~~~1

Alberto S. Molinari, MD, George L. Irvin lli, MD, George T. Denso, BS, andLeslie Bott, BS, Miami, Fla.

Background. Success/ul parathyroidedomy depends on recognition and excision o/ all hyperfunctioningparathyroid glands. Because histologic definition is limited, multiglandular disease (MGD) is usuallydetermined grossly by means o/ estimation o/ gland size and the experience o/ the surgeon, resulting infrequency varying from 8 % to 33 %. Normalization o/ elevated intraaperativeintad parathyroidhormone (iPTH) levels after excision o/ all hyperfunctioning glands is necessary /or postaperativenormocalcemia and indicates normal secretion o/ remaining parathyroids. Abnormal hormone secretionmeasured during aperation has been used to define the extent o/ excision and the incidence o/ MGD.Methods. One hundred ten consecutive parathyroidedomy patients with no previous neck surgery orhistory o/ multiple endocrine neoplasia had intraaperative iPTH assays performed be/ore and afterexcision o/ any suspected abnormal parathyroid gland(s). A drap in iPTH level after gland excisionpredided postaperative normal calcium levels..Results. Allpatients except one had normalization o/ serum calcium levels (average /ollourup, 15months). One hundred five patients had only one hyperfundioning gland removed, and all haveremained normocalcemic. Five (5%) patients had more than one gland involved: /our had two or morehyperfunctioning parathyroids and one patient, who had a large parathyroid cyst removed, remained

hypercalcemic.Conclusions. By using a biochemical assay, instead o/ estimated size, to predice which parathyroidglands are hypersecreting, the incidence o/ MGD in primary hyperparathyroidism was /ound to be 5%.

(Surgery 1996;120:934-7.)

From the Department o/ Surgery; University o/ Miami School o/ Mediand Veterans Affairs Medical Centers, Miami, Fla.

:nd

Jack:

Memori.

parathyroid honnone secretion during operation withexcision of abnonnal parathyroid glands and quantita-tively to detennine the incidence of multiglandular in-volvement in a series of patients with primary hyperpar-athyroidism.

THE OCCURRENCE OF unrecognizedmultiglandular di~ease in primary hype;rparathyroidism is often cited as acause of persistent hypercalcemia after parathyroidec-tomy. Althoughsuccess cates of95% to 98% have beenachievoo in large series of patients!' 2 these excellent

outcomes arenot always reported when an "occasion-al" parathyroidectomy is performed bysu~eons infre-quently treating this disease.3 To maintain excellentoperative results i?,patients with prim~ hype;rparathy-!oidism, many surgeons excise multiple parathyroidglands that ~ppear grossly enlarged, assuming that theincreasedsize. relates to excess hormone production.However ,-asshoWn iri Table 1, great variatioÍl exists intheie~rled &eguerigofltiriítiple glandinvolvement.c...,.. ~ "'", '" '

Thep~ose:'of;@s":stiidY"is ..tó'correlate "excess'" .."'.. ,."'. '" ,'-

MATERIAL AND METHODS

One hundred ten consecutive patients with fueestablished diagnosis of primary hypercalcemic hyper-parathyroidism undelWent cervical exploration andparathyroidectomy. The average agewas61 years (range,11

to 84 years) , and fue female to male ratio was 4: 1.5.All patients were hypercalcemic with an average preop-erativeserum calciumlevelof-12.2 mg/dl (rahge, 10.8to 17.0 trig/ dI) and hadintacfp~thyroid hormone(iPTH) levels abOve fue normaIrange forthe assays

c. ". " ;,c .used. AlI patlevts had normaI:renal functlon study

cre-

~~,r~~,t~8,j~~t?~!c~~gge~HH$ c't~~ tiple endocrineneolasia"'" drome'afid al1 ati.e:ritswith revious ar-p""c,~...cv;'.~_'c.",;;v p"" p paili""'oid~ttC;mf~s;óP;;h~k1:je "'iorations for th oíd dis-, Y!:""c" ".",,;,;c".'"";"t..,,~,c.c." , yr

Reprjnt ~ques~;G.LJIvin IJI.MP,Dep~~nf&f Surgery (R-310) ,c "c" ,,~,o""""".c""'""

UniverntyofMiarni &h9?1 of~~~cirie,'PO"&x"Ó16310.~.J.:L::~~~76322 "cé:c

934 SURGERY

Molinari el al. 935Number 6

Multiglandular disease in primary Table ll. Time offollow-up penad in 110 patients

Months monitored No. of patients--

>48 3

>36 12>24 26>12 50>6 89>2 110

Frequency(%)Author Year Patients

332826161511118

Tezelman et aI.5Bonjer et aI.6Rossi and Cady7Wallfelt et aI.s~Heerden and Grant2~roye et aI.9Attie et aI.lO glands requiring further resection and multiglandular

involvemerit.

RESULTSOne hundred nine patients had normal or low serum

calcium levels within 24 hours after parathyroidectomyand have maintained normocalcemia (average, 9.5mg/dl; range, 8.~ to 10.2 mg/dl) for fue follow-up pe-riod averaging 15 months (range, 2 to 61 months). Asshown in Table 11, 89 patients had been monitored for6 months or more. The intraoperative iPrH assays wereable to accurately identify excision of aIl hypersecretingglands and to predict postoperative calcium levels witha sensitivity of93%, specificity of 100%, and overall ac-

curacy of94%.On fue basis of fue measurement ofintraoperative

iPTH secretion, in 110 consecutive patients 105 re-tumed to normal serum calcium levels after resection ofa single,hypelfunctioning parathyroid gland. Fourpa-tients had normal postoperative calcium levels after re-section of multiple parathyroid gl~nds. Three of thesepatients were found to have two hyperfunctioningglands. The six resected glands ranged in size from3.9 x 2.0 x 1.2 cm to 1.6 x 0.7 x 0.4 cm. One patient hadfour enlarged glands and underwenta 3~ gland resec-tion. One operative failure occurred in a parient with alarge parathyroid cyst that ruptured during dissection.Although fue iPTH level did not fall sufficiently to meetcriteria (true negative), thesurgeon erroneously termi-nated fue operation without determining the status offue remaining parathyroid glands (considered multi-

glandular disease).

DISCUSSION

Excessive parathyroid hormone secretion by one ormore parathyroid glands in patients with primary hy-

percalcemic hyperparathyroidism is extremely impor-tant to fue endocrine surgeon. Failure to recognize andexcise all hypersecreting glands or an adequate amountof hypetfunctioning tissue in fue case of four gland hy-perplasia wiIl result in an unsuccessful operation andpersistent hyperparathyroidism. This fact ~ the un-derlying cause of fue controversy about how much par-

ease were excluded. Serum calcium levels were obtainedwithin 24 hours after parathyroidectomy and as close aspossible to a regularly scheduled protocol at2-, 6-, and12-month intervals. AlI patients in the series were mon-itored for a minimum of 2 months. As part of an ongo-ing study, 72% of the patients had a preoperative local-iZation study with technetium 99m sestamibi scintigra-phy (DUPont Merck Pharmaceutical, Billerica, MA).11

OUT methods of performing intraoperative assays ofiPTH have been previously described. Briefly, plasmasamples from a peripheral vein were obtained at thefoUowing times:after induction of anesthesia but beforeany incision; after dissection and just before tumor ex-cision; and 5, 10, and, occasionally, 20 minutes after ex-cision of each suspected abnormal parathyroid gland. Inthe first 36 patients in this study, intraoperative iPTHlevel was measured with a modification of a two-site an-

tibodyimmunoradiometric assay (INCSTAR Corp., Still-water, MN) by using a small portable gamma counter(MGM Electronics, Hamden, CT) .12 Since 1993 we haveused a modified immunochemiluminescence assay formeasuring iPTH (Nichols Institute Diagnostics, SanJuan Capistrano, CA) with a small, portable lumino-meter (MGM Electronics, Hamden, CT) ,13 A decreasein the iPTH levelof50% or more inthe 10-minute post-excision sample compared with the highest preopér:a-'. tive or preexcision sample was used to predict serumcalcium level after parathyroidectomy. Th-e assay is donein or clase to the operating room where fue results aremade available to the surgeon in approximately 10minutes.

The intraoperative iPTH assay was donebefore andafteréxcision of each suspected "abnormal" parathy-raid gland. When a significant drop in iPTH leveloccurred after ex~ision of all abno~al parathyroidgland, further dissection and identification of the otherglands secreting normal amounts ofhormone wereun-

1nece~ and the incisionwas closed.1f ~e iPTH levelremained elevated after fue first tumor excision, fue testindicated the presence of additional hyperfunctioning

936 Molinari et al. SurgeryDecember 1996

1980s and is still an issue with surgeons today.9 Manyexperienced endocrine surgeons use fue obseIVed sizeof a parathyroid gland as a correlation with hyperfunc-

tion. This is based ori fue exceIlent success ratesachieved by excising all grossly enlarged glands duringparathyroidectomy. With gland size, along with hjsto-pathology or fat content, as criteria for excision and de-termination of multiglandular involvement, varying re-ports of fue frequency of this phenomenon have beenreported. As shown in Table 1, recent reports rangefrom 33% to 8% in severallarge series of patients withexceIlent parathyroidectomy success rates. Becausethere does not appear to be a substantial difference infue patient populations in fuese studies, fue most likelyexplanation for fue wide variation in fue frequency ofmultiglandular disease is fue surgeon 's interpretation ofgland size. Moreover, fue gross appearance of anenlarged parathyroid gland mar not correlate with anexcessive hormone production.

The present study uses a quantitative biochemical as-say of circulating iPfH (1-84) in plasma tomeasure fueexcessive secretory product of all parathyroid glands inan individual patient. This hormone has a short half-lifeof 3 to 4 minutes and has been shown to accurately pre-dictpostoperative serum calcium levels when measured

during parathyroidectomy.14By relating fue decrease in plasma iPTH levels predict-

ing postoperative normal serum calcium levels to fue ex-cised number of hypersecreting parathyroid glands, fre-quency of multiglandular involvement in primary hyper-parathyroidism appears lower than usually described.

Because fue sensitivity and accuracy ofrJIese intraop-erative assays have proved a reliable indicator of post-operative calcium levels, fue remaining glands wererarely visualized after excision of a single hyperfunc-tioning gland. Therefore fue size of fue in-situ glandscould not be estimatedor correlated with postoperativeiPfH secretion. The foIlow-up of this series of patients,ave~ng less than 2 years, is toa short to determinewhether fue late recurrence rate wiIl be increased com-paredWith similar patients subjected to multiple exci-

e '-..

parathyroidism: an institutional perspective. World] Surg 1991;15:688-92.

3. Malmeus], Granberg PG, Halvorsen], Akerstrom G,]ohanssonH. Parathyroid surgery in Scandinavia. Acta Chir Scand 1988;

154:405-13.4. Weber C], Sewell W, McGarrity WC. Persistent and recurrent

sporadic primary hyperparathyroidism: histology, complications,and results ofreoperation. Surgery 1995;116:991-8.

5. Tezelman S, Rodriguez]M, Shen W, Siperstein AE, Duh Q-Y,Clark OH. Primary hyperparathyroidism in patients who havereceived radiation therapy and in patients who have not receivedradiation therapy.] Arn Coll Surg 1995;80:81-7.

6. Bonjer H], Bruining HA, Birkenhager ]C, Nishiyama RH,]ones

MA, Bagwell CB. Single and multigland disease in primaryhyperparathyroidism: clinical followup, histopathology, and flowcytometric DNA analysis. World] Surg 1992;16:737-44.

7. Rossi RL, Cady B. Surgeryof parathyroid glands. In: Cady B, RossiRL. Surgery of the thyroid and parathyroidglands. Philadelphia:WB Saunders, 1991:283-94.

8. Wal1felt C, Ljunghall S, Bergstrom R, Rastad], Akerstrom G.Clinical characteristics and surgical treatment of sporadic pri-mary hyperparathyroidism with emphasis on chief cell hyper-

plasia. Surgery 1990;107:13-9.9. Proye GAG, Carnaille B, Bizard JP, Quieureaux ]L, Leconte-

Houke M. Multiglandular disease in seemingly sporadic primaryhyperparathyroidism revisited: where are we in the early 1990s?a plea against unilateral parathyro¡d exploration. Surgery 1992;

112:1118-21.10. Attie]N, Boch G, Auguste L]. Multiple parathyroid adenomas:

repon of thirty-three cases. Surgery 1990;108:1014-20.11. Sfakianakis GN, Irvin GL, Foss], Mallin W, Georgiou M, Deriso

GT, et al. Efficient parathyroidectomy guided by SPECT-MIBIand hormonal measurements.] Nucl Med 1996;37:798-804.

12. Irvin GL, Dembrow VD, Prudhomme DL. Operative monitoringof parathyroidgland hyperfunction. Arn] Surg 1991; 162:299-302.

13. Irvin GL, Deriso GT. A new, practical intraoperative parathyroidhormone assay. Arn] Surg 1994;168:466-8.

14. Irvin GL, Dembrow VD, Prudhomme DL. Clinical usefulness ofan intraoperative "quick parathyroid hormone" assay. Surgery

1993;114:1019-23.

DISCUSSIONDr.John M. Moncbik (Providence, RI). 1 have had experi-

ente using intracellular fat as a means of determining normalfrom hyperfuDctioning parathyroid glands. This has proved tobe helpful in determining whether all abnormal glands havebeeu removed, which is fue topic that you have addressed byintraoperative measurement of iPTH level subsequent toremoval of abnormal parathyroid tissue in fue operating room.Some members of fue society are starting to use measurementsof iPTH level during operation to guide iuitial operations forprimary hyperparathyroidism, and slight1y more people areusing this technique in reoperative parathyroid surgery.

Dr. Charles Proye (Lille, France). How many of yourpatients with proveu primary hyperparathyroidism had base-line normal iPTH levels at fue beginning of operation?

Dr. Irvin. None. AlI of our patients had high PTH levels.Dr. Irving B. Rasen (Toronto, Ontario, Canada). Do you

not believe that fue frequency of multiglandular disease is pe-culiarly low, p~cularly in view of fue statistics that were basedon fue experience of other authors? .How long does fue PIHtake, an~ what is theexPc:Dseinvolved? 1 don't think that mostof us can really afford this kind of strategy. Last, doesn' t thisdefeat die notion of a multiglandular exploration?

monitoring of i}>TH allows quantita-.With this

for suc-

was

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.

');,1,'. ..:1 té.' ¡-

2. van Heerden lA. Grant cs. SUrgical treattnentof primary hyper-

" SurgeryVolume 120, Number 6 Molinari el al. 937

patients undergoing thyroid surgery who are eucalcemic.These glands aIl contained a normal distribution of intracel-luJar fato Therefore it certainly appears that there are enlargedglands that are not hyperfunctioning.

Dr. John P. Wei (Augusta, GA). It sounds like your opera-tive strategy is to open initially both sides of the neck and lookfor aIl four glands, find out which ones are enlarged, and thenstart measuring YfH levels. This entaiIs surgical dissection andidentification of aIl four glands.

Ifyou are doing this serially, what is fue effect ofyour sur-gical dissection, in that you mar be contusing orstunning apossible micronodular adenoma or a small gland hyperplasisthat you mar not pick up? Have you been obtaining histologicfrozen sections as you go along to ensure that you are not in-

advertently stunning a hyperplastic gland, which wiII thencome back to haunt you 6 months later?

Dr. Irvin. That is a good question. If you squeeze one ofthese glands or massage normal parathyroid glands, you canmake the YfH level rise.

We do not explore both sides of the neck. We now use a

preoperative localizátion study on aIl of these patients. With apositive sestamibi scan we go right to that area, take out thatgland, and measure the YfH level, and theoperation is overin an average time of 52 minutes. We don't look at the other

glands.

Dr. Irvin. We think that it can be done economically orcost-effectively if it shortens fue operating time, assures a highsuccess rate, and can be done in an ambulatory setting.Although not commercially available yet, fue intraoperadveassay is before fue Food and Drug Administration for approvalat this time.

Dr. George S. Leight, Jr. (Durham, NC). How many timesdid you remove a second gland that you thought was large onfue basis of your evaluation and fue iPTH level did not fall fur-ther?

Dr. Irvin. We don't remove second glands ifthe IYm levelhas already fallen with removal of a single large gland.

Dr. Bernardo Duarte (Chicago, IL). In yourpatientwith fueparathyroid cyst, did you measure IYm level in fue cyst fluid?That would have informed you whether it was functioning ornot functioning.

Dr. Irvin. We like to do that. The cysts have had IYm levelsup in fue thousands. Unfortunately, in our only operative fail-ure we ruptured fue cyst when we took it out. At that time fueplasma PTH level rose to 1100 pg/ml, and there was a delayeddrop. It did not come all fue way back clown. In bis impatiencefue surgeon did not explore fue other glands.

Dr. Monchik. I would like to address fue issue of fue corre-lation of enlarged parathyroid glands with function of fue par-athyroid gland. During the past 10 years I have identified en-larged parathyroid glands weighingbetween 70 and 110 mg in