these 62 patients, 49 (79 per cent)

had normal para thyroid function, 8 (13 per cent) had hypoparathyroidism and 5 (8 per cent) had hyperparathyroidism. The postoperative parathyroid function and operative procedures in 15 hyperplastic patients are summarized in Table 6. Total parathyroidectomy and autografting was carried out in 4 of 5 patients whose functional states have been good. Subtotal parathyroidectomy was car- fled out in 2 patients, one of whom became normofunct ional whereas the other devel- oped a hypofunct ional state. Extirpation of one or two glands was carried out in 5 patients before 1983, 4 o f whom remained in a hyperparathyroidal state and had second operations. Three of these 4 patients were MEN-I.

Volume 21 Number 6 Problems in parathyroid surgery 659

DIscussioN

According to Thompson, 4 the routine use of radionuclear imaging before pr imary neck exploration is unlikely to improve results, however, we cannot doubt the usefulness of any preoperat ive exploration for primary hyperparathyroidism, s,6 Concerning the accuracy of any imaging procedure, hyperplasia and a d e n o m a are entirely different? In this study, the accuracies of T1-Tc subtraction scintigraphy, CT and US were lower in the patients with hyperplasia than in those with adenoma, s-5 Is it possible to know in advance whether a case of pr imary hyperparathyroidism is caused by hyperplasia or a d e n o m a ? P T H levels are s igni f icant ly higher in those with a parathyroid adenom a than in those with hyperplasia (p(0,005)? In a patient with a s e r u m PTH tha t is barely above the upper range of normal , hyperplasia is more likely than a d e n o m a or carcinoma, However, when hyperplasia is sus- pected, staining during t h e operat ion by methylene blue is r e c o m m e n d e d to find at least four glands. ~

For current and persistent hypercalcemia cases, a r t e r i og raphy or selective venous sampling for the preoperat ive localization of missing parathyroid tumors is recom- mended, s There are, however, no advocates of these invasive exanfinations before a primary exploration. Moreover, the use of 2~ subtract ion 9 and magne t ic resonance TM to preoperatively evaluate patients with pr imary hyperparathyroidism has been reported and magneti c resonance found to be only 85 per cent sensitive and very expensive. 4

There are two main causes for multiple operations being per formed for recurrent or persistent hypercalcemia. One of the causes of recurrent or persistent hypercalcemia in this study was failure to find the four glands at the initial operation. T h o m p s o n 4 sug- gested that all patients should have bilateral neck explorations and an attempt be made to

identify at least four glands because of the possibility o f double adenomas a n d / o r asymptomat ica l pa ra thyro id hyperplasia . Another cause for multiple operations was mediastinal parathyroid adenoma, in which a mediasternotomy was required to excise the mediastinal adenoma, al Three of our cases needed to have the s ternum split to remove the aden0ma in the thymus. The ~~ scan is useful for detecting mediastinal parathyroid adenomas.

In parathyroid carcinoma, en bloc resec- tion is r ecommended by Chon, 12 to include an ipsilateral thyroid lobectomy and dissection of the t racheoesophageal groove without radical neck dissection. Since we ex- per ienced a case of metastasis of the cervical lymph nodes, we routinely perform a lobectomy with ipsilateral radical neck dissection for a diseased parathyroid.

Palmer 13 said that patients with multiple endocrine neoplasia or familial hyperparathyroidism should have a subtotal parathyroidectomy to avoid reoperat ion. Clark et al '4 said that in patients with multiple endocrine neoplasia or familial hyperparathyroidism, subtotal parathyroidectomy should be performed if more than one gland is involved, while o the r patients could be treated by selective removal o f an adenoma. The most important thing is to find the four glands ra ther than deciding whether it is multiple endocrine neoplasia or not.

Saaka 1~ said that:~twelve (4 per cent) out of 316 patients had a hypercalcemic crisis. The effectiveness of calcitonin for a hypercalcemic crisis caused by pr imary hyperparathyroidism has not been documented. In our case, high-dose calcitonin reduced the serum calcium level which was not decreased by only the intravenous fluid administration of over 10 1/day.

Lever TM repor ted that there was no differ- ence in the prevalence of au to immune or thyroid nodular disease between two groups except for seven cases of macroscopic non- medullary thyroid carc inoma in a primary hyperparathyroid group a n d an autopsy con-

660 Kobayashi et al. Jpn. J. Surz. November 1991

t rol group. We e x p e r i e n c e d 3 cases o f thyro id c a r c i n o m a ou t o f a to ta l 69 cases o f p r i m a r y h y p e r p a r a t h y r o i d i s m . T h e p r e v a l e n c e o f n o n - m e d u l l a r y d i f fe ren t i a t ed thyro id carci- n o m a in o u r g r o u p with p r i m a r y h y p e r p a r a - thy ro id i sm c o m p r i s i n g 3 cases o r 4 p e r cent, was s ignif icant ly h i g h e r t h a n tha t o f the autopsy g roup (1.5 p e r cent) (p<0.01). T h e r e s e e m e d to be some r e l a t i onsh ip be tween the occu r rence o f n o n - m e d u l l a r y thyro id carci- n o m a a n d tha t o f p r i m a r y h y p e r p a r a t h y - ro idism. However , a p rospec t ive investiga- t ion by Edis et al s seems to favor the m o r e conservat ive a p p r o a c h a n d s imi la r conclu- s ions have b e e n r e a c h e d f r o m some re t ro- spect ive s tudies d e m o n s t r a t i n g that the fre- quency o f pos tope ra t ive h y p o c a l c e m i a is re- la ted to surgical radicali ty. W h e n we per- f o r m e d r a d i c a l o p e r a t i o n s in t h e i n i t i a l p e r i o d , t h e p r e v a l e n c e o f p o s t o p e r a t i v e h y p o p a r a t h y r o i d i s m was h igher .

I n conc lus ion , e x p l o r i n g the b i la te ra l neck a n d a t t e m p t i n g to i d e n t i f y at l e a s t f o u r glands, r emova l o f the p a r a t h y r o i d a d e n o m a a n d b iopsy o r ex t i rpa t ion o f on ly o n e macro - scopical ly n o r m a l g l and is a fully sat isfactory p r o c e d u r e fo r most pa t i en t s with p r ima ry hype rpa ra thy ro id i sm.

(Received for pub l i ca t ion o n J u l . 24, 1990)

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the problems encountered in the surgical management of primary hyperparathyroidism

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