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Parathyroid Adenoma
PARATHYROID ADENOMA SAMUEL F. MARSHALL AND TIMOTHY A. LAMPHIER IN THE relatively short span of the past twenty-five years the early recognition and surgical treatment of hyperparathyroidism have been placed on a sound clinical basis. When the clinician's attention is directed to this syndrome and early diagnosis can be made, we will rarely see such crippling results of untreated hyperparathyroidism as bone deformities, recurrent renal stones with ultimate renal failure, or parathormone poisoning. The'common and even the uncommon disorders characteristic of pathologic physiology of the parathyroids are now so well known that they should in most instances be detected early and treatment instituted before the ensuing complications prove irreversible. Too often in the past, residual effects of the disease have progressed to such a point that amelioration rather than cure was all that could be hoped for. Signs and symptoms no longer need progress to their later stages for recognition, such as loss of height from collapse of de<~alcified vertebral bodies, nerve root pain resultant from pressure UPOI;l nerve roots by collapsing vertebral bodies, spontaneous fractures, recurring kidney stones and calcified kidneys. HISTORY
The first description of parathyroid glands was made by Sandstrom in 1880. In 1891 von Recklinghausen described bone lesions characteristic of hyperparathyroidism, but it was not realized that this phenomenon was the result of overactivity of the parathyroid gland. Weare indebted to Hanson12 , 13 (1923) and Collip and his associates8 (1925) for their preparations of parathormone. These physiologists demonstrated the effects of parathyroid gland extract on experimental animals, such as increases in blood calcium levels with concomitant low phosphorus levels. In 1926, Mandp9 treated a patient with von Recklinghausen's disease with parathyroid transplants. As the condition of the patient became much worse, he then carried out a cervical exploratien and excised a parathyroid adenoma. This was the first parathyroidectomy. From 1926 to 1932 it was assumed that bone changes were a necl:lssary aftermath of parathyroid disease. Only then was it realized that they were a complication of parathyroidism. In 1929, Albright and his co"' workers2 stated that the chief action of parathormone was to promote excretion of phosphates, whereas in 1932 COllip7 contended that parathyroid hormone acts directly on the solution of calcium salts from bone. Albright, Aub and Bauer1 at the Massachusetts General Hospital must 849
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SAMUEL F. MARSHALL AND TIMOTHY A. LAMPHIER
be given credit for placing the diagnosis on a sound clinical basis and by their investigations our knowledge of this disease has been greatly enhanced. In 1935, Albright and his associates 3 presented a new pathologic entity, that is, secondary hyperparathyroidism or hyperplasia of all parathyroid glands. More recently (1947), Norris, in an excellent article, discussed parathyroid adenoma, having collected 322 cases from the literature. Rienhoff, in a recent study of a group of 27 cases of hyperparathyroidism, gave an excellent review of the problem. He emphasized the need for early recognition of this syndrome and urged early surgical intervention in order to bring about successful treatment in these serious cases. Rienhoff added 27 cases of hyperparathyroidism to those reported since 1903 and brought the total number to 597. In a discussion of Rienhoff's paper, Royster added 19 more, making a sum total of 616 cases. As Rienhoff pointed out, there must be many other cases that have not been reported in the literature. EMBRYOLOGY
The parathyroid glands develop along with the thyroid and thymus glands from two distinct primordia. The parathyroid glands arise from the third and fourth branchial clefts, whereas the thymus gland originates near the third branchial cleft. The paired parathyroid structures develop as thickenings of the entoderm. These lateral anlagen are located between the middle layer of the deep cervical fascia (on the posterior aspect of the sternohyoid and sternothyroid muscles) and the posterior or prevertebral layer of the deep cervical fascia. Therefore, they can be found anywhere from the pharynx to the mediastinum. That pair which develops with the thymus descends with it in the neck to form the inferior parathyroids. It is for this reason that they are sometimes referred to as "parathymus glands." Moreover, the inferior glands are frequently intrathymic when found in the mediastinum. 9 The development of the superior parathyroids explains why they are sometimes found within the substance of the thyroid gland. As Cope has pointed out, it is largely because of the limited area of embryologic descent that the upper parathyroids have been easier to identify at operation. Adenomas of the inferior parathyroid glands, especially those in the mediastinum, can often be located by tracing arterial branches from the inferior thyroid artery. Norris, in his review of 322 cases (1903-1946), reported that 80 per cent of adenomas weigh less than 15 gm. Rienhoff stated that adenomas in his series varied in size from 0.5 to 6 gm. except for one adenoma which weighed 58 gm. Because of the small size of these adenomas and their position posterior to the thyroid gland they are rarely palpable.
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PATHOLOGY
Four types of lesion~ arise in the parathyroid gland:1s (1) discrete, nonfunctioning adenomas, (2) cystic degeneration within an adenoma, (3) hyperfunctioning parathyroid adenomas and (4) localized malignant disease in the neck arising from the parathyroid gland. The hyperfunctioning adenoma results in what is known as primary hyperparathyroidism (Fig. 278). This condition is to be distinguished from secondary hyperparathyroidism resulting from hyperplasia of all
Fig. 278.
Fig. 279.
Fig. 278. The adenoma was a smoothly nodular and well circumscribed mass measuring 4.9 by 2.4 by 1.5 cm. The tissue was moderately firm and resilient. Externally, the mass was covered by a thin capsule through which irregularly shaped zones of pale pink and gray-brown were seen fusing gradually with each other. Fig. 279. Adenoma of parathyroid, composed of pale chief cells. The solid structure, absence of intermingled fat, and variation in nuclear and cell sizes are characteristic of adenoma (X 1000, eosin-methylene blue stain).
parathyroid tissue because of increased physiologic demands, present in prolonged chronic nephritis, vitamin D deficiency or rickets. Microscopically (Fig. 279), adenomas are composed of chief cells whereas water-clear cells (wasserhelle) are found in hyperplastic glands. Albright 1 believed that parenchymal hyperplasia is hypertrophy of individual cells; such cells are up to sixty-four times the volume of the normal cell. The much enlarged adenoma has less proportional effect per unit weight on blood calcium, as was demonstrated by Castleman and Mallory in 1935, who pointed out that larger tumors are less biologically active
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SAMUEL F. MARSHALL AND TIMOTHY A. LAMPHIER
than smaller ones. It should be remembered, however, that hyperparathyroidism is a chronic and progressive disease. A frozen section should always be made at the time of operation to identify parathyroid tissue. PHYSIOLOGY
Parathormone controls the level of calcium and inorganic phosphate ions in the blood stream.10 Increased production of parathormone mobilizes skeletal calcium, resulting in a high blood calcium, hypercalcemia, and a high calcium urinary output, hypercalciuria, or a negative balance. Overproduction of hormone is caused by either an adenoma or hyperplasia of all glands (or by malignant disease) and, as we know, adenomas are the most common. As Keating and Cook have pointed out, the total calcium of the blood includes two chief fractions: (1) when combined with serum protein as calcium proteinate, and (2) ionic calcium. Calcium proteinate varies with alterations in protein concentration and is not influ,enced by parathyroid hormone. Ionic calcium is specifically affected by parathyroid hormone. Reduced serum proteins rarely mask hypercalcemia. Determination of an elevated serum protem, however, is a good method of avoiding an erroneous diagnosis of parathyroid disease. It is well known that dangerously low blood calcium levels occur forty-eight hours after parathyroidectomy and especially in those patients with extensive bone disease, or in other words, in those in whom there is a great demand for calcium. There is no adequate explanation for the development of osteitis fibrosa cystica in some cases whereas simple decalcification or osteoporosis takes place in others. In the latter instance, there is lessened activity of osteoblasts or a decrease in bone formation, whereas in osteitis fibrosa cystica there is increased resorption of bone in the region of osteoclasts. Elevation of serum alkaline phosphatase is a reflection of bone disease and not of hyperparathyroidism. In osteoporosis, blood phosphatase values are normal. Jaffe and Bodansky emphasized that the more marked the cystic bone changes the higher the phosphatase level. In turn, the hypocalcemia following successful parathyroidectomy is more difficult to control. They also pointed out that the blood phosphatase in patients having only renal complications remains within normal limits. The formatiori of renal stones occurs as a result of urine supersaturated with calcium. Since phosphate ions are always in excess in this condition, calcium is likely to precipitate as a phosphate salt, and this is particularly true of alkaline urine in which phosphates are insoluble. When oxalates and acid urine are present calcium oxalate stones will form. When ureasplitting organisms such as Proteus are present in the bladder, ammonia is produced and the resultant alkalinization of urine will precipitate calcium phosphate. A compensatory mechanism takes place when there is severe renal failure since excess calcium is then excreted by the large
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bowel. At this point the nonprotein nitrogen and blood chloride values will be elevated. Urinary calcium excretions are difficult to appraise as calcium balance varies with age, diet and body activity. Dental roentgenograms are often an aid in the diagnosis of parathyroid disease. Ordinarily, the lamina dura (a lamina of bone in the jaws bordering the tooth sockets) is present. Its generalized decalcification is strongly suggestive of hyperparathyroidism but it may also disappear in dental disease . SYMPTOMATOLOGY
Three main groups of symptoms are characteristic of hyperparathyroidism and these can be grouped under (1) symptoms resulting from hypercalcemia, (2) symptoms related to the skeletal system and (3) symptoms caused by transportation and excretion of calcium. The following classification by Shelling and Kyser adequately covers the majority of symptoms that are encountered. A. Hypercalcemia 1. Hypotonia 2. Chronic constipation 3. Lassitude 4. Muscle weakness 5. Cardiac arrhythmia and occasional slow pulse B. Transportation and Excretion of Calcium 1. Renal complications 2. Polyuria and polydipsia 3. Enuresis, nocturia and dysuria C. Skeletal System L Pain in joints and bones 2. Spontaneous fractures 3. Cysts in long bones and skull 4. Deformity of long bones 5. Kyphosis, scoliosis or deformity of thorax 6. Waddling gait and inability to walk STATISTICS
Since 1933, in the Lahey Clinic we have records of a total of 22 proven cases of primary hyperparathyroidism treated by surgery. This report of 22 cases is a preliminary report of a somewhat larger group reported by Lahey in discussion of Rienhoff's paper. We hope to present later a more comprehensive follow-up study of a somewhat larger series. To these 22 cases should be added one case in which no tumor was found on cervical exploration. When the patient failed to respond to x-ray therapy, a mediastinotomy at another hospital revealed the presence of an adenoma which was removed. One of the 22 patients who underwent parathy-
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SAMUEL F. MARSHALL AND TIMOTHY A. LAMPHIER
roidectomy can be classified as having had carcinoma of the parathyroid as microscopic sections demonstrated invasion of the capsule. Since this patient had characteristic bone changes, hypercalcemia and hypophosphatemia, she is included in this group. An additional 2 patients had an exploratory operation because of repeated recurrent renal stones and hypercalcemia, but no tumor was found. A normal parathyroid gland was excised in one of these patients and a four-year follow-up revealed that the patient no longer has renal stones. Follow-up studies of the second patient were incomplete because the patient could not be traced. A third patient underwent a neck exploration because of a mass present at the level of the bifurcation of the right carotid artery. The mass was reported by the pathologists as "adenocarcinoma, low grade, probably of parathyroid origin." Of the 22 patients who were found to have parathyroid adenomas, 19 were females and 3 males, a ratio of 6.3 to 1. The average age of the entire group of patients was 47.9 years. The youngest patient in the group was 18 years and the oldest 74 years of age. Of the 3 males the youngest was 18 and the oldest 70 years of age. Of the female patients, the youngest was 22 years and the oldest 74 years of age. The past histories of this group of patients were significant in 5, inasmuch as they had had renal stones on one or several occasions. Rienhoff, in his group of 27 cases noted renal complications far more frequently in males than in females; 18 of the 27 had renal changes only and but one male had bony changes, whereas 6 of 12 women had skeletal changes only without renal complications. Royster stated that the early or borderline cases are usually presented from the urologic clinic where blood calcium, phosphorus and phosphatase studies have directed the attention of the clinician to the possibility of hyperparathyroidism. In his group of 22 cases most diagnoses were made on the basis of skeletal rather than renal changes. Rienhoff pointed out that whenever attention is directed to this syndrome by observations of renal changes, there will be a noticeable increase in diagnosis of this disease since the most frequent complication of hyperparathyroidism is some form of renal lithiasis. Certainly, in any patient who repeatedly forms renal, ureteral or bladder stones, the possibility of hyperparathyroidism should be seriously considered. Approximately 10 per cent of all patients with renal stones have hyperfunctioning parathyroid glands. Three of the patients had previously undergone unsuccessful neck explorations before coming to the clinic. One patient had undergone several laparotomies for abdominal distress associated with constipation which was due to overactivity of a parathyroid adenoma. A second patient had a history of three spontaneous fractures in the six years before admission to this clinic. Three patients had noticed a loss in stature. Eighteen patients had complaints relative to the skeletal-muscular systems. The average duration of
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complaints in this group was 4.2 years, with a minimum time of eight months and a maximum of fifteen years. Two patients were referred to the clinic because of complications after tooth extractions. In one instance the patient stated that her "gums had failed to heal" following extraction of a tooth. Subsequent roentgenograms demonstrated a cyst in the mandible. In spite of this finding she did not undergo more definitive studies until she came to the clinic one year later. In the other patient, pain and swelling of the left lower jaw developed following removal of a tooth. Two years later roentgenograms were taken and the patient was found to have cysts of the mandible for which she had been treated with x-ray therapy for several months before coming to the clinic. Of this group of patients with complaints related to the skeletalmuscular systems, 12 had complaints referable to the lower extremities, such as pain or stiffness or both in the knee and ankle joints, increased bowing of the tibiae, and stiffness in the thighs especially along the posterior aspect of the hips. Two patients complained of loss of height or rounded dorsal spine. Low backaches, waxing and waning in severity but progressively increasing in intensity, occurred in 4 patients. One patient was referred to the clinic because of recurrent renal stones. In one patient, an adenoma, nonfunctioning because of cystic degeneration, was incidentally removed with a substernal goiter. One patient, a woman, had no symptoms related to the skeletal, muscular or renal systems. She complained of loss of 28 pounds in one year. Subsequent studies revealed that she had been distressed with polyuria, polydipsia, vomiting and constipation (this patient is reported in more detail by Bell and Arnold). In Norris' report of 322 cases of adenomas, only 1.5 per cent failed to show a degree of renal or skeletal change of clinical importance. Another patient stated that she had had headaches for ten years with dizzy and fainting spells in the three years prior to admission, plus a weight loss of 40 pounds. Skull and cervical plates revealed osteoporosis. The last patient to complete this group of 22 complained of constipation of twelve years' duration and had undergone many operations for correction of her supposed bowel disease. Although only 3 patients of the entire group had polyuria and polydipsia, they are symptoms not to be underestimated. Muscular weakness was a notable complaint of 2 patients. Postoperative psychosis and temporary personality changes occurred in 2 patients and no doubt were related to the prodromal signs of parathyroid tetany. Frequently, transient parathyroid insufficiency is accompanied by psychic symptoms of short duration. Five patients (22.7 per cent) of the 22 had palpable neck tumors. Nine patients, or 40.9 per cent, complained of weight loss; the average loss was 19.2 pounds. The minimal weight loss was 4 pounds and the maximal 40 pounds. In 19 patients changes of either osteitis fibrosa cystica or osteoporosis were noted in roentgen studies. Those who had no bone
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SAMUEL F. MARSHALL AND TIMOTHY A. LAMPHIER
changes had symptoms of weight loss and constipation. In addition in this group there was one nonfunctioning adenoma with cystic degeneration. Osteoporosis alone was present in the roentgenograms of 3 patients. Cystic changes with or without osteoporosis were present in the roentgenograms of 13 patients. Pathologic compression fractures of vertebrae were noted in 4 patients. Only one patient had vertebral epiphysitis. Pitting or mottling of the skull with loss of cranial tables was present in 7 patients. Loss of peridental membrane, spotty decalcification or absence of lamina dura or alveolar resorption occurred in 5 patients. This finding associated with a general derangement of the bony architecture is significant. Trabeculation or pronounced fibrillation of bone consistent with Paget's disease or hyperparathyroidism and coarsening of the texture of all bones were seen in the roentgenograms of 4 patients. Punctate calcification about renal papillae or calcinosis of the parenchyma of both kidneys was present in only 2 patients. In this group of 22 cases, preoperative studies demonstrated that the blood calcium levels (normal 9 to 11 mg. per 100 cc.) ranged from 11.4 to 17.2 mg. per 100 cc. with the exception of one case in which it was recorded as 9 mg. per 100 cc. In the latter instance, the adenoma was embedded in struma lymphomatosa tissue. As has been emphasized in other reports in the literature, those patients with more extensive bone disease had relatively higher blood calcium levels and in these cases the serum phosphatase was elevated. Total blood protein levels were followed for comparison in each case to evaluate the variances. Depression of blood phosphorus levels (normal 3 to 4 mg. per 100 cc.) was not as consistent as was elevation of blood calcium levels and is, therefore, not as true an index of parathyroid overactivity. Fifteen patients had levels recorded as between 0.9 to 2.9 mg. per 100 cc. In the other 7 cases, the blood phosphorus levels were normal. Alkaline phosphatase levels (normal 1 to 4.5 Bodansky units) were elevated in all but 2 patients, with a maximal level of 64.4 units and an average of 19.8 units. The Sulkowitch test, an easy qualitative method for detecting urine calcium, was elevated in all but two instances (normal 0 to 1+). This test also varies with diet, urinary function and so forth. Whenever there was any question of renal involvement, nonprotein nitrogen value of the blood was determined and renal function studies and pyelograms were carried out. Multiple adenomas were not found in this group of patients. The locations of the single adenomas are listed in Table 1. In the 3 remaining cases not included in Table 1 the adenomas were designated as being located in relation to the right lobe but were not further described. In reviewing the literature, Norris found that in 83.3 per cent of 322
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PARATHYROID ADENOMA
cases the adenomas were located in the region of the inferior glands, whereas right and left involvement were about equal. Cope has emphasized that if the hyperfunctioning adenoma cannot be demonstrated in the cervical dissection, normal parathyroid glands should be demonstrated and if one· is missing, that particular area must be searched especially before the chest is explored. Identification of normal parathyroid glands is most important in searching for a hyperfunctioning parathyroid adenoma. Gilmour and Martin found in autopsy material that 80 per cent had four glands, 6 per cent had more than four and 14 per cent had less than four glands. Walton and Churchill and Cope emphasized the need for thorough examination of the ce~ical region as well as the posterior-superior and anterior-superior mediastinal regions. Rienhoff believed that dissection of the anterior mediastinum should be done under direct vision only after failure to find the adenoma in the cervical region or in the posterior TABLE 1
I.
LOCATION OF SINGLE ADENOMAS
I
Location
Number
Right superior pole. . . . . . . . . . . . . . . . . . . . . . . . . . . .
2 (one of these within substance of the gland) Right inferior pole .......... ~ . . . . . . . . . . . . . . . . .. 11 I~eft superior pole .............. '............... . Left inferior pole ............................... .
1 5 (one of these within substance of the gland)
mediastinum, and advocated splitting the sternum down to the third rib and dissecting the anterior-superior mediastinum under direct vision. Postoperatively, blood calcium levels fell as low as 6.5 mg. per 100 cc. but in most instances they varied from 8 to 9 mg. per 100 cc. Lahey17 has emphasized that postoperative tetany develops on the second day and frequently two to three months are required for the other glands to produce an adequate amount of parathormone. Routinely, we attempt to anticipate postoperative tetany by the administration of calcium lactate, calcium gluconate, parathormone, tribasic calcium phosphate, dekatol or drisdol. As Mandl has emphasized, A.T.lO (dihydrotachysterol) is of no avail in acute attacks but is effective in chronic cases. CONCLUSIONS
The pertinent findings in 22 cases of hyperfunctioning parathyroid adenomas have been presented.
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SAMUEL F. MARSHALL AND TIMOTHY A. LAMPHIER
The importance of early diagnosis in preventing irreversible osseous and renal changes is strongly emphasized. Mediastinal exploration should be routine when a tumor cannot be located after search of the neck. The majority of the patients in this study (18 out of 22) had symptoms relative to the skeletal musculature system. Of this number, 12 patients had complaints pertaining to the lower extremities. Eighty-four per cent of the tumors in this series were located near the inferior poles of the thyroid gland. All patients troubled with urinary lithiasis should have routine blood calcium and blood phosphorus determinations t9 rule out the possibility of hyperparathyroidism. REFERENCES 1. Albright, F., Aub, J. C. and Bauer, W.: Hyperparathyroidism; common and polymorphic condition as illustrated by seventeen proved cases from one clinic. J.A.M.A. 102:1276-1287 (Apr. 21) 1934. 2. Albright, F., Bauer, W., Ropes, M. and Aub, J. C.: Studies of calcium and phosphorus metabolism. J. Clin. Investigation 7:139-181 (Apr.) 1929. 3. Albright, F., Bloomberg, E., Castleman, B. and Churchill, E. D.: Hyperparathyroidism due to diffuse hyperplasia of all parathyroid glands rather than adenoma of one; clinical studies on three such cases. Arch. Int. Med. 54:315-329 (Sept.) 1934. 4. Bell, G. O. and Arnold, W. T.: Primary hyperparathyroidism: report of two unusual cases. Lahey Clin. Bull. 6:197-203 (Jan.) 1950. 5. Castleman, B. and Mallory, T. B.: Pathology of the parathyroid gland in hyperparathyroidism; study of 25 cases. Am. J. Path. 11 :1-72 (Jan.) 1935. 6. Churchill, E. D. and Cope, 0.: Surgical treatment of hyperparathyroidism based on 30 cases confirmed by operation. Ann. Surg. 104:9-35 (July) 1936. 7. CoUip, J. B.: Quoted by Norris, E. H. (ref. 21). 8. CoUip, J. B., Clark, E. P. and Scott, J. W.: Effect of a parathyroid hormone on normal animals. J. BioI. Chern. 63:439-460 (Mar.) 1925. 9. Cope, 0.: Surgery of hyperparathyroidism. Ann. Surg. 114:706-733 (Oct.) 1941. 10. Cope, 0.: The endocrine aspect of enlargements of the parathyroid glands. Surgery 16:273-288 (Aug.) 1944. 11. Gilmour, J. R. and Martin, W. J.: Weight of parathyroid glands. J. Path. & Bact. 44:431-462 (Mar.) 1937. 12. Hanson, A. M.: Elementary chemical study of parathyroid glands of cattle. Mil. Surgeon 52:280-284 (Mar.) 1923. 13. Hanson, A. M.: Hydrochloric X of bovine parathyroid. Mil. Surgeon 52:434 (Apr.) 1923. 14. Jaffe, H. L. and Bodansky, A.: Serum-calcium; clinical and biochemical considerations. J. Mt. Sinai Hosp. 9:901-920 (Jan.-Feb.) 1943. 15. Keating, F. R., Jr. and Cook, E. N.: Recognition of primary hyperparathyroidism; analysis of 24 cases. J.A.M.A. 129:994-1002 (Dec. 8) 1945. 16. Kyser, F. A.: Hyperparathyroidism. Proc. Staff Meet., Mayo Clin. 15:179181 (Mar. 20) 1940. 17. Lahey, F. H.: Earlier diagnosis of hyperparathyroidism. Lahey Clin. Bull. 4:66-72 (Jan.) 1945. 18. Lahey, F. H.: Parathyroid tumors. S. CLIN. NORTH AMERICA 27:477-485 (June) 1947.
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19. MANDL, F.: Therapeutischer Versuch bei einem FaIle von Ostitis fibrosa generalisata mittels Exstirpation eines Epithelkorperchen-tumors. Zentralbl. f. Chir. 53:260-264 (Jan. 30) 1926. 20. Mandl, F.: Hyperparathyroidism: A review of historical developments and the present state of knowledge on the subject. Surgery 21 :394-440 (Mar.) 1947. 21. Norris, E. H.: Collective review; parathyroid adenoma; study of 322 cases. Internat. Abstr. Surg. 84:1-41, in Surg., Gynec. & Obst. (Jan.) 1947. 22. Recklinghausen, F. V.: Die fibrose odor deformirende Ostitis, die Osteomalacie und die osteoplastische Carcinose, in ihren gegenseitigen Beziehungen. Festschr. f. Rudolph Virchow, Berlin, George Reimer, 1891,89 pp. 23. Rienl;l.Off, W. F., Jr.: The surgical treatment of hyperparathyroidism, with a report of 27cases. Ann. Surg.131:917-943 (June) 1950. 24. Royster, H. P.: Discussion. Ann. Surg.131:943 (June) 1950. 25. Sandstrom, 1.: Om en my Kortel hos menniskan och I1tskilliga diiggdjur. Upsala Liikaref. Forh. 15:441-471, 1880. 26. Shelling, D. H.: The parathyroids in health and in disease. St. Louis, C. V. Mosby Company, 1935, 335 pp. 27. Walton, A. J.: Surgical treatment of parathyroid tumours. Brit. J. Surg. 19: 285-291 (Oct.) 1931.
The first description of parathyroid glands was made by Sandstrom in 1880. In 1891 von Recklinghausen described bone lesions characteristic of hyperparathyroidism, but it was not realized that this phenomenon was the result of overactivity of the parathyroid gland. Weare indebted to Hanson12 , 13 (1923) and Collip and his associates8 (1925) for their preparations of parathormone. These physiologists demonstrated the effects of parathyroid gland extract on experimental animals, such as increases in blood calcium levels with concomitant low phosphorus levels. In 1926, Mandp9 treated a patient with von Recklinghausen's disease with parathyroid transplants. As the condition of the patient became much worse, he then carried out a cervical exploratien and excised a parathyroid adenoma. This was the first parathyroidectomy. From 1926 to 1932 it was assumed that bone changes were a necl:lssary aftermath of parathyroid disease. Only then was it realized that they were a complication of parathyroidism. In 1929, Albright and his co"' workers2 stated that the chief action of parathormone was to promote excretion of phosphates, whereas in 1932 COllip7 contended that parathyroid hormone acts directly on the solution of calcium salts from bone. Albright, Aub and Bauer1 at the Massachusetts General Hospital must 849
850
SAMUEL F. MARSHALL AND TIMOTHY A. LAMPHIER
be given credit for placing the diagnosis on a sound clinical basis and by their investigations our knowledge of this disease has been greatly enhanced. In 1935, Albright and his associates 3 presented a new pathologic entity, that is, secondary hyperparathyroidism or hyperplasia of all parathyroid glands. More recently (1947), Norris, in an excellent article, discussed parathyroid adenoma, having collected 322 cases from the literature. Rienhoff, in a recent study of a group of 27 cases of hyperparathyroidism, gave an excellent review of the problem. He emphasized the need for early recognition of this syndrome and urged early surgical intervention in order to bring about successful treatment in these serious cases. Rienhoff added 27 cases of hyperparathyroidism to those reported since 1903 and brought the total number to 597. In a discussion of Rienhoff's paper, Royster added 19 more, making a sum total of 616 cases. As Rienhoff pointed out, there must be many other cases that have not been reported in the literature. EMBRYOLOGY
The parathyroid glands develop along with the thyroid and thymus glands from two distinct primordia. The parathyroid glands arise from the third and fourth branchial clefts, whereas the thymus gland originates near the third branchial cleft. The paired parathyroid structures develop as thickenings of the entoderm. These lateral anlagen are located between the middle layer of the deep cervical fascia (on the posterior aspect of the sternohyoid and sternothyroid muscles) and the posterior or prevertebral layer of the deep cervical fascia. Therefore, they can be found anywhere from the pharynx to the mediastinum. That pair which develops with the thymus descends with it in the neck to form the inferior parathyroids. It is for this reason that they are sometimes referred to as "parathymus glands." Moreover, the inferior glands are frequently intrathymic when found in the mediastinum. 9 The development of the superior parathyroids explains why they are sometimes found within the substance of the thyroid gland. As Cope has pointed out, it is largely because of the limited area of embryologic descent that the upper parathyroids have been easier to identify at operation. Adenomas of the inferior parathyroid glands, especially those in the mediastinum, can often be located by tracing arterial branches from the inferior thyroid artery. Norris, in his review of 322 cases (1903-1946), reported that 80 per cent of adenomas weigh less than 15 gm. Rienhoff stated that adenomas in his series varied in size from 0.5 to 6 gm. except for one adenoma which weighed 58 gm. Because of the small size of these adenomas and their position posterior to the thyroid gland they are rarely palpable.
PARATHYROID ADENOMA
851
PATHOLOGY
Four types of lesion~ arise in the parathyroid gland:1s (1) discrete, nonfunctioning adenomas, (2) cystic degeneration within an adenoma, (3) hyperfunctioning parathyroid adenomas and (4) localized malignant disease in the neck arising from the parathyroid gland. The hyperfunctioning adenoma results in what is known as primary hyperparathyroidism (Fig. 278). This condition is to be distinguished from secondary hyperparathyroidism resulting from hyperplasia of all
Fig. 278.
Fig. 279.
Fig. 278. The adenoma was a smoothly nodular and well circumscribed mass measuring 4.9 by 2.4 by 1.5 cm. The tissue was moderately firm and resilient. Externally, the mass was covered by a thin capsule through which irregularly shaped zones of pale pink and gray-brown were seen fusing gradually with each other. Fig. 279. Adenoma of parathyroid, composed of pale chief cells. The solid structure, absence of intermingled fat, and variation in nuclear and cell sizes are characteristic of adenoma (X 1000, eosin-methylene blue stain).
parathyroid tissue because of increased physiologic demands, present in prolonged chronic nephritis, vitamin D deficiency or rickets. Microscopically (Fig. 279), adenomas are composed of chief cells whereas water-clear cells (wasserhelle) are found in hyperplastic glands. Albright 1 believed that parenchymal hyperplasia is hypertrophy of individual cells; such cells are up to sixty-four times the volume of the normal cell. The much enlarged adenoma has less proportional effect per unit weight on blood calcium, as was demonstrated by Castleman and Mallory in 1935, who pointed out that larger tumors are less biologically active
852
SAMUEL F. MARSHALL AND TIMOTHY A. LAMPHIER
than smaller ones. It should be remembered, however, that hyperparathyroidism is a chronic and progressive disease. A frozen section should always be made at the time of operation to identify parathyroid tissue. PHYSIOLOGY
Parathormone controls the level of calcium and inorganic phosphate ions in the blood stream.10 Increased production of parathormone mobilizes skeletal calcium, resulting in a high blood calcium, hypercalcemia, and a high calcium urinary output, hypercalciuria, or a negative balance. Overproduction of hormone is caused by either an adenoma or hyperplasia of all glands (or by malignant disease) and, as we know, adenomas are the most common. As Keating and Cook have pointed out, the total calcium of the blood includes two chief fractions: (1) when combined with serum protein as calcium proteinate, and (2) ionic calcium. Calcium proteinate varies with alterations in protein concentration and is not influ,enced by parathyroid hormone. Ionic calcium is specifically affected by parathyroid hormone. Reduced serum proteins rarely mask hypercalcemia. Determination of an elevated serum protem, however, is a good method of avoiding an erroneous diagnosis of parathyroid disease. It is well known that dangerously low blood calcium levels occur forty-eight hours after parathyroidectomy and especially in those patients with extensive bone disease, or in other words, in those in whom there is a great demand for calcium. There is no adequate explanation for the development of osteitis fibrosa cystica in some cases whereas simple decalcification or osteoporosis takes place in others. In the latter instance, there is lessened activity of osteoblasts or a decrease in bone formation, whereas in osteitis fibrosa cystica there is increased resorption of bone in the region of osteoclasts. Elevation of serum alkaline phosphatase is a reflection of bone disease and not of hyperparathyroidism. In osteoporosis, blood phosphatase values are normal. Jaffe and Bodansky emphasized that the more marked the cystic bone changes the higher the phosphatase level. In turn, the hypocalcemia following successful parathyroidectomy is more difficult to control. They also pointed out that the blood phosphatase in patients having only renal complications remains within normal limits. The formatiori of renal stones occurs as a result of urine supersaturated with calcium. Since phosphate ions are always in excess in this condition, calcium is likely to precipitate as a phosphate salt, and this is particularly true of alkaline urine in which phosphates are insoluble. When oxalates and acid urine are present calcium oxalate stones will form. When ureasplitting organisms such as Proteus are present in the bladder, ammonia is produced and the resultant alkalinization of urine will precipitate calcium phosphate. A compensatory mechanism takes place when there is severe renal failure since excess calcium is then excreted by the large
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bowel. At this point the nonprotein nitrogen and blood chloride values will be elevated. Urinary calcium excretions are difficult to appraise as calcium balance varies with age, diet and body activity. Dental roentgenograms are often an aid in the diagnosis of parathyroid disease. Ordinarily, the lamina dura (a lamina of bone in the jaws bordering the tooth sockets) is present. Its generalized decalcification is strongly suggestive of hyperparathyroidism but it may also disappear in dental disease . SYMPTOMATOLOGY
Three main groups of symptoms are characteristic of hyperparathyroidism and these can be grouped under (1) symptoms resulting from hypercalcemia, (2) symptoms related to the skeletal system and (3) symptoms caused by transportation and excretion of calcium. The following classification by Shelling and Kyser adequately covers the majority of symptoms that are encountered. A. Hypercalcemia 1. Hypotonia 2. Chronic constipation 3. Lassitude 4. Muscle weakness 5. Cardiac arrhythmia and occasional slow pulse B. Transportation and Excretion of Calcium 1. Renal complications 2. Polyuria and polydipsia 3. Enuresis, nocturia and dysuria C. Skeletal System L Pain in joints and bones 2. Spontaneous fractures 3. Cysts in long bones and skull 4. Deformity of long bones 5. Kyphosis, scoliosis or deformity of thorax 6. Waddling gait and inability to walk STATISTICS
Since 1933, in the Lahey Clinic we have records of a total of 22 proven cases of primary hyperparathyroidism treated by surgery. This report of 22 cases is a preliminary report of a somewhat larger group reported by Lahey in discussion of Rienhoff's paper. We hope to present later a more comprehensive follow-up study of a somewhat larger series. To these 22 cases should be added one case in which no tumor was found on cervical exploration. When the patient failed to respond to x-ray therapy, a mediastinotomy at another hospital revealed the presence of an adenoma which was removed. One of the 22 patients who underwent parathy-
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SAMUEL F. MARSHALL AND TIMOTHY A. LAMPHIER
roidectomy can be classified as having had carcinoma of the parathyroid as microscopic sections demonstrated invasion of the capsule. Since this patient had characteristic bone changes, hypercalcemia and hypophosphatemia, she is included in this group. An additional 2 patients had an exploratory operation because of repeated recurrent renal stones and hypercalcemia, but no tumor was found. A normal parathyroid gland was excised in one of these patients and a four-year follow-up revealed that the patient no longer has renal stones. Follow-up studies of the second patient were incomplete because the patient could not be traced. A third patient underwent a neck exploration because of a mass present at the level of the bifurcation of the right carotid artery. The mass was reported by the pathologists as "adenocarcinoma, low grade, probably of parathyroid origin." Of the 22 patients who were found to have parathyroid adenomas, 19 were females and 3 males, a ratio of 6.3 to 1. The average age of the entire group of patients was 47.9 years. The youngest patient in the group was 18 years and the oldest 74 years of age. Of the 3 males the youngest was 18 and the oldest 70 years of age. Of the female patients, the youngest was 22 years and the oldest 74 years of age. The past histories of this group of patients were significant in 5, inasmuch as they had had renal stones on one or several occasions. Rienhoff, in his group of 27 cases noted renal complications far more frequently in males than in females; 18 of the 27 had renal changes only and but one male had bony changes, whereas 6 of 12 women had skeletal changes only without renal complications. Royster stated that the early or borderline cases are usually presented from the urologic clinic where blood calcium, phosphorus and phosphatase studies have directed the attention of the clinician to the possibility of hyperparathyroidism. In his group of 22 cases most diagnoses were made on the basis of skeletal rather than renal changes. Rienhoff pointed out that whenever attention is directed to this syndrome by observations of renal changes, there will be a noticeable increase in diagnosis of this disease since the most frequent complication of hyperparathyroidism is some form of renal lithiasis. Certainly, in any patient who repeatedly forms renal, ureteral or bladder stones, the possibility of hyperparathyroidism should be seriously considered. Approximately 10 per cent of all patients with renal stones have hyperfunctioning parathyroid glands. Three of the patients had previously undergone unsuccessful neck explorations before coming to the clinic. One patient had undergone several laparotomies for abdominal distress associated with constipation which was due to overactivity of a parathyroid adenoma. A second patient had a history of three spontaneous fractures in the six years before admission to this clinic. Three patients had noticed a loss in stature. Eighteen patients had complaints relative to the skeletal-muscular systems. The average duration of
PARATHYROID ADENOMA
1 i
855
complaints in this group was 4.2 years, with a minimum time of eight months and a maximum of fifteen years. Two patients were referred to the clinic because of complications after tooth extractions. In one instance the patient stated that her "gums had failed to heal" following extraction of a tooth. Subsequent roentgenograms demonstrated a cyst in the mandible. In spite of this finding she did not undergo more definitive studies until she came to the clinic one year later. In the other patient, pain and swelling of the left lower jaw developed following removal of a tooth. Two years later roentgenograms were taken and the patient was found to have cysts of the mandible for which she had been treated with x-ray therapy for several months before coming to the clinic. Of this group of patients with complaints related to the skeletalmuscular systems, 12 had complaints referable to the lower extremities, such as pain or stiffness or both in the knee and ankle joints, increased bowing of the tibiae, and stiffness in the thighs especially along the posterior aspect of the hips. Two patients complained of loss of height or rounded dorsal spine. Low backaches, waxing and waning in severity but progressively increasing in intensity, occurred in 4 patients. One patient was referred to the clinic because of recurrent renal stones. In one patient, an adenoma, nonfunctioning because of cystic degeneration, was incidentally removed with a substernal goiter. One patient, a woman, had no symptoms related to the skeletal, muscular or renal systems. She complained of loss of 28 pounds in one year. Subsequent studies revealed that she had been distressed with polyuria, polydipsia, vomiting and constipation (this patient is reported in more detail by Bell and Arnold). In Norris' report of 322 cases of adenomas, only 1.5 per cent failed to show a degree of renal or skeletal change of clinical importance. Another patient stated that she had had headaches for ten years with dizzy and fainting spells in the three years prior to admission, plus a weight loss of 40 pounds. Skull and cervical plates revealed osteoporosis. The last patient to complete this group of 22 complained of constipation of twelve years' duration and had undergone many operations for correction of her supposed bowel disease. Although only 3 patients of the entire group had polyuria and polydipsia, they are symptoms not to be underestimated. Muscular weakness was a notable complaint of 2 patients. Postoperative psychosis and temporary personality changes occurred in 2 patients and no doubt were related to the prodromal signs of parathyroid tetany. Frequently, transient parathyroid insufficiency is accompanied by psychic symptoms of short duration. Five patients (22.7 per cent) of the 22 had palpable neck tumors. Nine patients, or 40.9 per cent, complained of weight loss; the average loss was 19.2 pounds. The minimal weight loss was 4 pounds and the maximal 40 pounds. In 19 patients changes of either osteitis fibrosa cystica or osteoporosis were noted in roentgen studies. Those who had no bone
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SAMUEL F. MARSHALL AND TIMOTHY A. LAMPHIER
changes had symptoms of weight loss and constipation. In addition in this group there was one nonfunctioning adenoma with cystic degeneration. Osteoporosis alone was present in the roentgenograms of 3 patients. Cystic changes with or without osteoporosis were present in the roentgenograms of 13 patients. Pathologic compression fractures of vertebrae were noted in 4 patients. Only one patient had vertebral epiphysitis. Pitting or mottling of the skull with loss of cranial tables was present in 7 patients. Loss of peridental membrane, spotty decalcification or absence of lamina dura or alveolar resorption occurred in 5 patients. This finding associated with a general derangement of the bony architecture is significant. Trabeculation or pronounced fibrillation of bone consistent with Paget's disease or hyperparathyroidism and coarsening of the texture of all bones were seen in the roentgenograms of 4 patients. Punctate calcification about renal papillae or calcinosis of the parenchyma of both kidneys was present in only 2 patients. In this group of 22 cases, preoperative studies demonstrated that the blood calcium levels (normal 9 to 11 mg. per 100 cc.) ranged from 11.4 to 17.2 mg. per 100 cc. with the exception of one case in which it was recorded as 9 mg. per 100 cc. In the latter instance, the adenoma was embedded in struma lymphomatosa tissue. As has been emphasized in other reports in the literature, those patients with more extensive bone disease had relatively higher blood calcium levels and in these cases the serum phosphatase was elevated. Total blood protein levels were followed for comparison in each case to evaluate the variances. Depression of blood phosphorus levels (normal 3 to 4 mg. per 100 cc.) was not as consistent as was elevation of blood calcium levels and is, therefore, not as true an index of parathyroid overactivity. Fifteen patients had levels recorded as between 0.9 to 2.9 mg. per 100 cc. In the other 7 cases, the blood phosphorus levels were normal. Alkaline phosphatase levels (normal 1 to 4.5 Bodansky units) were elevated in all but 2 patients, with a maximal level of 64.4 units and an average of 19.8 units. The Sulkowitch test, an easy qualitative method for detecting urine calcium, was elevated in all but two instances (normal 0 to 1+). This test also varies with diet, urinary function and so forth. Whenever there was any question of renal involvement, nonprotein nitrogen value of the blood was determined and renal function studies and pyelograms were carried out. Multiple adenomas were not found in this group of patients. The locations of the single adenomas are listed in Table 1. In the 3 remaining cases not included in Table 1 the adenomas were designated as being located in relation to the right lobe but were not further described. In reviewing the literature, Norris found that in 83.3 per cent of 322
857
PARATHYROID ADENOMA
cases the adenomas were located in the region of the inferior glands, whereas right and left involvement were about equal. Cope has emphasized that if the hyperfunctioning adenoma cannot be demonstrated in the cervical dissection, normal parathyroid glands should be demonstrated and if one· is missing, that particular area must be searched especially before the chest is explored. Identification of normal parathyroid glands is most important in searching for a hyperfunctioning parathyroid adenoma. Gilmour and Martin found in autopsy material that 80 per cent had four glands, 6 per cent had more than four and 14 per cent had less than four glands. Walton and Churchill and Cope emphasized the need for thorough examination of the ce~ical region as well as the posterior-superior and anterior-superior mediastinal regions. Rienhoff believed that dissection of the anterior mediastinum should be done under direct vision only after failure to find the adenoma in the cervical region or in the posterior TABLE 1
I.
LOCATION OF SINGLE ADENOMAS
I
Location
Number
Right superior pole. . . . . . . . . . . . . . . . . . . . . . . . . . . .
2 (one of these within substance of the gland) Right inferior pole .......... ~ . . . . . . . . . . . . . . . . .. 11 I~eft superior pole .............. '............... . Left inferior pole ............................... .
1 5 (one of these within substance of the gland)
mediastinum, and advocated splitting the sternum down to the third rib and dissecting the anterior-superior mediastinum under direct vision. Postoperatively, blood calcium levels fell as low as 6.5 mg. per 100 cc. but in most instances they varied from 8 to 9 mg. per 100 cc. Lahey17 has emphasized that postoperative tetany develops on the second day and frequently two to three months are required for the other glands to produce an adequate amount of parathormone. Routinely, we attempt to anticipate postoperative tetany by the administration of calcium lactate, calcium gluconate, parathormone, tribasic calcium phosphate, dekatol or drisdol. As Mandl has emphasized, A.T.lO (dihydrotachysterol) is of no avail in acute attacks but is effective in chronic cases. CONCLUSIONS
The pertinent findings in 22 cases of hyperfunctioning parathyroid adenomas have been presented.
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The importance of early diagnosis in preventing irreversible osseous and renal changes is strongly emphasized. Mediastinal exploration should be routine when a tumor cannot be located after search of the neck. The majority of the patients in this study (18 out of 22) had symptoms relative to the skeletal musculature system. Of this number, 12 patients had complaints pertaining to the lower extremities. Eighty-four per cent of the tumors in this series were located near the inferior poles of the thyroid gland. All patients troubled with urinary lithiasis should have routine blood calcium and blood phosphorus determinations t9 rule out the possibility of hyperparathyroidism. REFERENCES 1. Albright, F., Aub, J. C. and Bauer, W.: Hyperparathyroidism; common and polymorphic condition as illustrated by seventeen proved cases from one clinic. J.A.M.A. 102:1276-1287 (Apr. 21) 1934. 2. Albright, F., Bauer, W., Ropes, M. and Aub, J. C.: Studies of calcium and phosphorus metabolism. J. Clin. Investigation 7:139-181 (Apr.) 1929. 3. Albright, F., Bloomberg, E., Castleman, B. and Churchill, E. D.: Hyperparathyroidism due to diffuse hyperplasia of all parathyroid glands rather than adenoma of one; clinical studies on three such cases. Arch. Int. Med. 54:315-329 (Sept.) 1934. 4. Bell, G. O. and Arnold, W. T.: Primary hyperparathyroidism: report of two unusual cases. Lahey Clin. Bull. 6:197-203 (Jan.) 1950. 5. Castleman, B. and Mallory, T. B.: Pathology of the parathyroid gland in hyperparathyroidism; study of 25 cases. Am. J. Path. 11 :1-72 (Jan.) 1935. 6. Churchill, E. D. and Cope, 0.: Surgical treatment of hyperparathyroidism based on 30 cases confirmed by operation. Ann. Surg. 104:9-35 (July) 1936. 7. CoUip, J. B.: Quoted by Norris, E. H. (ref. 21). 8. CoUip, J. B., Clark, E. P. and Scott, J. W.: Effect of a parathyroid hormone on normal animals. J. BioI. Chern. 63:439-460 (Mar.) 1925. 9. Cope, 0.: Surgery of hyperparathyroidism. Ann. Surg. 114:706-733 (Oct.) 1941. 10. Cope, 0.: The endocrine aspect of enlargements of the parathyroid glands. Surgery 16:273-288 (Aug.) 1944. 11. Gilmour, J. R. and Martin, W. J.: Weight of parathyroid glands. J. Path. & Bact. 44:431-462 (Mar.) 1937. 12. Hanson, A. M.: Elementary chemical study of parathyroid glands of cattle. Mil. Surgeon 52:280-284 (Mar.) 1923. 13. Hanson, A. M.: Hydrochloric X of bovine parathyroid. Mil. Surgeon 52:434 (Apr.) 1923. 14. Jaffe, H. L. and Bodansky, A.: Serum-calcium; clinical and biochemical considerations. J. Mt. Sinai Hosp. 9:901-920 (Jan.-Feb.) 1943. 15. Keating, F. R., Jr. and Cook, E. N.: Recognition of primary hyperparathyroidism; analysis of 24 cases. J.A.M.A. 129:994-1002 (Dec. 8) 1945. 16. Kyser, F. A.: Hyperparathyroidism. Proc. Staff Meet., Mayo Clin. 15:179181 (Mar. 20) 1940. 17. Lahey, F. H.: Earlier diagnosis of hyperparathyroidism. Lahey Clin. Bull. 4:66-72 (Jan.) 1945. 18. Lahey, F. H.: Parathyroid tumors. S. CLIN. NORTH AMERICA 27:477-485 (June) 1947.
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19. MANDL, F.: Therapeutischer Versuch bei einem FaIle von Ostitis fibrosa generalisata mittels Exstirpation eines Epithelkorperchen-tumors. Zentralbl. f. Chir. 53:260-264 (Jan. 30) 1926. 20. Mandl, F.: Hyperparathyroidism: A review of historical developments and the present state of knowledge on the subject. Surgery 21 :394-440 (Mar.) 1947. 21. Norris, E. H.: Collective review; parathyroid adenoma; study of 322 cases. Internat. Abstr. Surg. 84:1-41, in Surg., Gynec. & Obst. (Jan.) 1947. 22. Recklinghausen, F. V.: Die fibrose odor deformirende Ostitis, die Osteomalacie und die osteoplastische Carcinose, in ihren gegenseitigen Beziehungen. Festschr. f. Rudolph Virchow, Berlin, George Reimer, 1891,89 pp. 23. Rienl;l.Off, W. F., Jr.: The surgical treatment of hyperparathyroidism, with a report of 27cases. Ann. Surg.131:917-943 (June) 1950. 24. Royster, H. P.: Discussion. Ann. Surg.131:943 (June) 1950. 25. Sandstrom, 1.: Om en my Kortel hos menniskan och I1tskilliga diiggdjur. Upsala Liikaref. Forh. 15:441-471, 1880. 26. Shelling, D. H.: The parathyroids in health and in disease. St. Louis, C. V. Mosby Company, 1935, 335 pp. 27. Walton, A. J.: Surgical treatment of parathyroid tumours. Brit. J. Surg. 19: 285-291 (Oct.) 1931.