Huh
AYriMIkNk'UfNIVHrIiIW,¶ DUdU
Results of a Multidisciplinary Strategy for Management of Mediastinal Parathyroid Adenoma as a Cause of Persistent Primary Hyperparathyroidism GERARD M. DOHERTY, M.D.,* JOHN L. DOPPMAN, M.D.,4 DONALD L. MILLER, M.D.,4 MIMI S. GEE, M.D.,* STEPHEN J. MARX, M.D.,§ ALLEN M. SPIEGEL, M.D., || GERALD D. AURBACH, M.D.,§ HARVEY 1. PASS, M.D.,t MURRAY F. BRENNAN, M.D.,¶ and JEFFREY A. NORTON, M.D.*
Persistent primary hyperparathyroidism due to mediastinal parathyroid adenoma was effectively treated by either angiographic ablation or median sternotomy in this study of49 patients managed at the National Institutes of Health since 1977. Each patient presented here with symptomatic persistent primary hyperparathyroidism after failed initial surgical procedures done at other institutions. Each patient underwent extensive parathyroid localization procedures, including selective angiography, and most had a parathyroid adenoma localized to the mediastinum. Angiographic ablation, the deliberate injection of large doses of contrast material into the artery that selectively perfuses the adenoma, was initially successful in 22 of 30 procedures (73%) in 27 patients. Long-term control of persistent primary hyperparathyroidism was achieved in 17 of 27 patients (63%) by angiographic ablation. Each unsuccessful ablation could be easily salvaged by surgical resection. Surgical resection of the parathyroid adenoma by median sternotomy achieved immediate success in 24 of 24 procedures (p2 < 0.02 versus ablation), and long-term cure in 23 of 23 evaluable patients (P2 < 0.001 versus ablation). However, ablation did have benefits for the patients in whom it was successfully performed. It was associated with a significantly shorter hospital stay (median, 6 days versus 9 days for sternotomy, P2 < 0.003), much less pain, and easier recuperation. Complications of each procedure were transient and similar in both groups. Operative resection is the most effective single means to eradicate mediastinal parathyroid adenoma; however, angiographic ablation can provide similar longterm control of hyperparathyroidism in 63% of patients with less pain and shorter convalescence than that seen in patients after median sternotomy. Our results suggest that angiographic ablation should be attempted as the initial procedure for patients with persistent primary hyperparathyroidism caused by an angiographicaHly identified mediastinal parathyroid adenoma. Operation can be reserved for those who fail ablation.
From the Surgical Metabolism Section* and the Thoracic Oncology Section, t Surgery Branch, National Cancer Institute, the Diagnostic Radiology Department,f Warren Grant Magnuson Clinical Center, the Metabolic Diseases Branch§ and the Moiecular Pathophysiology Branch, || National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and the Memorial Sloan-Kettering Cancer Center,¶ New York, New York
RIMARY HYPERPARATHYROIDISM IS the most common cause of hypercalcemia, and can usually be cured by surgical excision of a single parathyroid adenoma." 2 The adenoma is most commonly located within or near the usual anatomic location of the parathyroid glands on the posterior capsule of the thyroid gland. In a small proportion ofpatients, however, cervical exploration for primary hyperparathyroidism fails because of ectopically located adenomatous parathyroid tissue within the mediastinum.3 The mediastinal parathyroid adenoma usually can be localized at subsequent evaluation with noninvasive and invasive radiographic studies.' Standard therapy for persistent primary hyperparathyroidism secondary to a mediastinal parathyroid adenoma is surgical resection; however, at the National Institutes of Health (NIH), some patients with mediastinal parathyroid adenomas have been successfully managed by selective infusion of large doses of ionic radiographic contrast into the vessel feeding the tumor.4'9~12 This procedure has been described previously to demonstrate the feasibility and the immediate success rates.10 " Initially, angiographic ablation was performed serendipitously by inadvertently wedging the catheter into a selective feeding artery. The procedure has been thought to be safest and
P
Address reprint requests to Jeffrey A. Norton, M.D., Head, Surgical Metabolism Section, Surgery Branch, National Cancer Institute/NIH, Building 10, Room 2B07, Bethesda, MD 20892. Accepted for publication July 25, 1991.
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have the best results when "staining" mediastinal adenomas. The role of purposeful selective angiographic ablation in the management of patients with persistent primary hyperparathyroidism secondary to a mediastinal parathyroid adenoma is unclear, because no studies have compared ablation with surgery. We have chosen purposeful ablation in patients with mediastinal parathyroid adenoma as a cause of persistent primary hyperparathyroidism, if it is angiographically identifiable, and if, based on the records of the prior operations, the patient does not appear to be at high risk for the development of postoperative hypoparathyroidism. We now compare our long-term results in patients treated with angiographic ablation with those in a concurrent group of patients who underwent surgical resection via median sternotomy, to determine the role of ablation in the management of mediastinal parathyroid adenomas.
Methods
Patients with either persistent or recurrent primary hyperparathyroidism are managed at the NIH according to an approved protocol that has been described in detail.'2 Briefly, the diagnosis of primary hyperparathyroidism is confirmed in each patient by demonstration of elevated serum levels of both calcium and parathyroid hormone, and the indications for reoperation are evaluated. Records and pathology specimens from the initial surgical procedures done at the referring institution are carefully reviewed to determine a working diagnosis of parathyroid adenoma, hyperplasia, or cancer and whether the patient has persistent (no disease-free interval) or recurrent (disease-free period of at least 6 months) primary hyperparathyroidism. After the identification of either persistent or recurrent symptomatic primary hyperparathyroidism, each patient that warrants reoperation then undergoes noninvasive localizing procedures including computed tomography (CT), magnetic resonance imaging, ultrasound and technetium-thallium scintigraphy; if the outcome of noninvasive studies are inconclusive, these are followed by selective angiography and venous sam-
pling.5"3"14 Since 1977, patients who could be identified as having mediastinal parathyroid adenoma as a cause for persistent primary hyperparathyroidism have been managed either by deliberate angiographic ablation via injection of ionic contrast into a feeding vessel or by planned surgical excision via median sternotomy. In general, if angiographic ablation was feasible, it was performed instead of median sternotomy because it appeared easier to undergo and was less painful. If two or three normal parathyroid glands had been removed at the initial procedure, however, median sternotomy and surgical resection of the parathyroid adenoma were performed because this ala
Ann. Surg. * February 1992
lowed cryopreservation of removed parathyroid tissue that could be reimplanted if the patient developed long-term hypoparathyroidism. Angiographic ablation was performed by superselective catheterization of the artery supplying the adenoma, and infusion of ionic contrast media to stain the tumor as previously described.4""' 5 Most patients who had a tumor deliberately stained with contrast had a CT scan 24 hours after staining to determine ifthe parathyroid adenoma retained the contrast as a predictor of procedure efficacy (Fig. 1). When ablation was not technically possible, or if it failed to correct the persistent primary hyperparathyroidism, adenomas were surgically resected. In this study, we included all patients who had attempted angiographic ablation of mediastinal adenomas from 1977 to 1989. They are compared with all patients. in the same period who underwent median sternotomy for parathyroid adenoma. Data were collected by retrospective chart review and telephone interviews with patients and their referring physicians. Endpoints evaluated include initial and long-term correction of hypercalcemia, need for subsequent interventions for hypercalcemia, postprocedure length of hospital stay, and complications of therapy. Statistical methods applied include the Wilcoxon rank sum test for comparison of nonparametric data, student's t test for comparison of parametric data, and Fisher's exact test for analysis of proportions. Significance was defined at P2 < 0.05.
Results Patient Characteristics The 27 patients who underwent angiographic ablation to manage persistent primary hyperparathyroidism and the 24 patients who underwent median stemotomy were very similar with respect to age, gender, and signs and symptoms of primary hyperparathyroidism (Table 1). A higher proportion of patients in the ablation group had had two or more prior operations for hyperparathyroidism compared with the sternotomy group (P2 < 0.01, Fisher's exact test). None of the 27 ablation patients had had prior median sternotomy for primary hyperparathyroidism. Five patients who had failed ablation subsequently underwent successful median sternotomy; these five patients were included in both groups. Each patient had persistent primary hyperparathyroidism and each had a diagnosis of parathyroid adenoma, based on prior pathology and either pathology at curative surgical resection or correction of hypercalcemia by angiographic ablation of a single gland. Localization Studies Selective angiography correctly identified a mediastinal parathyroid adenoma in each patient who had ablation
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ii
.4. x A'
I
i
V
r
FIG. 1. Angiographic ablation of a mediastinal parathyroid adenoma. This adenoma was supplied by a thymic branch of the left internal mammary artery. (A) After superselective catheterization of the feeding vessel, ionic radiographic contrast dye is infused into the tumor. (B) A delayed view shows contrast staining of the adenoma, as does (C) CT scan immediately after angiography. (D) CT scan 24 hr after angiographic ablation shows persistent complete staining of the adenoma.
attempted (Table 2). This result was expected because ablation was only performed if selective angiogram showed clear evidence of a tumor, which could be technically approached in a super-selective manner. Similarly, 15 of the 22 patients who had angiography and underwent median sternotomy for resection of a mediastinal parathyroid adenoma had evidence of a parathyroid adenoma on selective angiogram. Of all patients taken together, 37 of 44 patients (84%) with a confirmed mediastinal parathyroid adenoma had a true-positive angiogram. In other
respects, the utility of the localizing studies was similar in the two groups, with CT being the most effective noninvasive study (35% true-positive, Table 2). Of note, ultrasound and technetium-thallium scintigraphy were very poor at localizing glands in the mediastinum; each had TABLE 2. Localization Studies
Result TABLE 1. Patient Characteristics
Angiographic Ablation No. of patients No. of procedures Sex % Male Age (yr) Median (range) Prior operation for
Sternotomy
27 30
24 24
56%
46%
48 (17-78)
49 (17-74)
22 Indications for intervention* Nephrolithiasis Central nervous system (including lethargy, malaise, weakness, or psychological disturbance) Ca" > 3.0 mmol/L Bone disease *
Some
patients had
more
than
one
scan True positive False positive
8 19
20 4
14
15
Negative Ultrasound True positive False positive Negative Magnetic resonance scan True positive False positive Negative
8 17
Technetium/thallium scan True positive False positive Negative
hyperparathyroidism 1
Angiogram True positive False positive Negative Computed tomography
11 9 9
9
indication for intervention.
Ablation Group
Sternotomy Group
Total*
No. (%)
No. (%)
No. (%)
27/27 (100) 0/27 (0) 0/27 (0)
15/22 (68) 3/22 (14) 4/22 (18)
37/44 (84) 3/44 (7) 4/44 (9)
10/24 (42) 1/24 (4) 13/24 (54)
6/21 (29) 5/21 (24) 10/21 (48)
14/40 (35) 5/40 (13) 21/40 (53)
0/17 (0) 4/17 (24) 13/17 (76)
0/22 (0) 3/22 (14) 19/22 (86)
0/35 (0) 7/35 (20) 28/35 (80)
2/5 (40) 1/5 (20) 2/5 (40)
3/13 (23) 1/13 (8) 9/13 (69)
3/16 (19) 2/16 (13) 11/16 (69)
1/1 1 (9) 2/11 (18) 8/11 (73)
0/17 (0) 4/17 (24) 13/17 (76)
1/26 (4) 6/26 (23) 19/26 (73)
* Total includes all patients; patients whose ablation failed and who then underwent sternotomy are included in each of those columns.
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more false-positive than true-positive results. Computed tomography and magnetic resonance scans were slightly better than Tech-thal or ultrasound; however, nether approached the accuracy of angiography (Table 2).
Angiographic Ablation Thirty separate angiographic ablation procedures were performed in 27 patients with mediastinal parathyroid adenomas on selective angiogram. Three patients had repeat ablation after an initial failure; one repeat ablation was successful, whereas in two patients ablation failed again and operation was required. The blood supply of the parathyroid adenoma arose from the internal mammary artery in 21 patients and the inferior thyroid artery in six (Table 3, Fig. 1). Computed tomography scans were performed 24 hours after 21 of the 30 attempted ablation procedures. Computed tomography evidence of persistent staining of the parathyroid adenoma was thought to be complete in 8, partial in 6, and not present in 7 (Table 3). Of the 14 procedures that showed complete or partial staining, the long-term outcomes of two are unknown. Eight procedures were successful, as demonstrated by long-term resolution of hypercalcemia (8/12 evaluable, 67%). Despite CT evidence of staining, four procedures subsequently failed, as demonstrated by persistent hypercalcemia (4 failed/ 12 evaluable, 33%). Furthermore, 5 of the 7 procedures in which the delayed CT scan showed no staining were unsuccessful as determined by persistent hypercalcemia, but two patients have remained normocalcemic despite no CT evidence of staining after 24 hours. Therefore, persistent staining on the delayed CT scan may have some predictive value as to subsequent outcome, but some patients (33%) with evidence of delayed staining may fail and some patients (29%) without evidence of delayed staining may still be cured. Surgery Twenty-four patients underwent median sternotomy for resection of a parathyroid adenoma as a cause of perTABLE 3. Angiographic Ablation Procedures
No. No. of procedures No. of patients Tumor vessel Thymic branch of internal Inferior thyroid artery Successful vessel cannulation 24° computed tomographydemonstrated staining Positive Partial Negative Not done
Long-Term Cure
30 27 mammary
21 6 25 8 6 7 9
4 4 2 7
Ann. Surg.
Februlary 1992
TABLE 4. Procedure Outcome
Angiographic No. of procedures No. of patients Hospital length of stay after
procedures (days)
median (range) Serum calcium (mmol) Before proceduret Nadir after proceduret Initially successful intervention Long-term follow-up median
Ablation
Sternotomy
30 27
24 24
6.0 (1-60)* 3.0 ± 0.3 2.2 ± 0.4
22/38
9.0 (5-60) 3.0 ± 0.2 1.9 ± 0.1l§
24/2411
(range) Long-term parathyroid status Hypoparathyroid Normoparathyroid Required subsequent
63 m (1-156)
42 m (1-122)
3 14
5 18
hyperparathyroidism
10 1 2
OT 0 1
supplements Long-term serum calcium level (mmol)
3
5
intervention for
Remains hyperparathyroid No follow-up Long-term calcium or vitamin D
2.5 ± 0.3
2.3 ± 0.1
* Shorter hospital stay vs. sternotomy, P2 < 0.003, Wilcoxon rank t Mean ± SD. Normal range 2.10-2.65 mmol. t Lower serum level of calcium vs. preprocedure level, P2 < 0.01, Student's t test, paired. § Lower serum calcium level after procedure vs. ablation group, P2 < 0.01, Student's t test. || Higher proportion of initially successful intervention vs. ablation, P2 < 0.02, Fisher's exact test. ¶ Fewer patients required subsequent intervention compared with ablation, P2 < 0.002, Fisher's exact sum test.
test.
sistent primary hyperparathyroidism; the results of surgery were compared with the results of angiographic ablation (Table 4). Patients who had angiographic ablation of a
mediastinal parathyroid adenoma had less postprocedure
pain and a significantly shorter postprocedure hospital length of stay when compared with patients who underwent sternotomy (median, 6 days versus 9 days, P2 < 0.003, Wilcoxon rank sum test). Each group had sig-
nificant diminution in the serum level of calcium after the intervention, as compared with initial levels (P2 < 0.01, paired Student's t test). However, the mean postprocedure serum level of calcium was significantly lower in the patients who underwent stemotomy than in the patients who underwent ablation (P2 < 0.01, Student's t test). This is accounted for by the presence of some unsuccessful procedures in the angioblation group. Twenty-two of the thirty ablation procedures (73%) were initially determined to be successful, in other words, these procedures resulted in normocalcemia or hypocalcemia that was present throughout the postprocedure hospitalization. Each of the 24 patients (100%) who underwent sternotomy also had resolution of hypercalcemia, a significantly higher proportion than ablation P2 < 0.02, Fisher's exact test).
MEDIASTINAL PARATHYROID ADENOMA ABLATION
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Follow-Up
105
Discussion
Long-term follow-up showed that 17 of the 28 (61%) evaluable angiographic ablation attempts were followed by durable relief of the hypercalcemia and primary hyperparathyroidism and appear to be cured. Each of the 24 evaluable patients managed with median sternotomy, however, was cured (better than ablation, P2 < 0.001, Fishers exact test). In addition, 3 of20 patients who were initially rendered normocalcemic by ablation subsequently developed recurrent hyperparathyroidism more than 6 months after ablation. Therefore, 10 of the ablation procedures were followed by other interventions for persistent or recurrent hypercalcemia. Three patients had repeat ablation; one was successful long-term. Seven failed ablations were followed by successful surgical resection of the adenoma. Five were included in the sternotomy group, and two had a mediastinal parathyroid adenoma removed through a cervical incision. Each of the patients who had a failed ablation followed by surgical resection was cured.
Complications Three patients in the angiographic ablation group have persistent hypoparathyroidism that requires supplemental calcium and vitamin D to maintain normal serum levels of calcium (Table 5). Seven patients had evidence of persistent hypoparathyroidism after successful resection of a parathyroid adenoma by median sternotomy. Two of seven patients are now normocalcemic after implantation of fragments ofcryopreserved autologous parathyroid adenoma into the muscle of the nondominant forearm. Of the five remaining hypoparathyroid patients, after surgical resection of a parathyroid adenoma, two have no cryopreserved tissue because the viability of the gland appeared compromised as a result of failed prior staining, whereas three patients have cryopreserved tissue available but have not yet had attempted autograft at 9 months, 41 months, and 46 months after surgery. Two patients had complications after sternotomy for adenoma excision (Table 5). Five patients in the ablation group had complications referable to the procedure. All complications resolved with appropriate management. There were no deaths in either group. TABLE 5. Complications
Complication Stemotomy Pneumonia Deep venous thrombosis Angiographic ablation Peripheral nerve symptoms Bradycardia Acute renal failure
No. I 1
3 I I
Although operative resection is the most effective single means to eradicate functional mediastinal parathyroid adenomas and allows cryopreservation of removed tissue, many patients can have successful angiographic ablation with minimal discomfort and complications. If ablation fails, then either repeat ablation or, more effectively, surgical resection, will cure them. Angiographic ablation ofa mediastinal adenoma cured primary hyperparathyroidism in 17 of 25 evaluable selected patients with symptomatic persistent primary hyperparathyroidism. It was associated with a shorter hospital length-of-stay, and spared patients the greater pain and longer convalescence associated with median sternotomy. Although there was no substantial difference in morbid complications of the two approaches, it is clear from observation of these patients after the two procedures that the recovery from the angiographic procedure was much easier than that from median sternotomy. Thus, for the 17 patients whose ablation was curative, this approach eliminated the need for sternotomy. It has previously been stated4"'0 l that after ablation the appearance of the parathyroid adenoma on subsequent CT (24 hours later) can predict whether the staining procedure will be successful or unsuccessful. In general, this statement is true. The presence of persistent intense contrast enhancement detected 1 day later by CT usually indicates that the patient will have a successful outcome with resolution of hypercalcemia. This holds true in about two of three cases, but some patients with persistent evidence of staining still may not have a successful outcome. The converse is also true. If there is no evidence of persistent staining of the abnormal parathyroid gland on follow-up CT, the serum level of calcium will usually remain elevated. However, a small proportion (29%) of patients without staining still may have a successful outcome and resolution of hypercalcemia. Median sternotomy for resection of parathyroid adenoma cured persistent primary hyperparathyroidism in each patient studied here, including five patients who had failed angiographic ablation. Median sternotomy was clearly a more effective treatment than ablation, both in initial success rate and long-term control of hypercalcemia (Table 4). Importantly, there was no apparent disadvantage in the ability to undergo subsequent curative median stemotomy when patients have had prior attempted ablation. Each of the patients who had median sternotomy after failed ablation was successfully salvaged, and there were no complications of these operative procedures. Two patients who had had prior ablation of a parathyroid adenoma, however, appeared to have decreased viability of the parathyroid adenoma at the time of resection, eliminating our ability to cryopreserve some of the resected
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DOHERTY AND OTHERS
parathyroid adenoma. The ability to cryopreserve resected parathyroid tissue during surgery to remove abnormal parathyroid glands appears to be a distinct advantage of surgery over ablation because the incidence of hypoparathyroidism after successful reoperative parathyroid surgery is high. A disadvantage of ablation is that no tissue can be cryopreserved for potential delayed forearm autograft for the correction of hypoparathyroidism.8"6 All patients who come to ablation have had prior neck exploration as initial attempted therapy for their primary hyperparathyroidism. Most have had normal cervical parathyroid glands dissected and identified, often by biopsy. They are at risk for permanent hypoparathyroidism after ablation if the adenoma represents their sole remaining functional parathyroid tissue. Patients have a similar risk of hypoparathyroidism after surgical resection; however, cryopreservation of the tissue allows an autograft of parathyroid adenoma tissue to the nondominant forearm, as was successfully performed for two patients in the sternotomy group described here. A concern that previously may have limited clinicians' usage of this technique is the presumed risk of embolic complications to the brain or spinal cord.4 No patient in this series experienced any embolic sequelae. Thus, attempted angiographic ablation of mediastinal glands does not appear to add to the risk of diagnostic angiography. The theoretical risk of gland disruption by angioablation with mediastinal tumor seeding was not seen. In summary, angiographic ablation of mediastinal parathyroid glands is a safe, reasonable option for the management of functional parathyroid adenomas in patients with persistent primary hyperparathyroidism. This is accomplished by placing the catheter into the appropriate feeding artery and deliberately perfusing the adenoma with ionic contrast media. It can be performed with minimal pain, a short hospital stay, and a reasonable longterm cure rate. Although surgical resection offers higher initial and long-term cure rates, ablation can cure 60% of patients, thus obviating the need for surgery. Surgical resection after failed ablation is not more difficult and offers a 100% salvage rate for those not cured by angioblation. Finally, selection of patients who are likely to have functional parathyroid tissue remaining in the neck after their initial surgery may lower the incidence of permanent hypoparathyroidism and thus render the absence of cryopreserved tissue for autotransplantation less important. The strategy of attempting angiographic ablation in patients with persistent primary hyperparathyroidism who have failed prior neck surgery, have evidence of a mediastinal adenoma on angiography, and have a low probability ofpostoperative hypoparathyroidism appears war-
Ann.
Surg. February -
1992
ranted. Median sternotomy can be reserved for those patients in whom ablation is unsuccessful. This strategy will not reduce the cure rate because median sternotomy and surgical resection will cure the hyperparathyroidism in the subgroup of patients who have an unsuccessful outcome with ablation. Angiographic ablation will eliminate the pain and convalescent period required to recover from median sternotomy in the majority of patients for whom ablation will be successful.
Acknowledgments The authors thank Donald White, Alison McMullen, and Melissa Corbitt for the storage and retrieval of data from the database maintained for these patients, and Barbara Owen for her expert preparation of the manuscript.
References 1. Segre GV, Potts JT. Differential diagnosis of hypercalcemia. In DeGroot U., ed. Endocrinology. Philadelphia: WB Saunders, 1989, pp 984-1001. 2. Burt ME, Brennan MF. Incidence of hypercalcemia and malignant neoplasm. Arch Surg 1980; 115:704-707. 3. Clark OH. Mediastinal parathyroid tumors. Arch Surg 1988; 123: 1096-1100. 4. Miller DL, Doppman JL, Chang R, et al. Angiographic ablation of parathyroid adenomas: lessons from a 10-year experience. Radiology 1987; 165:601-607. 5. Miller DL, Doppman JL, Krudy AG, et al. Localization of parathyroid adenomas in patients who have undergone surgery: Part II. Invasive procedures. Radiology 1987; 162:138-141. 6. Eisenberg H, Pallotta J, Sacks B, Brickman AS. Parathyroid localization, three-dimensional modeling, and percutaneous ablation techniques. Endocrinol Metab Clin North Am 1989; 18:659699. 7. Levin KE, Gooding GAW, Okerlund M, et al. Localizing studies in patients with persistent or recurrent hyperparathyroidism. Surgery 1987; 102:917-925. 8. Brennan MF, Norton JA. Reoperation for persistent and recurrent hyperparathyroidism. Ann Surg 1985; 201:40-44. 9. Norton JA, Schneider PD, Brennan MF. Median sternotomy in reoperations for primary hyperparathyroidism. World J Surg 1985; 9:807-813. 10. Doppman JL, Marx SJ, Spiegel AM, et al. Treatment of hyperparathyroidism by percutaneous embolization of a mediastinal adenoma. Radiology 1975; 115:37-42. 11. Doppman JL, Brown EM, Brennan MF, Spiegel A, Marx SJ, Aurbach GD. Angiographic ablation of parathyroid adenomas. Radiology 1979; 130:577-582. 12. Norton JA. Reoperative parathyroid surgery: indication, intraoperative decision-making and results. Prog Surg 1986; 18:133-145. 13. Miller DL, Doppman JL, Shawker TH, et al. Localization of parathyroid adenomas in patients who have undergone surgery: Part 1. Noninvasive imaging methods. Radiology 1987; 162:133-137. 14. Miller DL. Preoperative localization and interventional treatment of parathyroid tumors: when and how? World J Surg 1991 (in press). 15. Doppman JL, Popovsky M, Girton M. The use of iodinated contrast agents to ablate organs: experimental studies and histopathology.
Radiology 1981; 138:333-340. 16. Wells SA, Ross RJ, Dale JK, Gray RS. Transplantation of the parathyroid glands. Surg Clin North Am 1979; 59:167-177.
AYriMIkNk'UfNIVHrIiIW,¶ DUdU
Results of a Multidisciplinary Strategy for Management of Mediastinal Parathyroid Adenoma as a Cause of Persistent Primary Hyperparathyroidism GERARD M. DOHERTY, M.D.,* JOHN L. DOPPMAN, M.D.,4 DONALD L. MILLER, M.D.,4 MIMI S. GEE, M.D.,* STEPHEN J. MARX, M.D.,§ ALLEN M. SPIEGEL, M.D., || GERALD D. AURBACH, M.D.,§ HARVEY 1. PASS, M.D.,t MURRAY F. BRENNAN, M.D.,¶ and JEFFREY A. NORTON, M.D.*
Persistent primary hyperparathyroidism due to mediastinal parathyroid adenoma was effectively treated by either angiographic ablation or median sternotomy in this study of49 patients managed at the National Institutes of Health since 1977. Each patient presented here with symptomatic persistent primary hyperparathyroidism after failed initial surgical procedures done at other institutions. Each patient underwent extensive parathyroid localization procedures, including selective angiography, and most had a parathyroid adenoma localized to the mediastinum. Angiographic ablation, the deliberate injection of large doses of contrast material into the artery that selectively perfuses the adenoma, was initially successful in 22 of 30 procedures (73%) in 27 patients. Long-term control of persistent primary hyperparathyroidism was achieved in 17 of 27 patients (63%) by angiographic ablation. Each unsuccessful ablation could be easily salvaged by surgical resection. Surgical resection of the parathyroid adenoma by median sternotomy achieved immediate success in 24 of 24 procedures (p2 < 0.02 versus ablation), and long-term cure in 23 of 23 evaluable patients (P2 < 0.001 versus ablation). However, ablation did have benefits for the patients in whom it was successfully performed. It was associated with a significantly shorter hospital stay (median, 6 days versus 9 days for sternotomy, P2 < 0.003), much less pain, and easier recuperation. Complications of each procedure were transient and similar in both groups. Operative resection is the most effective single means to eradicate mediastinal parathyroid adenoma; however, angiographic ablation can provide similar longterm control of hyperparathyroidism in 63% of patients with less pain and shorter convalescence than that seen in patients after median sternotomy. Our results suggest that angiographic ablation should be attempted as the initial procedure for patients with persistent primary hyperparathyroidism caused by an angiographicaHly identified mediastinal parathyroid adenoma. Operation can be reserved for those who fail ablation.
From the Surgical Metabolism Section* and the Thoracic Oncology Section, t Surgery Branch, National Cancer Institute, the Diagnostic Radiology Department,f Warren Grant Magnuson Clinical Center, the Metabolic Diseases Branch§ and the Moiecular Pathophysiology Branch, || National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; and the Memorial Sloan-Kettering Cancer Center,¶ New York, New York
RIMARY HYPERPARATHYROIDISM IS the most common cause of hypercalcemia, and can usually be cured by surgical excision of a single parathyroid adenoma." 2 The adenoma is most commonly located within or near the usual anatomic location of the parathyroid glands on the posterior capsule of the thyroid gland. In a small proportion ofpatients, however, cervical exploration for primary hyperparathyroidism fails because of ectopically located adenomatous parathyroid tissue within the mediastinum.3 The mediastinal parathyroid adenoma usually can be localized at subsequent evaluation with noninvasive and invasive radiographic studies.' Standard therapy for persistent primary hyperparathyroidism secondary to a mediastinal parathyroid adenoma is surgical resection; however, at the National Institutes of Health (NIH), some patients with mediastinal parathyroid adenomas have been successfully managed by selective infusion of large doses of ionic radiographic contrast into the vessel feeding the tumor.4'9~12 This procedure has been described previously to demonstrate the feasibility and the immediate success rates.10 " Initially, angiographic ablation was performed serendipitously by inadvertently wedging the catheter into a selective feeding artery. The procedure has been thought to be safest and
P
Address reprint requests to Jeffrey A. Norton, M.D., Head, Surgical Metabolism Section, Surgery Branch, National Cancer Institute/NIH, Building 10, Room 2B07, Bethesda, MD 20892. Accepted for publication July 25, 1991.
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DOHERTY AND OTHERS
102
have the best results when "staining" mediastinal adenomas. The role of purposeful selective angiographic ablation in the management of patients with persistent primary hyperparathyroidism secondary to a mediastinal parathyroid adenoma is unclear, because no studies have compared ablation with surgery. We have chosen purposeful ablation in patients with mediastinal parathyroid adenoma as a cause of persistent primary hyperparathyroidism, if it is angiographically identifiable, and if, based on the records of the prior operations, the patient does not appear to be at high risk for the development of postoperative hypoparathyroidism. We now compare our long-term results in patients treated with angiographic ablation with those in a concurrent group of patients who underwent surgical resection via median sternotomy, to determine the role of ablation in the management of mediastinal parathyroid adenomas.
Methods
Patients with either persistent or recurrent primary hyperparathyroidism are managed at the NIH according to an approved protocol that has been described in detail.'2 Briefly, the diagnosis of primary hyperparathyroidism is confirmed in each patient by demonstration of elevated serum levels of both calcium and parathyroid hormone, and the indications for reoperation are evaluated. Records and pathology specimens from the initial surgical procedures done at the referring institution are carefully reviewed to determine a working diagnosis of parathyroid adenoma, hyperplasia, or cancer and whether the patient has persistent (no disease-free interval) or recurrent (disease-free period of at least 6 months) primary hyperparathyroidism. After the identification of either persistent or recurrent symptomatic primary hyperparathyroidism, each patient that warrants reoperation then undergoes noninvasive localizing procedures including computed tomography (CT), magnetic resonance imaging, ultrasound and technetium-thallium scintigraphy; if the outcome of noninvasive studies are inconclusive, these are followed by selective angiography and venous sam-
pling.5"3"14 Since 1977, patients who could be identified as having mediastinal parathyroid adenoma as a cause for persistent primary hyperparathyroidism have been managed either by deliberate angiographic ablation via injection of ionic contrast into a feeding vessel or by planned surgical excision via median sternotomy. In general, if angiographic ablation was feasible, it was performed instead of median sternotomy because it appeared easier to undergo and was less painful. If two or three normal parathyroid glands had been removed at the initial procedure, however, median sternotomy and surgical resection of the parathyroid adenoma were performed because this ala
Ann. Surg. * February 1992
lowed cryopreservation of removed parathyroid tissue that could be reimplanted if the patient developed long-term hypoparathyroidism. Angiographic ablation was performed by superselective catheterization of the artery supplying the adenoma, and infusion of ionic contrast media to stain the tumor as previously described.4""' 5 Most patients who had a tumor deliberately stained with contrast had a CT scan 24 hours after staining to determine ifthe parathyroid adenoma retained the contrast as a predictor of procedure efficacy (Fig. 1). When ablation was not technically possible, or if it failed to correct the persistent primary hyperparathyroidism, adenomas were surgically resected. In this study, we included all patients who had attempted angiographic ablation of mediastinal adenomas from 1977 to 1989. They are compared with all patients. in the same period who underwent median sternotomy for parathyroid adenoma. Data were collected by retrospective chart review and telephone interviews with patients and their referring physicians. Endpoints evaluated include initial and long-term correction of hypercalcemia, need for subsequent interventions for hypercalcemia, postprocedure length of hospital stay, and complications of therapy. Statistical methods applied include the Wilcoxon rank sum test for comparison of nonparametric data, student's t test for comparison of parametric data, and Fisher's exact test for analysis of proportions. Significance was defined at P2 < 0.05.
Results Patient Characteristics The 27 patients who underwent angiographic ablation to manage persistent primary hyperparathyroidism and the 24 patients who underwent median stemotomy were very similar with respect to age, gender, and signs and symptoms of primary hyperparathyroidism (Table 1). A higher proportion of patients in the ablation group had had two or more prior operations for hyperparathyroidism compared with the sternotomy group (P2 < 0.01, Fisher's exact test). None of the 27 ablation patients had had prior median sternotomy for primary hyperparathyroidism. Five patients who had failed ablation subsequently underwent successful median sternotomy; these five patients were included in both groups. Each patient had persistent primary hyperparathyroidism and each had a diagnosis of parathyroid adenoma, based on prior pathology and either pathology at curative surgical resection or correction of hypercalcemia by angiographic ablation of a single gland. Localization Studies Selective angiography correctly identified a mediastinal parathyroid adenoma in each patient who had ablation
VOL. 215.- NO. 2
MEDIASTINAL PARATHYROID ADENOMA ABLATION
103
ii
.4. x A'
I
i
V
r
FIG. 1. Angiographic ablation of a mediastinal parathyroid adenoma. This adenoma was supplied by a thymic branch of the left internal mammary artery. (A) After superselective catheterization of the feeding vessel, ionic radiographic contrast dye is infused into the tumor. (B) A delayed view shows contrast staining of the adenoma, as does (C) CT scan immediately after angiography. (D) CT scan 24 hr after angiographic ablation shows persistent complete staining of the adenoma.
attempted (Table 2). This result was expected because ablation was only performed if selective angiogram showed clear evidence of a tumor, which could be technically approached in a super-selective manner. Similarly, 15 of the 22 patients who had angiography and underwent median sternotomy for resection of a mediastinal parathyroid adenoma had evidence of a parathyroid adenoma on selective angiogram. Of all patients taken together, 37 of 44 patients (84%) with a confirmed mediastinal parathyroid adenoma had a true-positive angiogram. In other
respects, the utility of the localizing studies was similar in the two groups, with CT being the most effective noninvasive study (35% true-positive, Table 2). Of note, ultrasound and technetium-thallium scintigraphy were very poor at localizing glands in the mediastinum; each had TABLE 2. Localization Studies
Result TABLE 1. Patient Characteristics
Angiographic Ablation No. of patients No. of procedures Sex % Male Age (yr) Median (range) Prior operation for
Sternotomy
27 30
24 24
56%
46%
48 (17-78)
49 (17-74)
22 Indications for intervention* Nephrolithiasis Central nervous system (including lethargy, malaise, weakness, or psychological disturbance) Ca" > 3.0 mmol/L Bone disease *
Some
patients had
more
than
one
scan True positive False positive
8 19
20 4
14
15
Negative Ultrasound True positive False positive Negative Magnetic resonance scan True positive False positive Negative
8 17
Technetium/thallium scan True positive False positive Negative
hyperparathyroidism 1
Angiogram True positive False positive Negative Computed tomography
11 9 9
9
indication for intervention.
Ablation Group
Sternotomy Group
Total*
No. (%)
No. (%)
No. (%)
27/27 (100) 0/27 (0) 0/27 (0)
15/22 (68) 3/22 (14) 4/22 (18)
37/44 (84) 3/44 (7) 4/44 (9)
10/24 (42) 1/24 (4) 13/24 (54)
6/21 (29) 5/21 (24) 10/21 (48)
14/40 (35) 5/40 (13) 21/40 (53)
0/17 (0) 4/17 (24) 13/17 (76)
0/22 (0) 3/22 (14) 19/22 (86)
0/35 (0) 7/35 (20) 28/35 (80)
2/5 (40) 1/5 (20) 2/5 (40)
3/13 (23) 1/13 (8) 9/13 (69)
3/16 (19) 2/16 (13) 11/16 (69)
1/1 1 (9) 2/11 (18) 8/11 (73)
0/17 (0) 4/17 (24) 13/17 (76)
1/26 (4) 6/26 (23) 19/26 (73)
* Total includes all patients; patients whose ablation failed and who then underwent sternotomy are included in each of those columns.
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DOHERTY AND OTHERS
more false-positive than true-positive results. Computed tomography and magnetic resonance scans were slightly better than Tech-thal or ultrasound; however, nether approached the accuracy of angiography (Table 2).
Angiographic Ablation Thirty separate angiographic ablation procedures were performed in 27 patients with mediastinal parathyroid adenomas on selective angiogram. Three patients had repeat ablation after an initial failure; one repeat ablation was successful, whereas in two patients ablation failed again and operation was required. The blood supply of the parathyroid adenoma arose from the internal mammary artery in 21 patients and the inferior thyroid artery in six (Table 3, Fig. 1). Computed tomography scans were performed 24 hours after 21 of the 30 attempted ablation procedures. Computed tomography evidence of persistent staining of the parathyroid adenoma was thought to be complete in 8, partial in 6, and not present in 7 (Table 3). Of the 14 procedures that showed complete or partial staining, the long-term outcomes of two are unknown. Eight procedures were successful, as demonstrated by long-term resolution of hypercalcemia (8/12 evaluable, 67%). Despite CT evidence of staining, four procedures subsequently failed, as demonstrated by persistent hypercalcemia (4 failed/ 12 evaluable, 33%). Furthermore, 5 of the 7 procedures in which the delayed CT scan showed no staining were unsuccessful as determined by persistent hypercalcemia, but two patients have remained normocalcemic despite no CT evidence of staining after 24 hours. Therefore, persistent staining on the delayed CT scan may have some predictive value as to subsequent outcome, but some patients (33%) with evidence of delayed staining may fail and some patients (29%) without evidence of delayed staining may still be cured. Surgery Twenty-four patients underwent median sternotomy for resection of a parathyroid adenoma as a cause of perTABLE 3. Angiographic Ablation Procedures
No. No. of procedures No. of patients Tumor vessel Thymic branch of internal Inferior thyroid artery Successful vessel cannulation 24° computed tomographydemonstrated staining Positive Partial Negative Not done
Long-Term Cure
30 27 mammary
21 6 25 8 6 7 9
4 4 2 7
Ann. Surg.
Februlary 1992
TABLE 4. Procedure Outcome
Angiographic No. of procedures No. of patients Hospital length of stay after
procedures (days)
median (range) Serum calcium (mmol) Before proceduret Nadir after proceduret Initially successful intervention Long-term follow-up median
Ablation
Sternotomy
30 27
24 24
6.0 (1-60)* 3.0 ± 0.3 2.2 ± 0.4
22/38
9.0 (5-60) 3.0 ± 0.2 1.9 ± 0.1l§
24/2411
(range) Long-term parathyroid status Hypoparathyroid Normoparathyroid Required subsequent
63 m (1-156)
42 m (1-122)
3 14
5 18
hyperparathyroidism
10 1 2
OT 0 1
supplements Long-term serum calcium level (mmol)
3
5
intervention for
Remains hyperparathyroid No follow-up Long-term calcium or vitamin D
2.5 ± 0.3
2.3 ± 0.1
* Shorter hospital stay vs. sternotomy, P2 < 0.003, Wilcoxon rank t Mean ± SD. Normal range 2.10-2.65 mmol. t Lower serum level of calcium vs. preprocedure level, P2 < 0.01, Student's t test, paired. § Lower serum calcium level after procedure vs. ablation group, P2 < 0.01, Student's t test. || Higher proportion of initially successful intervention vs. ablation, P2 < 0.02, Fisher's exact test. ¶ Fewer patients required subsequent intervention compared with ablation, P2 < 0.002, Fisher's exact sum test.
test.
sistent primary hyperparathyroidism; the results of surgery were compared with the results of angiographic ablation (Table 4). Patients who had angiographic ablation of a
mediastinal parathyroid adenoma had less postprocedure
pain and a significantly shorter postprocedure hospital length of stay when compared with patients who underwent sternotomy (median, 6 days versus 9 days, P2 < 0.003, Wilcoxon rank sum test). Each group had sig-
nificant diminution in the serum level of calcium after the intervention, as compared with initial levels (P2 < 0.01, paired Student's t test). However, the mean postprocedure serum level of calcium was significantly lower in the patients who underwent stemotomy than in the patients who underwent ablation (P2 < 0.01, Student's t test). This is accounted for by the presence of some unsuccessful procedures in the angioblation group. Twenty-two of the thirty ablation procedures (73%) were initially determined to be successful, in other words, these procedures resulted in normocalcemia or hypocalcemia that was present throughout the postprocedure hospitalization. Each of the 24 patients (100%) who underwent sternotomy also had resolution of hypercalcemia, a significantly higher proportion than ablation P2 < 0.02, Fisher's exact test).
MEDIASTINAL PARATHYROID ADENOMA ABLATION
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Follow-Up
105
Discussion
Long-term follow-up showed that 17 of the 28 (61%) evaluable angiographic ablation attempts were followed by durable relief of the hypercalcemia and primary hyperparathyroidism and appear to be cured. Each of the 24 evaluable patients managed with median sternotomy, however, was cured (better than ablation, P2 < 0.001, Fishers exact test). In addition, 3 of20 patients who were initially rendered normocalcemic by ablation subsequently developed recurrent hyperparathyroidism more than 6 months after ablation. Therefore, 10 of the ablation procedures were followed by other interventions for persistent or recurrent hypercalcemia. Three patients had repeat ablation; one was successful long-term. Seven failed ablations were followed by successful surgical resection of the adenoma. Five were included in the sternotomy group, and two had a mediastinal parathyroid adenoma removed through a cervical incision. Each of the patients who had a failed ablation followed by surgical resection was cured.
Complications Three patients in the angiographic ablation group have persistent hypoparathyroidism that requires supplemental calcium and vitamin D to maintain normal serum levels of calcium (Table 5). Seven patients had evidence of persistent hypoparathyroidism after successful resection of a parathyroid adenoma by median sternotomy. Two of seven patients are now normocalcemic after implantation of fragments ofcryopreserved autologous parathyroid adenoma into the muscle of the nondominant forearm. Of the five remaining hypoparathyroid patients, after surgical resection of a parathyroid adenoma, two have no cryopreserved tissue because the viability of the gland appeared compromised as a result of failed prior staining, whereas three patients have cryopreserved tissue available but have not yet had attempted autograft at 9 months, 41 months, and 46 months after surgery. Two patients had complications after sternotomy for adenoma excision (Table 5). Five patients in the ablation group had complications referable to the procedure. All complications resolved with appropriate management. There were no deaths in either group. TABLE 5. Complications
Complication Stemotomy Pneumonia Deep venous thrombosis Angiographic ablation Peripheral nerve symptoms Bradycardia Acute renal failure
No. I 1
3 I I
Although operative resection is the most effective single means to eradicate functional mediastinal parathyroid adenomas and allows cryopreservation of removed tissue, many patients can have successful angiographic ablation with minimal discomfort and complications. If ablation fails, then either repeat ablation or, more effectively, surgical resection, will cure them. Angiographic ablation ofa mediastinal adenoma cured primary hyperparathyroidism in 17 of 25 evaluable selected patients with symptomatic persistent primary hyperparathyroidism. It was associated with a shorter hospital length-of-stay, and spared patients the greater pain and longer convalescence associated with median sternotomy. Although there was no substantial difference in morbid complications of the two approaches, it is clear from observation of these patients after the two procedures that the recovery from the angiographic procedure was much easier than that from median sternotomy. Thus, for the 17 patients whose ablation was curative, this approach eliminated the need for sternotomy. It has previously been stated4"'0 l that after ablation the appearance of the parathyroid adenoma on subsequent CT (24 hours later) can predict whether the staining procedure will be successful or unsuccessful. In general, this statement is true. The presence of persistent intense contrast enhancement detected 1 day later by CT usually indicates that the patient will have a successful outcome with resolution of hypercalcemia. This holds true in about two of three cases, but some patients with persistent evidence of staining still may not have a successful outcome. The converse is also true. If there is no evidence of persistent staining of the abnormal parathyroid gland on follow-up CT, the serum level of calcium will usually remain elevated. However, a small proportion (29%) of patients without staining still may have a successful outcome and resolution of hypercalcemia. Median sternotomy for resection of parathyroid adenoma cured persistent primary hyperparathyroidism in each patient studied here, including five patients who had failed angiographic ablation. Median sternotomy was clearly a more effective treatment than ablation, both in initial success rate and long-term control of hypercalcemia (Table 4). Importantly, there was no apparent disadvantage in the ability to undergo subsequent curative median stemotomy when patients have had prior attempted ablation. Each of the patients who had median sternotomy after failed ablation was successfully salvaged, and there were no complications of these operative procedures. Two patients who had had prior ablation of a parathyroid adenoma, however, appeared to have decreased viability of the parathyroid adenoma at the time of resection, eliminating our ability to cryopreserve some of the resected
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DOHERTY AND OTHERS
parathyroid adenoma. The ability to cryopreserve resected parathyroid tissue during surgery to remove abnormal parathyroid glands appears to be a distinct advantage of surgery over ablation because the incidence of hypoparathyroidism after successful reoperative parathyroid surgery is high. A disadvantage of ablation is that no tissue can be cryopreserved for potential delayed forearm autograft for the correction of hypoparathyroidism.8"6 All patients who come to ablation have had prior neck exploration as initial attempted therapy for their primary hyperparathyroidism. Most have had normal cervical parathyroid glands dissected and identified, often by biopsy. They are at risk for permanent hypoparathyroidism after ablation if the adenoma represents their sole remaining functional parathyroid tissue. Patients have a similar risk of hypoparathyroidism after surgical resection; however, cryopreservation of the tissue allows an autograft of parathyroid adenoma tissue to the nondominant forearm, as was successfully performed for two patients in the sternotomy group described here. A concern that previously may have limited clinicians' usage of this technique is the presumed risk of embolic complications to the brain or spinal cord.4 No patient in this series experienced any embolic sequelae. Thus, attempted angiographic ablation of mediastinal glands does not appear to add to the risk of diagnostic angiography. The theoretical risk of gland disruption by angioablation with mediastinal tumor seeding was not seen. In summary, angiographic ablation of mediastinal parathyroid glands is a safe, reasonable option for the management of functional parathyroid adenomas in patients with persistent primary hyperparathyroidism. This is accomplished by placing the catheter into the appropriate feeding artery and deliberately perfusing the adenoma with ionic contrast media. It can be performed with minimal pain, a short hospital stay, and a reasonable longterm cure rate. Although surgical resection offers higher initial and long-term cure rates, ablation can cure 60% of patients, thus obviating the need for surgery. Surgical resection after failed ablation is not more difficult and offers a 100% salvage rate for those not cured by angioblation. Finally, selection of patients who are likely to have functional parathyroid tissue remaining in the neck after their initial surgery may lower the incidence of permanent hypoparathyroidism and thus render the absence of cryopreserved tissue for autotransplantation less important. The strategy of attempting angiographic ablation in patients with persistent primary hyperparathyroidism who have failed prior neck surgery, have evidence of a mediastinal adenoma on angiography, and have a low probability ofpostoperative hypoparathyroidism appears war-
Ann.
Surg. February -
1992
ranted. Median sternotomy can be reserved for those patients in whom ablation is unsuccessful. This strategy will not reduce the cure rate because median sternotomy and surgical resection will cure the hyperparathyroidism in the subgroup of patients who have an unsuccessful outcome with ablation. Angiographic ablation will eliminate the pain and convalescent period required to recover from median sternotomy in the majority of patients for whom ablation will be successful.
Acknowledgments The authors thank Donald White, Alison McMullen, and Melissa Corbitt for the storage and retrieval of data from the database maintained for these patients, and Barbara Owen for her expert preparation of the manuscript.
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