Parathyroid tumors

PARATHYROID TUMORS

PER-OLA GRANBERG, M.D. BJORN CEDERMARK, M.D. LARS-OVE FARNEBO, M.D. BERTIL HAMBERGER, M.D.

SIGBRITT WERNER, M.D.

0147-0272/85/11-001-052-$9.95 �9 1985, Year Book Medical Publishers, Inc.

C O N T E N T S

H I S T O R Y . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

R E G U L A T I O N OF C A L C I U M H O M E O S T A S I S . . . . . . . . . . . . . 6

D I F F E R E N T I A L D I A G N O S I S OF H Y P E R C A L C E M I A . . . . . . . . . . . 7

N A T U R A L H I S T O R Y OF 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 . . . . . . 1 3

P R E V A L E N C E , I N C I D E N C E , AND E T I O L O G Y . . . . . . . . . . . . . 14

C L I N I C A L M A N I F E S T A T I O N S . . . . . . . . . . . . . . . . . . . 15

E M B R Y O L O G Y AND H I S T O L O G Y . . . . . . . . . . . . . . . . . . 17

P A T H O L O G Y . . . . . . . . . . . . . . . . . . . . . . . . . . 2 3

P R E O P E R A T I V E L O C A L I Z A T I O N . . . . . . . . . . . . . . . . . . 2 5

S U R G I C A L T E C H N I Q U E . . . . . . . . . . . . . . . . . . . . . . 2 6

P E R N I C I O U S 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

( H Y P E R C A L C E M I C CRISIS) . . . . . . . . . . . . . . . . . . . 2 9

P E R S I S T E N T A N D R E C U R R E N T P H P T . . . . . . . . . . . . . . . 2 9

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 AND M E N - S Y N D R O M E S . . . . . . 3 1

P O S T O P E R A T I V E H Y P O C A L C E M I A . . . . . . . . . . . . . . . . . 3 2

M E D I C A L TREATMENT OF PHPT . . . . . . . . . . . . . . . . . 3 3

HPT IN C H I L D R E N . . . . . . . . . . . . . . . . . . . . . . . 35

H P T IN P R E G N A N C Y . . . . . . . . . . . . . . . . . . . . . . 3 5

P A R A T H Y R O I D C A R C I N O M A . . . . . . . . . . . . . . . . . . . . 3 6

H Y P E R P A R A T H Y R O I D I S M AND M A L I G N A N T T U M O R S . . . . . . . . . 4 1

is Professor of Surgery and Head of the Section of Endocrine Surgery at the Karo- linska Hospital, Stockholm, Sweden. Dr. Granberg received his M.D. and Ph.D. at the Karolinska Institute. Besides endocrine surgery his main interest has been the research and teaching of arctic survival. He is presently President of the In- ternational Association of Endocrine Sur- geons.

is Assistant Professor of Surgery at Karo- linska Hospital Institute, Stockholm, Swe- den. After receiving his M.D. from the Ka- rolinska Institute he spent his surgical residency at the St. Erik's and Karolinska Hospitals in Stockholm. In 1975-1976 Dr. Cedermark had a fellowship in Surgical Oncology at Roswell Park Memorial Insti- tute, Buffalo, New York. He received a Ph.D. in surgery in 1980. His major interests are surgical oncology and endocrinology.

t

is Assistant Professor of Surgery at Karo- linska Institute where he also received his M.D. and defended his Ph.D. thesis. He received his surgical training at Danderyd Hospital. Dr. Farnebo's primary clinical and research interests are in surgical endocrinology and gastroenterology.

is Associate Professor of Surgery at the Karolinska Hospital in Stockholm. He received his Ph.D. and M.D. degrees at the Karolinska Institute in neurohistology and his surgical training at Danderyds and Karolinska Hospitals. In 1980-1981 he was visiting clinician at the Mayo Clinic. Dr. Hamberger's clinical and research interests are in the field of endocrine surgery.

is Assistant Professor at the Department of Endocrinology, Karolinska Hospital. In 1967, she received her M.D. from the Ka- rolinska Institute, where she is a lecturer. Primary hyperparathyroidism and its association with neuroendocrine disturbance and other neoplasias is one of Dr. Werner's clinical research interests.

HISTORY

The para thyroid story is one of the most fascinating in medicine. Many great scientists have part icipated in the search for increased knowledge about the physiology and pathophysiology of these small glands. Men like Gley, Recklinghausen, Loeb, Erdheim, Mandl, and Albright all have thei r names in the books of medical history. The interested reader is referred to Goldman et al. 1 for a detailed review.

We would like to focus the interest on a pioneer, the anatomist Ivar SandstrSm, whose work has not been open to many readers, since it was presented in his native language, Swedish. He was only 28 years old when he published the first detailed description of the anatomy and histology of the parathyroid glands in 1880. 2

After having found a new structure close to the thyroid gland in the dog, cat, and rabbit, SandstrSm star ted to make postmortem dissections in humans. He states: "Although the possibility of finding something previously not described seemed to be so small tha t it was ra the r for the sake of completeness and not in

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the hope of finding something new, I started to scrutinize the surroundings of the thyroid. How animated was then my sur- prise, when I already in the first examined cadaver found on both sides at the lower border of the thyroid a growth, sized like a small pea, which by its appearance seemed to be not a lymph node or a glandula thyroidea accessoria and which at microscopic examination showed a very peculiar structure." He gives then a precise description of the anatomical localization of the parathyroids. "The glands should be sought in close proximity of the thyroid at the posterior aspect of the lateral lobes or in the ,vicinity of their lower border. Usual ly both glands are found close to the arteria thyroidea inferior, one above and the other below the entra.nce of the ar tery into the thyroid glands. It seems as if it usual ly is the lower glands which vary most often in their location." The il lustration of the anatomy in Sand- strSm's paper is shown in Figure 1.

For histologic studies SandstrSm used parathyroid glands prepared in Muller 's solution or in osmium tetroxide counter- stained with carmine. The drawings of parathyroid cells give a remarkably correct picture surpassed only by today's electron microscopic work (Fig 2). Of course, the possible function of

. jz.thyz

.9(,pt~. �9 m. ~ ph,.in~

Fig 1.--The anatomy of the parathyroid glands according to Sandstr6m 1880. The specimen is seen from behind after removal of the esophagus and the pharynx. (From SandstrSm I.: U p p s a l a L ~ k a r f S r e n i n g s f 6 r h a n d l i n g a r 15:441-471, 1880. 2 Used by permission.)

b Fig 2.--SandstrSm's drawing of a microscopic section of parathyroid gland. Stain-

ing with osmium-carmine: (a) cell nucleus, (b) and (c) intracellular fat. (From Sand- strSm I.: Uppsala L&karfSrenings fSrhandlingar 15:441-471, 1880. 2 Used by permission.)

the new glands was obscure to SandstrSm. However, it was obvious to him tha t they ought to be endocrine in nature. He suggested also tha t tumor formation of the parathyroids might take place and admonished the pathologists to pay great atten- tion to the new glands. He writes: "Once I found the gland oc- cupied by a nut-sized, thin-walled cyst with mucous content; unfortunately the preparation was in such an advanced state of rottenness tha t a more detailed investigation was impossible. It should be noted tha t the thyroid gland did not show any sign of goiter." Maybe this was the first parathyroid adenoma ever described!

The progress made since 1880 has in many respects been tre- mendous. Nevertheless it is challenging to see how much can be done by a single person who is totally devoted to science.

R E G U L A T I O N OF C A L C I U M H O M E O S T A S I S

The calcium ion is of critical importance not only for bone min- eralization but also for a number of biochemical processes such as membrane stability and permeability, membrane ion trans- port, skeletal and cardiac muscle contraction, endocrine, neuroendocrine and exocrine secretion, neural excitation, enzyme regulation, cell growth and cell-division.

The calcium ion concentration is regulated within a close 6

range of concentration; extracellular fluids contain approximately 10 -3 M calcium ion, and the cytoplasmatic concentration is around 10 -6 M. This is achieved principally through the ac- tions of two hormones, parathyroid hormone (PTH) and vitamin D and its metabolites. A fall in extracellular calcium concentration is a st imulus for PTH secretion, which in turn causes bone resorption and i.ncreased renal calcium reabsorption. Vitamin D from skin and diet is hydroxylated in the liver to 25-hydroxy- cholecalciferol, 25(OH)D. Parathyroid hormone stimulates its further hydroxylation in the kidney to 1.25-dihydroxycholecalciferol (1.25 (OH)2D), which is biologically active and controls bone metabolism and increases intest inal calcium absorption. Thus, parathyroid hormone increases the concentration of extracellular calcium by at least three mechanisms: bone resorption, calcium absorption from the gut, and calcium reabsorption from the glomerular filtrate.

For the clinician, the rigid homeostasis of extracellular calcium is i l lustrated by the calcium concentration in serum, which varies normally between 2.2-2.6 mmole/1 (total serum calcium) and 1.14-1.32 mmole/1 (ionized calcium). Approximately 50% of serum calcium is bound to albumin. A small fraction of serum calcium is nei ther ionized nor protein bound but complexed to anions (approximately 2%-3%). Ionized calcium is the biologically active fraction and is the one most closely regulated. How- ever, analysis of ionized calcium is still not in general clinical use. When hypercalcemia is found in clinical practice, a total serum calcium concentration should be corrected for low or high serum albumin. One formula for such correction is:

Corrected serum calcium = serum calcium (measured) - 0.018 (serum albumin - 43).

Other factors which affect total serum calcium are dehydration, abnormal calcium binding proteins in some cases of myeloma, and disturbed acid-base balance, in which acidosis increases and alkalosis (due to hyperventilation) decreases ionized calcium.

DIFFERENTIAL DIAGNOSES OF HYPERCALCEMIA

When a status of hypercalcemia is established, several causes have to be considered (Table 1).

Firstly, laboratory errors, hyperproteinemia, and the intake of lithium, thiazide diuretics, vi tamins D and A, and an abundance of milk and absorbable alkali should be excluded. Hypercal- cemia should be evaluated concomitantly with serum-phosphate, creatinine, alkaline phosphatase, ur inary excretion of 24-hour calcium and screening tests for malignancy such as sedimenta-

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TABLE 1.--DIFFERENTIAL DIAGNOSIS OF HYPERCALCEMIA ARRANGED ACCORDING TO

APPROXIMATE FREQUENCY

1. Primary hyperparathyroidism 2. Malignant diseases

a. producing humoral factors b. causing local osteolysis

3. Sarcoidosis 4. Vitamin D and vitamin A excess 5. Hyperthyroidism 6. Thiazide diuretics 7. Lithium 8. Addison's disease 9. Immobilization

10. Familial hypocalciuric hypercalcemia 11. Milk-alkali syndrome 12. Laboratory error

tion rate, hemoglobin, hematocri t , white blood cell count, serum potassium, sodium, and protein electrophoresis.

PRIMARY HYPERPARATHYROIDISM (PHPT)

Patients With Normal Renal Function Normal renal function is judged by serum-creat inine or pref-

erably by clearance determinations. Serum-phosphate is usually less than 1.2 mmole/1 and the hypercalcemia is moderate. In one of our series, serum-phosphate was 0.8 +_ 0.1 mmole/1 and serum-calcium 2 . 8 3 _+ 0.24 mmole/1 (n = 47, mean _+ SD). Serum ALP (alkaline phosphatase) is in the upper normal range, and ur inary excretion of calcium (dU calcium) is moderately increased, 9.2 _+ 3.5 mmole/24 hr in our series (n = 45). a Sedimentat ion rate, hemoglobin, white blood cell count, and protein electrophoresis are normal. Most of our patients with PHPT today belong to this group.

Patients With Impaired Renal Function Serum-calcium is usual ly above 3 mmole/1. Serum phosphate

is more than 1.2 mmolefl. Serum ALP is increased, and dU-calcium is low or within the normal range. Impaired renal function is also accompanied by an increased sedimentat ion ra te and anemia. In this group of patients, one does not find recurrent renal stones but radiologic signs of osteitis fibrosa cystica and nephrocalcinosis caused by a rapidly progressive PHPT. Today this form of pr imary hyperpara thyroidism is rare.

Increased serum PTH during hypercalcemia is highly indica- tive of pr imary hyperparathyroidism, part icular ly when anti- bodies are directed e i ther to the N te rminal or to intact PTH or recognize concomitantly the two biologically inactive midregion

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fragments 35-84 and 35-65 of the PTH molecule. The diagnostic sensitivit4Y of these PTH radioimmunoassays is approximately 95%. Present ly we determine serum PTH in cases where the cause of the hypercalcemia is difficult to establish.

Parathyroid hormone st imulates cyclic adenosine 3',5'-monophosphate (c-AMP), 5 and many investigators have used ur inary c-AMP as an indicator of pr imary hyperparathyroidism. ~' 7 How- ever, in the differential diagnosis of pr imary hyperparathyroidism, it is of lesser value. Increased ur inary c-AMP, whether ex- pressed as ~mole/24 hr, ~mole/g creatinine, btmole/100 ml glomerular filtrate or nephrogenous c-AMP, is also seen in malignancy and sarcoidosis. 2' s, 9

MALIGNANT TUMORS

Tumors associated with hypercalcemia occur in a frequency approximately equal to pr imary hyperparathyroidism. The two conditions account for more than 90% of the hypercalcemic syndromes. Malignancy-associated hypercalcemia is also the most difficult differential diagnosis in pr imary hyperparathyroidism.lO, 11, 12 Furthermore, it has been suggested that patients with pr imary hyperparathyroidism have an increased frequency of malignant tumors.

In most patients with malignancy-associated hypercalcemia, the hematologic or solid tumor disease is obvious. Among solid tumors, breast carcinoma accounts for 50% of the cases, followed by carcinoma of the lung, kidney, cervix, ovary, prostate, and liver, and squamous cell tumors of the head and neck. The hematologic malignancies are predominantly myeloma, lymphoma, and leukemia. At least two different biochemical mechanisms seem to be responsible for the hypercalcemia noted in malignancy. They are important to consider, since they are accompanied by varying laboratory findings.

Humoral Hypercalcemia of Malignancy The humoral hypercalcemia of malignancy depends on bone

resorption mediated by systemic tumor products tha t are not identical with native PTH but mimic the effect of PTH on some of its target cells. By interacting with the PTH receptors, the humoral factor(s) st imulates c-AMP and bone resorption, s' 9, 12, 13 One group of investigators has succeeded in partial purification of a human hypercalcemic factor which appears to be a basic protein of 25,000 daltons. 14 Other investigators are presently characterizing a protein of similar size with bone resorptive activity. 15

The patients with humoral hypercalcemia have low serum phosphorous levels, mimickh~g primary hyperparathyroidism, bu t they have low or not detectable PTH levels in serum. The

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hypercalcemia is often more advanced than in pr imary hyperparathyroidism. They show a m i l d metabolic alkalosis with serum chlorides in the lower, normal range, while patients with PHPT have slight metabolic acidosis with high or upper normal serum chloride concentrations.

Local Osteolytic Hypercalcemia This hypercalcemia is caused by local resorption of bone. At

present the most favored hypothesis is that this resorption is mediated by osteoclast activating factors (OAF) secreted by primary or metastat ic tumor cells in bone. 1~ The OAFs represent a group of factors tha t have similar biologic effects but are found in different cell systems, such as thymus-derived and bone marrow-derived lymphocytes. Furthermore, monocytes secrete two distinct types of bone resorbing factors, prostaglandin of the E series and interleukin I-like activity. Malignant cells from pa - t ients with T-cell lymphoma, myeloma, and Burkit t ' s lymphoma have been shown to secrete OAFs. 16' 17 Since these malignancies frequently are associated with hypercalcemia, it is tempting to suggest that the OAFs are the cause of hypercalcemia in these cases.11, 14

SARCOIDOSIS

Approximately 10% of patients with active sarcoidosis show hypercalcemia, the etiology of which may be an increased con- version of precursor vi tamin D in the sarcoid t issue to the biologically active 1.25 (OH)2D with ensuing increased resorption of intestinal and skeletal calcium, is In sarcoidosis serum PTH levels are low or normal, and the hypercalcemia is intermittent, more common during summer, and, in approximately a third of the patients, preceded by hypercalciuria. The hypercalcemia can be provoked by ul traviolet irradiation. The degree of the hypercalcemia is correlated to the advancement of the disease.

In the typical pat ient with normal renal function, the diagnosis is not a problem. Although these patients m a y have recurrent nephrolithiasis mimicking PHPT, the hypercalcemia is accompanied by serum phosphorus levels above 1.2 mmole/1, markedly increased ur inary calcium of more than 14 mmole/24 hr, and a history of previous sarcoidosis. However , in patients with sarcoidosis and renal impairment, the diagnosis may be more problematic; skeletal serum ALP is occasionally elevated due to general or focal bone resorption and hypercalciuria is ab- sent. If the patient lacks a history of sarcoidosis and has a normal x-ray picture of the lung, and our initial screening has lent no indications of lymphoma or myeloma, we perform the Kveim test. 19 When this is positive, the diagnosis o f sarcoidosis is highly probable. A cortison-suppression test, e.g., 50 mg cortison

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acetate three times daily for 5-7 days, will generally normalize serum-calcium in sarcoidosis. However, normalization of serum calcium is also seen in the most important differential diagnosis to sarcoidosis, malignancy associated hypercalcemia.

VITAMIN A AND D

Vitamin D excess is a common cause of hypercalcemia in hypoparathyroid patients but rare in patients with intact parathyroid glands and in those in whom there is a suspicion of pr imary hyperparathyroidism or malignancy-associated hypercalcemia. A careful screening of the patient 's use of medications and other heal th preparations will rule out vi tamin D as a cause of hypercalcemia. The metabolic events induced by vi tamin D is increased absorption of intestinal calcium and increased resorption of bone. Renal impairment makes a patient predisposed to primary hypercalcuria and later hypercalcemia from vitamin D intake. Early signs of vi tamin D-induced hypercalcemia are las- situde or polyuria.

Nephrocalcinosis, renal impairment, and extraskeletal calcifications are complications of prolonged vi tamin D intoxication. Since vi tamin D is stored in fat, the hypercalcemia may persist for weeks after the discontinuation of the hormone. Serum-calcium is promptly reduced by steroids. Interestingly, the serum concentrations of the biologically active form, 1.25(OH)D, are normal, while other metabolites are increased, e~

V i t a m i n A excess is rare but may cause advanced hypercalcemia, nephrocalcinosis, and periosteal calcificationsY The clinical picture and t rea tment of vi tamin A intoxication are similar to those of vi tamin D. Exogenous glucocorticoids will rapidly normalize serum calcium levels.

HYPERTHYROIDISM

The hypercalcemia seen occasionally in hyperthyroidism is not correlated to the activity of the disease. The current hypothesis is tha t tri-iodothyronin exerts a direct resorptive action on bone. The hypercalcemia is an extreme of the subtle increase within the normal range of total as well as ionized serum calcium seen in the majority of patients with hyperthyroidism. The activity of the parathyroid glands is depressed in hyperthyroidism. This is indicated by a serum phosphate level of 1.2 mmole/1 or more and low serum PTH. Since there is an increased association of PHPT and hyperthyroidism, the presence of hyperthyroidism should be considered before the t rea tment of PHPT is instituted. In a few patients with marked hypercalcemia but without primary hyperparathyroidism, the thyrotoxic

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syndrome may be masked by the uncharacteristic symptoms of hypercalcemia such as confusion, dehydration, and vomiting.

DIURETICS

The diuretics chlorothiazide, hydrochlorothiazide, and chlor- thalidone decrease calcium excretion and in some patients also increase total as well as ionized serum calcium. The mechanism behind this effect is still obscure. There is no correlat ion between the diuretic effects of the drugs and their increase of urinary calcium and serum calcium. One hypothesis is that thiazides may potentiate the calcium reabsorptive effect of PTH on the kidney tubules and the bone resorptive effect of PTH on bone. It is of importance to note tha t a substantial number of patients, being hypercalcemic on thiazides, will remain hypercalcemic after the discontinuation of the drug or redevelop hypercalcemia. Pr imary hyperparathyroidism can then in many cases be proved surgically. 22

LITHIUM

Lithium-induced hypercalcemia is rare considering the wide use of the drug nowadays. After withdrawal of the drug, elevated serum calcium may persist for several days. The etiology of lithium-induced hypercalcemia is unknown. Lithium increases PTH-release from parathyroid cells in vitro. 23 In a study on 6 heal thy men, therapeutic doses of l i thium did not alter serum calcium, PTH, calcium suppressibili ty of PTH secretion, or nephrogenic c-AMP. 24

ADDISON'S DISEASE

The hypercalcemia in Addison's disease is probably due to dehydration, since ionized calcium is normal in these patients. Af- ter rehydration, the more common electrolyte disturbances in Addison's disease will become evident- -hyponatremia with relative hyperkalemia. In hypercalcemic emergency cases who have responded promptly to the administrat ion of cortisol, this triad of electrolytic pathology is suggestive of Addison's disease rather than a malignancy-associated hypercalcemia.

IMMOBILIZATION

Immobilization causes loss of bone mineral, because bone resorption is increased in relation to bone deposition as long as the skeleton is not subject to weight and tension. Hypercalcemia due to immobilization is preferentially seen in patients with ex-

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tensive fractures or osteomyelitis, and when additive factors are present, such as the rapid bone turn-over in adolescence or in Paget 's disease, Immobilized patients also risk kidney stone for- mat ion which may impair renal function, whereby the decreased excretion of calcium may aggravate the hypercalcemia.

FAMILIAL HYPOCALCIURIC HYPERCALCEMIA

Familial hypocalciuric hypercalcemia is an autosomal domi- nant syndrome described in detail by Marx et al. 25 It is charac- terized b y early age of onset, probably from birth, benign clinical course, absence of renal stone disease, and absence of other endocrine adenomatoses such a s pi tui tary or pancreatic tumors. Marked hypocalciuria and increased serum magnesium are the hal lmarks of this syndrome, the etiology of which is unknown. These asymptomatic patients have normal kidney function and serum calcium and serum phosphorous levels similar to patients with pr imary hyperparathyroidism. Subtotal resection of the parathyroid glands (which are histologically normal or show chief celt hyperplasia) does not normal ize serum calcium and has no t been beneficial in the few patients in whom the syndrome has been complicated by pancreatitis. Pat ients with un- recognized familial hypocalciuric hypercalcemia probably consti- t u t e a substantial g roup in parathyroid re-operation patients. The prevalence of the syndrome is unknown; at the Karolinska Hospital we are aware of two kindreds.

MILK-ALKALI SYNDROME

The milk-alkali syndrome, due to chronic excessive milk in- t ake in combination with absorbable alkali, is today, according to our experience, a relic in the tables on differential diagnosis in hypercalcemia. The increased serum calcium is associated with normal or elevated serum phosphorous and azotemic alkalosis, Calcium excretion varies depending on the patient 's kidney function. Some of the early reports on the milk-alkali syndrome probably re fe r red to patients with peptic ulcer disease due to gastrinoma.

NATURAL HISTORY OF PRIMARY HYPERPARATHYROIDISM

The natural history of PHPT has not been subjected until recently to prospective studies. These have become of special interest with the discovery of the increasing number of patients having the asymptomatic form of the disease. So far, there are no known clinical or laboratory markers for those patients who will r e m a i n asymptomatic or those who will develop advanced

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hypercalcemia, metabolically active renal lithiasis, renal impairment, bone disease, or psychiatric disturbances, the five generally accepted indications for parathyroid surgery. The general impression has been that the benign form of PHPT will remain benign in its course and only rarely progress to symptomatic PHPT. This has been supported by van't Hoff et al. 26 who followed 32 patients with PHPT for a mean of 4.2 years (1-9 years) and by Christensson et al. 27 who observed 23 patients for 10 years. There was no significant change in mean serum calcium, serum creatinine or blood pressure during the periods of follow- up.

In a 10-year prospective s tudy from the Mayo Clinic 2s on 147 patients with hypercalcemia and suspected pr imary hyperparathyroidism serum calcium became normal in 11 patients during the period of study, and in 21 of 22 patients calcium levels remained unchanged. For a number of somatic but also psycho- logic and unknown reasons, 33 patients were referred to surgery. We share their recommendation that surgical exploration should be performed by an experienced parathyroid surgeon in patients whose clinical and laboratory data support the diagnosis of pr imary hyperparathyroidism; our reason for this is tha t according to our experience there are exceptionally few truly asymptomatic patients within the group of patients with so called "asymptomatic pr imary hyperparathyroidism." With re- fined and diversified testing equipment one almost invariably finds concentration difficulties, deteriorated memory, mental depression, and muscular weakness, all symptoms which may be relieved by successful parathyroid surgery.

PREVALENCE, INCIDENCE, AND ETIOLOGY

Today in our society, pr imary hyperparathyroidism is a ra ther frequent disease representing the most common cause ofhypercal- cemia in nonhospitalized patients. Previously, severe bone or kidney disease eventual ly lead to the diagnosis. With the introduction of routine determination of serum calcium and in particular the use of mult ichannel chemical profiles for health-screening, the diagnosis of pr imary hyperparathyroidism has increased considerably. In the early seventies a large health-screening program including 16,000 persons in Stockholm revealed a prevalence of hypercalcemia in 0.6%, of which 0.36% were shown to have primary hyperparathyroidism. 22 A prevalence of 1.3% was observed in females older than 65 years. In another study of 1,100 geriatric pa- t ients 0.15% were found to have primary hyperparathyroidism. 29

The annual incidence of pr imary hyperparathyroidism has been thoroughly studied in the Olmsted County study, Minne- sota, and was found to be 51 per 100,000 population and was noted as high as 188 per 100,000 among women aged 60 years

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or older. 3~ Other studies have reported an incidence of 25 per 100,000 a year. TM 32

Whether pr imary hyperparathyroidism has in fact increased or merely reflects the detection of the disease can be only spec- ulation. It is likely tha t the diagnosis of pr imary hyperparathyroidism is now made at an earlier stage of the disease and tha t previously undiagnosed patients with weak symptoms increase the numbers. In Swedish patient material on almost 1,000 investigated autopsies without kidney impairment, 5% proved to have enlargements of the parathyroid gland. 33' 34 This finding supports the theory that the increased incidence of the disease reflects a more thorough diagnosis.

Very little is known about the etiology of pr imary hyperparathyroidism. It has been speculated tha t chronic ur inary loss of calcium or vi tamin D deficiency represents a stimulus for parathyroid secretion, eventually leading to adenoma or hyperplastic glands. This theory is less probable, since most patients operated on for an adenoma have no recurrences. The only factor proven to be of etiologic importance is external low-dose irradiation. Since the first reports of Rosen et al., 197535 and Tisell et al., 1976, 36 it has now been reported from many studies, including our own s e r i e s y that 6%-25% of patients in consecutive series of primary hyperparathyroidism have previously been treated by radiotherapy. This is further supported by the finding of primary hyperparathyroidism in 11% of patients irradiated for tu- berculous cervical nodes more than 30 years earlier. 38

CLINICAL MANIFESTATIONS

The symptomatology of PHPT has undergone remarkable changes during the last 50 years. A comparison under taken at our institution be tweenpat ients operated on in 1930-60 and during the period 1972-813~demonstrates a marked decrease of bone and renal disease but increases of cardiovascular, neuromuscular, and psychiatric symptoms. These findings are in agreement with previous reports. 3~ 40 The main reason for this changed panorama is the increase in heal th screening programs, which has led to detection of a considerable number of patients with mild PHPT. There is, however, no data to support tha t PHPT per se has changed its appearance. Instead, patients with severe disease have been "di- luted" by the large number of patients with mild disease.

A retrospective review of signs and symptoms in 400 of our own consecutive patients is shown in Table 2.

RENAL STONES

Previously the most common finding in patients with PHPT, 41 renal stones, are today only encountered in about one third of

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TABLE 2.--CLINICAL PRESENTATION OF 400 PATIENTS WITH SUSPECTED PHPT OPERATED

1972--1981"

SIGNS AND SYMPTOMS NUMBER PERCENT

Neuromuscular symptoms 151 37.8 Urolithiasis 141 35.2 Hypertension 116 29.0 Psychiatric symptoms 113 28.3 Cardiovascular symptoms 86 21.5 Gastrointestinal symptoms 82 20.5 Bone disease 72 18.0

*Adapted from Farnebo, L.-O., et al.: Acta Chir. Scand. (Suppl.) 520:11, 1984.

our pat ients (see Table 2). Urinary calcium_ excretion is decreased after a successful operation, 41' 42 and the frequency of urolithiasis is reduced. 43

BONE DISEASE

Nowadays bone disease is mostly registered as an asymptomatic general demineralization of the skeleton. Severe forms of bone disease, e.g., generalized osteitis fibrosa cystica, is extremely rare. Bone mineral content measured by bone density determination was found to be reduced in PHPT and has been proved t o increase following successful surgery.44, 45

GASTROINTESTINAL MANIFESTATION

Gastritis, peptic ulcer disease, pancreatic disease, and cholelithiasis occur in increased frequency in patients with PHPT and a causal relationship has been suggested. However, a more critical evaluation does not support a l inkage for peptic ulcer disease, 46 pancreatitis, 47 or cholelithiasis. 4s

THE PREVALENCE OF HYPERTENSION

In patients with PHPT hypertension has been reported in be- 41 49 tween 20% and 60% of cases. ' A significantly increased risk

for hypertension has been shown using age- and sex-matched controls, s~ Several theories to explain this association have been suggested, but no single factor has been found responsible. 5~ Even following a successful operation for PHPT, hypertension usually persists. 4~' 51, 52 Hypertension seems not to be directly affected by correction of the hyperparathyroid state. Prospective

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studies are needed to evaluate whether t rea tment of PHPT can prevent development of hypertension in the "asymptomatic" patients.

PSYCHIATRIC SYMPTOMS

In patients with PHPT, psychiatric symptoms appear mainly in mild degree, 53 and EEG abnormalities which improved postoperatively have been demonstrated. 54 A recent prospective study from our insti tution (Lindner et al., to be published) demonstrated highly significant improvement in mental perfor- mance following successful parathyroid surgery. No change was observed in a control group undergoing hemithyroidectomy.

NEUROMUSCULAR SYMPTOMS

Neuromuscular symptoms include many diffuse symptoms such as muscular weakness and fatigue and is reported in 20%- 80% of patients with PHPT. 4~ In a prospective study Pat ten et al. 5~ demonstrated atrophy of skeletal muscle, particularly atrophy of the type II fibers. The patients improved their neuromuscular function after operation. In two recent studies, 5~' 57 isoki- netic muscle force was determined in consecutive patients before and after surgery for PHPT. A mean increase in muscular force of 19% was registered after 1-2 months while a control group undergoing uni lateral thyroid surgery showed no improvement.

"ASYMPTOMATIC PATIENTS"

"Asymptomatic patients" with PHPT are being diagnosed with increasing frequency due to the routine determination of serum calcium. Up to one fourth of patients with PHPT has been reported to have "asymptomatic disease. ''2s'3~ The proper management of these patients has been a subject of discussion. 5s An important question in this connection is whether or not these patients are asymptomatic, or whether the patients ' perceptions or the doctor's ability and tools are sensitive enough to reveal symptoms. To answer this question, prospective studies on "asymptomatic patients" aimed to reveal improvement after successful operation must be done. We favor surgical neck exploration also in these patients unless there are obvious contraindi- cations.

EMBRYOLOGY AND HISTOLOGY

The parathyroid glands develop from the endodermal pharyngeal pouches of the foregut. 59' 60 The inferior.glands arise from

17

the third pharyngeal pouches, which also develop into the thymus, while the superior glands emanate from the fourth pharyngeal pouches and are associated with the so called lateral thyroid anlages.

Thus, the lower parathyroids, which are initially the most cranially located, descend during development in a caudal direction, thereby passing the superior glands. During the early stage of descent, the lower glands are intimately associated with the thymic anlage in the third pharyngeal pouch. Occasionally , fragmentation of this tissue occurs, leaving small fragments of parathyroid and thymus tissue along the line of descent (Fig 3). This probably explains the occurrence of accessory parathyroid glands in the thymic pathway or in the thymus itself. The caudal migration of the inferior glands usually stops when they separate from the thymic anlages, which then descend further into the upper part of the thoracic cavity. Sometimes, this separation is delayed, and the lower parathyroids can be displaced anywhere in the thymic gland and thus be located in the thoracic cavity. This ectopic position is reached before adult life.

The dorsal part of the fourth pharyngeal pouch is differen-

"the garage"

"the h ighwa

Fig 3.--Localization of the inferior parathyroid gland. The gland may be found close to its origin in the pharyngeal pouch ("the garage"), or along the line of descent ("the highway"), or far down in the thymus. The most common location is at the lower border of the thyroid or in the thyro-thymic ligament. The thymus is like an index finger pointing to the gland.

18

t iated into the superior parathyroid, while the ventral nonpara- thyroid part fuses with the corresponding lobe of the developing thyroid gland. This fusion prevents further descent of the upper glands and explains both the more cranial position and the more int imate relation to the thyroid gland of these glands. Rarely, the superior parathyroids are completely embedded in the thyroid gland.

NUMBER OF GLANDS

In the majority of cases there are four parathyroid glands. In several autopsy series, a few cases with less than four glands have been reported. However, there seems to be a unanimous agreement tha t in these patients the investigation has been in- complete with one or two glands being overlooked. The reason for this assumption is tha t the combined weight of the retrieved glands is below tha t expected. Of great clinical importance is the possibility of supernumerary glands. Several investigations have aimed at elucidating the frequency of this condition. Gilmour 61 found five parathyroids in 6% and six parathyroids in 0.5% of 428 examined postmortem cases. In Alveryd's material of 352 autopsies 33 3.7% had five glands. Wang 62 found 3 cases with five glands and 1 case with six glands in a total of 160 autopsies.

In a recent series of 503 unselected autopsy cases, AkerstrSm et al. 63 found 3.6% having five glands, 0.6% having six glands, and 0.6% having more than six glands. One of their cases had as much as 11 glands weighing more than 5 mg each.

If the four series referred to above are added together, they comprise 1,336 cases where four or more glands could be found. Of these 1,336 cases 4.4% had five glands, 0.3% six glands, and 0.2% seven glands or more. There is of course a possibility tha t even more supernumerary glands may have been overlooked. For practical clinical purposes, however, it seems safe to con- clude tha t at least 5% of the patients with primary hyperparathyroidism may have more than four glands.

LOCALIZATION

The superior parathyroid glands are usually (about 80% of cases) located at the cricothyroidal junction close to the thyroid, about 1 cm cranially to the crossing between the recurrent laryngeal nerve and the inferior thyroid ar tery 62' 63 (Fig 4). In 15%-20%, they are found more cranially behind the upper pole of the thyroid. A t ruly intrathyroida163 position of the superior gland is seen in only 0.2%. Rarely (about 1%) a normal superior parathyroid is located more posteriorly in the retropharyn- geal, retroesophageal space. On the other hand, a pathologically

19

Fig 4.--Local izat ion of the parathyroid glands. The glands are in 75% of all cases localized within the hatched areas cranial and caudal to the crossing between the inferior thyroid artery and the recurrent laryngeal nerve. f

enlarged superior gland may descend in the retroesophageal re- 6~4 ~ , , gion. It is swallowed by the esophagus outside the gastroin-

testinal tract and pushed downwards and posteriorly into the thorax (Fig 5). Due to developmental reasons, the lower parathyroid glands have a wider area of distribution than the superior parathyroids. They descend into the mediast inum during embryologic life but do not migrate during adult life (Fig 6). They can be found anywhere between the lower pole of the thyroid and the thymus. The thymus points to the lower parathyroid like an index finger (see Fig 3). The most frequent localization (40%-60%) is close to the lower thyroid pole (inferior, posterior or lateral). Not infrequently it is found on the anterior aspect of the thyroid, closely at tached to the thyroid, but never

63 t ruly in the thyroid parenchyma. In a high proportion of cases it is located in or close to the thyro-thymic l igament or in the cranial part of the thymus (Wang: 39%; 62 Akerstr6m et al.: 26%63). In 2% of the cases, the lower parathyroid is found further down in the mediastinum. On rare occasions the lower parathyroid has not descended, but is encountered cranial to the superior gland together with thymus, so called parathymus. 64

Alveryd 33 has pointed out tha t the right glands tend to lie more closely together in the cranio-caudal direction, while the left glands lie slightly more apart. Otherwise, there is a conspic- uous symmetry in the position of both glands on the two sides in

2o

Fig 5.--An enlarged superior parathyroid gland may be "swallowed" by the esophagus outside the gastrointestinal tract and pushed downwards and posteriorly into the thorax. (The thyroid has in this drawing been rotated forwards to disclose the retrothyroid anatomy).

about 60% of the cases.63 In 53% the superior and inferior pairs are located respectively above and below the crossing between the inferior thyroid ar tery and the recurrent laryngeal nerve. In 5%, all four glands are located below this plane, and in only 2% above this plane. In the remaining 40%, some kind of asymmetry exists, most commonly regarding one of the inferior glands which in 13% of cases is located well below the thyroid in the thymus. 63 When a supernumerary gland is present, it is most commonly located in the thyro-thymic ligament or in the thymus.

MACROSCOPIC APPEARANCE

The color of normal parathyroid glands varies from reddish to yellowish tan. The glands are soft and pliable and their shape is dependent on the anatomical position. When located in loose connective t issue (more than 80%), they are oval, spherical, bean-shaped or teardrop-formed. On the other hand, in the more rare condition when located subcapsularly, they are flattened, with sharp edges. The true size may be underest imated when the gland is located subcapsularly. The gland must be freed from surrounding connective tissue to adequately judge size.

21

Fig 6,--Unusual locations of the parathyroids. The inferior glands may be found down in the thymus, but this is the result of descent during embryologic life and not migration during adult life. On the other hand, the superior gland may be dislocated (A) downwards into the posterior mediastinum due to pathologic enlargement during adult life (B).

According to AkerstrSm et al., 66 the weight of a normal parathyroid gland in an individual without renal or skeletal disease is less than 59 mg in 95% of all cases. The average weight in Wang's series 62 was 35-40 mg.

MICROSCOPIC APPEARANCE

The parathyroid glands are surrounded by a thin collagenous capsule which extends into the parenchyma as septa. The parenchymal cells are arranged in trabecular, alveolar, or acinar con- figurations within a framework of reticular fibers.

Intermingled with the parenchymal cells are varying amounts of fat cells. The number of fat cells increases with age until about 25 years, but is then fairly constant. However, the amount of fat in the parathyroid glands is int imately related to the com- position of the body as a whole. Obese individuals usually have abundant stromal fat in the parathyroid glands while slim individuals have more sparse stromal fat. 67 The distribution of fat

22

cells within a single gland is sometimes uneven, a fact which might make the evaluation of small biopsy specimens difficult. 67

There are two main types of parenchymal cells, the chief cell and the oxyphilic cell. The chief cell is a polygonal cell, 7-10 in diameter, with a centrally placed vesicular nucleus and pale cytoplasm. Special staining procedures reveal considerable amounts of glycogen and fat in the chief cells. With the electron microscope, a Golgi apparatus and granular endoplasmatic retic- u lum can be demonstrated. Furthermore, small granules, probably secretory granules, can be seen. 6s

The oxyphilic cell is larger than the chief cell and has a small dark nucleus and strongly acidpphilic cytoplasm. Electron microscopy shows that it contains numerous mitochondria. The number of oxyphilic cells increases with age. There is good evidence tha t both the chief cell and the oxyphilic cell produce parathyroid hormone. In addition to these cell types, several forms of transit ional cells have been described. These are sup- posed to be intermediates between the two main cell types. Spe- cial interest has been focused on the water-clear cell, which is sometimes seen in abundant numbers in water-clear cell hyperplasia. This cell contains large vacuoles, the content of which is unknown.

PATHOLOGY

Primary HPT can be caused by 1) adenoma, 2) hyperplasia, or 3) cancer. The histopathologic differentiation between these three entities, and also between pathologic and normal tissue, is difficult.69, 70, ~1 This is probably the main reason for the great variation in frequency of the different entities published from different centers.

ADENOMA

A single adenoma is responsible for hypercalcemia in more than 80% of instances. The frequency does not seem to have changed over the years. 39' 72 More rarely, double adenomas occur 1%_3%.73, 74

The adenoma is macroscopically an ovoid reddish-brown tumor which is darker in color than the yellowish tan normal parathyroid. It is more firm in consistency than the normal gland and is therefore readily recognized by the experienced surgeon. The histopathologic diagnosis of adenoma is based on the following criteria: the presence of a rim of normal parathyroid adjacent to the adenoma, the occurrence of nuclear pleomorphism, and the relative absence of fat cells in the gland. The predominating cell type in the adenoma is the chief cell, al though in some cases the oxyphil cell predomi-

23

nates. The chief cells of an adenoma have very little intracel- lu la r fat, a criterion which has been used to corroborate the diagnosis75

HYPERPLASIA

Two main forms of hyperplasia exists�9

Chief Cell Hyperplasia Chief cell hyperplasia was first described by Cope and co-

workers in 1958. 76 In most series it constitutes about 10%-20% of all cases o f HPT. This type of hyperplasia involves all four

g lands , a l though sometimes to a varying extent; t w o o r t h r e e glands may be considerably enlarged, while one or two may be normal sized. T h e color of the gland is usually reddish. Two subgroups can be recognized: the dif fuse chief cell hyperplas ia and the nodular chief cell hyperplasia. The diffuse hyperplasia is sometimes difficult to differentiate from normal para thyro id tissue. It is not possible to base the diagnosis on the relative amount of parenchymal cells and fat cells in single sections of parathyroid tissue, since the amount of fat cells may vary considerably between different parts of the gland. The amount of intracellular fat in the chief cells is usua l ly low, indicating hy- perfunction. 77 The value of fat stain is, however, limited, since a normal finding with abundant intracellular fat in one gland does not preclude abnormali ty in other glands. 7s

Since no definite histologic criteria exists, it has been suggested by some authors that the diagnosis should be :based on the parenchymal cell weight. 66 By this definition hyperplasia is considered to be present if two or more glands have an increased parenchymal cell weight, and the total parenchymal cell weight

�9 6 6 exceeds 1 4 4 m g (no adenoma criteria fulfilled).

Water-Clear Cell Hyperplasia The water-clear cell hyperplas ia was described already in the

1930s, 79 but is seldom seen nowadays. 72 It always involves all four glands, which are considerably enlarged with a total weight nearly always exceeding 1 gm and often exceeding 10 gm. Ma- croscopically the glands tend to form pseudopods and are generally dark brown.

CANCER

Cancer constitutes less than 1% of all cases of PHPT and is described in detail in a separate chapter.

Due to the great difficulties in establishing a n unequivocally correct histologic diagnosis in parathyroid disease, especially in frozen section preoperatively, it is the opinion of most authors,

24

surgeons, and pathologists tha t the final diagnosis must be based not only on the histologic appearance, but also to a great extent on the gross findings at the operation. 7s' 70, so, 71, 7s

PREOPERATIVE LOCALIZATION

ULTRASONOGRAPHY

Many methods to locate preoperatively enlarged parathyroid glands have been tried. Ultrasonography has turned out to have a high degree of accuracy if a missed, enlarged gland is located in the neck. sl' s2

However, in elective surgery for PHPT, when no previous neck surgery has been performed, ul trasonography probably will not improve the 90%-95% cure rate obtainable by experienced parathyroid surgeons, s3

Thus, it seems obvious tha t preoperative sonography localization of an enlarged parathyroid gland is not of decisive importance for a t rained parathyroid surgeon. However, the operation time can be reduced if the size and location of the enlarged gland i s known preoperatively.

COMPUTERIZED TOMOGRAPHY

Computerized tomography combined with intravenous con- t rast has been claimed to visualize parathyroid tumors in ectopic p o~i~ons.S4, s5, ss Our experience with this technique is limited.

ARTERIOGRAPHY

In our series of 9 patients, arteriography has not been successful in localizing enlarged parathyroid glands. In only 1 instance the adenoma was visualized. On the other hand, neurological complications occurred in 3 patients, 1 of which was serious. Even if the technique is combined with high-resolution magni- fication, subtraction, and thyroid scans, accurate preoperative localization is achieved only in about 50% of cases. ~7 Therefore the method should be considered only in highly selected cases.

SELECTIVE VENOUS SAMPLING

Reitz 88 first reported selective venous sampling with analysis of parathyroid hormone levels in serum in 1969. This technique was early in use at our hospital, and the first promising results reported by Hjern et al. s9 have thereafter been confirmed. Thus, today 43 patients with recurrent or persistent PHPT have been examined with this technique before reexploration. Out of 27

25

patients with an adenoma verified at surgery, 21 (78%) were correctly lateralized. Of 16 patients with mult iglandular disease, the parathyroid t issue was localized in 13 instances (81%).

SURGICAL TECHNIQUE

A .surgeon aiming to perform a neck exploration for hyperparathyroidism should be experienced with this type of operation. He must have a thorough knowledge of the embryology and anatomy of the parathyroid glands: A pathologist experienced in the histopathology of the parathyroid glands should be available.

PREOPERATIVE ARRANGEMENTS

The exploration is made under general anesthesia with the patient 's trachea intubated. The respiration is controlled by a ventilator. By this technique the anesthesiologist does not need constant and direct access to the patient 's head. Thus, the patient's face and the lateral and upper par t of the head and neck can be draped in a sterile fashion giving the surgeon and his assistants ample room.

A deflatable vacuum pillow is placed under the patient 's shoulders and lower neck. After the pillow has been squeezed to support the patient 's shoulders and the dorsally extended neck, the pillow is deflated. By this ar rangement the head is kept in an optimal position during the operation and maximal exposure of the operative field is achieved (Fig 7). The head end of the operation table is raised to minimize venous stasis and bleeding, and the legs are slightly raised to avoid pooling of blood in the lower extremities.

SURGERY

According to our experience, it is advantageous to use magni- fying glasses (2.5 • ) during the operation (this holds also for younger surgeons!). A 10-12-cm symmetric collar incision is made about 3 -4 cm above the sternal jugulum. An upper and lower flap including the platysma is prepared. The upper flap is fixed to the drape around the head with two sutures. The strap muscles are separated in the midline but not transected.

The dissection of the thyroid and the parathyroids should start on the side where ul trasonography might have indicated the existence of an adenoma. The lateral and posterior areas of the thyroid are visualized by gentle dissecting close to the thyroid surface. Already at the beginning of this dissection a thorough and methodical search for the parathyroids should begin, since

26

Fig 7.--Preoperative arrangement: Patient in position with the head, neck, and shoulders resting on and held in position by a deflated vacuum pillow. A flexible support is mounted to protect the patient's face and the endotrachial tube.

especially the lower glands are sometimes located anteriorly on the thyroid capsule.

It is of utmost importance that the dissection is performed very gently so that bleeding is avoided. Blood in the operative field will easily obscure the typical brownish color of the parathyroid glands, which is of great importance for their identification. Except for the color, the consistency of the glands facili- tates their identification. They are softer and more homogenous than thyroid tissue but denser than fat lobules. Also the existence of a vascular pedicle may be helpful.

The middle thyroid veins are divided, and the thyroid lobe can then gradually be elevated and rotated medially. The most common location for the parathyroids is in the vicinity of the intersection between the inferior thyroid artery and the recurrent laryngeal nerve, "the hot region." Thus, this area should first be searched. The upper gland is often found slightly above the intersection. Many t imes an adenoma may be located behind the intersection in the tracheal-esophageal groove with only its vascular pedicle reaching up to the posterior thyroid surface. The inferior gland is usual ly located more inferiorly and anteriorly on the thyroid or in its capsule. Often it is found close to the junction between the inferior thyroid pole and the thymus.

If at this point of operation the superior gland has not been found, the dissection should be continued cranially along the posterior thyroid surface. To reach the very posterior par t of the superior thyroid pole and above it, it is advisable to divide the superior thyroid artery and veins. Then the thyroid lobe can be retracted downwards and medially, and good exposure can be 0b-

27

tained. The superior gland may also be found in a retropharyn- geal and retroesophageal position. If a complete neck exploration has failed to reveal an adenoma, and only two normal or hyperplastic inferior glands have been detected, hemithyroidectomy is indicated. However, true intrathyroidal glands are very rare, and a meticulous search for glands in and beneath the thyroid capsule should be made before a blind hemithyroidectomy is performed.

The search for a missing inferior parathyroid gland should continue by exploring the upper part of the thymus. Thymec- tomy should, however, be performed only if no adenoma but only normal or hyperplastic glands have been found on both sides of the neck. When thymectomy is indicated, it can be done through the cervical incision. By slow and gentle upward traction, step by step, while the thymic vessels are cauterized and divided, most of the thymus can be exposed. Sternotomy and mediastinal exploration should not be done at primary exploration unless the patient suffers from hypercalcemic crisis. Undescended inferior glands may be found above the thyroid and rarely an ectopic gland could be located in the carotid sheet, Sometimes an adenoma may be found very close to the esophageal wall. In this location it may be difficult to detect because of the similar colors of parathyroid adenomas and the esophagus.

In about 85% of explorations for primary hyperparathyroidism, a single adenoma will be found. In parathyroid hyperplasia, all glands are involved, although the sizes of the glands may differ. Accordingly, a large hyperplastic gland may be misdiagnosed as an adenoma. To minimize the risk for such mistakes, we advocate that in addition to excision of the adenoma, a small biopsy from an apparently normal parathyroid gland should be examined histologically by frozen section, For the same reason and to detect a possible second: adenoma, both sides of the neck should always be explored,

If the frozen section shows chief cell hyperplasia, the gland should be removed, and only about 50 mg of parathyroid tissue (usually at least half a gland) should be preserved. Routine biopsy of all glands is not indicated. Parathyroid glands left in situ should be marked by nonabsorbable sutures with long ends and placed close to the gland without disturbing their blood supply. This is of great help if the patient has to be reexplored. A picture of the final operative field should be drawn after conclusion of the operation indicating the localizations of the glands.

If an adenoma is found to be of an unusually hard consistency and appears firmly adherent to adjacent tissues, parathyroid carcinoma should be suspected. This requires special precautions.

The wound is closed with absorbable sutures to adapt the strap muscle in the midline and for suturing of the platysma. The skin is closed with an intracutaneous suture or with surgical tape. Drainage is seldom indicated.

28

PERNICIOUS PRIMARY HYPERPARATHYROIDISM (HYPERCALCEMIC CRISIS)

Most patients with P H P T run a prolonged insidious course. However, especially in elderly women, the disease may lead to rapidly increasing serum calcium levels to values above 3.5 mmole/1, a hypercalcemic crisis. This situation is life-threaten- ing. Often there are prodromes, with polyuria and polydipsia caused by the inability of the kidneys to concentrate the urine. Nausea and vomiting further increase the dehydration and cause inappropriately high serum calcium levels. The mental state rapidly deteriorates into drowsiness, dizziness, confusion, and coma.

Romanus et al. 9~ found hypercalcemic crises in approximately 10% of 274 patients. In almost one fourth of the patients the crises occurred in connection with a surgical procedure for another disease. Due to an increased awareness of the disease, the percentage of pernicious PHPT has decreased during the last decade.

The t rea tment is surgical after correction of fluid and electrolyte imbalance. If renal function is adequate, intravenous administrat ion of furosemide can augment the calcium excretion. Calcitonin infusion often lowers serum calcium to "operable" levels but usually has only a temporary effect. If other treatment fails, Mithramycin, which inhibits the bone absorption, has a dramatic effect on the hypercalcemia. Mithramycin treatment is, however, burdened with several side effects, of which some may be severe. 91

If possible it is important to t ry to localize a parathyroid adenoma by ultrasound. Preoperatively in some patients an adenoma may even be palpated. Compared to thyroid nodules, a parathyroid adenoma is soft and often tender.

PERSISTENT AND RECURRENT PHPT

Reexploration for PHPT involves morbidity for the patient and is sometimes frustrat ing for the surgeon. Accordingly an adequate primary exploration is the simple solution. However, the continuing need for reoperations proves tha t the issue is not yet resolved.

Persistent PHPT is defined as hypercalcemia still present at the time of the patient 's discharge and/or reappearing within one year after the operation. Recurrent hyperparathyroidism de- notes the reappearance of hypercalcemia after at least one year postoperative with normal serum calcium and phosphate levels in the interim.

We analyzed 53 patients undergoing reoperation for PHPT at the Karolinska Hospital over the 25-year period 1955-1979. 92

29

Twenty-nine of the patients had been operated upon previously at other hospitals. The diagnosis of PHPT was incorrect in 6 patients, true recurrences were found in 4, while the over- whelming part, 43 patients, had persistent hyperparathyroidism.

The four patients presenting with recurrent PHPT were all primarily operated on at our hospital with the removal of a typical adenoma. After periods of normocalcemia ranging from 5 to 18 years, they again became hypercalcemic because of parathyroid adenomas. In two of these patients we cannot exclude the possibility of tumor "spillage" at the initial operation, since the second adenoma was found at the same location as the first.

Of the 43 cases with persistent PHPT, two thirds (29 patients) were due to "surgical failure," and one third (14 patients) was due to incorrect pathologic diagnoses. Surgical failures occurred most often when there was a less-than-optimal exposure of the neck and adjacent regions at the pr imary operation. The histopathologic errors were due to incorrect diagnoses of adenomas in cases of parathyroid hyperplasia.

As many of the patients were referred from other hospitals, they give no true picture of the need for reexploration in PHPT. In a series of 461 patients operated on for pr imary hyperparathyroidism beween 1930 and 1979, 28 (6%) required reoperation. 92

All pat ients with persistent hyperparathyroidism do not re- quire operation. An asymptomatic patient with a moderately elevated serum calcium level should probably be observed ra ther than operated on, part icularly if the diagnosis is parathyroid hyperplasia and previous surgery resulted in adequate reduction of the serum calcium level. Since reoperation for pr imary hyperparathyroidism can be a demanding and difficult undertaking, a preoperative a t tempt to localize the source of disease should always be made. Not until the metabolic diagnosis is firmly established is the need for reoperation obvious.

The planning of a parathyroid reexploration includes: the aforementioned careful metabolic reinvestigations, localizing procedures, reexamination of histologic slides, a survey of the earlier operative report, and, if possible, a personal interview with the surgeon responsible for the first operation. It is helpful to summarize all available data on a schematic drawing before the reoperation.

We aim at postponing a reexploration until at least 4 months after the initial operation. In 15 of our 43 reoperations we have performed sternotomy and exploration of the mediastinum. This procedure proved necessary in only 5 instances, demonstrating the infrequent need for this procedure, as has previously been pointed out. 93' 94, 95

So far we have a cure rate of 83% in our series of reoperation 3o

for P H P T and no mortalities. The operative morbidity has been low. These results are comparable with those reported by other investigators.93, 94, 95, 96

PRIMARY HYPERPARATHYROIDISM AND MEN-SYNDROMES

Whenever hyperparathyroidism due to hyperplasia of the parathyroid glands is diagnosed, one must be aware of the possibility of coexisting multiple endocrine neoplasia. Already in 1903, Erdheim described the occurrence of multiple endocrine tumors in a patient with acromegaly. Autopsy showed a pitu- i tary adenoma and four enlarged parathyroid g l andsY Wermer proposed a familial basis for multiple endocrine neoplasia in 1954 and the enti ty carries his name, Wermer 's syndrome, which nowadays most often is called MEN I (Multiple Endocrine Neoplasia). 98 This syndrome includes: parathyroid hyperplasia, a pi tui tary adenoma, and pancreatic endocrine neoplasms.

Sipple in 1961 described 6 patients with thyroid cancer and pheochromocytoma. 99 Two years later, Manning reported pa- t ients with parathyroid hyperplasia in connection with these two tumors, and the syndrome was termed MEN II a or Sipple's syndrome. 16~ MEN II b, a var iant of the disorder, is character- ized by a concomitant marfanoid habi tus and multiple mucosal neuromas, lol

Multiple endocrine neoplasia syndromes are found in about 10% of patients with PHPT. In MEN I about 90% of the patients have parathyroid involvement, many of which have only mild hyperparathyroidism. In older patients, however, severe hypercalcemia with renal and bone complications are encountered, l~ In MEN II a, the corresponding figure is about 80%. 1~ Pat ients with MEN II b do not have hyperparathyroidism. 1~

The histopathology in MEN-associated hyperparathyroidism reveals primarily chief-cell hyperplasia. In MEN I patients the enlargement of the glands are often asymmetric. As sometimes only one gland may be clearly enlarged, the findings can be mis- taken for an adenoma. On the other hand, since a normal parathyroid gland contains about 50% fat, the active cell mass can be doubled without visible enlargement of the gland. If hyperplasia is not recognized preoperatively, there will be an inade- quate resection result ing in persistent hypercalcemia.

Reports of a high recurrence rate of hypercalcemia in MEN I syndromes have st imulated some surgeons to remove all parathyroid tissue and graft a portion of it into a forearm muscle. TM

However, our polic~} is to perform a subtotal parathyroidectomy at the pr imary operation. Whenever parathyroid hyperplasia is encountered, bilateral cervical thymectomy should be performed; thereby, the persistence of the hyperparathyroidism due to supernumerary glands, which may occur in up to 13% of the

31

patients, may be avoided. 1~ As extra glands can also be located in the fat surrounding normal glands, this fat should be excised as well.

POSTOPERATIVE HYPOCALCEMIA

A successful operation results in a normalization of serum calcium. The decrease becomes apparent within 2-3 days after the operation. When there is a dramatic decrease, even to subnor- mal levels, this is mostly due to "bone hunger," which occurs after correction of the hyperparathyroid state. The lowered serum calcium is in this situation linked with decreasing serum phosphate. The hypocalcemia can also be due to a too-aggressive surgery result ing in hypoparathyroidism. As the parathyroid hormone has a phosphaturic effect, this form of hypocalcemia is associated with an increase in serum phosphate.

When there is a rapid decrease in serum calcium concentration, clinical symptoms frequently appear. In fact, such symptoms may occur even when serum calcium levels are within the normal range. However, the increased tonic muscular contrac- tions are only a motor phenomenon, but in a wider sense the clinical picture is due to increased neural excitabil i ty) ~ The symptoms start with tingling of the finger tips and around the mouth, often followed by numbness. Muscle spasm may super- vene with adduction of the thumb, flexion of the metacarpopha- langeal joints together with extension of the interphalangeal joints, and flexions of the wrist and elbow joints (dacoucheur posture). Hyperventi lat ion may occur due to a reflex component of the syndrome or to anxiety.

Most patients experience only a la tent tetany. This may be diagnosed by tapping the facial nerve with the finger anterior to the ear just below the zygomatic process. This provokes twitch- ing of ipsilateral facial muscles (Chvostek's sign).

Symptom-free hypocalcemia in direct connection with surgery needs no t reatment , while patients with symptoms should re- ceive oral calcium. Usually the serum calcium becomes normal within a week. If symptoms of te tany appear, calcium should be administered by intravenous injection. It is mandatory to have the serum calcium levels determined before the calcium is administered to exclude the possibility tha t the te tany is caused by hyperventilation alkalosis.

Medication with calcium may provoke gastrointestinal symptoms such as diarrhea, abdominal cramps, and even hard stools. In those situations it is preferable to give vi tamin D instead. Most often we use Dihydrotachysterol. However, the more short- acting 1.25-Dihydroxycholecalciferol seems to control the serum calcium levels better in certain patients.

32

Every patient on vi tamin D therapy has to be informed about the reasons for the medication and its risks. Discontinuation of vi tamin D does not always lead to acute clinical symptoms. Prolonged hypocalcemia may cause such hazards as cataracts and mental slowing due to brain calcifications. 1~ The patients often recognize symptoms of hypocalcemia but must also be aware of signs of hypercalcemia as nausea, polyuria, and polydipsia. Hypercalcemia in a hypoparathyroid state is much more deleterious for the kidney function than when parathor- mone is present. Impairment of glomerular and tubular function occur early and may be irreversible in a short period of time.

The serum calcium levels may vary considerably even if the vi tamin D therapy remains unchanged. These patients have to be controlled three to four times a year. It is important to re- member tha t extensive sunbathing may increase the levels of vi tamin D. Accordingly the medication may have to be lowered if the sun exposure lasts more than one week.

MEDICAL TREATMENT OF PHPT

Medical t rea tment may be considered when surgery or medical follow-up alone is avoided, for example, in symptomatic pa- t ients who refuse surgery or are definitely unfit for surgery due to advanced systemic disease, such as pulmonary or cardiac in- sufficiency. Few studies on the medical management of pr imary hyperparathyroidism are well controlled, covering both possible beneficial effects on clinical symptoms and on serum-calcium.

INORGANIC PHOSPHATE

The earliest at tempts were made with inorganic phosphate, and recently a detailed evaluation of this therapy was reported; 2 of 10 patients improved in terms of symptoms. The conclusion being tha t oral phosphate was not a safe long-term antihyper- calcemic agent. 1~

~-ADRENERGIC BLOCKING AGENTS

These agents have been tried, without consistent beneficial effects, l~

CIMETIDINE

Initially reported as an effective agent in pr imary hyperparathyroidism, cimetidine has been proved inefficient in controlling hypercalcemia in primary hyperparathyroidism. 1~

33

DIPHOSPHONATES

Lately, several groups have tried diphosphonates (sodium etidronate or dichloromethylene diphosphonate), which are hy- drolysis resistant analogs of pyrophosphate and which inhibit bone resorption. In a double-blind, placebo-controlled, cross-over study completed in 14 patients, diphosphonates decreased serum and ur inary calcium. Serum calcium, however, was not consistent ly normalized. 11~ In another report, 7 patients showed similar changes in calcium and 2 of 7 patients were relieved from bone pain. 111 Some patients on prolonged t rea tment with diphosphonates have, however, developed osteomalacla. 112

ESTROGEN

Estrogen therapy in pr imary hyperparathyroidism has been tried during the last 15 years, but few reports on controlled studies have emerged. Estrogens inhibit bone resorption and lowers serum and ur inary calcium. It has been recommended as a t rea tment of patients who constitute the largest group, postmenopausal women with pr imary hyperparathyroidism, pro- vided that they lack a previous history of thrombosis or liver disease. A recent s tudy of interest on 14 postmenopausal women with pr imary hyperparathyroidism showed that 10 of the 14 patients were clearly responsive to the treatment; serum calcium became normal and remained so in 9 patients for up to 26 months. When stopping t rea tment the typical laboratory findings of pr imary hyperparathyroidism recurred. The report does not clarify whether the t rea tment improved any clinical symptom typical of pr imary hyperparathyroidism. 113 Our own experience with estrogen is limited, with a high frequency of drop outs.

PTH ANTAGONIST

The recent development and synthesis of a PTH antagonist, which can inhibit the action of PTH, may benefit patients with symptomatic pr imary hyperparathyroidism that cannot be cured by surgery. The analog consists of the amino acid residues 3-34, the domain of the nat ive PTH molecule, which is responsible for receptor binding. It lacks the critical region for hormone action, residue 1-2. Animal studies in vivo and in vitro are impres- sive. 114 Data on humans are still lacking. Since malignancy-associated hypercalcemia is mediated by factors which may inter- act with the PTH receptor, this analog ought to be beneficial also in treating malignancy-associated hypercalcemia. Today this hypercalcemia is symptomatically treated with glucocorticoids, calcitonin, and mithramycin.

34

HPT IN CHILDREN

Primary HPT is rare in infants and children. Until 1980 only 85 cases had been reported. 115 The signs and symptoms as well as the histopathologic diagnosis differ considerably between neonates and children older than 1 year. In neonates, the symptoms appear a few days or weeks after birth. Failure to thrive, lethar- gy, hypotonia, constipation, and respiratory distress may be seen. Serum calcium is notably high, usually above 3.70 mmole/1, somes even above 5.00 mmole/1. Most infants have skeletal abnormalities, such as demineralization of ribs and long bones, deformed lower extremities, and rib fractures. 116 All reported cases in this group have had parathyroid hyperplasia. 11~

The optimal t rea tment is total parathyroidectomy with auto- t ransplantat ion of parathyroid tissue, either at the initial operation or after cryopreservation of parathyroid tissue. If subtotal parathyroidectomy is performed, there is a considerable risk for persistent hypercalcemia. 117 The mortal i ty rate in the published cases was 50%. Recently a few cases of HPT in infancy associated with familial hypercalciuric hypercalcemia have been described, suggesting tha t a genetic defect may be responsible for the disorder. 11s' 119

In children older than 1 year the symptoms are nonspecific. Gastrointestinal symptoms such as dyspepsia, poor appetite, weight loss, abdominal pain, nausea, and vomiting are commonly seen. Nephrolithiasis and nephrocalcinosis are not uncommon. More than 90% of the children have a single adenoma and will be cured by its removal. With the more seldom-occurring hyperplasia, the patient will be cured by subtotal parathyroidectomy.

HPT IN PREGNANCY

Hyperparathyroidism during pregnancy is also rare. Never- theless, when it occurs, it is a serious condition associated with high morbidity in the mother as well as in the fetus. In a recent survey of the English literature, Kristoffersson and co-workers 198512~ found 72 cases of proven HPT during pregnancy.

Moderate hypercalcemia during pregnancy may be completely symptomless. Since routine analysis of calcium is not performed, many cases may go unnoticed. The only sign may be a tendency to hypocalcemia and te tany in the newborn child.

Calcium ions move freely across the placenta, while PTH cannot pass from the mother to the fetus. Thus, when HPT occurs in the mother, an increased serum calcium is found also in the fetus, leading to suppression of fetal PTH secretion. After birth, serum calcium falls rapidly and te tany may then occur, due to

121 parathyroid gland suppression. Severe hypercalcemia during pregnancy may be accompanied by unspecific symptoms typical

35

for pregnancy per se, such as nausea, muscular weakness, fatigue, menta l symptoms, and hypertension. Sometimes it is accompanied by urolithiasis, which draws the a t tent ion to the possibility of HPT.

The complication rate, if PHPT is not treated, ranges between 50% and 80% with neonatal t e tany being the most common disorder. More serious and not at all infrequent are stillbirths, spontaneous abortions, and neonata l deaths. 122' 120 Some authors recommend operation only in symptomatic hypercalcemia, 123 while others strongly recommend operation in all cases of veri- fled hypercalcemia. 12~ 124 The optimal t ime to perform the operation is during the second tr imester . Postoperatively it is essen- tial to avoid hypocalcemia in the mother, and rout ine t rea tment with a calcium supplement is advocated. 122

PARATHYROID CARCINOMA

INCIDENCE

The parathyroid glands rare ly exhibit mal ignant tumors. The most common form is the hyperfunct ioning parathyroid carcinoma, of which only about 120 cases have been reported in the literature.41, 91, 125-13s, 142-145, 156-157 Because of differing diagnostic criteria, the reported incidence varies between 0.5% and 4% of pat ients with pr imary hyperparathyroidism. 12~' 132, 136, 137 Since, however, the increased incidence of p r imary hyperparathyroidism experienced during the last two decades has not resulted in any increase in reports on parathyroid carcinomas, the t rue incidence is l ikely to be less than 1%.

In contrast to para thyroid adenoma, which has a 3:1 prepon- derance in womeln ~ parathyroid carcinoma is equally common in men and women. 1 6, 136 In addition, pat ients with carcinoma are often younger than those with benign para thyroid disease. Thus, the mean age found in independent l i tera ture reviews of 46 and 62 patients was 44 and 48 years respectively. 126' 134, 136

ETIOLOGY

The etiology of para thyroid carcinoma is unknown. There are a few reports on carcinomas occurring in connection with famil-

140 141 147 1 4 g ial hyperparathyroidism. ' ' ' In those instances concur- rent chief cell hyperplasia or adenoma were found. There are also reports on tumors obviously occurring within an adenoma

91 41 128 139 157 or in hyperplastic glands. ' ' ' ' It cannot be stated whether the reported cases represent chance occurrence or indicate an increased risk of mal ignant t ransformat ion in familial hyperparathyroidism or in hyperfunctioning glands.

36

S Y M P T O M S AND D I A G N O S I S

Symptoms of hyperfunctioning parathyroid carcinoma are mainly those of hypercalcemia. Thus, the symptomatology is similar to that in pr imary hyperparathyroidism. Since the serum calcium levels usually are markedly higher than those commonly seen in patients with benign parathyroid disease, the symptoms are often more severe. 126' i41 Of 41 patients reported in the l i terature and reviewed by Shane and Bilezikian, all but 1 were clearly symptomatic. 126 The most common symptoms were polyuria and polydipsia, occurring in 35% of the patients, followed by general weakness, fatigue, anorexia, nausea, vomiting, and weight loss. Renal and bone symptoms are frequent. Shane and Bilezikian found renal involvement in 37 of 47 eval- uable patients. Seventy-two percent of those had nephrolithiasis, and renal function impairment was recorded in 19 patients. Holmes et al., in an earlier l i terature review of 46 patients, found renal disease in 32 percent, many with symptoms of renal colic. 136 Skeletal disease appears in the form of osteoporosis, subperiostal bone resorption, and osteitis fibrosa cystica, with symptoms of bone pain and pathologic fractures. In Holmes's and Shane's series, involvement of the skeleton was reported in 73% and 53% respectively. 126' 136 Contrary to what is seen in benign hyperparathyroidism, concomittant renal and skeletal disease occur frequently. Acute, often recurrent pancreatit is has been reported in several patients, and anemia is more common than in patients with benign parathyroid dis- e a s e . 9 1 , 133, 134, ]36, 143

Although the diagnosis of parathyroid carcinoma is vir tual ly never established preoperatively and often not even at the primary operation, there are some signs which should raise suspicion. As previously pointed out, the hypercalcemia is often more pronounced in patients with carcinoma than in those with benign parathyroid disease. Schantz and Castleman, in a review of 70 patients, found an average initial serum calcium level of 3.8 mmole/1, with 62% of the pat ients showing levels above 3.5 mmole/1.15 The corresponding figures reported by Holmes et al. were 3.98 mmole/1 and 75%, and those of Shane and Bilezikian were 3.88 mmole/1 and 70%. 126' 136 These figures should be compared with the milder elevations of 2.75-3.0 mmole/1 usual ly seen in benign disease. There are usual ly very high levels of circulating parathyroid hormones and marked hypophospha-

91 128 1-38 temia. ' ' Serum alkaline phosphatases are often elevated. A striking difference from benign parathyroid disease is the

high frequency of a palpable neck mass. In benign parathyroid disease, a neck mass can be felt in less than 10% of the patients. 135 According to the reviews by Holmes et al., Shane and Bilezikian, and Schantz and Castleman, a neck tumor can be felt

37

in 30%-50% of the patients with parathyroid carcinoma.128, 138, 137 Unilateral paralysis of the recurrent laryngeal nerve in connection with hyperparathyroidism is another sign suggestive of cancer.

Most cases of parathyroid carcinoma have not been diagnosed at the first operation but only at the time of tumor recurrence.91,128, 138,157 The reason for this is the rar i ty of the disease, and the fact tha t there is no single diagnostic histologic feature to prove the diagnosis. Thus, recurrent hypercalcemia after a previous operation for hyperparathyroidism is suggestive of parathyroid cancer. This is particularly true if a single large gland was removed and the operation resulted in interim relief of the hypercalcemia for a significant period of time.

PATHOLOGY

Grossly, parathyroid carcinoma usually presents as a relatively large, often multilobular, parathyroid "adenoma," but with a firm consistency and surrounded by a dense fibrous capsule, which often gives the tumor a whitish color. In Schantz's and Castleman's review of 24 cases, the greatest diameter was an average 3.3 cm and the average weight, 12 gm. 15 The tumor is usually adherent to adjacent structures such as the thyroid gland, the muscles, the esophagus, and the recurrent laryngeal nerve, and it often grows invasively. Regional lymph node metastases can sometimes be found but seems to appear relatively late in the disease.

Microscopically the diagnosis can be difficult to establish. Shantz and Castleman, after reviewing the slides of 70 cases of parathyroid carcinoma, listed the following histologic features tha t distinguish a carcinoma from an adenoma or hyperplasia: 137 (1) trabecular pattern, (2) mitotic figures in parenchymal cells, (3) thick fibrous bands, and (4) capsular and blood vessel invasion. Of these features, they rated the presence of mitotic figures as the single most important criteria. However, there are reports on obvious parathyroid carcinoma in which no mitotic figures have been detected and, according to Snover and Foucar, mitotic activity is quite frequently seen in parenchymal cells of adenomas and hyperplasia, r49 Thus, the presence of mitotic figures may not be as reliable an indication as suggested. In a review of 14 cases van Heerden et al. found the criteria of trabecular pat tern to be of limited value and found the mitotic activity to be variable. 138 On the other hand, capsular invasion was obvious in all lesions they examined. They also noted a tendency towards more monotonous cell proliferation and a lack of the bizarre large cells frequently seen in adenomas. Other commonly seen features are calcification and necrosis. The ultrastructural appearance of parathyroid carcinoma has been ex-

38

amined by electron microscopy in a few instances, but no firm differentiation between benign parathyroid disease and carcinoma could be made. 13~ 131

TREATMENT

The t rea tment of parathyroid carcinoma is primari ly surgical. Although there has been some controversy about the initial surgical management , we, like most investigators, advocate radical excision of the lesion with ipsilateral thyroidectomy including the isthmus. Some surgeons have in addition suggested routine ipsilateral neck dissection of lymph nodes. 138' 13s In our opinion, this is unnecessary if the tumor is confined within the capsule and there is no apparent lymph node involvement. J a rman reported on 6 patients treated with excision of the tumor only. No recurrence was recorded during an average follow-up time of 4 years. 143 Since most recurrent parathyroid carcinomas reported on have been primarily misdiagnosed as benign disease and thus treated with local excision, this t rea tment appears insufficient.

To reach more gratifying results in the t rea tment of parathyroid cancer, it is of importance tha t surgeons keep the possibility of parathyroid carcinoma and its clinical appearance in mind. Only then can adequate resection be performed primarily. Care must also be taken to avoid rupture of the capsule and spilling of tumor cells, since such spilling may give rise to tumor growth.

If the primary operation is successful, still 30%-65% of the patients will develop recurrent disease. 138' 137 Local tumor recurrence is most common but metastases also appear, especially in cervical nodes (30%-32%), lung (10%-40%), liver (10%), and bone (7%). 128' 138-13s Recurrence manifests itself by rising serum calcium levels due to the release of parathyroid hormone from the recurrent tumor. Since patients dying from parathyroid carcinoma usually succumb from the effects of the hypercalcemia, recurrent disease should be treated with aggressive surgical excision of loco-regional tumor and distant metastases. Thereby the source of parathyroid hormone can be removed or at least reduced. As parathyroid carcinoma usually is a ra ther slow- growing tumor, significant palliation may be achieved for a considerable period of time by this approach. Only very rarely, though, may a patient with recurrent disease be cured.

When surgery is not effective, other modalities of t rea tment should be tried. Radiotherapy has been given to a limited number of patients but without significant effect. 128' 128, 138 Treat- ment with estrogen and testosterone, tried in a fewpat ients , re-

129 134 sulted in only minimal and transient success. ' There are only scattered reports on patients t reated with chemotherapy. Nitrogen mustard has been given to two patients without effect.13-4. 1so In one patient, a combination of fluorouracil, cyclo-

39

phosphamid, and dacarbazine resulted in the complete disappearance of pulmonary metas tases and regress of hypercalcemia for over 5 months. 157 Chahinian e t al. t reated o n e patient with a combination of methot rexate , adriamycin, cyclophosphamide, a~d CCNU and reported par t ia l disappearance of metas tases and clinical improvement for a period o f 18 months, 151

Mithramycin, a cytotoxic antibiotic mainly used in the treatment of testicuIar carcinoma, has been proved effective in the t rea tment of hypercatcemia from many different causes and also has been successful in a few patients w i t h parathyroid carcinoma.91, 152, 153 It is a potent inhibitory of R N A synthesis and inactivates osteoclasts despite the presence of high levels of parathyroid hormone. 1"~4' t55 Although it has no apparent effect on the tumor itself, its effect on the hypercalcemia is prompt. Mithra- mycin, which must be given intravenously, has several severe side effects which are dose-related and quite common, Those include: bone marrow depression, hypokalemia, and renal, hepatic, neurologic, and gastrointestinal toxicity. However, by t i t rat ion of the lowest possible effective dose, hypercalcemia m a y be kept under control with Mithramycin infusions for long periods of time. 91

Other drugs, including chelating agents, sodium sulphate, steroids, calcitonin, and phosphate, could also b e tried. From a theoretical standpoint, calcitonin should be the drug of choice, because of its ability to inh ib i t the parathyroid hormone-stimulated bone resorption and its lack of toxic side effects. However, an encouraging initial effect o f calcitonin is often difficult to susta in for more extended periods of time.126, 133, 152, 153, 156

PROGNOSIS

The ul t imate prognosis of patients with parathyroid carcinoma is poor. 126' 12v, 135, 136, 136 The 5-year survival appears to :be less than 50% and the 10-year survival less than 35%. However, since most pat ients die from their sustained parathyroid hormone excess, significant palliation can be achieved with re- peated surgery and medical t r ea tmen t a imed t o control t h e hypercalcemia.

With more tumors being recognized a l r eady at: the primary operation and thus adequately resected, more gratifying results could be expected in the future.

NONFUNCTIONING PARATHYROID CARCINOMAS

Whether nonfunctioning parathyroid carcinoma exists has been a question of controversy. The lack of clear-cut diagnostic histologic criteria, and the histologic resemblance to other ma-

40

l ignant tumors, such as follicular thyroid carcinoma and meta- s ta t ic hypernephroma, and the rar i ty with which such tumors will occur, makes its existence difficult to prove. Holmes et al. accepted four cases for the diagnosis, t36 Two more cases were reported by Aldinger et al. in 1979 and another patient by Chahinian in 1981.12s' 151 Based on these scattered reports, it is impossible to make any statements regarding the clinical behav- ior and prognosis of these tumors, but at the University of Texas M.D. Anderson Hospital, in two cases, the outcome was poor.*

HYPERPARATHYROIDtSM AND MALIGNANT TUMORS

Malignant neoplasms are a common cause of hypercalcemia. The development of hypercalcemia in patients with bone metastases has mainly been at tr ibuted to osteolysis by the metastases with release of calcium and phosphate. 15s In patients without bone involvement, hypercalcemia may be the effect of altered bone metabolism caused by different, tumor-released, hormone- like substances. Thus, some tumors, especially bronchial carcinoma and hypernephroma, may secrete a peptide with parathyroid-like immunoreactivity. 1~9-167 This condition has been termed pseudoparathyroidism. 1~1 Also, members of the prostaglandin family and vitamin D-like sterols, released by tumors, may cause hypercalcemia. 15s The biochemical mechanisms responsible for hypercalcemia associated with mal ignant tumors are discussed elsewhere in this article.

Except for tumor-related factors, the hypercalcemia in malig- nan t disease could be caused by other concomitant conditions, such as sarcoidosis, hyperthyrosis, and primary hyperparathyroidism. In 1970, Katz and co-workers reported the findings on 6 women with breast cancer who were found to have coexistent pr imary hyperparathyroidism, l~s Four of the patients had parathyroid adenomas and 2, hyperplasia. The following year, the same group of investigators presented a retrospective study aimed at finding out whether there was an increased incidence of mal ignant tumors in patients with parathyroid adenoma. 169 One hundred and four patients with a surgically confirmed parathyroid adenoma and 62 patients with adenomas found at autopsy were compared with a control group of 200 consecutive autopsies with similar age and sex distributions. They found tha t 42% of the patients with adenomas detected at autopsy and 16% of those with surgically confirmed adenomas had mal ignant tumors of other organ systems. The incidence was markedly lower in the control group. The authors also reviewed the liter-

*Anderson B.J., Samaan N.A., Sassilopoulou-Sellin R., Ordonez N.G., Hickey R.C.: Parathyroid carcinoma: Features and difficulties in diagnosis and management. Surgery 94:906-915, 1983.

41

ature and found reports on an additional 75 patients with parathyroid adenomas and mal ignant tumors. The major anatomical sites of the malignancies were, in decreasing order, the gastrointestinal tract, the breast, the thyroid, the genitourinary tract, the respiratory tract, and the skin.

Farr et al. in a retrospective study from Memorial Sloan-Ket- tering Cancer Center found tha t 34 of 100 patients with confirmed parathyroid ~denoma had cancer diagnosed either ante- cedent, coincident, or subsequent to the hyperparathyroidism. 17~ Also in that study, cancer of the gastrointestinal tract and the breast were the tumors most commonly encountered. A parallel survey at the New York Hospital revealed a cancer incidence of 10% in patients with primary hyperparathyroidism, and Kre- mentz et al. recorded an incidence of 18% in a study of 100 patients. 171

Following these retrospective studies, other investigators have focused on the same problem. Thus, Samaan et al. recorded tha t 9 of 23 patients operated on for pr imary hyperparathyroidism had mal ignant tumors of different origin, and Purnell and co- workers found 15 cases of hypernephroma among 1,600 patients with primary hyperparathyroidism. 172' 173

At Karolinska Hospital 147 consecutive patients operated upon for primary hyperparathyroidism during the years 1973- 1978 were studied regarding the incidence of neoplasms. 174 In the study, the recorded incidence was compared with the expected age-specific incidence for various tumors in a comparable group of patients as calculated from the incidence of neoplastic diseases registered in the Swedish Cancer Registry during the years 1958-1972. The figures were also compared with those recorded in a group of 195 patients with the same age and sex distribution and undergoing cholecystectomy during the years 1974-1976. Twenty-four of the patients with primary hyperparathyroidism had a mal ignant tumor diagnosed prior, concomitant, or subsequent to the diagnosis of hyperparathyroidism. According to the Cancer Registry, the expected number of ma- l ignant tumors in a population of the same size and with the same sex and age distributions was thirteen. In the cholecystectomy group, 13 patients with mal ignant tumors were found. Thus, the incidence of mal ignant tumors in the patients with hyperparathyroidism was almost twice that calculated from the Cancer Registry and tha t found in the control group. However, another similar Swedish study on 441 patients with hyperparathyroidism failed to reveal any increase in the incidence of ma- l ignant neoplasms, and preliminary data from an ongoing survey of 939 patients who were operated on in Stockholm between 1970 and 1982 indicate no association between parathyroid adenomas and mal ignant neoplastic disease. 17~' 176

42

Since Ogburn and Black in 1956 observed 4 patients with primary hyperparathyroidism and nonmedullary thyroid carcinoma, there have been several reports on the association between these two diseases. 171" 177-ts6 According to the literature, between 3% and 11% of the patients with pr imary hyperparathyroidism harbor a coexisting, nonmedullary thyroid carcinoma, a prevalence higher than expected. To explain this association, several possible etiologic factors have been suggested, such as the goitrogenic effects of calcium, genetic factors, excessive calcitonin production because of the hypercalcemia, and prior external irradiation to the head and neck region.iTs-is1, 1s4-1s9 Of those, external irradiation to the head and neck region has been the most extensively investigated and today a number of studies support the theory of prior irradiation as a common etiologic factor in inducing thyroid and parathyroid tumors. 184-~87

In conclusion, some evidence suggests tha t patients developing pr imary hyperparathyroidism may be more prone to develop mal ignant tumors than others. The evidence seems con- vincing with regard to nonmedullary thyroid carcinoma. As to other neoplasms, several studies suggesting an association between cancer and hyperparathyroidism have been conducted at cancer t rea tment centers, and the observed association may very well be at tr ibuted to the specific pat ient populations in those centers. Since other investigators have failed to show an association, it is obvious tha t further, well-controlled studies are needed before any final s ta tement can be made. Neverthe- less, it deserves sharp at tention tha t pr imary hyperparathyroidism may be the cause of hypercalcemia in patients with mal ignant tumors. By a low-risk operation, patients with this condition may be readily relieved from the symptoms and the destructive effects of the hypercalcemia tha t in fact may be a more immediate threa t to the patient 's life than the cancer itself.

PARATHYROID METASTASES

In clinical practice, metastatic disease to the parathyroid glands is a rare finding. However, in autopsy studies frequencies

109 192 as high as 12% have been reported. - The most common primary tumors causing parathyroid metastases are breast cancer, leukemia, mal ignant melanoma, lung cancer, soft-tissue sar- coma, and lymphoma. There are also three reports of metastases found in parathyroid adenomas. 193-195

Apparently, metastases to the parathyroid glands mainly reflects widespread tumor dissemination. Their clinical signifi- cance should be negligible.

43

ACKNOWLEDGMENT

For excellent secretarial help, we are deeply in debt to Miss Ann-Cathrin Hjorth and for skillful artistic help we thank Mrs. Inga Nordlander.

The study was supported by the Swedish Medical Research Council (MFR 02330), Karolinska Institute, Torsten and Ragnar S6derbergs Stiftelser and CancerfSreningen in Stockholm.

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Parathyroid tumors