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Treatment of Hyperparathyroidism by Percutaneous Embolization of a Mediastinal Adenoma 1

Diagnostic Radiology

John L. Doppman, M.D., Stephen J. Marx, M.D., Allen M. Spiegel, M.D., Lawrence E. Mallette, M.D., Ph.D., Dorothy R. Wolfe, B.A., Gerald D. Aurbach, M.D., and Glenn Geelhoed, M.D. Percutaneous embolization of parathyroid adenomas was attempted in three hypercalcemic patients with previously unsuccessful neck explorations. Two adenomas were in the mediastinum and the third was within the thyroid lobe. Autologous clot, Gelfoam, and silicone rubber were used to obstruct feeding arteries. The intrathyroidal adenoma failed to respond but both mediastinal adenomas were infarcted. Hyperparathyroidism recurred after 7 monthsin one patient but the other remains normocalcemic8 months postembolizatlon.

INDEX TERMS: neoplasms

Embolism, therapeutic. Parathyroid, hyperparathyroidism. Parathyroid,

Radiology 115:37-42, April 1975

HE ARTERIAL SUPPL Y of the parathyroid gland is particularly suitable for therapeutic embolization. Each gland is fed by a single artery entering at a clearly defined vascular hilus (1, 8, 17). Although there is a "fern-like pattern of vessels radiating out over the capsule" (7), little collateral blood supply enters the gland through extrahilar sites. In fact, the existence of such a vascular pedicle and the negligible capsular attachments to surrounding tissues may account for the glands' mobility and tendency to ptose into the mediastinum when enlarged. This solitary arterial supply occasionally allows the infarction of normal or adenomatous glands during a biopsy or a difficult dissection. Adenomatous or hyperplastic glands retain this reniform pattern with a single major hilar artery. Thus, occlusion of this vessel by embolization through a catheter might produce sufficient ischemic damage to disrupt parathyroid function permanently. In this report we describe the initial experience with this form of therapy for primary hyperparathyroidism.

roid hormone were obtained in a single radioimmunoassay with a separate control for tracer damage on each individual specimen. The lower limit of detection, i.e., presented by a 10% change from the bound to free ratio in the absence of added hormone, was 0.15 ng per

T

ml. CASE REPORTS CASE I: This 36-year-old white woman was referred to the National Institutes of Health for evaluation of hypercalcemia. Her health was good until an attack of renal, colic in 1971. A second attack in July 1972 prompted medical evaluation; hypercalcemia was discovered, and the neck was explored. The search was thorough andlncluded removal of part of the mediastinal fat pad, but only three parathyroid glands were identified, and two and one-half were removed. Histological sections revealed normal parathyroid tissue, and the serum calcium remained in the range of 12 mg per 100 ml postoperatively. An incidental finding at surgery was papillary carcinoma of the thyroid metastatic to regional lymph nodes. A total thyroidectomy was performed, and the patient was given L-thyroxine. In December 1972 the patient suffered a third bout of renal colic and was referred to the National Institutes of Health. Physical examination was normal save for the scar on the neck. Chemical analyses of serum showed the following: magnesium 1.7 mEq per liter, calcium 12.7 mg per 100 ml (normal 8.6 to 10.5 mg per 100 ml), phosphorus 2.4 mg per 100 ml, and creatinine 0.7 mg per 100 ml. Tubular reabsorption of phosphate was 78 % (normal is greater than 85 %). Skeletal radiographs demonstrated mild generalized osteopenia. A 75Se-methionine scan of the neck and thorax showed no localizeduptake. Bilateral selective superior and inferior thyroid arteriography was performed. All thyroidal arteries were small or occluded, as wouldbe anticipated after total thyroidectomy. No staining of residual thyroid or parathyroid tissue was observed in the neck. Theatrophic right inferior thyroid artery gave rise to a branch that descended into the mediastinum and supplied a densely staining 1.1 X 1.5-cm mass at the level of the carina (Fig. 1, A). Oblique projections indicated an anterior.position, suggesting localization within the thymic capsule

METHODS Techniques for selective arteriography and venous sampling of the parathyroid glands have been reported in detail (12-14, 34). Cyclic 3 ',S/-adenosine monophosphate (AMP) (10, 35) and parathyroid hormone (32) were determined by radioimmunoassay. The same highly purified bovine parathyroid hormone was used as standard and as substrate for iodination by the lactoperoxidase method (25). The antiparathyroid hormone antiserum (GP-1) at a final dilution of 1:400,000 detects both N- and C-terminal portions of the parathyroid hormone molecule (32). Serial determinations of parathy-

1 From the Department of Diagnostic Radiology, Clinical Center (J. L. D.), and the Metabolic Diseases Branch, National Institute of Arthritis, Metabolism and Digestive Diseases (5. J. M., A. M.S., L. E. M., D. R. W., G. D. A.), National Institutes of Health, Bethesda, Md.,and the Department of Surgery (G. G.), George Washington University Hospital, Washington, D.C. Presented at the Sixtieth Scientific Assembly and Annual Meeting of the Radiological Society of North America, Chicago, III., Dec. 1-6, 1974, ah

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JOHN

L. DOPPMAN

AND OTHERS

Apri/1975

Fig. 1. Selective arteriograms of right inferior thyroid artery . A. Anteroposterior projection . Arrows identify descending mediastinal branch and densely staining tumor blush. B. Steep oblique project ion with spine to the right. The adenoma lies far anterior, probably within the thymic capsule. C. Anteroposterior project ion following embolization. Arrows identify obstructed mediastinal branch. The adenoma no longer stains.

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RT.INT. MAMMARY

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Fig. 2. Results of selective venous sampling. The right thymic vein contains a thirtyfold step-up in parathyroid hormone concentration. Note absence of a gradient in the left thymic vein, and hence the importance of defining the venous drainage pattern on a preliminary arteriogram. (Fig. 1, B). The venous drainage was via the right thymic vein into the right internal mammary vein. The results of selective venous sampling for parathyroid hormone are presented in Figure 2. Markedly elevated concentrations of hormone were found in the effluent from the right thymic vein, confirming the area of the mediastinal tumor stain as the source of parathyroid hormone ,

In order to embolize the presumed parathyroid adenoma, a catheter was introduced through the right axillary artery to afford a short and direct approach to the feeding vessel. The catheter tip was placed deeply into the right inferior thyroid artery at the origin of the mediastinal branch. Autologous clot (26,31) and Gelfoam (11) were used to occlude both the ascending inferior thyroid remnant and the descending branch to the mediastinal adenoma (Fig. 1, C). The patient's course following embolization was benign. There was no discomfort in the chest nor were there symptoms suggestive of ischemia to vital structures. The serum calcium fell at a rate similar to that seen after a successful parathyroidectomy and mild tetany developed within seven days. The concentration of parathyroid hormone in plasma and the ratio of urinary excretion of 3',5 /-cyclic adenosine monophosphate to creatinine also declined, paralleling the course usually seen after successful surgery. By the fifth day after treatment the concentration of parathyroid hormone in plasma and the rate of urinary excret ion of 3,'5 '-cyclic adenosine monophosphate had returned to values slightly above normal, at a time when the patient remained hypocalcemic. Two months after the procedure the serum calcium was in the normal range and the patient was taking neither calcium nor vitamin D. Seven months postembolization, serum calcium was slightly elevated (10.8 mg/l00 ml) and serum phosphorus was 2.8 mg/l00 ml. The concentration of parathyroid hormone has risen to 0.54 ng/ml (normal values are less than 0.27 ng/ml). CASE II: This 35-year-old black woman was found to have hypercalcemia (Ca = 12.8 mg/l00 ml, normal 8.6-10.5 mg/l00 ml) while being investigated for dyspepsia. A diagnosis of peptic ulcer or pancreatit is was never established. Neck exploration revealed three biopsy-proved normal parathyroid glands (right superior, left superior, left inferior). Two and one-half glands were removed, leaving a portion of the normal left superior gland. A right thyroid lobectomy was performed because inability to identify a right Inferior gland. Postoperatively, the hypercalcemia persisted and the patient was referred to us for localization studies. Bilateral selective arteriography of the superior and inferior thyroid arteries revealed no evidence of an adenoma in the neck but a 1.0 X 1.6 cm stain was demonstrated

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Fig. 3. A. Right internal mammary arteriogram shows a densely staining parathyroid adenoma (arrowheads) supplied by a single proximally arising feeding artery (arrows) . B. Prolonged selective perfusion of the adenoma (arrowheads) with contrast medium immediately before embol ization. C. Right internal mammary arteriogram 10 minutes following embolic occlusion of the feeding artery (arrowheads). Note persisting dense stain of the adenoma, suggesting ischemic extravasation. Fig. 4. A. Selective left inferior thyroid arteriogram, early phase, demonstrates staining of the margin of left inferior parathyroid adenoma (arrowheads) . B. Later phase demonstrates a more uniform staining adenoma (arrowheads) superimposed upon a less densely staining thyroid lobe. Also visualized is an inferior draining vein (arrows) in which a marked step-up of PTH was measured. C. A cast of silicone rubber opacified with tantalum powder fills the inferior thyroid artery and its branches. Note opacification of the periphery of the adenoma (arrowheads) comparable to the early arteriographic appearances (compare with 4, A).

in the mediastinum by selective right internal mammary arteriography (Fig. 3, A). Venous drainage occurred via a left thymic vein into the left innominate vein. This draining thymic vein was selectively catheterized but the sample was unfortunately lost. However, in view of the classic arteriographlc findings, the previous operative demon" stration of three normal glands and the obvious need for sternal split-

ting thoracotomy in this obese woman , it was decided to attempt embolization. Immediately preced ing embolization, the adenoma was selectively perfused with 50 ml of meglumine lothalamate (Conray 60, Mallinckrodt Chem., St. Louis, Mo.) (Fig. 3, B). This produced an intense staining of the adenoma which persisted for an hour following occlusion of the feeding artery (Fig. 3, C). The patient experi-

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April 1975

DISCUSSION

Fig. 5. 1) Normal parathyroid gland or adenoma has a single feeding artery without significant transcapsular collateral inflow. 2) Embolic occlusion of this single feeder stimulates collateral development probably before total necrosis of the gland. Histology of spontaneously infarcted glands and CASE I support this conclusion. 3) Obturating the entire capillary bed prevents collateral inflow and favors complete destruction of glandular parenchyma .

enced no symptoms during or following embolization. Serum calcium dropped precipitously to 6.5 mg/l00 ml within 72 hours of embolization. Calcium lactate and vitamin D were required to control hypocalcemic symptoms. These medications were discontinued after 3 months and the patient remains normocalcemic (Ca = 10.1 mg/l00 ml) 7 months postembolization . CASE III: This 59-year-old black man had persistent hypercalcemia (Ca 13.2 mg/l00 ml, normal 8.6-10.5 mg/l00 ml) following an unsuccessful neck exploration for primary hyperparathyroidism. Three normal parathyroid glands were identified at the initial operation (both superior glands and one Inferior gland, side not specified). He was referred to N.I.H. for localization studies. Bilateral selective superior and inferior thyroid and Internal mammary arterlograms were obtained. A 1.5 X 0.7 em oval stain overlying the left thyroid lobe was opacified at left inferior thyroid arteriography (Fig. 4, A). Selective venous sampling revealed high levels of parathyroid hormone in the left inferior thyroid vein (Fig. 4, B). Since a discrete feeding artery to the adenoma had not been demonstrated, we elected to use a rapidly polymerizing silicone rubber preparation (16) in an attempt to fill up or completely obturate the capillary bed of the adenoma. Figure 4, C demonstrates obturation 01 the inferior thyroid artery and the periphery of the adenoma by a polymerized silicone rubber cast. Following embolization, mild left sided neck pain and muscle spasm persisting for 24-48 hours developed. We have observed a similar syndrome of ischemic muscle injury consisting of pain, muscle spasm, and elevated serum creatine phosphokinase following lumbar artery embolization for spinal cord arteriovenous malformations. Serum calcium levels did not fall following embolization and serial films over 24 hours demonstrated migration of the silicone cast out of the obstructed inferior thyroid artery. Nonadherence or silicone rubber to vascular walls and collateral inflow from the contralateral inferior thyroid and ipsilateral superior thyroid arteries probably accounted for this migration but cautions against the use of silicone in vascular beds, such as the thyroid, with potential retrograde collateral inflow. The patient subsequently underwent surgical exploration of the left neck . When no parathyroid tissue could be identified, a left thyroid lobectomy was performed and hemisection of the lobe revealed a large. totally Intrathyroidal parathyroid adenoma. He has remained normocalcemlc following surgery.

=

Arterial embolization through percutaneously placed catheters is being used more frequently in the therapy of diverse disorders, lncludinq intestinal bleeding (2, 31), arteriovenous malformations (4, 11, 23), and pelvic trauma (26). This technique can be employed to ablate any tissue with an accessible arterial supply that does not feed other critical structures. It is especially useful when the alternative is a difficult surgical dissection. A mediastinal exploration, though it has been rarely required in our experience (15, 36), seemed virtually obligatory in CASES I and II because of the deep intrathoracic location of the adenoma and the anticipated scarring low in the neck from previous partial removal of the mediastinal fat pad. Embolization in these cases seemed thus to be appropriate therapy. In CASE III, previous extensive neck dissection influenced our decision to attempt embolization. Both the totally intrathyroidal location of the adenoma and the abundant sources of collateral blood supply to cervical as opposed to mediastinal adenomas contributed to the failure of embolization in this case . However, the concept of completely obturating the capillary bed of an adenoma as opposed to simply occluding its feeding artery remains a valid one (Fig. 5), as evidenced by the recurrence of mild hyperparathyroidism in CASE I. The most effective technique will probably combine deliberate parenchymal injury (50 % glucose solution or concentrated contrast medium), followed by embolic occlusion of the arterial supply (CASE II), or " vascular casting" with a rapidly polymerizing plastic (CASE III). Ablating endocrine glands with embolic techniques involves considerations beyond those generally entertained when controlling hemorrhage or occluding angiomatous lesions. The following potential risks and shortcomings were given careful consideration and discussed in detail with each patient before the procedure was undertaken. 1. Precipitation of Hyperparathyroid Crisis: Howard et al. (19) reported spontaneous infarction of a parathyroid adenoma with short-lived but severe hypercalcemia preceding the development of hypoparathyroidism. Chodack et al. (5), DeGroote (9), and Lemann et al. (21) cured patients with parathyroid intoxication by removing acutely hemorrhagic parathyroid adenomas. However, most cases of hyperparathyroid crisis have not been associated with infarcted adenomas. From 70 such cases reviewed by Payne and Fitchett (30), only two parathyroid glands showed evidence of hemorrhage or necrosis. On the other hand, in three cases of so-called spontaneous infarction reported in the literature (20, 27, 28), acute hypocalcemia and tetany , not uncontrollable hypercalcemia, were the major treatment problems. Hyperparathyroid crisis is rare but arises more as a complex of delayed diagnosis, prolonged bed rest, and dehydration than as a consequence of a sudden burst of hormone secretion. Parathyroid glands contain only small amounts of hormone (about 0.01 % by weight) (29, 33)

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that is rapidly synthesized and secreted. Thus, with total release of all hormone from a 1-g adenoma, only 100 ~g could enter the circulation. This should lead to a maximal increase in peripheral hormone concentration of 4 ng per ml. We in fact observed no significant increase in hormone concentration in CASE I; indeed, the hormone content of plasma fell rapidly after arterial occlusion as did the rate of urinary excretion of cyclic 3',5/-adenosine monophosphate. Thus, although sudden release of "toxic" amounts of parathyroid hormone is remotely possible, it would seem to be an unlikely complication. 2. Infarction or Ischemia of Critical Structures: The vertebral artery and costocervical trunk arise from the subclavian artery adjacent to the thyrocervical trunk, and each gives rise to important branches to the posterior fossa and cervical spinal cord. Particular care was taken to avoid reflux of embolic material into the subclavian artery by deeply wedging the catheter into the inferior thyroid or internal mammary arteries and by gently injecting the embolizing material. We have carefully scrutinized several hundred subtracted inferior thyroid arteriograms and have never observed branches to the cervical cord arising from this vessel. 3. Hemorrhagic Infarction: The parathyroid glands are quite susceptible to hemorrhage when traumatized at surgery. We monitored CASES I and II for this potential complication with frequent clinical examinations and serial radiographs; no chest symptoms or mediastinal widening occurred. 4. Lack of Histological Diagnosis: In over 95 % of patients in large series of primary hyperparathyroidism the involved tissue has been benign (6, 18, 22, 24). The lack of a family history of multiple endocrine adenomatosis and the prior identification by biopsy of three normal glands made the diagnosis of multiglandular hyperplasia unlikely. Parathyroid or nonparathyroid cancer seemed unlikely. 5. Permanent Hypoparathyroidism: A high risk of permanent hypoparathyroidism was accepted in all our patients. This risk would have been similar had the tumor been removed surgically. 6. Recurrence of Hyperparathyroidism: Recanalization of clot-occluded arteries probably occurs within 24 to 48 hours (4). If in fact a parathyroid adenoma were supplied by a single artery, irreversible necrosis should have occurred within this period. However, spontaneously infarcted glands usually contain a rim of normal parathyroid tissue (18, 27, 28), and the gradually rising levels of serum calcium and parathyroid hormone in CASE I suggest that the adenoma is recovering function. CASE II remains euparathyroid but the length of followup is only 8 months. Unsuccessful embolization, as in CASE III, appears not to interfere with subsequent surgery. We were impressed with the smooth course and uneventful recovery in CASES I and II. This form of therapy, however, is clearly experimental and in any event would

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Diagnostic Radiology

be limited in application to cases requiring repeated surgery (we restrict use of arteriography to this category (3)) in which multiglandular hyperplasia is considered unlikely. ACKNOWLEDGMENT: We wish to thank Dr. Robert Levine of New Haven, Conn., for referring our first patient and for his continuing cooperation.

Department of Diagnostic Radiology Building 10, Room 6S211 National Institutes of Health Bethesda, Md. 20014

REFERENCES 1. Alveryd A: Anatomy of parathyroid glands. Acta Chir Scand Supp 389, 1968 2. Baum S, Rosch J, Dotter CT, et al: Selective mesenteric arterial infusions in the management of massive diverticular. hemorrhage. N Engl J Med 288:1269-1272. 14 Jun 1973 3. Bilezikian JP, Doppman JL, Shimkin PM, et al: Preoperative localization of abnormal parathyroid tissue. Am J Med 55:505-514, Oct 1973 4. Bookstein JJ, Goldstein HM: Successful management of postbiopsy arteriovenous fistula with selective arterial embolization. Radiology 109:535-536, Dec 1973 5. Chodack P, Attie IN, Groder MG: Hypercalcemic crisis coincidental with hemorrhage in parathyroid adenoma. Arch Intern Med 116:416-423, Sep 1965 6. Cope 0: Story of hyperparathyroidism at the Massachusetts General Hospital. N Engl J Med 274:1174-1182, 26 May 1966 7. Cope 0: Surgery of hyperparathyroidism: the occurrence of parathyroids in the anterior mediastinum and the division of the operation into two stages. Ann Surg 114:706-730, Oct 1941 8. Curtis GM: The blood supply of human parathyroids. Surg Gynec Obstet 51:805-809, Dec 1930 9. DeGroote JW: Acute intermittent hyperparathyroidism with hemorrhage into a parathyroid adenoma. JAMA 208:2160-2161, 16 Jun 1969 10. Desbuquois B, Aurbach GD: Use of polyethylene glycol to separate free and antibody-bound peptide hormones in radioimmunoassays. J Clin Endocr Metab 33:732-738, Nov 1971 11. Doppman JL, DiChiro G, Ommaya AK: Percutaneous embolization of spinal cord arteriovenous malformations. J Neurosurg 34:48-55, Jan 1971 12. Doppman JL, Hammond WG: The anatomic basis of parathyroid venous sampling. Radiology 95:603-610, Jun 1970 13. Doppman JL, Hammond WG, Melson GL, et al: Staining of parathyroid adenomas by selective arteriography. Radiology 92: 527-530, Mar 1969 14. Doppman JL, Melson GL, Evens RG, Hammond WG: Selective superior and inferior thyroid vein catheterization: venographic anatomy and potential applications. Invest Radiol 4:97-99, Mar-Apr 1969 15. Doppman JL, Wells SA, Shimkin PM, et al: Parathyroid localization by angiographic techniques in patients with previous neck surgery. Brit J Radiol 46:403-418, Jun 1973 16. Doppman JL, Zapol W, Pierce J: Transcatheter embolization with a. silicone rubber preparation: experimental observations. Invest Radiol 6:304-309, Sep-Oct 1971 17. Halsted WS, Evans HM: The parathyroid glandules: their blood supply and their preservation in operations upon the thyroid gland. Ann Surg 46:489-506, 1907 18. Hellstrom J, Ivemark BI: Primary hyperparathyroidism: clinical and structural findings in 138 cases. Acta Chir Scand Suppl 294:1-113,1962 19. Howard JE, Follis RH Jr, Yendt ER, et al: Hyperparathyroidism: case report illustrating spontaneous remission due to necrosis of adenoma, and a study of the incidence of necroses in parathyroid adenomas. J Clin Endcicr 13:997-1008, Aug 1953

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20. Johnston CC Jr, Schnute RS: A case of primary hyperparathyroidism with spontaneous remission following infarction of the adenoma with development of hypocalcemic tetany. J Clin Endoer 21:186-200, Feb 1961 21. Lemann J Jr, Donatelli AA: Calcium intoxication due to primary hyperparathyroidism: a medical and surgical emergency. Ann Intern Med 60:447-461, Mar 1964 22. Lloyd HM: Primary hyperparathyroidism: an analysis of the role of the parathyroid tumor. Medicine 47:53-71, Jan 1968 23. Luessenhop AJ, Kachmann R Jr, Shevlin W, et al: Clinical evaluation of artifical embolization in the management of large cerebral arteriovenous malformations. J Neurosurg 23:400-417, Oct 1965 24.

Mallette LE, Silezikian JP, Heath DA, et al: Primary hyperparathyroidism: clinical and biochemical features. Medicine 53:

127-146,1974 25. Marchalonis JJ: An enzymic method for the trace iodination of immunoglobulins and other proteins. Biochem J 113:299305, Jun 1969 26. Margolies MN, Ring EJ, Waltman AC, et al: Arteriography in the management of hemorrhage from pelvic fractures. N Engl J Mad

287:317-321, 17 Aug 1972 27. Norris EH: Primary hyperparathyroidism: report of 5 cases that exemplify special features of this disease (infarction of parathyroid adenoma; oxyphil adenoma). Arch Path 43:261-273, Sep

1946 28.

Northcutt RC, Levinson JD, Earnest JB: Hypocalcemia re-

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suiting from infarction of a parathyroid adenoma. Ann Intern Med

70:353-356, Feb 1969 . 29. O'Riordan JLH, Potts JT Jr, Aurbach GO: Isolation of human parathyroid hormone. Endocrinology 89:234-239, Jul 1971 30. Payne RL Jr, Fitchett CW: Hyperparathyroid crisis: survey of the literature and a report of two additional cases. Ann Surg 161: 737-747, May 1965 31. Rosch J, Dotter CT, Brown MJ: Selective arterial embolization: a new method for control of acute gastrointestinal bleeding. Radiology 102:303-306, Feb 1972 32. Segre GV, Habener JF, Powell 0, et al: Parathyroid hormone in human plasma: immunochemical characterization and biological implications. J Clin Invest 51:3163-3172, Dec 1972 33. Sherwood LM, Mayer GP, Ramberg CF Jr, et al: Regulation of parathyroid hormone secretion: proportional control by calcium, lack of effect of phosphate. Endocrinology 83: 1043-1 051, Nov

1968 34.

Shimkin PM, Doppman JL, Pearson KD, et al: Anatomic considerations in parathyroid venous sampling. Am J Roentgenol 118:654-662, Jul 1973 35. Steiner AL, Kipnis OM, Utiger R, et al: Radioimmunossay for the measurement of adenosine 3' ,5'-cyclic phosphate. Proc Natl Acad Sci USA 64:367-373, Sep 1969 36. Wells SA, Doppman JL, Bilezikian JP, et al: Repeated neck exploration in primary hyperparathyroidism: localization of abnormal glands by selective thyroid arteriography, selective venous sampling, and radioimmunossay. Surgery 74:678-686, Nov 1973