Surgery for sporadic primary hyperparathyroidism: controversies and evidence-based approach

Introduction Sporadic primary hyperparathyroidism is due to single adenoma in over 90–95% of instances. Careful medical history and precise preoperative identification of the enlarged gland by parathyroid Tc-mibi scintigraphy and neck ultrasound
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  CURRENT CONCEPTS IN ENDOCRINE SURGERY Surgery for sporadic primary hyperparathyroidism:controversies and evidence-based approach Antonio Sitges-Serra  &  Prieto Rosa  & Mónica Valero  &  Estela Membrilla  & Joan J. Sancho Received: 20 July 2006 /Accepted: 18 January 2008 /Published online: 21 February 2008 # Springer-Verlag 2008 Abstract  Introduction  Sporadic primary hyperparathyroidism is dueto single adenoma in over 90  –  95% of instances. Carefulmedical history and precise preoperative identification of the enlarged gland by parathyroid Tc-mibi scintigraphy andneck ultrasound allow selecting patients for minimallyinvasive parathyroidectomy, a focused intervention withminimal skin opening and tissue dissection. Small(<300 mg) adenomas continue to challenge preoperativeimaging, and most of them will still require a bilateralexploration. Conclusion  Surgery should never be indicated on the basisof positive or negative preoperative localization studies.Intraoperative quick parathyroid hormone measurementsseem particularly helpful for cases with equivocal localiza-tion studies. The best minimal access approach is still amatter of debate, and options include small central incision,video-assisted parathyroidectomy, minimal lateral openapproach, and purely endoscopic access via lateral ap- proach. Radioguided surgery does not seem to have a rolein routine cases but may be useful to find adenomas duringreintervention on scarred difficult surgical fields. Keywords  Parathyroidadenoma.Focusedparathyroidectomy.Controversies.Gammaprobe.Endoscopy.Hyperparathyroidism Introduction Preoperative investigations and surgical approach to spo-radic primary hyperparathyroidism (SPHPT) have changedsubstantially in the last two decades due to advances madein parathyroid imaging, quick parathyroid hormone (PTH)assays, and endoscopic techniques. Currently, parathyroid 99 Tc-sestamibi scintigraphy and neck ultrasound are carriedout almost systematically in patients with SPHPT, and thismakes preoperative localization of single adenomas possi- ble in many patients. Precise localization of enlarged glandshas, in turn, rendered selective or focused approach tosingle adenomas much more secure. When properlyindicated and performed, the results of selective parathy-roidectomy, as assessed by prospective randomized trials,are equivalent to bilateral parathyroid exploration in termsof persistence or recurrence of disease and superior in termsof cosmesis, duration of the intervention, postoperativestay, and hypocalcemia [1, 2]. Limited parathyroidectomy  by a  “ unilateral approach ”  was pioneered by Sten Tibblin inthe early 1980s [3] when localization techniques were stillrudimentary. Some 10 years later, a positive scintigraphymade unilateral exploration much more secure [4]. Cur-rently, the refinement of localization techniques has led tothe focused or selective approach  —  ignoring the normalipsilateral gland  —  which implies an even shorter interven-tion and further reduction of tissue dissection. New technologies, however, have given rise to severalcontroversies regarding the yield of preoperative imagingtechniques, the indications of selective parathyroidectomy, Langenbecks Arch Surg (2008) 393:239  –  244DOI 10.1007/s00423-008-0283-9A. Sitges-Serra :  P. Rosa :  M. Valero : E. Membrilla : J. J. SanchoDepartment of Surgery, Endocrine Surgery Unit,Hospital del Mar,Barcelona, SpainA. Sitges-Serra ( * )Department of Surgery, Hospital del Mar,Passeig Marítim, 25-29,08003 Barcelona, Spaine-mail:  the advantages and failures of intraoperative PTH determi-nation, and the use of other technological equipment.Furthermore, the issue is compounded by the fact that technology may be especially appealing to non-fully trainedsurgeons with the hope that it will  “  protect  ”  them against the anatomical intricacies of parathyroid surgery.In this review, the authors summarize the critical issuesregarding some of these  “ hot topics ” . Although a whole articlecould be devoted to each of the subjects presented, a synthesiseffort has been made to present to the reader the issues in aconceptualized rather than in an exhaustive review way. Preoperative localization techniques and indicationsof selective parathyroidectomy in SPHPT Before considering selective parathyroidectomy, a careful past medical history should be obtained to rule out conditions in which multiple gland disease is common or even any form of hereditary hyperparathyroidism, lithium-associated hyperparathyroidism, or chronic renal failure.The coexistence of a goiter is a relative contraindicationdepending on thyroid size, need for thyroidectomy, andresults of localizing techniques.SPHPT is due to a single adenoma in over 90% of theinstances. This is the first evidence on which selective parathyroidectomy is based, the second one being the possibility of identifying the diseased gland by preoperativeimaging. In many institutions, single adenomas are current-ly being localized by neck ultrasound and/or parathyroidscintigraphy in over 75  –  80% of the patients. This has ledsurgeons to progressively implement selective parathyroid-ectomy [5, 6], which can now be regarded as a well- established procedure. The yield of imaging techniques,however, is dependent on the equipment, operator, andtechnique, and this has a major impact on local decision-making policies. For example, the methodology of para-thyroid scintigraphy (collimator, dual-phase, subtraction,etc.) influences the rate of adenoma localization, this beinghighest for the single photon emission computed tomogra- phy (SPECT) technique and lower for simple antero- posterior planar projection [7  –  9]. In the study of Schachter et al., sensitivity for the planar projection was 78% and96% for the SPECT study. Neck ultrasound requires anexperienced operator to obtain the best results. Currently,there is a growing consensus that both techniques should becarried out because the best results of selective parathy-roidectomy are obtained when both localize the adenoma inthe same position. In recent series, this has happened inaround 60% of cases [6, 10, 11]. When there is discrepancy  between the two localization techniques, either a bilateralexploration should be carried out or a focused one withintraoperative PTH measurements [11].In countries with a high prevalence of nodular thyroiddisease, both parathyroid scintigraphy and ultrasound posespecific problems that make identification of parathyroidadenomas more difficult [12, 13]. In these circumstances where, in addition, thyroid resection may be considered,sound decision making in selecting the best approach on acase-to-case basis is essential to avoid surgical failures [14].Preoperative imaging can, in addition, diagnose unsus- pected multiple gland disease which contraindicates aselective approach. About 30  –  80% of patients with doubleadenomas will show a double uptake, and around 40  –  60%of patients with parathyroid hyperplasia will show at least two hot spots in the parathyroid scan [6, 15  –  17]. The  “ small-adenoma ”  paradox Despite the increasing accuracy of preoperative imaging,the current trend of earlier diagnosis of primary hyperpara-thyroidism implies that an increasing number of patientswill present in the future with s-Ca<11 mg/dl and smalladenomas. Although some cellular metabolism factorsinfluence the visualization of parathyroid adenomas in theTc-mibi scan [18, 19], the positivity of parathyroid scintigraphy is very much dependent on the weight of theenlarged glands. Biertho et al. [20] classified Tc-mibiuptake by parathyroid adenomas from 0 (false negative) to3 (high uptake). The 0-type adenomas had a median weight of 250 mg (interquartile range (IQR), 165  –  410 mg) andaccounted for 8% of their patients. The 1-type adenomas(equivocal uptake) were observed in 26% of cases and hada median weight of 340 mg (IQR, 247  –  647 mg). PTHvalues were also lower in these two categories: 113 and151 pg/ml, respectively. Thus, based on Tc-mibi uptakealone, one third of the patients would not have been eligiblefor a selective approach. Data from a recent study [21] areconcordant with those of Biertho et al. [20]; about one thirdof 150 patients had a negative scan, and there was a clear-cut relationship between mean gland weight and scan positivity: 1,180 vs. 517 mg for visualized vs. nonvisual-ized adenomas. The relationship between adenoma weight and localization also holds true for ultrasonography. At theMayo Clinic, adenomas of 1,000 mg or more are visualized by neck ultrasonography in over 95% of instances. For adenomas weighing less than 200 mg, however, thelocalization rate is below 50% [6].In the future, endocrine surgeons may thus face the paradox of operating on more patients with small adenomasand negative preoperative localization studies making bilateral exploration a must. In this setting, endocrinologistsmay be tempted to not refer patients for parathyroidectomyin the absence of preoperative localization of the adenoma.Surgeons should not let this occur because, first, a negative 240 Langenbecks Arch Surg (2008) 393:239  –  244  study does not necessarily imply a mild disease; second, it may indicate multiple gland disease; and, third, surgery isthe only treatment for hyperparathyroidism. Furthermore, it has been shown that patients with negative scans alsoobtain a clear-cut benefit from parathyroidectomy [22].Patients without preoperative localization of a parathyroidadenoma, however, should only be operated on byspecialist surgeons having thorough knowledge of normaland pathological parathyroid anatomy. In expert hands, bilateral parathyroid exploration can be done with a short incision ensuring good cosmesis, low cost, few complica-tions and, most importantly, a cure rate close to 100% [23,24]. Intraoperative PTH measurements Controversies around quick intraoperative PTH assayinvolve its indications, the criteria for cure, and failures(false decline and false non-decline). An in-depthreview of the subject is available [25]. For the sake of clarity, the authors refer in the following paragraphs to themost used and tested Miami criteria for cure: a drop of PTH values at least 50% below the highest PTH value (at induction of anesthesia or pre-excision) 10 min after adenoma resection.  Indications  Intraoperative PTH assay should have anaccuracy superior to the expected failure rate when not implemented. In addition, it should not spuriously prolongthe surgical intervention by waiting for results that will not alter the surgical strategy or that will alter it erroneously.These are the main reasons why some experts feel that intraoperative PTH measurement is not indicated whenadenoma localization is unequivocal, that is, when bothultrasound and scintigraphy are concordant. In thesecircumstances, surgical failure is less than 2  –  3% [11, 26], and PTH measurement only adds potential confusion due tothe inherent limitations of the technique. It will be unable toreduce this minimal failure rate while, at the same time, it may lead the surgeon to unnecessarily explore the contra-lateral side in 5  –  10% of cases [11, 26, 27]. Others, based on preoperative localization by scintigra- phy alone, [28  –  30] have found that intraoperative PTHmeasurement is essential to attain the best results from aselective approach. Again, this may be the case or, as analternative explanation, there may be a crucial problem inthe selection of patients. To date, no randomized studieshave been published on the benefits of PTH measurement depending on the accuracy of preoperative localizationstudies.Equivocal localization studies could be the most power-ful reason to implement intraoperative PTH measurements[11, 27, 28, 30]. In this circumstance, starting the operation on the suspicious location would be appropriate and then, if the adenoma is correctly identified, a 50% PTH declineshould be required. If the adenoma is not found in thesuspected location or PTH fails to decline, the surgeonshould proceed to a bilateral exploration. Criteria for cure  Some refinements of criteria for cure and persistence may still be needed to increase the accuracy of intraoperative PTH measurement. False declines are prob-ably rare if patients have been properly selected for focused parathyroidectomy but still occur in 1  –  3% of cases [6, 30, 31]. In a series of bilateral explorations validating intra-operative PTH testing, some 50  –  75% of patients withmultiglandular disease have shown an inappropriate 50%drop of PTH values [31  –  36]. This may be due to theinitial removal of the most active gland (which, inaddition, may be the only one showing on the scan) or to latent multiple endocrine neoplasia type 1 disease [31,32]. Others have suggested that concomitant thyroidsurgery, by interfering with the adenoma blood supply,may also be a reason for some of these PTH false declines[37]. Finally, Irvin et al. [38] have controversially put  forward that there may be enlarged nonfunctioning glandsthat will be disclosed only if a bilateral exploration is performed. In these circumstances, selective parathyroidec-tomy based on a purely immediate functional basis (>50%PTH decline) would be appropriate. Furthermore, thiswould be the explanation for the lower incidence of multiglandular disease found in series of selective parathy-roidectomies implementing PTH measurements comparedto that reported in a series of bilateral cervical exploration[28, 38]. To avoid false non-declines, two alternatives have been proposed and are currently under evaluation: (1) extendingthe sampling period to 15  –  20 min after the resection of theadenoma [39, 40] and/or (2) requiring normalization of the PTH values (<60 pg/ml). Both may increase the specificityof the intraoperative PTH testing at the expense of unduly prolonging the anesthesia time thus losing one of the mainadvantages of selective parathyroidectomy. The endoscopic approach Minimally invasive techniques have also interested endo-crine surgeons. What this exactly means in thyroid and parathyroid surgery, however, is far from clear [24, 41]. Simple extrapolation from abdominal procedures has ledsome authors to propose a purely endoscopic approach to(selected) neck endocrine pathologies. Others have com- bined the open with the endoscopic approach (video-assisted surgery). Although there are a number of studies Langenbecks Arch Surg (2008) 393:239  –  244 241  showing the feasibility of these approaches, a few havereported data hard enough to demonstrate that they arereally minimally invasive and that they offer advantagesover conventional minimal incision surgery.Miccoli et al. [42] have published a feasibility uncon-trolled study based on their experience in 370 cases of video-assisted selective parathyroidectomy study. Theyused a central 1.5  –  2-cm incision (at the beginning of the procedure) with external lateral retraction through whichendoscopic instruments are introduced. The operation wasaccomplished in 36 min, and patients were discharged theday after with a complication rate of 2.7%, a cure rate of 98.3%, and a 6.2% conversion rate. No data are givenconcerning the superiority of this approach over theconventional mini-incision central or lateral selectiveapproach. The first randomized study comparing video-assisted vs. open central (Kocher incision) parathyroidec-tomy has been recently published by Barczynski et al. [43].Although they state that central incision for the open procedure was 2  –  3 cm long, their follow-up data indicatethat patients finally had a conventional 3.8±4-cm scar  probably because using a central approach, a moreextensive muscular dissection, and thyroid mobilization isrequired in comparison with targeted lateral approaches inwhich the infrahyoidal muscles are minimally retracted andthe thyroid lobe is left almost untouched. This on its owncould explain the minimal (five to eight points on a scale of 100) albeit significant differences found in the pain scoreand analgesic requirements. At 6 months, there were nosignificant differences in cosmetic satisfaction. The operat-ing time for both procedures was similar, but the costs werehigher for the video-assisted procedure.Henry et al. [44] have published a feasibility uncontrolledstudy based on their experience in 279 cases of purelyendoscopic selective/unilateral parathyroidectomy study.They used a central 1.5-cm gasless approach (at the beginning of the procedure) for inferior/anterior adenomasand a lateral three-trochar approach with neck insufflation for the remaining adenomas. The operation was accomplished in49 min, and there was a 13.4% conversion rate. No precisedata are given on day of discharge nor on morbidity.The authors of the present review see no reason toapproach inferior parathyroid adenomas through a central(either open or video-assisted) or a lateral endoscopicapproach. These adenomas can be safely and expeditiouslyresected through a lateral minimal incision between thestrap and the sternocleidomastoid muscles. The issue ismore debatable for deep-seated superior adenomas that areanyway more difficult to excise whatever the approach.Perhaps, in those cases, vision is better by a purelyendoscopic approach, but a vertical incision along theanterior border of the sternocleidomastoid muscle wouldalso be appropriate [45].Potential disadvantages for minimallyinvasiveparathyroidsurgery, which may apply to open and/or endoscopicapproaches, are capsular rupture of adenomas (more likelyto occur when small surgical fields or long-range instrumentsare used), increased expenses due to single-use instruments,neck insufflation, need for conversion, and unexpectedfindings related to concomitant thyroid disease or complex parathyroid anatomy. Large adenomas (>3 cm) may bedifficult to excise through a small skin opening because theyoccupy almost all the available working space. Finally, somewill find the term  “ minimally invasive ”  difficult to accept for central approaches (either open or video-assisted) and, evenmore, for the endoscopic lateral approach with gas insuffla-tion. In terms of duration, tissue dissection, and structuremobilization, they may be at least as  “ minimally aggressive ” as conventional bilateral parathyroidectomy. Has radioguided parathyroidectomy a future? Intravenous injection of Tc-mibi before parathyroid surgeryallows identification of parathyroid tumors and imagingthem with a gamma camera (MIBI Scan) as well as with ahand-held gamma detector intraoperatively. This is the basisfor the so-called minimally invasive radioguided parathy-roidectomy (MIRP).In both cases, the key limiting factor lies in the fact that thyroid tumors can also retain the radioisotope, reducing both sensitivity and specificity of the technique. Repeatedscans and comparison with a thyroid scan allows parathy-roid scintigraphy to attain a sensitivity of 75  –  85% [46],whereas there is no way to avoid false-positive results dueto concomitant thyroid pathology when using MIRP.The technique involves injecting 2 to 20 mCi TC-99msestamibi a few hours before surgery and performing a parathyroid scan. If the scan is considered positive for asingle adenoma, patients are taken to the operating roomand surgery is performed through a small incision; thedissection down to the adenoma is guided by a miniaturehand-held probe [47], a similar approach used to localizethe sentinel node in breast cancer or melanoma excision. In brief, any excised tissue containing more than 20% of  background radioactivity in a patient with a positivesestamibi scan is considered a solitary parathyroid adeno-ma. Theoretically, this alleviates the need to identify other glands, obtain frozen sections, or measure serum parathy-roid hormone levels intraoperatively.The majority of reports assessing the use of MIRP areeither retrospective series with no control group or  prospective but nonrandomized trials with erratic inclusioncriteria, including in one study [48] the exclusion of every patient with thyroid pathology (up to 68% of the screened population). 242 Langenbecks Arch Surg (2008) 393:239  –  244  To assess the value of this technique, a case  –  controlstudy was performed with 62 patients having MIRP and 60 patients having conventional parathyroid explorations. Thesensitivity rates of the MIBI probe in single and multiplegland disease were 84.6% and 63.0%, respectively [49],illustrating the narrow margin of usefulness of MIRP. Inanother comparative study, a directed operation wasfacilitated by sestamibi scan in 22 of 24 patients, byintraoperative gamma probe detection in only five of 23 patients, and by the rapid intraoperative parathyroidhormone assay in 15 of 15 patients [50].The experience reported by Costello and Norman [51] inwhich radio guidance eliminated the need for preoperativeimaging could not be reproduced by other groups with alarge experience in parathyroid surgery [52], while othersfound the information given by the probe confusing or inaccurate [53].Regarding the impact of the MIRP on final results, therates of success, temporary and permanent hypoparathy-roidism, and injury of the recurrent laryngeal nerve were at  best similar in patients who underwent probe-guidedsurgery and those who had conventional surgery. Inaddition, controversies persist on the best dose of MIBI,as well as on how to achieve the optimal time interval between injection and exploration.It has been suggested by some investigators that intra-operative probe may facilitate a directed operation when preoperative imaging is equivocal, and no concomitant thyroid pathology exists, as in two out of eight patients ina Mayo Clinic prospective nonrandomized study [52]; but this narrow scope of use has to be assessed in future studies.In conclusion, although the MIRP probe may seem to bea useful tool in parathyroid surgery, its use has not improved the outcome of such surgery. The enthusiasmand results that elicited in some teams could not be sharedand reproduced by the remaining majority. References 1. Bergenfelz A, Lindblom P, Tibblin S, Westerdahl J (2002)Unilateral versus bilateral neck exploration for primary hyper- parathyroidism: a prospective randomized controlled trial. AnnSurg 236:543  –  5512. 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