O~iginalArtrc!~'",,_.~.~_.,_,,~_......_. ~.o:-'';:...:/-.~. ~'.:::.., MINIMALLY INVASIVE RADIO-GUIDED PARATHYROIDECTOMY IN 152 CONSECUTIVE PATIENTS WITH PRIMARY HYPERPARATHYROIDISM Douglas Politz, MD, FACS, Charles D. Livingston, MD, FACS, Brant Victor, MD; FACS, Robert Askew, [r., MD, FACS, and Lamar Jones, Jr., MD, FACS ABSTRACT Objective: To examine the results of minimally invasive radio-guided parathyroidectomy (MIRP) in the treatment of patients with primary hyperparathyroidism, including factors associated with negative technetiumlabeled sestamibi scanning. Methods: We retrospectively analyzed the findings in, a group of 152 consecutive patients encountered during the period 2001 through 2004. The overall accuracy of preoperative sestamibi scanning was assessed, and the success of MIRP was determined on the basis of operative time, duration of hospital stay, and rate of complications. Results: All 152 patients underwent preoperative ses-: tamibi scanning; 118 (78%) had positive scans and were treated with MIRP, whereas 34 (22%) had negative scans and underwent traditional neck explorations. Patients with negative sestamibi scans had 5 times the incidence of concomitant thyroid disease in comparison with those who had positive sestamibi scans (P<O.Ol), and they had higher rates of parathyroid hyperplasia (26% versus 0%; P<O.Ol). In comparison with traditional neck dissection, MIRP-treated patients had shorter operative times (38 minutes versus 86 minutes; P<O.OI) and shorter hospital stays (0.67 day versus 1.09 days; P<O.Ol). Among the MIRP-treated patients, 67% were discharged the same day as performance of the outpatient surgical procedure. Correction of hypercalcemia was accomplished in 116 of 118 patients (98%) who underwent MIRP. Complications in the MIRP group were low, including 1 postoperative hemorrhage. No cases of recurrent laryngeal nerve injury occurred. There were 2 false-positive sestamibi scans (1.3%). Conclusion: Parathyroid hyperplasia and concomitant thyroid pathologic conditions are associated with negative preoperative sestamibi scans. MIRP is applicable in Submitted for publication February 15, 2006 Accepted for publication May 18, 2006 From the Austin Surgeons, PLLC, Seton Medical Center, Austin, Texas. Address correspondence and reprint requests to Dr. Charles D. Livingston, Austin Surgeons, PLLC, Seton Medical Center, Suite 200, 3901 Medical Parkway, Austin, TX 78746. 2006AACE. 78% of patients with primary hyperparathyroidism and is a safe, effective operation that results in shorter surgical time, reduced hospital stay, and minimal complications. (Endocr Pract. 2006;12:630-634) Ab~ie~ati~~:., ~:~"x.. ",,.. -,.,07; CT,= computed tqrnogtaphic;mirp:;:: minimally inyit~('. sive n1dio-g1!ided, paia!ly.rq.idectoini;par~ parathy~ roid i'adenoma. ratio;:ptr'=:.:pi;trathyroid hormone;] "yats b vid~of<iss~sted,~tf:1oiacoscapy..... INTRODUCTION :--", -.,c' - ','-"'~ - _,c" '.." _,._.'~.~'" _.~.,."...~'"M"_.~.~.,~,~,... ~. '-"'-"--'''' AND BACKGROUND For many years, the standard treatment for patients with primary hyperparathyroidism was bilateral neck dissection with identification of all parathyroid tissue by using intraoperative frozen sections. Bilateral neck dissection is still appropriate for patients with multiple endocrine neoplasia type 1 or 2A, familial hyperparathyroidism, or secondary hyperparathyroidism (L). For treatment of patients with sporadic hyperparathyroidism, however, it has been shown that unilateral neck exploration will fail to identify multiple adenomas in only 2% of patients (1). In 1981, Wang (2) reported that routine use of bilateral neck exploration has been associated with increased cost, risk, and morbidity. Subsequent studies showed that unilateral exploration of the neck resulted in cure rates of 94% to 100% (1); however, inaccurate preoperative imaging made unilateral operations in all patients more problematic. With the advent of technetium-labeled sestamibi scanning, the site of the adenoma could be determined preoperatively in 80% to 90% of patients (3). Sestamibi is taken up by tissues that are rich in mitochondria and is avidly acquired by hypermetabolic parathyroid tissue. It is also taken up by thyroid adenomas but is taken up poorly (55%) in parathyroid hyperplasia (4). Norman and Chheda (5) combined preoperative sestamibi scanning with unilateral exploration using intraoperative nuclear mapping and ex vivo examination of the adenoma with the gamma probe. They also quantified the relationship of the adeno- 630 ENDOCRINE PRACTICE Vol 12 No.6 November/December 2006
Minimally Invasive Parathyroidectomy, Endocr Pract. 2006;12(No. 6) 631 ma and the remaining background in the 20% rule, defined as the ratio of the radioactivity of the ex vivo adenoma to the remaining background radioactivity (6,7)-a rule that avoided frozen sections and considerably reduced the operating time. Some investigators (8) also reported the clinical usefulness of intraoperative measurement of parathyroid hormone (PTH) levels to determine whether the adenoma had been found. The initial outlay for the assay equipment, however, is considerable. Hutchinson et al (9) have shown that minimally invasive radio-guided parathyroidectomy (MIRP) is less expensive in comparison with either traditional bilateral neck dissection or bilateral neck dissection in conjunction with PTH assay. Our current retrospective analysis of 152 consecutive patients treated during the period 2001 through 2004 was undertaken to evaluate our results with MIRP. Specifically, we wished to determine the overall accuracy of preoperative sestamibi scanning as well as the accuracy of the gamma probe for intraoperative mapping. We also wished to identify factors that are associated with a nega, tive sestamibi scan. We undertook to measure our own results by using the 20% rule. In addition, we wished to determine our overall success with MIRP, as measured by hospital length of stay, operative time, complication rate, and ability to correct hypercalcemia. Finally, w,e wished to ascertain whether there was a rate of failure with MIRP that we could reasonably hope to correct with the addition of PTH assay. PATIENTS AND METHODS Study Subjects The study cohort consisted of 152 consecutive patients with primary sporadic hyperparathyroidism, who were treated during the period 2001 through 2004 at our medical center. Patients with multiple endocrine neoplasia, familial hyperparathyroidism, or secondary hyperparathyroidism were excluded from the study. Patients were included who were found to have primary hyperparathyroidism, as evidenced by elevated serum calcium concentration, elevated PTH level, and elevated or normal urinary calcium excretion. Study Procedures All patients were evaluated and examined preoperatively by one of us and then underwent sestamibi scanning of the neck. Patients who had a negative sestamibi scan underwent traditional neck dissection. Those patients who had a positive sestamibi scan, defined as "a solitary focus distinct from the thyroid," were treated by MIRP. Patients in the MIRP group received an injection of 20 mci of technetium (99mTc)-labeled sestamibi 2 hours preoperatively. General anesthesia was used in all patients. MIRP-treated patients underwent unilateral neck exploration through a 3- to 4-cm collar incision. The Neoprobe 2000 gamma probe was used intraoperatively to locate the area of highest radioactivity by using the preoperative sestamibi scan as a guide. When tissue was removed and grossly suspected to be a parathyroid adenoma, the gamma probe was used to measure the radioactivity of the excised tissue as well as the radioactivity of the bed from which the specimen was removed. If the ratio of adenoma to background-the parathyroid adenoma ratio (PAR)-was at least 20% and if no other asymmetric radioactive hot spots were found, the operation was terminated. Frozen sections were not used if the 20% rule was satisfied. Likewise, no attempt was made to perform additional dissection to visualize the remaining parathyroid gland ipsilaterally. Patients were then dismissed in accordance with the operating surgeon's individual comfort level. Follow-up serum calcium levels were determined during subsequent office consultations.. RESULTS Of the 152 study patients, 118 (78%) had a positive preoperative sestarnibi scan (73% female and 27% male patients; mean age, 57 years), and 34 (22%) had a negative sestamibi scan (70% female and 30% male patients; mean age, 45 years). There were no statistically significant differences between patients with positive versus those with negative sestamibi scans with regard to preoperative serum calcium levels (mean value, 11.0 mgldl versus 10.9 mg/dl; normal, 10.5), preoperative PTH levels (mean value, 148 pg/ml versus 154 pglml; normal, <80), and parathyroid adenoma mass (mean, 942 mg versus 702 mg). The mean operative time was shorter for MIRP-treated patients (38 minutes) than for those patients who underwent traditional neck dissections (86 minutes) (P<O.Ol). Likewise, the mean hospital length of stay was shorter for patients treated by MIRP (0.67 day) than for patients who underwent traditional neck dissections (1.09 days) (P<O.Ol) (Table 1). Among the MIRP-treated patents, 67% were discharged within 6 hours after the outpatient surgical procedure. Application of the 20% rule to identify the parathyroid adenoma proved accurate, with no false-positive results. The mean PAR was 148% (range, 30% to 294%). All patients had pathology reports consistent with parathyroid adenoma. Follow-up serum calcium levels confirmed the correction of hypercalcemia in 116 of 118 patients (98%) who underwent MIRP. There were no instances of recurrent laryngeal nerve injury. Of the 118 patients in the MIRP group, only 1 had a postoperative neck hematoma that was recognized in the surgical recovery room, and that patient was returned to the operating room for treatment. Of the 152 sestamibi scans, 2 (1.3%) showed falsepositive results, 1 of which was equivocal and resulted in no parathyroid adenoma being identified at the first operation. This patient was found on subsequent computed tomographic (CT) scan to have a parathyroid adenoma in
632 Minimally Invasive Parathyroidectomy, Endocr Pract. 2006j12(No. 6) Table 1,Comparison of Mean Time Investment '.,.foroperative ProcedtJe and Hospital Stay.. ',:in 2 Treatment Groups. -:. With Primary Hyperparathyroidism'" Operative time (min)t -:'y- :- :.~~_-, ~;::l~:~;. ':~_~~~'f...:_ ;'~~~-'\'''''~'., ~ -. ';.. :~,: *MIRP:;:I]liri!.IMlly'invasive radio-guided parathyroidectomy. 'ti'.~():91;~95o/&;~9p.fi(lencelevel.. _.~""' _.;"''-''':;'' c,~'':':.. M~_.:;",;"" ~;';'.i'.."",:;~~,_,::':;'~'.~. 38 86 Hospital ',s,tay< (days)t Q:(i7. 1.09, " the mediastinum, which was removed with video-assisted thoracoscopy (VATS). The second patient is still undergoing further assessment. Patients who had a negative preoperative sestamibi scan (and thus underwent traditional neck dissection) were more likely to have associated thyroid disease in comparison with MIRP-treated patients (25% versus 5%;, P<O.Ol), and they had higher rates of parathyroid hyperplasia (26% versus 0%; P<O.Ol) (Table 2). Pathologic findings in the 34 patients with negative sestamibi scans included parathyroid adenoma in 24 (71 %) and parathyroid hyperplasia in 9 (26%). In 1 patient (3%) with a negative neck exploration, the preoperative sestamibi scan suggested a mediastinal parathyroid adenoma, but findings on a CT scan did not reinforce this interpretation. Treatment with VATS is pending in this patient. DISCUSSION We found that 22% of the 152 study patients presenting with primary hyperparathyroidism had a negative preoperative sestarnibi scan. No significant differences were noted between patients with positive and those with negative sestarnibi scans relative to preoperative serum calcium level, PTH level, or parathyroid adenoma mass. Taillefer et al (4) reported that sestamibi images result from increased uptake of the sestamibi by mitochondriarich tissues; uptake is increased in thyroid adenomas and is poor in parathyroid hyperplasia. Our patients with negative sestamibi scans were 5 times more likely than those with positive sestamibi scans to have an associated thyroid pathologic condition. In addition, 26% of our study patients with negative sestamibi scans had parathyroid hyperplasia versus none of the patients with positive sestamibi scans. These factors contributed to the failure of sestamibi scans to identify the location of the parathyroid tissue in these patients. In 78% of our patients, however, we found that sestamibi scanning was accurate and allowed for a unilateral neck exploration. We also found that proper use of the gamma probe intraoperatively facilitated rapid identification of the adenoma. Although sestamibi scanning indicates the general location of the suspected adenoma, the intraoperative use of the gamma probe enables the surgeon to probe the neck in three dimensions and focus on the area of interest. This technique is particularly helpful in obese patients. In addition, this technique of using a handheld gamma probe encourages the surgeon to persist in an area of high radioactivity when an obscure parathyroid adenoma may be deep in the neck or superior mediastinum. Moreover, use of the 20% rule, as outlined by Murphy and Norman (6), allowed us to dispense with time-consuming frozen sections. More importantly, it yielded no false-positive results. There were no failures in patients in whom the 20% rule was satisfied. Our mean ratio of adenoma to background radioactivity (PAR) was 148%, and no adenoma was less than 30%, a finding that gave us confidence in terminating the operation once this criterion was met. Furthermore, we found that other tissue such as lymph nodes and fat, in the past sometimes submitted for frozen section, was never radioactive and did not come close to satisfying the 20% rule. This process of elimination also contributes to time savings. The use of the aforementioned techniques allowed us to perform the MIRP procedure much faster than traditional neck exploration. Thus, the operating room time was reduced by more tban a half (P<O.Ol), and the mean duration of hospital stay was decreased by a third (P<O.OI). Only individual surgeon preference during this phase of instituting MIRP at our institution prevented a higher percentage of same-day discharge of patients than the already substantial 67%. Hypercalcemia was corrected in 98% of patients treated with MIRP and 97% of patients who underwent
Minimally Invasive Parathyroidectomy, Table 2...Pathologic FirtdiIigs in Study Patients..~..::_".:,~'-.-~.::'~ Wi~h Piim~ Hyperparathyroidism;.' -.,.-.. i: ;tf.h;~t~~t!fiedbyltestuts ~f SestaJmbi~;can~.,,, <!'5 Resfiitsof.; "'~~:sesfajnibr Concomitant.fhyroid pathology=.. -. -. Parathyroid hyperplasl~:,. ";;-'<:L ip.dj:61;.95%,confidence level.' traditional neck dissections. Sestamibi scanning yielded 2 false-positive results. On review, neither of these scans met the "solitary focus distinct from the thyroid" rule, and, both were equivocal. This situation emphasizes the need to recruit a few dedicated radiologists to interpret the scans and to minimize the tendency to judge a sestarnibi scan as positive because of lack of experience. One of our study patients was found on CT scan to have a mediastinal mass and subsequently underwent removal of a parathyroid ade-: noma by VATS. The other patient is currently undergoing additional evaluation. One patient with a sestarnibi scan interpreted as negative preoperatively, suggesting a possible mediastinal mass, had a subsequent negative CT scan followed by negative results of traditional neck dissection. This patient is pending treatment with VATS but likely had an unclear sestarnibi scan and harbors a mediastinal adenoma. With regard to mediastinal parathyroid adenomas, it is comforting to remember that the rate of mediastinal adenomas is approximately 2 per 100 patients and that the rate of negative preoperative sestamibi scans is 1 per 5 patients. Therefore, the random chance that a patient would have both a negative sestamibi scan and a rnedi.astinal parathyroid adenoma is about 2 in 50G-much better odds. The complication rate with MIRP was low and included no recurrent laryngeal nerve injuries and only 1 case of postoperative hematoma of the neck that necessitated reexploration. An added benefit for MIRP in comparison with traditional bilateral neck dissection is that the overall incidence of recurrent laryngeal nerve injury, although low in both groups, must be lower with only unilateral dissection. In addition, tissue planes and parathyroid tissue on the opposite side of the neck are left in an undisturbed state. The key, of course, is being able to obtain a good and accurate sestamibi scan preoperatively. As previously stated, this result is best accomplished by performing the sestarnibi scans in one location and enlisting the help of a few dedicated radiologists to interpret all Endocr Pract. 2006;12(No. 6) 633 the scans, coupled with surgeon review of all scans. Even with institution of these procedures, however, there will continue to be patients in whom the sestamibi scan is negative or equivocal, especially (as pointed out in this study) in those patients who have associated thyroid pathologic conditions. Since the compilation of these data, during an 18month period we have incorporated the use of preoperative parathyroid ultrasonography (performed by the surgeon) in all patients with hyperparathyroidism. In patients who have a positive sestamibi scan, the surgeon, using his intimate knowledge of the local anatomy, is able to learn the usual appearance of a parathyroid adenoma (hypoechoic, a few internal echoes, a sharp border, and a flat or rounded appearance). Accordingly, when the surgeon is faced with a patient who has a negative sestamibi scan, he or she will be able, using the ultrasound study as another "set of eyes," to examine the neck carefully in real time and, with a high degree of accuracy, predict the location of the adenoma in most cases. One of the reasons we undertook this study was to ascertain whether we needed to add intraoperative PTH assay to our operative procedures. We were considering the addition of the ability to perform this assay in our hospital pathology department, but the projected $200,000 price made us endeavor to justify the expense. In addition to the initial cost, the performance of intraoperative PTH assay does entail a finite length of time for allowing the level to decline and for performing the assay and reporting the results. On the contrary, use of the 20% rule only required that we use our gamma probe, which cost $25,000 and our hospital already owned and used for sentinel node biopsy. Moreover, the 20% rule can be applied and calculated instantaneously in the operating room. In light of these considerations of added time and not inconsiderable expense and because of the excellent results we had had with use of the MIRP technique, the gamma probe, and the 20% rule, we could not justify the addition of intraoperative PTH assay. CONCLUSION We conclude that MIRP is a safe, effective procedure that results in correction of hypercalcemia, shorter operative time, and briefer hospital stay in comparison with traditional neck dissection. On the basis of our current study, preoperative sestamibi scans will identify the location of the parathyroid adenoma in 78% of patients with primary hyperparathyroidism. The 20% rule is an accurate method for determining that the parathyroid adenoma has been removed; thus, the need for frozen sections in these patients can be eliminated. Patients with negative preoperative sestamibi scans have a higher rate of concomitant thyroid disease and parathyroid hyperplasia than do those with positive sestamibi scans.
634 Minimally Invasive Parathyroidectomy, Endocr Pract. 2006;12(No. 6) DISCLOSURE The authors have no conflicts of interest to disclose. REFERENCES l. Howe JR. Minimally invasive parathyroid surgery. Surg Clin North Am. 2000;80: 1399-1426. 2. Wang CA. Surgery of hyperparathyroidism: a conservative approach. J Surg Oneal. 1981; 16:225-228. 3. Denham OW, Norman J. Cost-effectiveness of preoperative sestamibi scan for primary hyperparathyroidism is dependent solely upon the surgeon's choice of operative procedure. J Am Call Surg, 1998; 186:293-305. 4. Taillefer R, Boucher Y, Potvin C, Lambert R. 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. 1992;33:1801-1807. 5. Norman J, Chheda H. Minimally invasive parathyroidectomy facilitated by intraoperative nuclear mapping. Surgery. 1997; 122:998-1003. 6. Murphy C, Norman J. The 20% rule: a simple, instantaneous radioactivity measurement defines cure and allows elimination of frozen sections and hormone assays during parathyroidectomy. Surgery. 1999; 126: 1023-1028. 7. Norman J, Chheda H, Farrell C. Minimally invasive parathyroidectomy for primary hyperparathyroidism: decreasing operative time and potential complications while improving cosmetic results. Am Surg, 1998;64:391-395. 8. Irvin GL III, Dembrow VD, Prudhomme DL. Clinical usefulness of an intraoperative "quick parathyroid hormone" assay. Surgery. 1993; 114: 1019-1022. 9. Hutchinson JR, Yandell DW, Bumpous jm, Fleming MM, Flynn MB. Three-year financial analysis of minimally invasive radio-guided parathyroidectomy. Am Surg, 2004;70: 1112-1115.