Efficacy of preoperative dual-phase sestamibi scanning in hyperparathyroidism

Original Contributions Efficacy of Preoperative Dual-Phase Sestamibi Scanning in Hyperparathyroidism C.W. David Chang, MD,* Terance T. Tsue, MD,† Arlo S. Hermreck, MD,‡ Kirkman G. Baxter, MD,§ and Larry A. Hoover, MD† Purpose: The objective of this article is to evaluate our experience with sestamibi scanning in patients with primary and secondary hyperparathyroidism. Patients and Methods: A retrospective review of patients referred to the radiology department at the University of Kansas Medical Center for parathyroid studies between January 1, 1993, and August 1, 1998, was done. Patients included in the study were those who underwent both dual-phase technetium (Tc-99m) sestamibi scanning and subsequent parathyroidectomy at our institution (n ⫽ 34). Twenty-six patients had primary hyperparathyroidism and 8 patients had secondary hyperparathyroidism. Fifteen had previous history of neck exploration. Results: Sensitivity of sestamibi scans in detection of all abnormal pathology in cases of primary hyperparathyroidism was 60% overall. Among the subset of adenoma cases, sensitivity was 82% (14/17). Among cases of primary parathyroid hyperplasia, no scan correctly localized all abnormal glands; however 60% (3/5) showed localization of at least one hyperplastic gland. Of the 2 patients with parathyroid carcinoma, in only one case was there evidence of sestamibi retention in the correct thyroid lobe. In patients with secondary hyperparathyroidism, sestamibi scanning was successful in identifying all hyperplastic tissue in only one case (sensitivity 13%). In 7 of the 8 cases of secondary hyperparathyroidism, the scan localized at least one hyperplastic gland. Conclusion: Sestamibi scanning is useful in the localization of abnormal pathology in cases of primary hyperparathyroidism, especially adenomas. In cases of hyperplasia, whether attributable to primary or secondary hyperparathyroidism, sestamibi imaging is less successful. (Am J Otolaryngol 2000;21:355-359. Copyright © 2000 by W.B. Saunders Company)

Although parathyroid glands are generally found near the superior and inferior poles of the thyroid, their precise number and location are not always constant.1 With such potential variation in parathyroid gland position, preoperative localization of adenomas would be able to accurately pinpoint abnormal tissue, thereby eliminating unnecessary surgical dissection and decreasing operating time.

From the *Department of Otolaryngology—Head and Neck Surgery, Vanderbilt University, Nashville, TN, the †Department of Otolaryngology—Head and Neck Surgery, the ‡Department of Surgery, and the §Department of Radiology, University of Kansas School of Medicine, Kansas City, KS. Address reprint requests to Terance T. Tsue, MD, Assistant Professor, Department of Otolaryngology— Head and Neck Surgery, University of Kansas School of Medicine, 3901 Rainbow Blvd, Kansas City, KS 66160. Copyright © 2000 by W.B. Saunders Company 0196-0709/00/2106-0001$10.00/0 doi:10.1053/AJOT.2000.18868

Various noninvasive methods of parathyroid localization including ultrasound, computed tomography, magnetic resonance imaging, and radionucleotide scanning have all been attempted with only limited success.2,3,4 Invasive methods such as parathyroid hormone (PTH) venous sampling are riskier and more technically difficult to perform. A new radionucleotide, Tc-99m sestamibi (hexakis2-methoxyisobutyl isonitrile; has brought renewed interest in parathyroid imaging. Sestamibi is a small protein labeled with Tc-99m that localizes in mitochondria found most abundantly in metabolically active cells. In abnormal parathyroid glands, mitochondria-rich oxyphil cells have been theorized to be responsible for increased sestamibi uptake,5,6 although this contention is still under debate.7 Tc-99m sestamibi activity is initially found in both thyroid and parathyroid glands shortly after intravenous injection. However,

American Journal of Otolaryngology, Vol 21, No 6 (November-December), 2000: pp 355-359

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its half-life and uptake is considerably greater in abnormal parathyroid tissue than in both regular parathyroid and thyroid tissue. One popular method of parathyroid imaging, the “dual-phase” technique, takes advantage of the delayed washout of sestamibi in abnormal parathyroid tissue compared with faster washout in thyroid tissue and normal parathyroid glands. After intravenous administration of technetium-labeled sestamibi, images are taken at 20 minutes and 2 hours postinjection with a gamma camera to create a planar image. The 20-minute image shows sestamibi retention in both thyroid and parathyroid tissue. However, after 2 hours, sestamibi remains in abnormal parathyroid tissue only. This present study assesses the efficacy of preoperative sestamibi scanning in detecting parathyroid pathology. MATERIALS AND METHODS A retrospective chart review of all patients referred to the radiology department at the University of Kansas Medical Center for parathyroid studies between January 1, 1993, and June 30, 1998, was conducted. Patients included in the study were those who underwent both dual-phase sestamibi scanning and subsequent parathyroid exploration at our institution. Thirty-four individuals qualified for the study. All patients presented with the diagnosis of primary or secondary hyperparathyroidism as evidenced by hypercalcemia (Ca ⬎ 11.0 mg/dL) and/or elevated intact PTH (iPTH ⬎ 65.0 pg/mL). The diagnosis of secondary hyperparathyroidism was supported additionally with a history of renal failure and high serum phosphate levels. Sestamibi studies were done by using 8 to 31 mCi (mean 21.0 mCi), intravenously injected Tc-99m sestamibi (Cardiolite; DuPont Pharmaceutical, Wilmington, DE). Images were captured with a gamma camera (Siemens Basicam LFOV or Siemens Orbiter LFOV; Siemens, Hoffman Estates, IL) with a high-resolution collimator. The dual-phase imaging protocol consisted of scans taken 20 minutes and 2 hours postinjection. Some patients underwent other additional parathyroid localization studies. Scan outcomes were determined by the following criteria. True positive scans were those that showed on delayed image a persistent focus or foci corresponding to parathyroid pathology resected from the same location in the neck. Designation of parathyroid location was commonly made in reference to the 4 poles of the thyroid and other ectopic sites. In patients whose thyroid had been surgically removed, localization specifying simply the right or left side was deemed sufficient. In addition, all true positive scans were confirmed by postoperative normalization of serum calcium in patients

CHANG ET AL

with primary hyperparathyroidism and postoperative normalization of PTH levels in patients with secondary hyperparathyroidism. False positive scans were those that had focal retention of sestamibi in an area that did not correspond to any abnormal parathyroid tissue. False negative scans included those scans that (1) failed to localize all parathyroid pathology surgically removed, or (2) failed to account for the source of hyperparathyroidism, including cases where PTH level failed to resolve post parathyroidectomy. Because all patients chosen for this study were hyperparathyroid, by definition there were no true negative scans. All removed tissue, except reimplanted tissue, was submitted for histologic analysis. For statistical analysis, calculations were figured on a per-patient basis only, not by individual glands.

RESULTS Thirty-four patients diagnosed with primary or secondary hyperparathyroidism underwent dual-phase sestamibi localization and surgery. The study group consisted of 11 men and 23 women ranging in age from 22 to 82 years old, with a mean age of 54 years. Fifteen patients (44%) had previously undergone neck exploration. Primary Hyperparathyroidism Subset Twenty-six patients had primary hyperparathyroidism, of which 17 had parathyroid adenomas, 5 had parathyroid hyperplasia (including one with multiple endocrine neoplasm type 1), and 2 had parathyroid carcinoma (Table 1). Ten patients (38%) had previously undergone neck surgery, with 9 (35%) for suspicion of parathyroid pathology. Sensitivity of sestamibi scans in detection of all abnormal pathology in primary hyperparathyroidism was 58% (15/26) overall. Among only the adenoma cases, sensitivity was 82% (14/17). Two patients categorized under primary hyperparathyroidism had elevated PTH levels, but falsely negative scans (patients 23 and 25), as no source was discovered. A false positive focus of retention found in one adenoma patient (patient 8) was shown to be chronic lymphocytic thyroiditis with Hurthle cell changes. Among cases of parathyroid hyperplasia, none correctly localized all abnormal glands; however 60% (3/5) showed localization of at least one hyperplastic gland.

SESTAMIBI SCANNING IN HYPERPARATHYROIDISM

357

Of the 2 patients with parathyroid carcinoma, in only one case (patient 26) was there evidence of sestamibi retention in the vicinity of the cancer. In that case, parathyroid carcinoma was found to be present in both right and left thyroid beds, although only one side was visualized on the sestamibi study. The scan was, therefore, only of marginal benefit (false negative).

TABLE 1.

Secondary Hyperparathyroidism Subset Eight patients had secondary hyperparathyroidism (Table 2). Four patients (50%) had previous parathyroid exploration. Mean preoperative serum calcium was 9.7 mg/dL, which is within normal physiologic limits. All 8 patients were undergoing dialysis treatment at the time of operation. Sestamibi scan-

Primary Hyperparathyroidism

Patient Age No. (yr)

Previous Preoperative Neck Preoperative iPTH Surg? Ca (mg/dL) (pg/mL)

Parathyroid Adenoma 1 72 Yes 2 79 No 3 56 Yes 4 66 Yes 5 55 Yes 6 60 No 7 33 No 8 42 Yes

Sestamibi Uptake*

Excised Glands with Confirmed Pathology*

L — L — RI LI RS L, minor R L RI RI LI LI — LI L RI

L LI L LS RI LI RS RI, L chronic lymphocytic thyroiditis LS RI RI LI LI LI LS L RI

11.8 11.5 11.3 12.9 10.9 11.3 13.7 11.2

2.4† 69.1 630.0 168.5 458.0 103.0 451.0 108.0

10.9 11.4 12.4 11.5 12.1 11.5 11.0 12.0 11.3

168.3 75.1 8.3§ 63.1 1236.3 88.9 121.8 93.6 76.2

10.3 11.1 10.9 11.4 12.0

185.0 81.0 370.0 196.9 529.7

LI LI, RI — — LI

LS LI, thymus LS LS, LI LI, LS, RI, RS

Parathyroid Carcinoma/Other 23 74 Yes 11.2 24 81 No 12.5 25 62 No 11.4

223.6 562.0 85.0

RI — —

975.1

Diffuse R

RI Hurthle cell nodule Parathyroid carcinoma Thyroid adenoma with focus of thyroid papillary carcinoma Parathyroid carcinoma along both inferior poles

9 10 11 12 13 14 15 16 17

74 48 60 82 73 77 61 74 67

No No No No No No Yes No No

Parathyroid Hyperplasia 18 36 Yes 19 37 Yes 20 32 Yes 21 71 No 22 60 No

26

44

Yes

10.3

Postoperative Scan Ca (mg/dL) Outcome

8.1 9.8 8.9 8.8 9.2 8.6 7.2 8.5

TP FN TP FN TP TP TP TP‡

7.2 9.8 8.7 9.6 10.2 8.5 9.2 9.6 9.9

TP TP TP TP TP FN TP TP TP

9.2 9.8 8.9 9.2 8.4

FN㛳 FN FN FN FN

11.0 7.7 9.7

FN㛳 FN FN

9.8

FN¶

Abbreviations: Ca, calcium; L, left; TP, true positive; LI, left inferior; FN, false negative; LS, left superior; RI, right inferior; RS, right superior; R, right. *Parathyroid location in relation to thyroid. †Value given for midmolecule measurement (normal ⬍0.9 ng/mL). ‡Retention of sestamibi in right neck corresponds to adenoma found in surgery. Left-sided retention corresponds to left thyroid lobe, which showed presence of chronic lymphocytic thyroiditis with Hurthle cell changes. §iPTH normal 1.0-5.2 pmol/L. 㛳PTH levels still elevated postoperatively. ¶Incomplete resolution of all parathyroid carcinoma.

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CHANG ET AL

ning was successful in identifying all hyperplastic tissue in only one case (sensitivity 13%). In this case, the hyperfunctioning tissue was localized to the left sternocleidomastoid muscle (LSCM) in a patient who had previously undergone total parathyroidectomy with autologous parathyroid implantation to the LSCM. In 7 of the 8 patients, sestamibi scanning localized at least one hyperplastic gland. Of the surgically excised glands, sestamibi scintigraphy detected 48% (10/21) of the individual glands. Second-Look Cases Sixteen patients in our study had previously undergone neck explorations. Overall, the sensitivity of sestamibi scans for these patients was 40% (6/15). Among those with adenomas, 83% had true positive scans. None of the second-look patients with primary hyperparathyroidism caused by hyperplasia or carcinoma had true positive scans. In patients with secondary hyperparathyroidism, the sestamibi scan showed a sensitivity of 25% (1/4). DISCUSSION In our study, we found the sensitivity of the dual-phase sestamibi scan in localization of parathyroid adenomas to be 82% (14/17). A meta-analysis by McBiles et al8 calculated that dual-phase sestamibi scanning was 73% TABLE 2.

sensitive for the detection of adenomas. Subsequent studies have shown better results, with some sensitivities reportedly near 90%.9-13 Some report a high enough sensitivity in dual-phase sestamibi scans to permit accurate selection of patients for cost-effective unilateral neck exploration.14 The performance of sestamibi scanning in patients with primary hyperplasia within our survey was disappointing. No scan correctly localized all abnormal glands; however 60% (3/5) showed localization of at least one hyperplastic gland. Others reported sensitivities for gland hyperplasia range from 55% to 79%.7 Comparison of the sensitivity rates is difficult because each study uses varying criteria for scan positivity. Our definition of a true positive scan requires (1) all abnormal surgically removed glands to be detected by sestamibi, and (2) postoperative calcium and/or PTH levels to be normalized. This definition is somewhat more stringent than many previous studies, which considered scans with 2 or more areas of sestamibi retention as positive for hyperplasia regardless of the actual number of hyperplastic glands.8,11,15 Admittedly, such a stringent definition fails to give credit to any partial accuracy of sestamibi scanning. However, we contend that the use of sestamibi localization studies should lie in its ability to affect clinical outcome. Therefore, our endpoints include confirmation of the biochemical resolution of hyperparathyroidism.

Secondary Hyperparathyroidism

Preoperative Previous iPTH Patient Age Neck Preoperative Preoperative (pg/mL) No. (yr) Surgery? Ca (mg/dL) PO4 (mg/dL) 27 28 29 30

49 38 64 21

Yes Yes Yes No

8.3 8.5 11.9 8.2

7.5 7.4 7.6 6.6

1184.7 860.4 540.0 1536.5

31

41

Yes

9.9

8.0

644.5

32 33 34

55 22 33

No No No

11.5 9.4 9.6

6.0 10.6 4.7

959.9 1360.0 602.3

Sestamibi Uptake1 LI RS L lateral RI, LI

Excised Glands with Confirmed Postoperative Scan Pathology1 iPTH (pg/mL) Outcome2 LI RS LSCM3 RS, LS, RI, thymus LSCM, thymus

L, L mediastinum LI, R LI, LS, RI, RS LI LI, LS, RI, RS — LI, LS, RI, RS

142.5 321.5 54.3 5.0

FN FN TP FN4

632.0

FN

2.5 14.8 169.3

FN FN FN

Abbreviations: Ca, calcium; LI, left inferior; FN, false negative; RS, right superior; L, left; LSCM, left sternocleidomastoid muscle; TP, true positive; RI, right inferior; LS, left superior; R, right. *Parathyroid location in relation to thyroid. †Pathologic tissue found in previously autogenously implanted parathyroid gland in left sternocleidomastoid muscle. ‡Postoperatively, calcium level remained moderately elevated although PTH level had declined. However, 1 year and 5 months later, serum PTH was 128.7 pg/mL.

SESTAMIBI SCANNING IN HYPERPARATHYROIDISM

Detection of hyperplastic glands in patients with secondary hyperparathyroidism was equally disappointing. In our series, sensitivity was only 12.5%. Many other studies report higher sensitivities largely attributable to variation in criteria for positivity and patient selection.7,16,17,18 Theoretically, parathyroid imaging improves surgical success in second-look cases.19 Scans of our previously operated patients with adenomas had a sensitivity rate (83%) comparable with our overall adenoma detection rate (82%). The similarity of these values is expected, as detection of pathologic tissue should be dependent on the sensitivity of the scans and not the surgical history of the patient. The sestamibi scan, among our other second-look cases, failed to show any usefulness. This result, too, is expected because of poor sensitivity. CONCLUSION Dual-phase sestamibi scans are useful in the localization of abnormal pathology in cases of primary hyperparathyroidism, especially adenomas. In cases of hyperplasia, whether attributable to primary or secondary hyperparathyroidism, sestamibi imaging is less successful. Currently, the Tc-99m sestamibi offers the best noninvasive method for parathyroid adenoma or hyperplasia localization. It is of probable benefit for cases of reoperation for recurrent hyperparathyroidism or in cases suspicious for ectopic and/or supranummary parathyroid glands.19 Whether localization studies prove to affect therapeutic outcomes and surgical strategies is yet to be determined, and requires a rigid prospective study. References 1. Taillefer R: 99mTc sestamibi parathyroid scintigraphy, in Nucl Med Ann 1995. New York, Raven Press, 1995, pp. 51-79 2. Van Heerden JA, James EM, Casell PR, et al: Small part ultrasonography in primary hyperparathyroidism. Ann Surg 195:774-780, 1982

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3. Mitchell BK, Merrell RC, Kinder BK: Localization studies in patients with hyperparathyroidism. Surg Clin North Am 75:483-498, 1995 4. Miller DL: Preoperative localization and interventional treatment of parathyroid tumors: When and how? World J Surg 15:706-715, 1991 5. Sandrock D, Merina MJ, Norton JA, et al: Light and electron-microscopic analyses of parathyroid tumours explain results of T1-201/Tc-99m parathyroid scintigraphy. Eur J Nucl Med 15:410, 1989 (abstr) 6. Carpentier A, Jeannotte S, Verreault J, et al: Preoperative localization of parathyroid lesions in hyperparathyroidism: Relationship between technetium-99m-MIBI uptake and oxyphil content. J Nucl Med 39:1441-1444, 1998 7. Ishibashi M, Nishida H, Okuda S, et al: Localization of parathyroid glands in hemodialysis patients using Tc99m sestamibi imaging. Nephron 78:48-53, 1998 8. McBiles M, Lambert AT, Cote MG, et al: Sestamibi parathyroid imaging. Semin Nucl Med 25:221-234, 1995 9. Sofferman RA, Nathan MH, Fairbank JT, et al: Preoperative technitium Tc 99m sestamibi imaging. Arch Otolaryngol Head Neck Surg 122:369-374, 1996 10. Taillefer R, Boucher Y, Potvin C, et al: Detection and localization of parathyroid adenomas in patients with hyperparathyroidism using a single radionuclide imaging procedure with technetium-99m-sestamibi (double-phase study). J Nucl Med 33:1801-1807, 1992 11. Klieger P, O’Mara R: The diagnostic utility of dual phase Tc-99m sestamibi parathyroid imaging. Clin Nucl Med 23:208-211, 1998 12. George EF, Komisar A, Scharf SC, et al: Diagnostic value of the preoperative sestamibi scan in intraoperative localization of parathyroid adenomas: A case study. Laryngoscope 108:627-629, 1998 13. Sinha CK, Hamaker R, Hamaker RC, et al: Utility of preoperative radionuclide scanning for primary hyperparathyroidism. Laryngoscope 107:753-758, 1997 14. Denham DW, Norman J: Cost-effectiveness of preoperative sestamibi scan for primary hyperparathyroidism is dependent solely upon the surgeon’s choice of operative procedure. J Am Coll Surg 186:293-305, 1998 15. Blanco I, Carril JM, Banzo I, et al: Double-phase Tc-99m sestamibi scintigraphy in the preoperative location of lesions causing hyperparathyroidism. Clin Nucl Med 23:291-297, 1998 16. Pons F, Torregrosa JV, Vidal SS, et al: Preoperative parathyroid gland localization with technetium-99m sestamibi in secondary hyperparathyroidism. Eur J Nucl Med 24:1494-1498, 1997 17. Piga M, Bolasco P, Satta L, et al: Double phase parathyroid technetium-99m-MIBI scintigraphy to identify functional autonomy in secondary hyperparathyroidism. J Nucl Med 37:565-569, 1996 18. Chesser AM, Carroll MC, Lightowler C, et al: Technetium-99m methoxy isobutyl isonitrile (MIBI) imaging of the parathyroid glands in patients with renal failure. Nephrol Dial Transplant 12:97-100, 1997 19. Norton JA: Reoperation for missed parathyroid adenoma. Adv Surg 31:273-297, 1998