ORIGINAL ARTICLES
TWENTY YEARS' EXPERIENCE W I T H PARATHYROID
EXPLORATION
J. FREIDIN Prince Henry's Hospital a n d Monash University, Department of Surgery, Melbourne
Eighty-four patients have undergone surgical exploration following a clinical diagnosis of hyperpathyroidism over a 20-year period. Urinary tract calculi were the major indicationfor exploration,and 90% of these patients had recurrent calculi. Osteitis fibrosa was a rare presentation of hyperparathyroidism. Lethargy, sometimes profound, was an important symptom, in some instances the dominant feature. Persisitent hypercalcaemia remains Ihe chief diagnostic investigation, with helpful confirmation from estimation of the parathyroid hormone level. Little attempt was made in this series to utilize preoperative localization techniques, reliance being placed on meticulous bloodless surgery to find normal and abnormal parathyroid tissue. Eight-five explorations were carried out in the 84 patients. Seventy-four of the explorations were successful, converting the patient lo a normocalcaemic state. Of these, 63 had a single adenoma (86%).
HYPERPARATHYROIDISM is a relatively uncommon indication for surgery, even within the wider field of endocrine surgery, but to the afflicted patient, the arrival at a correct diagnosis and the subsequent appropriate surgical management are of vital importance. The best results are obtained where an expert endocrinological team is complemented by a surgeon trained in recognizing parathyroid tissue and versed in anatomical variations of parathyroid development, together with a team of pathologists prepared to make confident pronouncements on minute fragments of tissue examined by frozen section techniques. Eighty-four patients were subjected to surgical exploration for hyperparathyroidism from December 1957 to March 1978. All by two of the operations were carried out in one institution, Prince Henry's Hospital, in order to have available the services of its team of pathologists and thus ensure uniformity in frozen section reporting. All patients had their biochemical estimations either performed solely at Prince Henry's Hospital or else repeated there for the sake of uniformity. S e x distribution. - There were 46 females and 38 males in the series of exploration. One female patient underwent two operations three years apart. Age distribution. - There was a wide distribution of age incidence at the time of exploration, with Reprints: 24 Collins Street. Melbourne
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maximal incidence in the fourth and fifth decades (Figure 1). INDICATIONS FOREXPLORATION The chief presenting symptoms of the 84 patients who underwent surgical exploration were analysed and placed into appropriate groups (Table 1). Several facts emerge from an analysis of the presenting problems. (1) Recurrent renal calculus disease is the chief presentation. (2) Relatively few cases are diagnosed with their first stone. If a more aggressive investigation policy were followed with each new case of renal calculus, fewer patients would go on to the risks attendant upon repeated stone formation. (3) Osteitis fibrosa is a rare presentation of hyperparathyroidism. (4) Patients with profound fatigue undergoing diagnostic tests should have serum calcium estimations included in their investigations, as lethargy and accompanying depression may be the sole symptoms of hyperparathyroidism. (5) Thirst, polyuria, and abdominal pain have not been major features of hyperparathyroidism. If one combines the data related to age and sex distribution with the presenting symptoms, then it 26 1
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*O
NUMBER
I
OF CASES
I I I
15
7
.
'
10
5
AGE FIGURE 1: Histogram showing age incidence of patients subjected to operation.
will be seen that the group of patients most likely to suffer from hyperparathyroidism are young or middle-aged women, who have developed kidney stones and admit to unusual tiredness.
Diagnosis The biochemical abnormalities necessary to confirm suspicion of hyperparathyroidism are hypercalcaemia, hypophosphataemia, a level of serum chloride in the upper ranges of normal, and an elevated parathyroid hormone level. Hypercalcaemia is the central investigation and should be looked for in every case of renal colic TABLE 1 Chrel Presenting Features Leading fo Explerafion
~___--___
______
URINARY TRACT CALCULI Recurrent renal calciili First presentalien renal calctilus Haematiiria and nephrocalcinosis SYMPTOMS RELATED TO HYPERCALCAEMIA Fatigue Persistent hvoercalcaemia after thyrotoxiiosls control Asymptomatic hypercalcaemia BONE DISEASE Primary osteitis fibrosa Osteitis fibrosa secondary to chronic renal failure ENDOCRINE Multiole endocrine adenoma with pancreatic islet cell tumours OTHER Pancleatitis and hypercalcaemia Milk-alkali syndrome?
262
___
NO of Patients
Approx
58 6 2
69 7 25
%
6
7
1
1
1 1
2
25
4
4
1
2 1 -~
1
2.5 1
where a radio-opaque calculus is shown on the Xray film, and even if this is not present, suggesting that the stone has been passed. T o delay biochemical investigation until recurrent calculi are evident puts the patient at risk of all the well-known complications of obstruction to the renal tract from stones. A minimum of three estimations of calcium and phosphate levels should be requested, either on successive days or spread over a week or two. I t is imperative that both the patient and the laboratory be aware that the blood should be taken early in the day, following a period of overnight fast, and that the venous tourniquet used to distend the forearm vein be let down for 15 seconds before the blood is drawn. This diminishes the risk of artifically high readings of the serum calcium level. The laboratory chosen for estimation should be one that gives consistently accurate results. The accepted range of normal serum calcium is 2.2 to 2.70 mmol/l. If three estimations fall in the middle of this range, the matter need not be pursued further, but recurrent stone formation should be followed by further biochemical tests. Three levels of calcium above the normal range with corresponding low phosphates and a high parathyroid hormone level are an adequate basis for surgical exploration. Difficulties are encountered when only one or two estimations are high and perhaps only just above or just below the upper range of normal, e.g., 2.69 or 2.72 mmol/l. Such patients are very likely to have hyperparathyroidism as the cause of their renal calculus, since it is characteristic in those patients with hyperparathyroidism who have had a large number of estimations of serum calcium performed to find a wide fluctuation in levels. The fluctuation is set about a high mean, at or above the upper limit of normal. Presumably this is due to a variation of output of hormone by the adenoma. Thus patients with calcium levels near the upper limit of normal should be referred for three, six, or nine more serum calcium estimations until a general pattern emerges of high normal and above-normal readings. Many patients with calcium levels not higher than 2.72 mmol/l have been explored successfully. Patients with recurrent renal calculi with normocalcaemia have been rejected for exploration in this series. Hypophosphataemia is usually present, but may be less pronounced if there is a degree of renal impairment. High levels of serum chloride (106 mmol/l) are usually present, but are not in themselves an adequate indication for exploration. A high alkaline phosphatase level is seen only in a bony case and is therefore a rare biochemical finding. The finding of a high alkaline phosphatase AUST.N.Z. J. SURG.. VOL.48-No. 3, JUNE, 1978
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level with renal calculus diseaseshould in fact make one look for a cause of rapid bone turn-over other than hyperparathyroidism. Clinically there appears to be a dichotomy between renal and bony presentation of hyperparathyroidism, each presentation remaining the same even when it is obvious that the disease has been present for 10 or 15 years. Abnormally high levels of calcium in the urine are not always present; thus failure to show elevated urinary calcium excretion does not negate the diagnosis of hyperparathyroidism. Hence 24-hour collection of urine for calcium estimations have been abandoned in the last 10 years or so in this series. The availability of reliable estimation of parathyroid hormone has been a welcome addition to investigations. However, at the present time, ifthe parathyroid hormone assay is equivocal, the test s h o u l d be i g n o r e d p r o v i d e d that calcium, phosphate and chloride levels are appropriately abnormal. So far, no case showing the combination of normocalcaemia and elevation of parathyroid hormone level has been seen. Should the elevation be definite over repeated estimations and be associated with recurrent calculi, a strong case could be made for surgical exploration. The f i n d i n g of hypercalcaemia requires considerations of other causes of this abnormality before hyperparathyroidism is accepted. In fact, malignant disease ( w i t h or w i t h o u t b o n y involvement) and multiple myeloma are commoner causes of hypercalcaemia than hyperparathyroidism. The use of thiazide diuretics, sarcoidosis, excessive intake of vitamin D, hyperthyroidism, and the milk-alkali syndrome, should be considered in the differential diagnosis. An important aspect of the differential diagnosis of hypercalcaemia is that only hyperparathyroidism is associated with renal calculi. Thus the more difficult cases are those without stones. In this series a few patients were subjected to measurement of tubular reabsorption of phosphate, but subsequently this test was abandoned because of equivocal results. As in all endocrine tumours, estimation of excessive hormone production should ultimately become the most reliable index of abnormal activity. Estimation of the serum calcium level is a more indirect investigation, but it has stood the test of time by its reliability.
Expioration for Hyperparathyroidism Of 85 explorations, 10 have failed to reveal an abnormality of the parathyroids and therefore must AUST N.Z. J. SURG, VOL 48-No
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be classed as failed explorations. One patient underwent exploration of the neck which revealed four normal glands, and three years later had her mediastinum explored, but no adenoma could be found. Another patient had only two normal glands discovered in the neck, but he subsequently proceeded to a dramatic fall in serum calcium and tetany, a syndrome which never occurs i f afunctioning adenoma has been left i n the neck. Table 2 lists the incidence of failures in five-year blocks. The data suggest a poor rate of selection in TABLE2 Results of 85 explorations
1957-1963 1 964-1968 1969-1973 1974-1978
in 5-year blocks
Success
Failure
4
5 1 1 4 11 -
22 20 28 74 -
the first five years of surgery for hyperparathyroidism, with a more acceptable surgical result thereafter. Some details about the failed explorationsand the possible causes of the patients’ symptom are listed in Table 3. THEOPERATION Ideally, accurate preoperative localization of the hyperfunctioning parathyroid tissue would be invaluable to the surgeon. Various techniques have been tried, the simplest of which is a barium swallow X-ray examination to demonstrate a retrooesophageal adenoma. Isotope scanning on the whole has been unrewarding. Arteriography may show a tumour by its vascular blush. Venography with venous sampling for parathyroid hormone assay has many advocates (Bilezikian et alii, 1973, Doppman et aiii, 1968). The techniques of vascular radiology need a degree of expertise which radiologists can only acquire in centres with a large number of cases. Computerized axial tomography may be found to be of value in the future. In practice, sufficiently good results appear to have been achieved by following a meticulous surgical approach. Arteriography and venography have not been requested, with one exception, the case of unrewarding exploration of the neck which revealed four normal glands. Venography and venous sampling performed on this patient suggested a general rise in the level of parathyroid hormone in the neck and mediastinum, but a mediastinal exploration three years later failed to
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TABLE3 Analysis of Unsuccessful Explorations Year
Sex
Age [years)
1959
M
27
1960
M
44
1961
M
46
1962
F
46
1963
F
77
1966
M
28
1973
M
60
1974
F
60
1977
F
63
1975
F
63
1977
M
53
1977
F
77
Definitive diagnosis
Indicalion foi exploration'
Operative findings
Recurrent calculi. calcium 12 3 mq/100 mi Recurrent calciili. calcium 12 0 mgl100 ml Fatigue. duodenal ulcer. calcium 12 0 mgI100 ml Recurrent calculi. calcium 11 9 mgf100 ml
4 normal glands
Unk now 11
3 normal glands
Unknown
2 normal glands
7 milk-alkali
Fatigue, renal impairment, calciiim 11 2 mgI100 ml Reciirrent calciili. calcium 11 5 mgllOO ml Recurrent calcdi. calcium 12 0 mgl100 ml Reciirrent calculi. calcium 12 4 mgI100 ml Recurrent calculi. calcium 12 4 m g l l 0 0 ml Recurrent calculi calcium 2 75 mmolll Recurrent calculi. calcium 2 80 mmolIl Lethargy, calcium 2 74 mmolll
4 normal glands 4 slightly enlarged glands 2 normal glands, unexpected tall of calcium to 7 5 mg % 4 normal glands, Subtotal thyroidectomy 4 normal glands Mediastinal exploration but n o abnormality found 2 normal glands
syndrome Unknowri mediastiiial adeiioma 7 secondary hyperparathyroidism 7 infarcrioii o f undetected adenoma 7 mediastinal adeiionia 7 mediaslinal adenoma Unknown
Unknown
4 normal glands
Unknown
Neck exploration abandoned due l o dense adhesions from thyroidectomy 30 years previously
undetected adenoma in the neck 7
' Prior to 1975 Serum Calcium expressed in mgl100 ml Following 1975 Serum Calcium expressed i r i mmol/l
has a group of small vessels supplying it or has a vascular pedicle which may arise from the surface of the thyroid, the oesophageal wall, or the fat lying below the thyroid gland. The embryological development of the parathyroid glands influences their ultimate location (Langman, 1975). The inferior gland arises from the dorsal wing of the third pharyngeal pouch, the thymus arising from the ventral wing. As the thymus migrates into the anterior mediastinum, it pulls the parathyroid gland down with it. The inferior gland of the adult may thus be found on the lower pole of the thyroid gland, in the fat below its lower pole, or within the thymus itself, either in the tongue of thymus which protrudes above the manubrium or in the deeper section in the anterior mediast in um. The fourth pharyngeal pouch gives rise to the superior gland of the adult. The gland becomes attached to the side of the thyroid during the latter's downward migration and comes to rest on the lateral aspect of the sharp posterior edge of the thyroid gland, near the upper pole (Figures 2, 3). In addition to the wide range of position of parathyroid tissue dictated by development, there 264
show any abnormality. An attempt to reexplore the neck was abandoned because of dense adhesions between the thyroid gland, the strap muscles, and the carotid sheaths. The surgeon embarking on parathyroid surgery must be familiar with the appearance of normal and abnormal parathyroid tissue and also be conversant with the anatomical variations in the position of the glands. Normal parathyroid glands are flat, of oval shape, and measure approximately 4 m m x 6 mm, with a thickness of 2 mm. They are often embedded in fat. When teased out of the fatty tissue, they are found to have a shiny and smooth surface with a characteristic light brown colour. To discover these glands it is vital that no blood should stain the operative field, since blood-stained fat and bloodstained parathyroids are indistinguishable to the naked eye. The blood supply to the gland arises from whatever structure the parathyroid happens to be resting on. There is no support in this series for the statement sometimes made that the blood supply comes frequently from a branch of the inferior thyroid artery and that tracing out this artery will lead to an adenoma. In practice, an adenoma either AUST N.Z. . i sURG,
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FIGURE2 Side veiw of the thyroid gland with the parathyroids in black The superior parathyroid sits on the side of the thyroid, near its posterior border close to the superior pole vessels The lower parathyroids are more inconstant in their/ position and may be found on the side of the lower pole of the thyroid, below the gland or within the thymus The middle thyroid vein is also shown
SP
SQ
9: SUPERIOR PARATHYROID FIGURE3: Transverse section at the level of the upper pole of the thryoid gland. The superior glands are seen to lie well to the back, close to the sharp posterior edge of the thyroid and in proximity to the oesophagus. Division of the middle thyroid vein is necessary to roll the thyroid up out of its bed.
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~
also appear to be mechanical influences that place adenomas at positions remote from the normally accepted anatomical locations. These influences are thought to be large size of the adenoma and swallowing movements. When a superior parathyroid cannot be located in its usual position, a large adenoma may be revealed behind the oesophagus, remaining quite undetected until a deliberate search is made for it. Such an adenoma may migrate down into the posterior mediastinum. When an inferior gland cannot be found on the lower pole of the thyroid, a wide search should be made to include the full depth of tissue from the deep fascia to the cervical spine. If unsuccessful, the search continues into both the anterior and the posterior mediastinum. The thymus is identified by its smooth contour and opaque pale-yellow colour which stands out from the deeper yellow lobular fat. The upper poles of the thymic lobes can be dissected out between the inferior thyroid veins, above the manubrium, traced into the anterior mediastinum, and pulled up. If no lower parathyroid tissue can be identified, a worthwhile manoeuvre is to excise as much thymus as presents in the neck and then to cut it into fine transverse slices looking for a normal or enlarged parathyroid gland. The brown colour of parathyroid tissue makes a vivid contrast against the pale yellow thymus. The glands of the upper and lower groups are not necessarily situated at the same levels on the two sides. However, the correlation of levels is sufficiently good, that having found two glands on one side, the surgeon should proceed to look forthe other two glands at corresponding levels on the other sides.
THESURGICAL PROCEDURE The position of the patient on the operating table is similar to that for thyroid surgery. A low collar incision is made, with elevation of the upper flap to the level of the upper edge of the thyroid cartilage and of the lower flap to the top of the manubrium. Division of the deep fascia in the midline vertically is followed by elevation of the deep fascia and strap muscles from the thyroid gland. Horizontal division of the fascia and strap muscles is optional, depending on the ease of exposure. The surgeon now concentrates on a thorough search of one side of the neck. The middle thyroid vein is identified, divided, and ligated. Three stay sutures are inserted through the substance of the thyroid lobe on each side, avoiding surface veins. This is done in order to roll the gland up out of its bed and to reveal its posterior border. This is made
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SURGERY FOR HYPERPARATHYROIDISM
possible by the previous division of the middle thyroid vein. The search is commenced for normal parathyroid glands, parathyroid adenoma, or hyperplastic tissue. A thorough search should be made on the side initiallychosen until twoglandsarefound. Failureto discipline oneself to makea thorough search on one side means that one is left in doubt whether to pursue a difficult exploration on one side or the other, if only one gland has been found on each side. If two normal glands are found on a particular side, then that side need not be explored further. The field must at all times be kept free of blood. Any spilt blood must be immediately washed out with saline and mopped up with swabs. The sucker must not be used, as a previously identified parathyroid gland is so delicately attached to its bed (usually the thyroid gland) that it can disappear up the sucker. The operation is carried out in conjunction with an experienced pathologist. Ideally, four glands will be identified, one of which is an adenoma. The adenoma is recognized b y i t s naked-eye appearance, being usually dark brown, oval, shiny, with its greater diameter approximately 1.5 c m in an average case. A portion of the suspected adenoma is excised and subjected to frozen section examination for confirmation of parathyroid structure. It is essential to d o this, as even with experience, one can mistake a pigment-laden lyrnphnode, or one bruised by the dissection, for a parathyroid adenoma. The normal glands are also subjected to biopsy for histological confirmation of the diagnosis. A fragment of 1 mm3 is cut off with fine scissors from one end of the oval gland. This procedure is perfectly safe, as even in those cases of hyperplasia where three glands are completely removed and the fourth normal gland subjected to biopsy, there is no evidence of permanent hypocalcaemia. Biopsy is followed by bright red capillary bleeding from the cut surface of the gland. Diathermy or ligature should not be used to control bleeding because of the risk of damaging the tissue by such measures. Gauze pressure stops the bleeding. Failure to demonstrate a gland in its usual anatomical position leads to a search being made behind the oesophagus or in the anterior mediastinurn as far as is possible by a cervical approach. In the classical case where all four glands have been identified and one of them is the seat of an adenoma, the adenoma is removed (Figure 4). There is debate whether it is adequate to remove an obvious adenoma or to d o a more extensive resection. the argument has been used that there is
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FlGURE4: Exploration for adenorna behind the oesohagus in a case where the upper parathyroid cannot be located. After division of the middle thyroid vein and rolling the thyroid gland out of its bed with three stay sutures, the inferior thyroid artery and the recurrent laryngeal nerve are identified. The index finger explores behind the oesophagus down to the posterior rnediastinum.
a risk of recurrence unless in all cases three or three and a half glands are removed. The author’s experience is that removal of the obviously abnormal tissue suffices, and one should not routinely do a three and a half gland parathyroidectomy. There have been no known cases in this series of recurrent hyperparathyroidism except the failed explorations where hypercalcaemia has persisted in some instances. Once the obviously abnormal tissue has been removed, either adenoma or hyperplastic glands, and provided that there has been the rapid fall of serum calcium 48 hours following surgery, recurrent hyperparathyroidism has not been seen. In summary, all four glands should be identified and their nature confirmed by biopsy. An obvious adenoma is excised. If no obvious adenoma is found, the larger two of the fourglandsare removed in the hope that one or other will contain a microadenoma. Should the enlargement of the glands appear to be hyperplastic, then all these glands are removed. In practice, one is then left with one normal gland, a small part of which has been subjected to biopsy. Mediastinal exploration may be carried out forthwith after a failed cervical exploration, but this is an unusual step. More commonly the patient is AUST.N.Z. J. SURG., VOL.48-No. 3, JUNE, 1978
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reinvestigated to confirm persistence of the biochemical changes of hyperparathyroidism, radiological investigations with venous sampling are carried out, and mediastinal exploration is then carefully considered. PATHOLOGICAL FINDINGS Table 4 lists the incidence of the various pathological states encountered in this series. The commonest pathological abnormality was single adenoma. No case of carcinoma was encountered. TAELE4 Palhological Findrngs in 74 Successful Explorafions
No of Patients
Approx
63
a8
1
1
Oto
~
Siriqle parathyroid adenoma Two parathyroid adenomas Parethyroid adenomas (3)with pancreatic islet cell adenomas Multiple qland hyperplasia of 3 qlands of 4 qlands Tertiary hyperparathyroidism of 4 qlands of 1 qland
1
1
4 1
46 1
3
34
-1
1
74 -
1000
Single adenoma. - The average size of a single adenoma was 1.5 cm in the greatest diameter. One retrooesophageal tumour arising from an upper parathyroid gland measured 7.5 cm. At the other end of the scale some single adenomas were really "microadenomas" in so far as these adenomas only measured 3 mm in diameter and were completely surrounded by normal parathyroid tissue. Such microadenomas produce slight enlargement of the parathyroid gland without the dark brown colour coming through. Thus when-all four glands have been localized and none looks obviously adenomatous. one should decide whether to remove one or two of the larger ones. This has proved to be a useful procedure, as in some cases the serum calcium has dropped to a low level even before the pathologist was able to report the presence of a microadenoma on paraffin section examination. The histological appearance of normal parathyroid tissue is characterized by cords of epithelial cells with intervening areas of fat cells. The cells are typically chief cells or oxyntic cells. In an adenoma the outstanding feature is the absence of fat cells. The sheets of epithelial cells are either chief cells or "water-clear" cells. Some adenomas show cystic changes consistent with an acinar structure, which AUST N.Z. J. SURG..VOL. 48-No
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the pathologist must be careful not to confuse with thyroid acini. Hyperplasia Hyperplasia of multiple glands is difficult to separate dogmatically from multiple adenomas. Statistically, multiple large adenomas are rare as a primary cause of hyperparathyroidism; there was only one case in this series. Hyperplasia is relatively more common. Hyperplastic glands usually have a more irregular surface than adenomas. being somewhat pseudopodial. In chronic renal failure of long standing, including transplant patients, the secondary hyperplastic glands become progressively autonomous. These patients develop progressive hypercalcaemia in the presence of hyperphosphataemia. Clinically hyperparathyroidism, said to be "tertiary" is heralded by bone pain. X-ray examination and bone biopsy reveal all the classical features of osteitis fibrosa. In fact, this situation is a commoner cause of osteitis fibrosa than primary von Recklinghausen's disease. In the three cases of tertiary hyperparathyroidism where four large adenomas were found, all four glands were removed, curing the bone pain, but causing profound hypocalcaemia and tetany which were difficult to control. In one case of chronic renal failure with the classical bone changes of osteitis fibrosa. a single large adenoma was found together with two other normal glands. Removal of the adenoma produced a drop of the serum calcium level to 1.95 rnrnol/l, with tetany within 48 hoursand cure of bone pain. Thus the doubt arose whether the adenoma was primary or "tertiary". Anatomical localization. - Figure 6 shows the distribution of 63 cases of single adenoma. It will be seen that no particular gland position is favoured by the adenomatous process. INVESTIGATION POSTOPERATIVE No matter h o w successful the surgical exploration appears to be, the hyperparathyroid state cannot be considered to have been cured until a sharp drop of the serum calcium level to within the normal range has been demonstrated. Usually this occurs in the first 24 hours and is maximal at 48 hours. Patients experience tetany even when the serum calcium is still with the normal biochemical range. Presumably this happens because of the sharp drop of calcium and internal cellular readjustments (Figure 5). The patient must be warned that the early symptoms of tetany are a sensation of tingling around the mouth and at the tips of the fingers. It is
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RECURRENT CALCULI
I
TRANSIENT TETANY
13
calc
mmol /1
12
calc. mg% I101
2-70
9 8
2-20
I
MRS
I
s. s.
EXC I SION INTRA-THY i“lIC PARATHYROID ADENOMA
52 YEARS
FIGURE 5 Serum calcium levels in a patient observed over five years following first presentation with a renal calculus requiring pyelolithotomy I n addition to recurrent stones, she suffered from progressive lethargy Note the fluctuation of serum calcium levels about a high mean After excision of the adenoma situated within the thymus a dramatic fall of calcium occurred, with tetany and subsequent return to normal level
I3
II
16
1 6
inadequate just to warn the nursing staff about these symptoms, for i f they do not communicate this information to the patient, the patient may think that the symptoms are in some way related to the anaesthetic. If the patient is warned before operation that parasthesiae may develop, then he or she will quickly notify the nursing staff. Frank tetany with a positive Trousseau sign is unusual, but may be demonstrated after prolonged arm compression. Again, this may be noted by the nursing staff when taking the blood pressure. It is usual for the calcium to adjust itself to a normal level even if only one gland has been preserved intact. If the tetany is worrying, patients should be given calcium intravenously, and for this reason it is wise to maintain an intravenous line for 48 hours after surgery. If the patient is not nauseated, calcium tablets are quite useful and may be continued intermittentlyas requiredfora weekor so. There has been no case in this series where vitamin D has been required for persistent hypcalcaemia other than in the cases of tertiary hyperparathyroidism with ablation of all four glands.
a-/-fL 1
R: 32 FIGURE6.
268
I I
I1
I
L 31
Anatomical distribution of 63 cases of single parathyroid adenoma.
DISCUSSION This series highlights the “traditiona1”experience with parathyroid exploration, an incidence of at least 80% of single adenoma the removal of
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which cures the hyperparathyroid state. Experience at the Massachusetts General Hospital (St Goarand Roth, 1974) and the Mayo Clinic (Van Heerden et alii, 1977) confirms a similar incidence of the pathological causes of hyperparathyroidism. Other authors quote a high incidence of chief cell hyperplasia (Esselstyn et alii, 1974; Haff and Armstrong, 1974), with the corollary that a more radical approach should be followed with regard to parathyroid gland excision. The team of pathologists at Prince Henry's Hospital has considered its brief in parathyroid exploration to be the positive identification of parathyroid tissue; this is extended to the recognition of normal glands by their fat content and the identification of abnormal glands by virtue of their solid structure. An adenoma is equally obvious to surgeon and pathologist. The changes of hyperplasia are more subtle. Much depends on the surgeon's ability to expose all four glands and to confirm their parathyroid nature by biospy. It isthen a matter more for the surgeon than the pathologist to make up his mind which patient has a single adenoma, which has two adenomas, or which has hyperplasia of three or all four glands. Moderate enlargement of three glands, particularly if they have an irregular "pseudopodial" configuration, would class them as hyperplastic and dictate their removal. The subject is complicated by the existence of microadenomas when the gland has a normal colour, but its size is slightly larger than usual.
AUST.N.Z. J. SURG.,'VOL. 48-No. 3, JUNE, 1978
Twenty years' experience with 74 successful explorations suggests that there is no need to depart from the policy of searching for all four glands and removing the single adenoma when this appears to be the sole pathological finding. More extensive parathyroidectomy is indicated by definite macroscopic evidence of hyperplasia. ACKNOWLEDGEMENTS I am most grateful for the support of the urologists and physicians on the Staff of Prince Henry's Hospital, for their keen awareness of hyperparathroidism, and the referral of patients for surgical exploration. My special thanks go to the Prince Henry's Hospital pathologists, headed for many years by Dr J. Funder and now by Dr M. Drake, who have pondered laboriously over so many frozen sections over 20 years. REFERENCES BILEZIKIAN, J.B., DOPPMAN. J.L. and SHIMKIN. P.M. (1973), Amer. J. Med., 55: 505. J.L., MALLETTE. L.E. and MARX,S.J.(1968). Radiology, DOPPMAN. 115: 31. ESSELSTYN, C.B.. LEVIN. H.S. and EVERSMAN. J.J. (1974). Sufg. Clin. N. Amer.. 54: 443. HAFF.R.C. and ARMSTRONG. R.G. (1974), Surgery, 95: 715. LANGMAN. J. (1975). Medical Embryology, The Williams & Wilkins Co.. Baltimore: 266. ST GOAR.W.T. and ROTH.S.I.(1974), N. Engl. J. Med.. 297: 913. VAN HEERDEN, J.A.. BEAHRS, O.H. and WOOLNER,L.B. (1977). Surg. Clin. N. Amer., W.B. Saunders & Co., Philadelphia: 557.
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TWENTY YEARS' EXPERIENCE W I T H PARATHYROID
EXPLORATION
J. FREIDIN Prince Henry's Hospital a n d Monash University, Department of Surgery, Melbourne
Eighty-four patients have undergone surgical exploration following a clinical diagnosis of hyperpathyroidism over a 20-year period. Urinary tract calculi were the major indicationfor exploration,and 90% of these patients had recurrent calculi. Osteitis fibrosa was a rare presentation of hyperparathyroidism. Lethargy, sometimes profound, was an important symptom, in some instances the dominant feature. Persisitent hypercalcaemia remains Ihe chief diagnostic investigation, with helpful confirmation from estimation of the parathyroid hormone level. Little attempt was made in this series to utilize preoperative localization techniques, reliance being placed on meticulous bloodless surgery to find normal and abnormal parathyroid tissue. Eight-five explorations were carried out in the 84 patients. Seventy-four of the explorations were successful, converting the patient lo a normocalcaemic state. Of these, 63 had a single adenoma (86%).
HYPERPARATHYROIDISM is a relatively uncommon indication for surgery, even within the wider field of endocrine surgery, but to the afflicted patient, the arrival at a correct diagnosis and the subsequent appropriate surgical management are of vital importance. The best results are obtained where an expert endocrinological team is complemented by a surgeon trained in recognizing parathyroid tissue and versed in anatomical variations of parathyroid development, together with a team of pathologists prepared to make confident pronouncements on minute fragments of tissue examined by frozen section techniques. Eighty-four patients were subjected to surgical exploration for hyperparathyroidism from December 1957 to March 1978. All by two of the operations were carried out in one institution, Prince Henry's Hospital, in order to have available the services of its team of pathologists and thus ensure uniformity in frozen section reporting. All patients had their biochemical estimations either performed solely at Prince Henry's Hospital or else repeated there for the sake of uniformity. S e x distribution. - There were 46 females and 38 males in the series of exploration. One female patient underwent two operations three years apart. Age distribution. - There was a wide distribution of age incidence at the time of exploration, with Reprints: 24 Collins Street. Melbourne
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maximal incidence in the fourth and fifth decades (Figure 1). INDICATIONS FOREXPLORATION The chief presenting symptoms of the 84 patients who underwent surgical exploration were analysed and placed into appropriate groups (Table 1). Several facts emerge from an analysis of the presenting problems. (1) Recurrent renal calculus disease is the chief presentation. (2) Relatively few cases are diagnosed with their first stone. If a more aggressive investigation policy were followed with each new case of renal calculus, fewer patients would go on to the risks attendant upon repeated stone formation. (3) Osteitis fibrosa is a rare presentation of hyperparathyroidism. (4) Patients with profound fatigue undergoing diagnostic tests should have serum calcium estimations included in their investigations, as lethargy and accompanying depression may be the sole symptoms of hyperparathyroidism. (5) Thirst, polyuria, and abdominal pain have not been major features of hyperparathyroidism. If one combines the data related to age and sex distribution with the presenting symptoms, then it 26 1
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*O
NUMBER
I
OF CASES
I I I
15
7
.
'
10
5
AGE FIGURE 1: Histogram showing age incidence of patients subjected to operation.
will be seen that the group of patients most likely to suffer from hyperparathyroidism are young or middle-aged women, who have developed kidney stones and admit to unusual tiredness.
Diagnosis The biochemical abnormalities necessary to confirm suspicion of hyperparathyroidism are hypercalcaemia, hypophosphataemia, a level of serum chloride in the upper ranges of normal, and an elevated parathyroid hormone level. Hypercalcaemia is the central investigation and should be looked for in every case of renal colic TABLE 1 Chrel Presenting Features Leading fo Explerafion
~___--___
______
URINARY TRACT CALCULI Recurrent renal calciili First presentalien renal calctilus Haematiiria and nephrocalcinosis SYMPTOMS RELATED TO HYPERCALCAEMIA Fatigue Persistent hvoercalcaemia after thyrotoxiiosls control Asymptomatic hypercalcaemia BONE DISEASE Primary osteitis fibrosa Osteitis fibrosa secondary to chronic renal failure ENDOCRINE Multiole endocrine adenoma with pancreatic islet cell tumours OTHER Pancleatitis and hypercalcaemia Milk-alkali syndrome?
262
___
NO of Patients
Approx
58 6 2
69 7 25
%
6
7
1
1
1 1
2
25
4
4
1
2 1 -~
1
2.5 1
where a radio-opaque calculus is shown on the Xray film, and even if this is not present, suggesting that the stone has been passed. T o delay biochemical investigation until recurrent calculi are evident puts the patient at risk of all the well-known complications of obstruction to the renal tract from stones. A minimum of three estimations of calcium and phosphate levels should be requested, either on successive days or spread over a week or two. I t is imperative that both the patient and the laboratory be aware that the blood should be taken early in the day, following a period of overnight fast, and that the venous tourniquet used to distend the forearm vein be let down for 15 seconds before the blood is drawn. This diminishes the risk of artifically high readings of the serum calcium level. The laboratory chosen for estimation should be one that gives consistently accurate results. The accepted range of normal serum calcium is 2.2 to 2.70 mmol/l. If three estimations fall in the middle of this range, the matter need not be pursued further, but recurrent stone formation should be followed by further biochemical tests. Three levels of calcium above the normal range with corresponding low phosphates and a high parathyroid hormone level are an adequate basis for surgical exploration. Difficulties are encountered when only one or two estimations are high and perhaps only just above or just below the upper range of normal, e.g., 2.69 or 2.72 mmol/l. Such patients are very likely to have hyperparathyroidism as the cause of their renal calculus, since it is characteristic in those patients with hyperparathyroidism who have had a large number of estimations of serum calcium performed to find a wide fluctuation in levels. The fluctuation is set about a high mean, at or above the upper limit of normal. Presumably this is due to a variation of output of hormone by the adenoma. Thus patients with calcium levels near the upper limit of normal should be referred for three, six, or nine more serum calcium estimations until a general pattern emerges of high normal and above-normal readings. Many patients with calcium levels not higher than 2.72 mmol/l have been explored successfully. Patients with recurrent renal calculi with normocalcaemia have been rejected for exploration in this series. Hypophosphataemia is usually present, but may be less pronounced if there is a degree of renal impairment. High levels of serum chloride (106 mmol/l) are usually present, but are not in themselves an adequate indication for exploration. A high alkaline phosphatase level is seen only in a bony case and is therefore a rare biochemical finding. The finding of a high alkaline phosphatase AUST.N.Z. J. SURG.. VOL.48-No. 3, JUNE, 1978
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level with renal calculus diseaseshould in fact make one look for a cause of rapid bone turn-over other than hyperparathyroidism. Clinically there appears to be a dichotomy between renal and bony presentation of hyperparathyroidism, each presentation remaining the same even when it is obvious that the disease has been present for 10 or 15 years. Abnormally high levels of calcium in the urine are not always present; thus failure to show elevated urinary calcium excretion does not negate the diagnosis of hyperparathyroidism. Hence 24-hour collection of urine for calcium estimations have been abandoned in the last 10 years or so in this series. The availability of reliable estimation of parathyroid hormone has been a welcome addition to investigations. However, at the present time, ifthe parathyroid hormone assay is equivocal, the test s h o u l d be i g n o r e d p r o v i d e d that calcium, phosphate and chloride levels are appropriately abnormal. So far, no case showing the combination of normocalcaemia and elevation of parathyroid hormone level has been seen. Should the elevation be definite over repeated estimations and be associated with recurrent calculi, a strong case could be made for surgical exploration. The f i n d i n g of hypercalcaemia requires considerations of other causes of this abnormality before hyperparathyroidism is accepted. In fact, malignant disease ( w i t h or w i t h o u t b o n y involvement) and multiple myeloma are commoner causes of hypercalcaemia than hyperparathyroidism. The use of thiazide diuretics, sarcoidosis, excessive intake of vitamin D, hyperthyroidism, and the milk-alkali syndrome, should be considered in the differential diagnosis. An important aspect of the differential diagnosis of hypercalcaemia is that only hyperparathyroidism is associated with renal calculi. Thus the more difficult cases are those without stones. In this series a few patients were subjected to measurement of tubular reabsorption of phosphate, but subsequently this test was abandoned because of equivocal results. As in all endocrine tumours, estimation of excessive hormone production should ultimately become the most reliable index of abnormal activity. Estimation of the serum calcium level is a more indirect investigation, but it has stood the test of time by its reliability.
Expioration for Hyperparathyroidism Of 85 explorations, 10 have failed to reveal an abnormality of the parathyroids and therefore must AUST N.Z. J. SURG, VOL 48-No
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be classed as failed explorations. One patient underwent exploration of the neck which revealed four normal glands, and three years later had her mediastinum explored, but no adenoma could be found. Another patient had only two normal glands discovered in the neck, but he subsequently proceeded to a dramatic fall in serum calcium and tetany, a syndrome which never occurs i f afunctioning adenoma has been left i n the neck. Table 2 lists the incidence of failures in five-year blocks. The data suggest a poor rate of selection in TABLE2 Results of 85 explorations
1957-1963 1 964-1968 1969-1973 1974-1978
in 5-year blocks
Success
Failure
4
5 1 1 4 11 -
22 20 28 74 -
the first five years of surgery for hyperparathyroidism, with a more acceptable surgical result thereafter. Some details about the failed explorationsand the possible causes of the patients’ symptom are listed in Table 3. THEOPERATION Ideally, accurate preoperative localization of the hyperfunctioning parathyroid tissue would be invaluable to the surgeon. Various techniques have been tried, the simplest of which is a barium swallow X-ray examination to demonstrate a retrooesophageal adenoma. Isotope scanning on the whole has been unrewarding. Arteriography may show a tumour by its vascular blush. Venography with venous sampling for parathyroid hormone assay has many advocates (Bilezikian et alii, 1973, Doppman et aiii, 1968). The techniques of vascular radiology need a degree of expertise which radiologists can only acquire in centres with a large number of cases. Computerized axial tomography may be found to be of value in the future. In practice, sufficiently good results appear to have been achieved by following a meticulous surgical approach. Arteriography and venography have not been requested, with one exception, the case of unrewarding exploration of the neck which revealed four normal glands. Venography and venous sampling performed on this patient suggested a general rise in the level of parathyroid hormone in the neck and mediastinum, but a mediastinal exploration three years later failed to
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TABLE3 Analysis of Unsuccessful Explorations Year
Sex
Age [years)
1959
M
27
1960
M
44
1961
M
46
1962
F
46
1963
F
77
1966
M
28
1973
M
60
1974
F
60
1977
F
63
1975
F
63
1977
M
53
1977
F
77
Definitive diagnosis
Indicalion foi exploration'
Operative findings
Recurrent calculi. calcium 12 3 mq/100 mi Recurrent calciili. calcium 12 0 mgl100 ml Fatigue. duodenal ulcer. calcium 12 0 mgI100 ml Recurrent calculi. calcium 11 9 mgf100 ml
4 normal glands
Unk now 11
3 normal glands
Unknown
2 normal glands
7 milk-alkali
Fatigue, renal impairment, calciiim 11 2 mgI100 ml Reciirrent calciili. calcium 11 5 mgllOO ml Recurrent calcdi. calcium 12 0 mgl100 ml Reciirrent calculi. calcium 12 4 mgI100 ml Recurrent calculi. calcium 12 4 m g l l 0 0 ml Recurrent calculi calcium 2 75 mmolll Recurrent calculi. calcium 2 80 mmolIl Lethargy, calcium 2 74 mmolll
4 normal glands 4 slightly enlarged glands 2 normal glands, unexpected tall of calcium to 7 5 mg % 4 normal glands, Subtotal thyroidectomy 4 normal glands Mediastinal exploration but n o abnormality found 2 normal glands
syndrome Unknowri mediastiiial adeiioma 7 secondary hyperparathyroidism 7 infarcrioii o f undetected adenoma 7 mediastinal adeiionia 7 mediaslinal adenoma Unknown
Unknown
4 normal glands
Unknown
Neck exploration abandoned due l o dense adhesions from thyroidectomy 30 years previously
undetected adenoma in the neck 7
' Prior to 1975 Serum Calcium expressed in mgl100 ml Following 1975 Serum Calcium expressed i r i mmol/l
has a group of small vessels supplying it or has a vascular pedicle which may arise from the surface of the thyroid, the oesophageal wall, or the fat lying below the thyroid gland. The embryological development of the parathyroid glands influences their ultimate location (Langman, 1975). The inferior gland arises from the dorsal wing of the third pharyngeal pouch, the thymus arising from the ventral wing. As the thymus migrates into the anterior mediastinum, it pulls the parathyroid gland down with it. The inferior gland of the adult may thus be found on the lower pole of the thyroid gland, in the fat below its lower pole, or within the thymus itself, either in the tongue of thymus which protrudes above the manubrium or in the deeper section in the anterior mediast in um. The fourth pharyngeal pouch gives rise to the superior gland of the adult. The gland becomes attached to the side of the thyroid during the latter's downward migration and comes to rest on the lateral aspect of the sharp posterior edge of the thyroid gland, near the upper pole (Figures 2, 3). In addition to the wide range of position of parathyroid tissue dictated by development, there 264
show any abnormality. An attempt to reexplore the neck was abandoned because of dense adhesions between the thyroid gland, the strap muscles, and the carotid sheaths. The surgeon embarking on parathyroid surgery must be familiar with the appearance of normal and abnormal parathyroid tissue and also be conversant with the anatomical variations in the position of the glands. Normal parathyroid glands are flat, of oval shape, and measure approximately 4 m m x 6 mm, with a thickness of 2 mm. They are often embedded in fat. When teased out of the fatty tissue, they are found to have a shiny and smooth surface with a characteristic light brown colour. To discover these glands it is vital that no blood should stain the operative field, since blood-stained fat and bloodstained parathyroids are indistinguishable to the naked eye. The blood supply to the gland arises from whatever structure the parathyroid happens to be resting on. There is no support in this series for the statement sometimes made that the blood supply comes frequently from a branch of the inferior thyroid artery and that tracing out this artery will lead to an adenoma. In practice, an adenoma either AUST N.Z. . i sURG,
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FIGURE2 Side veiw of the thyroid gland with the parathyroids in black The superior parathyroid sits on the side of the thyroid, near its posterior border close to the superior pole vessels The lower parathyroids are more inconstant in their/ position and may be found on the side of the lower pole of the thyroid, below the gland or within the thymus The middle thyroid vein is also shown
SP
SQ
9: SUPERIOR PARATHYROID FIGURE3: Transverse section at the level of the upper pole of the thryoid gland. The superior glands are seen to lie well to the back, close to the sharp posterior edge of the thyroid and in proximity to the oesophagus. Division of the middle thyroid vein is necessary to roll the thyroid up out of its bed.
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~
also appear to be mechanical influences that place adenomas at positions remote from the normally accepted anatomical locations. These influences are thought to be large size of the adenoma and swallowing movements. When a superior parathyroid cannot be located in its usual position, a large adenoma may be revealed behind the oesophagus, remaining quite undetected until a deliberate search is made for it. Such an adenoma may migrate down into the posterior mediastinum. When an inferior gland cannot be found on the lower pole of the thyroid, a wide search should be made to include the full depth of tissue from the deep fascia to the cervical spine. If unsuccessful, the search continues into both the anterior and the posterior mediastinum. The thymus is identified by its smooth contour and opaque pale-yellow colour which stands out from the deeper yellow lobular fat. The upper poles of the thymic lobes can be dissected out between the inferior thyroid veins, above the manubrium, traced into the anterior mediastinum, and pulled up. If no lower parathyroid tissue can be identified, a worthwhile manoeuvre is to excise as much thymus as presents in the neck and then to cut it into fine transverse slices looking for a normal or enlarged parathyroid gland. The brown colour of parathyroid tissue makes a vivid contrast against the pale yellow thymus. The glands of the upper and lower groups are not necessarily situated at the same levels on the two sides. However, the correlation of levels is sufficiently good, that having found two glands on one side, the surgeon should proceed to look forthe other two glands at corresponding levels on the other sides.
THESURGICAL PROCEDURE The position of the patient on the operating table is similar to that for thyroid surgery. A low collar incision is made, with elevation of the upper flap to the level of the upper edge of the thyroid cartilage and of the lower flap to the top of the manubrium. Division of the deep fascia in the midline vertically is followed by elevation of the deep fascia and strap muscles from the thyroid gland. Horizontal division of the fascia and strap muscles is optional, depending on the ease of exposure. The surgeon now concentrates on a thorough search of one side of the neck. The middle thyroid vein is identified, divided, and ligated. Three stay sutures are inserted through the substance of the thyroid lobe on each side, avoiding surface veins. This is done in order to roll the gland up out of its bed and to reveal its posterior border. This is made
265
SURGERY FOR HYPERPARATHYROIDISM
possible by the previous division of the middle thyroid vein. The search is commenced for normal parathyroid glands, parathyroid adenoma, or hyperplastic tissue. A thorough search should be made on the side initiallychosen until twoglandsarefound. Failureto discipline oneself to makea thorough search on one side means that one is left in doubt whether to pursue a difficult exploration on one side or the other, if only one gland has been found on each side. If two normal glands are found on a particular side, then that side need not be explored further. The field must at all times be kept free of blood. Any spilt blood must be immediately washed out with saline and mopped up with swabs. The sucker must not be used, as a previously identified parathyroid gland is so delicately attached to its bed (usually the thyroid gland) that it can disappear up the sucker. The operation is carried out in conjunction with an experienced pathologist. Ideally, four glands will be identified, one of which is an adenoma. The adenoma is recognized b y i t s naked-eye appearance, being usually dark brown, oval, shiny, with its greater diameter approximately 1.5 c m in an average case. A portion of the suspected adenoma is excised and subjected to frozen section examination for confirmation of parathyroid structure. It is essential to d o this, as even with experience, one can mistake a pigment-laden lyrnphnode, or one bruised by the dissection, for a parathyroid adenoma. The normal glands are also subjected to biopsy for histological confirmation of the diagnosis. A fragment of 1 mm3 is cut off with fine scissors from one end of the oval gland. This procedure is perfectly safe, as even in those cases of hyperplasia where three glands are completely removed and the fourth normal gland subjected to biopsy, there is no evidence of permanent hypocalcaemia. Biopsy is followed by bright red capillary bleeding from the cut surface of the gland. Diathermy or ligature should not be used to control bleeding because of the risk of damaging the tissue by such measures. Gauze pressure stops the bleeding. Failure to demonstrate a gland in its usual anatomical position leads to a search being made behind the oesophagus or in the anterior mediastinurn as far as is possible by a cervical approach. In the classical case where all four glands have been identified and one of them is the seat of an adenoma, the adenoma is removed (Figure 4). There is debate whether it is adequate to remove an obvious adenoma or to d o a more extensive resection. the argument has been used that there is
266
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FlGURE4: Exploration for adenorna behind the oesohagus in a case where the upper parathyroid cannot be located. After division of the middle thyroid vein and rolling the thyroid gland out of its bed with three stay sutures, the inferior thyroid artery and the recurrent laryngeal nerve are identified. The index finger explores behind the oesophagus down to the posterior rnediastinum.
a risk of recurrence unless in all cases three or three and a half glands are removed. The author’s experience is that removal of the obviously abnormal tissue suffices, and one should not routinely do a three and a half gland parathyroidectomy. There have been no known cases in this series of recurrent hyperparathyroidism except the failed explorations where hypercalcaemia has persisted in some instances. Once the obviously abnormal tissue has been removed, either adenoma or hyperplastic glands, and provided that there has been the rapid fall of serum calcium 48 hours following surgery, recurrent hyperparathyroidism has not been seen. In summary, all four glands should be identified and their nature confirmed by biopsy. An obvious adenoma is excised. If no obvious adenoma is found, the larger two of the fourglandsare removed in the hope that one or other will contain a microadenoma. Should the enlargement of the glands appear to be hyperplastic, then all these glands are removed. In practice, one is then left with one normal gland, a small part of which has been subjected to biopsy. Mediastinal exploration may be carried out forthwith after a failed cervical exploration, but this is an unusual step. More commonly the patient is AUST.N.Z. J. SURG., VOL.48-No. 3, JUNE, 1978
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reinvestigated to confirm persistence of the biochemical changes of hyperparathyroidism, radiological investigations with venous sampling are carried out, and mediastinal exploration is then carefully considered. PATHOLOGICAL FINDINGS Table 4 lists the incidence of the various pathological states encountered in this series. The commonest pathological abnormality was single adenoma. No case of carcinoma was encountered. TAELE4 Palhological Findrngs in 74 Successful Explorafions
No of Patients
Approx
63
a8
1
1
Oto
~
Siriqle parathyroid adenoma Two parathyroid adenomas Parethyroid adenomas (3)with pancreatic islet cell adenomas Multiple qland hyperplasia of 3 qlands of 4 qlands Tertiary hyperparathyroidism of 4 qlands of 1 qland
1
1
4 1
46 1
3
34
-1
1
74 -
1000
Single adenoma. - The average size of a single adenoma was 1.5 cm in the greatest diameter. One retrooesophageal tumour arising from an upper parathyroid gland measured 7.5 cm. At the other end of the scale some single adenomas were really "microadenomas" in so far as these adenomas only measured 3 mm in diameter and were completely surrounded by normal parathyroid tissue. Such microadenomas produce slight enlargement of the parathyroid gland without the dark brown colour coming through. Thus when-all four glands have been localized and none looks obviously adenomatous. one should decide whether to remove one or two of the larger ones. This has proved to be a useful procedure, as in some cases the serum calcium has dropped to a low level even before the pathologist was able to report the presence of a microadenoma on paraffin section examination. The histological appearance of normal parathyroid tissue is characterized by cords of epithelial cells with intervening areas of fat cells. The cells are typically chief cells or oxyntic cells. In an adenoma the outstanding feature is the absence of fat cells. The sheets of epithelial cells are either chief cells or "water-clear" cells. Some adenomas show cystic changes consistent with an acinar structure, which AUST N.Z. J. SURG..VOL. 48-No
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the pathologist must be careful not to confuse with thyroid acini. Hyperplasia Hyperplasia of multiple glands is difficult to separate dogmatically from multiple adenomas. Statistically, multiple large adenomas are rare as a primary cause of hyperparathyroidism; there was only one case in this series. Hyperplasia is relatively more common. Hyperplastic glands usually have a more irregular surface than adenomas. being somewhat pseudopodial. In chronic renal failure of long standing, including transplant patients, the secondary hyperplastic glands become progressively autonomous. These patients develop progressive hypercalcaemia in the presence of hyperphosphataemia. Clinically hyperparathyroidism, said to be "tertiary" is heralded by bone pain. X-ray examination and bone biopsy reveal all the classical features of osteitis fibrosa. In fact, this situation is a commoner cause of osteitis fibrosa than primary von Recklinghausen's disease. In the three cases of tertiary hyperparathyroidism where four large adenomas were found, all four glands were removed, curing the bone pain, but causing profound hypocalcaemia and tetany which were difficult to control. In one case of chronic renal failure with the classical bone changes of osteitis fibrosa. a single large adenoma was found together with two other normal glands. Removal of the adenoma produced a drop of the serum calcium level to 1.95 rnrnol/l, with tetany within 48 hoursand cure of bone pain. Thus the doubt arose whether the adenoma was primary or "tertiary". Anatomical localization. - Figure 6 shows the distribution of 63 cases of single adenoma. It will be seen that no particular gland position is favoured by the adenomatous process. INVESTIGATION POSTOPERATIVE No matter h o w successful the surgical exploration appears to be, the hyperparathyroid state cannot be considered to have been cured until a sharp drop of the serum calcium level to within the normal range has been demonstrated. Usually this occurs in the first 24 hours and is maximal at 48 hours. Patients experience tetany even when the serum calcium is still with the normal biochemical range. Presumably this happens because of the sharp drop of calcium and internal cellular readjustments (Figure 5). The patient must be warned that the early symptoms of tetany are a sensation of tingling around the mouth and at the tips of the fingers. It is
267
SURGERY FOR HYPERPARATHYROIDISM
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PYELO L ITHOTO MY
RECURRENT CALCULI
I
TRANSIENT TETANY
13
calc
mmol /1
12
calc. mg% I101
2-70
9 8
2-20
I
MRS
I
s. s.
EXC I SION INTRA-THY i“lIC PARATHYROID ADENOMA
52 YEARS
FIGURE 5 Serum calcium levels in a patient observed over five years following first presentation with a renal calculus requiring pyelolithotomy I n addition to recurrent stones, she suffered from progressive lethargy Note the fluctuation of serum calcium levels about a high mean After excision of the adenoma situated within the thymus a dramatic fall of calcium occurred, with tetany and subsequent return to normal level
I3
II
16
1 6
inadequate just to warn the nursing staff about these symptoms, for i f they do not communicate this information to the patient, the patient may think that the symptoms are in some way related to the anaesthetic. If the patient is warned before operation that parasthesiae may develop, then he or she will quickly notify the nursing staff. Frank tetany with a positive Trousseau sign is unusual, but may be demonstrated after prolonged arm compression. Again, this may be noted by the nursing staff when taking the blood pressure. It is usual for the calcium to adjust itself to a normal level even if only one gland has been preserved intact. If the tetany is worrying, patients should be given calcium intravenously, and for this reason it is wise to maintain an intravenous line for 48 hours after surgery. If the patient is not nauseated, calcium tablets are quite useful and may be continued intermittentlyas requiredfora weekor so. There has been no case in this series where vitamin D has been required for persistent hypcalcaemia other than in the cases of tertiary hyperparathyroidism with ablation of all four glands.
a-/-fL 1
R: 32 FIGURE6.
268
I I
I1
I
L 31
Anatomical distribution of 63 cases of single parathyroid adenoma.
DISCUSSION This series highlights the “traditiona1”experience with parathyroid exploration, an incidence of at least 80% of single adenoma the removal of
AUST N.Z. J. SURG, VOL 48-40.3,JUNE, 1978
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which cures the hyperparathyroid state. Experience at the Massachusetts General Hospital (St Goarand Roth, 1974) and the Mayo Clinic (Van Heerden et alii, 1977) confirms a similar incidence of the pathological causes of hyperparathyroidism. Other authors quote a high incidence of chief cell hyperplasia (Esselstyn et alii, 1974; Haff and Armstrong, 1974), with the corollary that a more radical approach should be followed with regard to parathyroid gland excision. The team of pathologists at Prince Henry's Hospital has considered its brief in parathyroid exploration to be the positive identification of parathyroid tissue; this is extended to the recognition of normal glands by their fat content and the identification of abnormal glands by virtue of their solid structure. An adenoma is equally obvious to surgeon and pathologist. The changes of hyperplasia are more subtle. Much depends on the surgeon's ability to expose all four glands and to confirm their parathyroid nature by biospy. It isthen a matter more for the surgeon than the pathologist to make up his mind which patient has a single adenoma, which has two adenomas, or which has hyperplasia of three or all four glands. Moderate enlargement of three glands, particularly if they have an irregular "pseudopodial" configuration, would class them as hyperplastic and dictate their removal. The subject is complicated by the existence of microadenomas when the gland has a normal colour, but its size is slightly larger than usual.
AUST.N.Z. J. SURG.,'VOL. 48-No. 3, JUNE, 1978
Twenty years' experience with 74 successful explorations suggests that there is no need to depart from the policy of searching for all four glands and removing the single adenoma when this appears to be the sole pathological finding. More extensive parathyroidectomy is indicated by definite macroscopic evidence of hyperplasia. ACKNOWLEDGEMENTS I am most grateful for the support of the urologists and physicians on the Staff of Prince Henry's Hospital, for their keen awareness of hyperparathroidism, and the referral of patients for surgical exploration. My special thanks go to the Prince Henry's Hospital pathologists, headed for many years by Dr J. Funder and now by Dr M. Drake, who have pondered laboriously over so many frozen sections over 20 years. REFERENCES BILEZIKIAN, J.B., DOPPMAN. J.L. and SHIMKIN. P.M. (1973), Amer. J. Med., 55: 505. J.L., MALLETTE. L.E. and MARX,S.J.(1968). Radiology, DOPPMAN. 115: 31. ESSELSTYN, C.B.. LEVIN. H.S. and EVERSMAN. J.J. (1974). Sufg. Clin. N. Amer.. 54: 443. HAFF.R.C. and ARMSTRONG. R.G. (1974), Surgery, 95: 715. LANGMAN. J. (1975). Medical Embryology, The Williams & Wilkins Co.. Baltimore: 266. ST GOAR.W.T. and ROTH.S.I.(1974), N. Engl. J. Med.. 297: 913. VAN HEERDEN, J.A.. BEAHRS, O.H. and WOOLNER,L.B. (1977). Surg. Clin. N. Amer., W.B. Saunders & Co., Philadelphia: 557.
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