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Primary Hyperparathyroidism in the 1990sChoice oi Surgical Procedures ior This Disease

EDWIN L. KAPLAN, M.O., TOHAU YASHIAO, M.O., and GEOAGE SALTI, B.A.

From the Department o( Surgery, The University o( Chicago,Pritzker School o( Medicine, Chicago, /IIinois

Many advances ha ve occurred in recent years in the diagnosis,localization, and treatment of primary hyperparathyroidism.Several different operative choices for primary hyperparathy-roidism also ha ve been pro po sed-a unilateral approach versusthe standard bilateral parathyroid exploration. The unilateralapproach is based on the concept that if an enlarged parathyroidgland and a normal gland are found on the first sirle of the neckthat is explored, then this is an adenoma and the second sirleshould not be explored. Gnly if both glands on the initial sirleare recognized to be abnormal is the second sirle explored. Thetheoretical advantages ofthis unilateral approach are a decreasein operative morbidity rates-hypoparathyroidism and nerve in-juries-and a decrease in operative time. Furthermore, propo-nents argüe that if persistent hyperparathyroidism occurs, thesecond sirle can be easily explored because it \\'as previouslyuntouched. In the hands of several expert parathyroid surgeons,excellent results ha ve been achieved. However, the unilateralapproach has a number of disadvantages. It places considerablepressure on the surgeon and pathologist, for they have only oneparathyroid gland other than the large one to examine. There isa significant potential risk of missing double adenomas or asym-metric hyperplasia because the second, ipsilateral parathyroidgland mar appear normal or near normal in these conditions.This could lead to an increased incidente of persistent or recurrenthyperparathyroidism. Furthermore, a significant reduction ofopera ti ve time mar be questioned, especialIy when the time forperforming special fat stains, \\'hich often are performed \\'Íthunilateral explorations, is added. FinalIy, even if the intent is toperform a unilateral exploration, a bilateral exploration \\'Í1I benecessary about half of the time. The authors strongly recom-mend a bilateral parathyroid exploration for alI patients under-going an initial parathyroid operation. In cases of adenoma, bi-lateral visualization of normal parathyroid glands and carefulbiopsy of only one of them \\'Í1I minimize hypoparathyroidism.This operative approach will lead to better results, especialIyfor the less experienced parathyroid surgeon.

S URGERY FOR PRIMARY hyperparathyroidism

(HPT) is usually one of the most gratifying of all

operations; however, at times, it can be one ofthemost frustrating. Parathyroidectomy has been practicedfor about 65 years.1 During that time, a great deal ofknowledge of the anatomy, embryology, pathology, andphysiology of this disease has been acquired. The mea-surement of circulating parathyroid hormone (PTH) byradioimmunoassay2 made the diagnosis much easier. Theuse of newer assays for parathyroid hormone (midmole-cule and immunoradiometric assays [IRMA] assaYS)3 andfor parathyroid hormone-related peptide (PTH-RP),4which is elaborated by some nonparathyroid cancers, hasmade the diagnosis of primary HPT more exact and thechance of misdiagnosis far less common. Localizationstudies of enlarged parathyroid glands have improved inrecent years,5 but problems of accuracy are still associatedwith their use. No single study in general use has beendemonstrated to be more than about 80% accurate, andeach procedure is associated with both false-positive andfalse-negative results of varying incidences.

In the Cace of these improvements, it is not surprisingthat changes in the philosophy and practice of parathy-roidectomy have been suggested. Foremost among theseis the use of unilateral neck exploration,6.7 often guidedby localization studies,8 if the surgeon thinks that an ad-enoma is present on that sirle. This report surveys thepotential strengths and weaknesses of this approach andcompares it with bilateral neck exploration. Because arandomized study comparing these surgical approacheshas not been performed, the following comments repre-sent the opinions of the authors based on their personalexperience and on a review of the literature. First of all,there is no substitute for experience. Although unilateral

Supported in part by the Nathan and Frances Goldblatt Society forCancer Research.

Address reprint requests to Edwin L. Kaplan, M.D, The UniversityofChicago Medical Center, 5841 South Maryland Avenue, Box 402,Chicago, IL 60637.

Accepted for publication August 12, 1991.

l/.l."C ,,¿ _~~4h~~Jo 300

;"(.

PRIMARY HYPERPARATI

parathyroid exploration has been practiced with greatsuccess by experts such as Professors C. A. Wang6 andSten Tibblin,7 the authors believe that the chance offailurewhen practiced by less sophisticated parathyroid surgeonsfar outweighs any potential benefit. The use of bilateralneck exploration with careful,judicious use ofparathyroidbiopsy of only one normal appearing gIand when an ad-enoma is present9 greatly decreases the chance ofmissingasymmetric hyperplasia or double adenomas, results in alow incidence of postoperative hypocalcemia, and givessuperior results, especially for the less experienced para-thyroid surgeon.

Vol.2IS-No.4

Prevalence

Primary HPT is no longer an uncommon disease. Infact, it appears to be the most common cause of hyper-calcemia in nonhospitalized patients. It occurs in about1 in every 500 women ayer 40 years of age and in about1 in every 2000 men.5

Symptoms

When first described, primary HPT was a disease ofthe bones. It soon became apparent, however, thatkidneystones were more common than severe bone disease.Gradually other symptoms and signs were added to thissyndrome, largely because of the work of Oliver Copel4and bis associates (Table 1). Later, an increased incidenceof chondrocalcinosis, pseudogout, and gout was recog-nized as well.

As medical students, we alllearned that primary HPTis associated with "painful bones, renal stones, abdominalgroans, and psychic moans." Today many other individ-uals are discovered to have this disorder beca use of therecognition of hypercalcemia on multiphasic chemicalblood screening tests. Many of these patients are thoUghtto be "asymptomatic" by their physicians. By this des-ignation, many physicians mean that they have none ofthe classical symptoms and signs that are listed in Tablel. However, a careful history often discloses subtle or evenprofound symptoms of fatigue, weakness, depression,

TABLE l. Clues lo Ihe Diagnosis o[ H}'perparalhyroidism in IheFirs1343 Cases allhe Massachusells General Hospilal

No. of CasesClue

1958027109763321

Renal stonesBone diseasePeptic ulcerFatiguePancreatitisCentral nervous system signsHypertensionMental disturbanceMultiple endocrine abnormalitiesNo symptoms (routine laboratory test)Lump in neck

Historical Perspective

In 1925, the first parathyroidectomy was performed inVienna1o on "Albert," the now famous troIley car oper-atoro Albert had developed severe bone disease, a condi-tion that was thought by many pathologists at that timeto be due to parathyroid insufficiency. Only after failureof injections of parathyroid extract and the failure of aparathyroid transplant was surgical excision considered.In 1925, a parathyroidectomy was performed by a youngsurgeon, Dr. Felix Mandl. One large gland was removed,and the operation resulted in symptomatic improvementof Albert's condition for about 6 years; then bis boneproblems recurred.JI

The first patient who was operated on in the UnitedStates for primary hyperparathyroidism was a merchantmarine captain, Charles MarteIl.12 ayer the years, CaptainMartel1 had developed a debilitating bone disease, withsevere pain, "brown tumors," fractures, and kyphoscoli-osis. He was recognized to have hypercalcemia and hy-pophosphatemia. These blood abnormalities, it was noted,were similar to changes that occurred when parathyroidextract was given to children with chronic lead poisoningto mobilize lead from their bones. They too developedhypercalcemia and low circulating phosphate levels. Thusit was postulated that MarteIl had an overactivity of theparathyroid gIands. Unaware of the successful parathy-roidectomy in Vienna, doctors at Massachusetts GeneralHospital explored bis neck in 1926.13 Unfortunately, onlynormal structures were found. Five other unsuccessfulneck operations were'performed over the foIlowing yearsuntil, in 1933, a large parathyroid gIand was found in bismediastinum. Ninety per cent of it was resected; the re-maining part was intentional1y left in place to try to pre-vent tetany. Despite this, as might be expected in a patientwith very severe bone disease, postoperative tetany oc-curred. Six weeks later, Charles MarteIl died in chronicrenal failure after an operation to remove a kidney stonethat had blocked bis ureter.

How ironic it seems that the first two patients who wereoperated on for primary hyperparathyroidism had serious Reprinted with permission from COpe.14

IYROIDISM IN THE 1990S 301

difficulties associated with their surgical therapies. Thesame problems still concem us even today. Albert appearsto have demonstrated recurrent hyperparathyroidism.Charles Martell had an ectopic parathyroid adenoma andrequired multiple neck operations with removal of most,if not all, of bis normal parathyroid glands before it wasfound in bis chest. Severe hypocalcemia, which was dif-ficult to treat, followed removal of most of this mediastinaltumor.

302 KAPLAN, Y ASHI

polyuria, polydipsia, arthralgia, or constipation.s Furthertesting often shows an accelerated course of osteoporosis.Studies from Uppsaia,IS for example, have documentedthat alterations in neurotransmitter levels comparable tothose found in endogenous depression are present in pa-tients with primary HPT. These abnormalities, they haveshown, revert to normal after successful parathyroidec-tomy. Thus, the definition of"asymptomatic" in patientswith primary parathyroidism often differs according to"the eye ofthe beholder."

._::~,¿

Diagnosis

To be successful, the clinician must dlagnose those ill-dividuals who have primary hyperparathyroidism anddistinguish them from the many others who have hyper-calcemia of other causes (Table 2). The diagnosis of pri-mary HPT is usually made by findings of elevated serumcalcium levels associated with elevated parathyroid hor-mane concentrations. .The newer assays for circulatingparathyroid hormone have made the diagnosis ofprimaryHPT much more secure. In our laboratory, an elevationof midmolecular PTH in patients with hypercalcemia hascorrelated very well with primary hyperparathyroidismThe newer, double-antibody IRMA assays3 that measureintact PTH may be even more exact, for they ~_}essinfluenced by the presence of renal failure or renal im-pairment. U~ing this new assay, it may be possible tomeasure changes in circulating PTH intraoperatively afterremoval of all abnormal parathyroid glands to assure thatthe operation has been curative. This procedure has notyet been perfected, however.

The importance of properly measured serum calciumvalues in the chemistry laboratory cannot be overempha- Indications for Parathyroidectomy

The purpose ofthe parathyroidectomy in primary HPTis to restore the patient to a normocalcemic, euparathyroidstate and to reverse the symptoms associated with thisdisease. With correction of the hyperparathyroid state,~ost but not all ofthe svmDtoms and signs ofthe diseaseare reversedI7,1~ (Table 3). ~one disease (osteitis) is uni-v~rsally benefited. Roentgenographic evidence is seen ofhealing of bone cysts; the "salt and pepper" osteolysis ofthe skull, and subperiosteal bone resorption are corrected.Patients with nephrolithiasis develop far fewer new stones.Renal function also has been shown to improve in somestudies, but not in all. Malaise, fatigue, weakness, anddepression, often classified as neuropsychiatric symptoms,improve or disappear in as many as three fourths of pa-tients. Up to half of all peptic ulcers will improve or heal.Uric acid levels decrease in many-.individuals. Nausea,polyuria, polydipsia, and constipation are frequently re-lieved. Only hypertension, seen in many patients withthis disease, is not benefited in most patients with primary

hyperparathyroidism.

T ABLE 2. Differenlial Diagnosis 01 Hypercalcemia

MalignancySalid tumors with or without bony metastasesMultiple myelomaLymphomas and leukemias

EndocrineHyperparathyroidismHyper- and hypothyroidismAddison's diseaseVIPomas, pheochromocytoma

Granulomatous diseaseSarcoidosisTuberculosis

lncreased intakeCalciumVitamin D and vitamin A intoxicationMilk a!kali syndrome

MiscellaneousBenign familial hypocalciuric hypercalcemiaPaget's disease with immobilizationThiazidesLithium

Reprinted with permission from Clark and Duh.s

RO, ANO SAL TI Ann. Surg.. April1992

sized. Sometimes hypercalcemia may be subtle, althoughsymptoms such as repeatedkidney stones may be severe.The better laboratories usualIy have upper levels of serumcalcium concentrations of 10.3 mg/dL or less. In mostsuch laboratories, the diagnosis of normocalcemic hyper-parathyroidism is very uncommon. In cases of hypopro-teinemia, an elevation of ionized calcium levels may bediagnostic of primary HPT in the Cace of normal totalcalcium levels.

Serum phosphate levels are low in about 80% of cases.Alkaline phosphatase values are not often elevated, onlywhen severe boDe disease is presento In virtually alI casesof primary HPT, the urinary calcium output is 200 mg/day or greater when the patient eatsa standard diet. Valueslower than these are suggestive of familial hyPocalciurichypercalcemia,16 a condition that should not be treated

surgicalIy.A list of the differential diagnoses of h)rpercalcemia is

shown in Table 2. A detailed discussion of each diseasestate is beyond the scope of this paper. It should be ob-served, however, that although metastatic boDe disease isthe most common cause ofhypercalcemia in hospitalizedpatients, primary HPT is the most common cause of hy-percalc~;ia am~ng outpatients5 and is the second most~ommon cause in the ho-spital setting. An uncommon butdifficult problem in the past has been the fact that so metumors elaborate a PTH-like peptide that is thought tobe the cause ofhypercalcemia. A recently discovered pep-tide, PTH-RP,4 can be measured in the blood of manysuch patients and can be used to differentiate them fromothers with primary HPT; thus inappropriate parathy-roidectomy can be avoided.

Vol.2IS.No.4 PRIMARY HYPERPARATHYROIDI5M IN THE 19905 303T ABLE 3. Respon.l'e vi S)'I/IPIVI/IS and Signs lO Paralh)'rvid Surger)' al 5- Year Follow-up

Preoperative Prevalence (%) Long-term Improvement (%)

Ronni-Sivulaand Sivula(n = 289)

Laft'erty andHubay

(n = 100)

Ronni-Sivulaand Sivula(n = 289)

Laftel1y andHubay

(n = 68)Symptoms and Signs

42

3461t143

311435

63

18211516481549

10010090726325

343

O

10010092717045

OstcitisPancreatitisRenal calculiNeuropsychiatric*ConstipationPeptic ulcerHypertensionImpaired renal functionAsymptomatic

oo

15%.Adapted from Lafferty and Hubay.18

.Includes fatigue, lethargy, malaise, wc:akness, depression, headache,irritability, and confusion.

t Combinl:s malaise, fatigue, and wl:akness in 46% plus depression in

Because ofthe success ofparathyroidectomy, most cli-nicians believe that if a patient is symptomatic and is nota prohibitive medical risk, a parathyroidectomy shouldbe performed. So me differences of opinion exist aboutthe value of parathyroidectomy for patients who areasymptomatic. Scholz and Purnell19 at the Mayo Clinicdemonstrated, for example, that about half ofthe asymp-tomatic patients with clear hyperparathyroidism whocould be successfully followed for 10 years developed someproblem associated with their disease. They recommendedparathyroidectomy in such patients because follow-up wasdifficult and the operation was very successful at theirinstitution. Other studies have demonstrated the value ofparathyroidectomy in patients with primary hyperpara-thyroidism and asymptomatic osteoporosis, as measuredby bone densitometry.20 Not all investigators agree, how-ever.18 Thus, the value of parathyroidectomy in trulyasymptomatic patients is still being debated. AII agree,however, that the most important prerequisite for successis an experienced parathyroid surgeon.

Pitfalls for the Surgeon

Difficulties associated with parathyroidectomy for pri-mary HPT relate to the variability in the number of para-thyroid glands, the different locations of normal andpathologic glands, and problems distinguishing normalglands from others that are subtly diseased. To be suc-cessful, a parathyroid surgeon must ha ve an excellentknowledge ofthe anatomy, embryology, and pathophys-iology of the parathyroid glands.

very rarely. Other anatomists and surgeons have foundmore than six glands to be present in some cases. Thisvariability creates difficulties for the surgeon in severalsituations. First of all, four normal glands may be presentin the neck, whereas a fifth, a supernumerary gland, whichis adenomatous, may be present in the mediastinum. Thissituation occurred in 5 of 14 mediastinal parathyroid ad-enomas that were reported from the Mayo Clinic priorto 1970,22 for example.

A second example in which the number of glands playsan important role is in primary parathyroid hyperplasia.Particularly in the multiple endocrine neoplasia type 1(MEN-l) or other familial syndromes, recurrent hyper-parathyroidism occurs frequently, even after subtotal re-section of parathyroid glands in the neck?3.24 A thymec-tomy must be included as part of the standard parathy-roidectomy for this condition to remove other parathyroidglands that might be present in this tissue.

Location o/ Parathyroid Glands

Embryology. The upper parathyroid glands arise em-bryologically from the dorsal part ofthe fourth branchialpouches, along with the laterallobes of the thyroid, theultimobranchial bodies21.25 (Fig. 1). They descend onlyslightly during embryologic life along with the thyroidand continue to remain in close association with the upperportion of the lateral thyroid lobes. Because of their rel-atively circumscribed migration, their position in adultlife remains quite constant.

The lower parathyroids arise from the dorsal part ofthe third branchial pouches along with the thymus andthey descend with the thymus. Because they travel so farin embryologic life, they ha ve a very wide range of dis-tribution in the adulto They may be found all the wayfrom just beneath the mandible anterior to the carotidartery bifurcation, to the pericardium (Fig. 2). When the

Number 01 Parathyroid Glands

Gilmour,21 in an extensive autopsy study, found thatroughly 80% of individuals had four glands, 6% had five,and 13% had three. Two glands or six glands were present

KAPLAN, YASHIRO, AND SALTI Ann. Surg. .April 1992

lI.porom,/

304Lt. Rt. poro m ~ poro' Rt.porOt. , J,2:

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LQt. thyrl

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A

remaining individuals, the lower parathyroid gland isfound within the tongue of the thymus (called the thy-rothymic ligament). The tongue of the thymus usuallycan be identified just below the lower pole of the thyroidgland on each sirle, adjacent to the inferior thyroid veins.Less frequently, normal inferior parathyroids can be 10-cated in the superior mediastinum within the thymus.Finally, rarely they are found high in the neck, the so-called undescended parathyroid glands.

Gilmour21 found that the parathyroids occasionally areincluded within the thyroid capsule or líe beneath it.

n~"' /' ,

~ -tiB""t~~"::::"( r

":,::" ,-"" .-,..

I

~II

fVI,,

~'\~I

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* LDt.thyroid-olso colledA ultimobronchiol body

'l ,11" Ó"I( l""',n..,I,K,s

c

FIG. l. (A and B) Schematic representation ofthe embryologic shifts inlocationsofthe thyroid, parafollicular, and parathyroid tissues. (C) Ap-proximate adult position. Reprinted with permission from Sedgwick andCady.2S

Upperl5araThyroid(Stationary)I

LowerPOrathyroid(Migratory)

~.,

¡

lower parathyroid gland descends into the mediastinum,it is almost always anterior to the recurrent laryngealnerve.

Location o/ Nonnal Glands. The average weight of anormal parathyroid gland is 35 to 50 mg. So me may beslightly heavier. They can be thought of as being abouthalf the size of one's little fingernail; thus they are smalland they can be difficult to identify. Normal giands areusually yellowish-brown and sometimes look like fat, par-ticularly to the inexperienced eye. They are also difficultto find because of their various possible locations.

In most cases, the normal upper giand may be foundon the posterior portion ofthe middle third ofthe thyroid,usually toward the superior part ofthis afea, either undera delicate fascia on the thyroid lobe or on a projectingnodule21.26 (Fig. 3A, B). It usually is found cephalad tothe inferior thyroid artery and close to the recurrent la-ryngeal nerve as it enters the larynx.

The normal inferior parathyroid glands are morevariable21 (Fig. 3A, B). In somewhat more than 50% ofcases, the lower parathyroid is found on the lateral orposterior surface of the lower pole of the thyroid giand,or not more than 0.5 cm below the lower poleo The nextmost common location, in 12.8% of the cases, is within1 cm below the lower pole of the thyroid. In most of the

I

Some poss ible ~ /"--locations for the ~lower parathyroid \ I

gland \ 6

FIG. 2. Descent ofthe lower parathyroid. The upper parathyroid occupiesa relatively constant position in relation to the middle or upper third ofthe lateral thyroid lobe, but the lower parathyroid norrnally migrates inembryonic life and may end up anywhere along the course ofthe dottedline. When this gland is in the chest, it is nearly always in the anteriormediastinum. Reprinted with permission from Kaplan!6

Vol.2IS.No.4 PRIMARY HYPERPARATHYROIDISM IN THE 1990S 305

UPPER PARATHYROID:N:

LOWER PARATHYROIDJII

~V~/

11;::>

' ,:~~:2%/7%J

"J

FIG. 3. (Left) Most frequent locations for the normal parathyroid (anteriorview). The locations for the upper parathyroid are shown at the left andfor the lower at the right The relative frequency with which the glandsare found in the various locations is indicated on the diagram. (Below)Most frequent locations for normal parathyroid glands (lateral view).Reprinted with permission from Gilmour!l

Cm BELOWLOWER POLE

-No! oye, 0.5 cm--1 cm

--2cm

---3cm

4cm

(-Thymus:DI:

I O. Isololed instonces II v t~i~ii~9 i~¡ I

000

306 KAPLAN, YASHIRO, AND SAL TI

Sometimes, a parathyroid is completely covered by thethyroid. These intrathyroidallesions usually involve theinferior patathyroid glands. Normal lower parathyroidglands are usually anterior to the recurrent laryngealnerves, whereas the upper parathyroid glands are usuallysituated more posteriorly.

Abnormal Parathyroid Glands. When parathyroidglands enlarge and become adenomatous or hyperplastic,their position can change.27 Large upper parathyroidglands frequently fall back, posterior to the recurrent la-ryngeal nerve and under the inferior thyroid artery, andare found along the esophagus down into the posterior-superior mediastinum. Lower parathyroid glands are dis-placed into the anterior-superior mediastinum, eitherseparately or along with the thymus gland. Usually theyremain anterior to the recurrent laryngeal nerves.

Although 80% to 85% of parathyroid adenomas arefound adjacent to the thyroid gland in their normal 10-cations, 15% to 20% are ectopically placed. Ectopic glandscan be found in the anterior-superior mediastinum, eitherwithin or outside ofthe thymus, along the esophagus intothe posterior-superior mediastinum, or very rarely in themiddle mediastinum.28 Uncommonly they can be foundwithin the carotid sheath or even lateral to the carotidsheath?9 Rarely, an "undescended" lower parathyroidgland is found high up in the neck, anterior to the carotidartery bifurcation. Finally, 3% to 5% of all parathyroidadenomas are intrathyroidal, usually within the lower paJeof the thyroid gland. Fortunately, most of these can befelt or recognized as a mass within the thyroid lobe, butin other instances they are found only after thyroid ex-cision or thyroidotomy. Locating and removing ectopicparathyroid glands during the initial neck operation re-mains one ofthe majar pitfalls to successful parathyroidsurgery.

Ann. Sur¡. .April J 992

Pathology o/ Primary Hyperparathyroidism

One of the most difficult aspects for the surgeon is therecognition of the pathologic process that is present, forappropriate treatment is dependent on this. Primary hy-perparathyroidism may be due to a parathyroid adenoma,to hyperplasia of the parathyroid glands, or rarely to aparathyroid carcinoma. The symptoms ofthe disease aresimilar regardless of the actual cause.

Originally in the treatment ofhyperparathyroidism, allpatients were believed to have either single or multipleadenomas or water clear hyperplasia, the latter being acondition rarely if ever diagnosed today. Primary chiefcell hyperplasia was not recognized as an entity until Copeand co-workers described it in 1958.30 Hence, studies thatinclude data from before this time are misleading, formultiple enlarged glands were usually called multiple ad-enomas instead of hyperplasia.

In the late 1960s and early 1970s, the difficulties ofdiagnosing mild chief cell hyperplasia pathologically be-carne evident. As shown in Table 4, the prevalence ofchief cell hyperplasia varied considerably in series fromdifferent institutions, from 3% to 65%. It was finalIy con-cluded that the pathologists were being greatly intluencedby the operation that was performed.31 When subtotalparathyroidectomy was performed routinely, more hy-perplasia was diagnosed. When a more conservative op-eration was performed with removal of a single gland, itwas most likely called an adenoma. The importance ofmild hyperplasia and the best way of diagnosing ibis con-dition are questions that still are being debated.32

T oday, however, it is generally agreed that primary HPTis caused by a single adenoma in 80% to 85% of cases andthat chief cell hyperplasia is found in 15% to 20% of cases.In the MEN- 1, MEN-2A and the familial hyperparathy-

T ABLE 4. Re/atil'e Frequency o/ ParathJ'I"oid Adenoma, Hyperp/asia, and Carcinoma in Reported Series

PrimaryHyperplasia

(%)No. ofPatients

Adenoma

(%)Carcinoma

(%)Author and Year

96969390909082848281806057515033

33679

1011141419204043495065

1113

<1

I

4

Goldman et al., 1971Krementz et al., 1971Hoehn et al., 1969Davies, 1974Palmer et al., 1975Myers, 1974Werner et al., 1974Wang, 1976Romanus et al., 1973Block et al., 1974Bruining, 1971Haffand Armstrong, 1974Esselstyn et al., 1974Haffand Balinger, 1971Paloyan et al., 1973

Reprinted with permission.26

Vol. 215. No. 4 PRIMARY HYPERPARATHYROIDI5M IN THE 19905 307SINGLE GLAND ENLARGEMENT

IN 433 PATIENTS

111 109 112 101

DOUBLE TUMORS IN 106 PATIENTS

B C O EA F

8 32 12 28 9 17

TRIPLE TUMORS IN 43 PATIENTS

G H I J

6 9 8 20

AG. 4. Location of parathyroid turnors in a series of 582 patients. Re-printed with perrnission frorn Bruining}7

ficult, most surgeons believe that they play the major roleas diagnostician as well as therapist. Obviously, the moregiands the surgeon can see and evaluate, the more reliablewill be the diagnosis and, hence, the treatment.

roidism syndromes, hyperplasia is the rule. Parathyroidcancer is found in less than 1% of cases in many series,including the authors' experience,26 but makes up 3% to5% of others. Perhaps it is being overdiagnosed in someinstitutions.

Classically, an adenoma has been defined pathologicallyas an enlarged gland with a rim ofnormal tissue. However,Roth33 and other pathologists state that this histologic ap-pearance can be found in cases ofhyperplasia as well, andthat it is nol possible lO tell the difference between hyper-plasta and adenomafi.om looking at only one gland; otherglands must be examined.

The greatest differences of opinion relate to what con-stitutes mild hyperplasia and whether or not mildly hy-perplastic glands are of physiologic importance.32 Somepathologists consider normal-sized or mildly enlargedglands to be hyperplastic if they do not contain enoughextracellular fato Others do not feel that such glands arenecessarily abnormal, and consider the amount ofinlracellular fat to be the most important criterion in thisdifferentiation.34 Some pathologists use fat stains or os-mium stains at the time of frozen section to evaluate in-tracytoplasmic fat in normal-appearing or mildly enlargedglands. However, the validity of these techniques has notbeen accepted by all pathologists, and they present sometechnical complexities as well. Many pathologists andsurgeons believe that the differentiation of a mildly hy-perplasic from a normal gland by frozen section exami-nation is very difficult.

The major problem for the surgeon at the time of op-eration is to differentiate an adenoma from chief cell hy-perplasia, or single gland disease from multiglandular dis-ease of the parathyroids. In general, most experiencedsurgeons think that by evaluating the size, shape, and colorofthe parathyroid glands at operation, they can distinguishnormal glands from abnormal ones. If one gland is en-larged and the others are perfectly normal visually andby biopsy with frozen section, this is an adenoma. If allglands are enlarged this is hyperplasia (or multiglandular

disease).A significant difficulty at the time of operation is that

the glands of parathyroid hyperplasia may be asymmetric;not all of the glands exhibit the same degree of enlarge-mento Some, in fact, may appear normal or near normal.Bruining27 has demonstrated that two and three glandenlargements were present in a number of bis cases (Fig.4) Each ofthese patients had one or more normal or nearnormal appearing glands. Most authors agree that doubleadenomas24.35 occur in 5% or fewer cases; however, othersbelieve that this represents a form of multiglandular dis-ease. Thus, beca use the microscopic differentiation of anadenoma from hyperplasia is difficult when examiningone enlarged gland and because frozen section differen-tiation of mild hyperplasia from normal is also very dif-

Localization Procedures

Clark and Duh5 have written an excellent summary ofthe advances that have been made in the preoperativelocalization of parathyroid tumors. With experienced ra-diologists and modero equipment, about 75% to 80% ofall parathyroid tumors can be localized using either ul-trasonography, thallium-technetium scanning, magneticresonance imaging (MRI) or computed tomography (CT).In the best studies, using multiple techniques, as many as80% to 90% ofsingle parathyroid tumors have been iden-tified.

In every series, however, both false-positive and false-negative results have been obtained. The tests are bestwhen a single parathyroid gland enlargement is present,when the tumor is larger than 1 g in weight, and whenno thyroid nodules are presento Only 20% of multiplegland enlargements are correctly identified. Thus, local-ization studies of patients with hyperplasia can be verymisleading. Other problems relate to the small size ofmany parathyroid tumors, their position deep in the neckor chest, and the fact that thyroid nodules are frequently

308 KAPLAN, YASHIRO, ANO SALTI

present, especially in elderly female patients, the very in-dividuals who have the highest prevalence ofprimary hy-perparathyroidism.

Ultrasonography is very operator dependent. Althoughexperts may localize 80% or more correctly, others withless experience correctly localize far less than half.8 Thistechnique is good only in the neck, and is best when a10-mHz real-time, small parts scanner is used. It usuallycannot identify smalllesions, especially those deep in theneck or behind the esophagus. It cannot be used for lesionsunder the sternum. In some centers, needle aspiration ofthe suspected tumor is performed under ultrasound guid-ance. Cytologic examination and parathyroid hormonemeasurement of the aspirate may add to the certainty ofthe findings. The appearance of an intrathyroidal para-thyroid on ultrasonography is shown in Figure 5.

Thallium-technetium scanning, although done in manyhospital s, is very difficult to do well. Thallium (2oITI) istaken up by both the thyroid and by enlarged parathyroidgIands, whereas technetium (99mTc) pertechnetate is taken

Ann. Sur¡.. April 1992

up only by the thyroid. Images with each isotope are ob-tained and then the technetium scan is subtracted fromthe thallium scan by computer analysis. What remains isthe image ofthe enlarged parathyroid gland.

Potential problems with this technique create false-positive results in 10% to 20% of the cases. The patientmust not move; for this reason we use a harness. Thyroidnadules interfere with the subtraction procedure. We havefound, however, that this scan, when done well, is excellentfor imaging ectopic parathyroid glands, those a»'ay fromthe thyroid gland (Figs. 6 and 7).

Although we have used CT examinations less fre-quently, these can be ofvalue especially for mediastinal,substernal tumors (Figs. 7 and 8). Magnetic resonanceimaging examinations do not require contrast material,and parathyroid tumors are usually bright on T2-weightedimaging (Fig. 9). In OUt experience, small tumor size,movement ofthe carotid arteries, and technical difficultiesassociated with the lower neck and upper chest make MRIexamination less rewarding.

Venous catheterization with blood sampling for para-thyroid hormone has largely been replaced by the othermodalities; however, it still plays a role in lateralizing thesirle of the disease in very difficult cases. Arteriography israrely done in out experience because ofthe potential forsevere complications. Finally, we have not found toluidineblue or methylene blue used intraoperatively to be ofvalue.

To Localize or Not To Localize

There is no question that localization studies shouldbe used before all reoperative parathyroidectomies, orwhen one is contemplating parathyroidectomy in a patientwho has had extensive thyroid surgery in the past (Fig.10). This latter situation is not uncommon, because low-dose radiation to the neck is known to be followed by anincreased incidence of both thyroid cancer and primaryHPT .36,37 The mean latency period for development ofthe hyperparathyroidism is longer than for thyroid cancer,so that a number of individuals who have had total ornear-total thyroidectomy may later need a parathyroid-ectomy. Correct localization ofthe enlarged parathyroidgland before reoperative parathyroidectomy, as reportedby Levin and Clark,38 was between 45% and 68% for thevarious tests. Combinations of tests were better. Thus,although not perfect, localization studies greatly aid thesurgeon and are mandatory before reoperative surgery.

When operating in the "virgin neck," most surgeonsagree that there is no need to do-.localization studies.Common localization studies are about 75% to 80% ac-curate when done well. Because virtually all expert para-thyroid surgeons cure 95% or more of such patients al-though they have not had localization studies, one could

FIG. 5. Intrathyroidal parathyroid adenoma. (Top) Visualized preoper-atively within the right thyroid robe by sonography. The parathyroidadenoma (arrow) appears hypoechoic re!ative to the surrounding thyroidtissue. Courtesy ofDr. David Yousefzadeh. (Bottom) Gross appearanceof a different intrathyroidal parathyroid adenoma. T, thyroid; P, para-thyroid adenoma.

Vol.2IS-No.4 PRIMARY HYPERPARATHYROIDISM IN THE 1990S 309

FIG. 6. Localization of ectopic parathyroid adenomas by thallium-technetium scanning. (Top) Adenoma ofthe left neck lateral to the carotid sheath(arrow), anterior (left) and lateral (right) views ofthe neck. Reprinted with permission from Udekwu et al.29 (Bottom left) Undescended right lowerparathyroid adenoma (arrow) located at the carotid bifurcation. The thyroid gland is seen clearly inferior to the adenoma. (Bottom right) Intrathymicparathyroid adenoma (arrow), seen inferior to the thyroid gland and superior to the heart. Courtesy of Drs. James Ryan, William Martin, andMalcolm Coopero

argue that the best localization procedure is to find anexcellent parathyroid surgeon. Furthermore, it has notbeen demonstrated uniformly that localization tests savetime intraoperatively. Finally, the cost of both an ultra-sound and a thallium-technetium scan at our institutionis nearly $1100.00. On the other hand, by doing ultra-sound preoperatively, a small number of intrathyroidalparathyroid adenomas may be localized, whereas a thal-

lium-technetium scan may recognize the occasional "ec-topic" gland. We use these studies especially in cases ofhyperparathyroid crisis, for example. Thus, although notcasi effective, preoperative localization tests may help asmall number of patients.

There is a potential down-side, however, to the routineuse of preoperative localization testing in patients whohave not previously had surgery. Apparent localization of

KAPlAN. YASHIRO, AND SALTI Ann. Sur¡.. April 1992310

FIG. 7. Mediastinal parathyroid adenoma found in the thymus gland a1the level of the root of the pulmonary artery. (left) localization bythallium scintigraphy (arrow). (Right) Visualization of parathyroid ad-enoma (arrow) by computed tomography.

one enlarged gland may serve as an invitation for the in-experienced surgeon to venture into the neck to removethat gland. perhaps not realizing that hyperplasia may be

presento Remember that multiglandular disease is missedby 10calization studies in 80% of cases.38 The first explo-ration is the best time to cure the hyperparathyroid state;the second parathyroidectomy is always much more dif-ficult and less successful than the first.

Strategy of the Initial Parathyroid Exploration

The role of the surgeon in the first parathyroid explo-ration is to remove the offending gland or glands and thuscure the disease, or to assure himself or herself that noabnormal parathyroid tissue remains in the neck or inany ectopic 10cation that might be reached by this expo-sure at the conclusion of a negative exploration.

Sllbtotal Parathyroidectomy

In the early 1970s, the incidence of parathyroid hyper-plasia was found to be very high in a number of series.26Paloyan and Pickleman39 proposed that correction ofthiscondition required sllbtotal parathyroidectomy for all pa-tients ifpersistent and recurrent hyper:Parathyroidism wereto be prevented. Although this operation could be per-formed with very low morbidity rate by many of its pro-ponents, in the hands of other surgeons, perhaps thoseless experienced, it resulted in a higher incidence ofpost-

FlG. 8. Cyslic mediaSlinal paralhyroid adenoma (arrow) causing Irachealcompression as seen by compuled lomography.

PRIMARY HYPERPARATHYROIDlSM IN THE 1990S 311Vol.2ISoNo.4

lalion of parathyroid tissue at the time of the initial op-eration,41 have greatly diminished this problem. Perhapsas a reaction to the proposal that all patients require sub-total parathyroidectomy, however, other operations wereproposed or reexamined.

AG. 9. Left cervical paralhyroid adenoma (arrow) 10caled by magneticresonance imaging. This lesion is bright on T2-weighted imaging.

Unilateral Neck Explorationfor Adenoma

Unilateral neck exploration is now practiced in 17% ofthe major parathyroid centers around the world, butmostly in Scandinavia and other European centers.42Wang6 and Tibblin et al.7 have long advocated that onlyone side of the neck be explored when an adenoma anda normal giand are found on the same side. These surgeonshave considerable experience, and in their hands, the re-sults of operation are excellent. They contend that theunilateral approach reduces operating time and hence,patient costs. Furthermore, they relieve tha~ the morbidityrate (recurrent laryngeal nerve injuries and postoperativehypoparathyroidism) is lessened, and the results ofpara-thyroidectomy are just as good as with bilateral explora-tion. Reoperation~ they believe, is not a problem, becausethe second side was untouched.

Wang43 recently presented data that demonstrated thathe performed a unilateral exploration in 70% of800 first-time parathyroid explorations for adenoma. In these op-erations, he had a 4% failure rateo In 30% of the time

operative hypoparathyroidism, The subsequent use ofcryopresen'ation of parathyroid tissue with the possibilityof later reimplantation,40 and the use of alltotran.'iplan-

TI-20 1 Tc-99mf)G]O Th,]]i'm",h",i"m~,""r"4"y""o'd m",.ho",d,~'m'ow-do~rodi,'iM,h",py",'o"i']i'i"',ohi]dA'",35h,w,,",'d

wh",p,pi]',ry'hyro,do,",,"'d",d,~om"'ru'i,o'm"'hyroid"'omyrOllowoóhy"dioiodi"'h,ropyFi',y""'",,prim,ryhyp"p'n'h'roidi,mw"di",o~dO,"'h"o'i,m~,",i,,'ri,h']'o"p"',i'~""i"iryi"'ho""'O,or,'hyroid",,dO"h,lIi,mim'gJ',O,ft, 'h,p""hyroid ,d"om,i,",""",d 00 ,h, ,,",ido ,",h,'noh" ',primedwi'hp',mi.iM from K,dow,'ict""

312 KAPLAN, YASHIRO, ANO SAL TI

when an adenoma was present, (262 of 800 cases), heperformed a bilateral operation, either because he exploredthe wrong sirle first, beca use the second giand on the ip-silateral sirle could not be identified, or because the ade-noma was in an ectopic position. Six per cent of these262 patients had persistent hyperparathyroidism, largelydue to ectopic parathyroid adenomas in the mediastinum.This is clearly a superb series. If one adds the patientswho had hyperplasia to the 30% who required explorationof both sides for adenoma, however, it should be notedthat, in as many as 50% of all cases of primary HPT,Professor Wang performs a bilateral neck exploration.

Potential problems exist with unilateral neck explora-tions. These include failure lO recognize hyperplasia. Asshown in Figure 4,.hyperplasia often mar be asymmetric.The second giand might look very normal to the surgeon,especially to an inexperienced surgeon. The surgeon hasonly one giand other iban the large one to evaluate andthus could easily misinterpret it. Wang propases the useof a "gradient solution" in which a normal giand fIoatsand a hyperplastic giand sinks. Tibblin et al.42 emphasizethe use offat stains during frozen section. There also marbe a failure to recognize double adenomas, a setting inwhich the two other giands are perfectly normal. Theseoccur in 2% to 5% of cases in some series24.3S and in 9%of patients ayer 65 years of age in the Michigan series.3SBoth hyperplasia and cases of double adenoma are mucheasier to diagnose, opponents argue, if both sides are ex-amined. It has been estimated that exploration ofthe sec-ond side adds only 12 to 20 minutes of operating time.Finally, the practice of using localization studies to de-termine the sirle of the enlarged gland followed by uni-lateral exploration on ibis basis8 mar lead to increasednumbers of patients with persistent or recurrent hyper-parathyroidism, for localization tests only recognize 20%of the cases of hyperplasia.s

Thus, there are potential dangers for those who use ibistechnique, especially for the inexperienced surgeon. Wetell our residents that when they are as experienced asProfessors Wang and Tibblin, they mar use a unilateralapproach. Until then, they and we should look at bothsides ofthe neck.

Ann. Sur¡. .Aprill992

Bilateral Operations

In a recent survey, 83% of major centers performingparathyroidectomies for primary HPT reported that theyuse a bilateral neck exploration.42 This, they believe, per-mits a better assessment of the pathologic process that ispresento

erative field should be kept as blood free as possible. Atthe University ofChicago Medical Center, a bilateral op-eration has beeri the roleo If one gland is enlarged and theothers are normal, this is an adenoma. In the last 10 years,our operative approach for adenoma has changed. In thelate 1970s, our aim was to search for all normal glandswhen an adenoma was present and to carefully performbiopsies on each of them. This technique was modifiedin the early 1980s, when we demonstrated that a lesserdegree of transient postoperative hypocalcemia occurredwhen all normal glands were visualized butwhen biopsieswere done on only one or two ofthem.9 We continue tobe very pleased with this "middle ground approach,"which was favored by two thirds ofNorth American para-thyroid centers in a recent survey.42 In recent years wehave performed biopsies on fewer normal glands.

If four glands are found to be enlarged, this is hyper-plasia. In such cases, at least a subtotal parathyroidectomyis necessary. Three glands and part ofthe fourth are ex-cised, leaving a welI-vascularized remnant of about 50 mgtissue. Each thymic tongue also should be excised rou-tinely as part of this procedure, to be certain that super-numerary parathyroid glands are not presento The partialresection ofthe parathyroid gland that is to be left alwaysshould be performed first, so that one can see that theremnant remains welI vascularized before removing theother three glands. In cases offamilial hyperparalhyroid-ism or lhe MEN-J syndrome, one should strongly considerdoing a total parathyroidectomy with an autotransplantofparathyroid tissue to the arm, as recommended by Wellset al.44 This technique is advantageous because it is kI'lownthat recurrent hyperparathyroidism occurs with some fre-quency, especially in patients with these familial, genet-icalIy induced syndromes.23,24 If graft-dependent hyper-parathyroidism recurs in the arm, this afea can be exploredunder local anesthesia without the risk of a recurrent nerveinjury, as would occur ifthe neck were re-explored. Wellset al.44 recommend this approach for alI cases of hyper-plasia, familial and otherwise.

So-called double adenomas occur in a nonfamilial set-ting when two glands are enlarged and two others appearperfectly normal, grossly and histologically. This multi-glandular disease is curable by removal of both enlargedparathyroid glands and biopsy of the two normal ones.

Searchfor EClopic Paralhyroid Glands

If an adenoma cannot be found in the usuallocationsat exploration, each normal parathyroid gland should beexplored by biopsy and marked, and after positive iden-tification as parathyroid tissue on frozen section, a dia-gram should be made of its location for later reference.Do nol remove normal parathyroid glands; this compli-cates the situation when the adenoma is ultimately found.If three normal parathyroid glands are found and the

Initial Neck Exploration- The Authors' Approach

AII surgeons agree that a parathyroidectorny should beperformed in an unhurried, careful, delicate way. The op-

PRIMARY HYPERPARATHYROIDI5M IN THE 19905 313Vol.2IS.No.4

tissue has been removed. This probably occurs when anadenoma is infarcted by accidentalligation of its arterialsupply. Finally, it is well known that in almost all casesofpersistent hyperparathyroidism, the offending gland orglands can later be removed through a neck incision, par-ticularly ifthe first surgeon is not very experienced in thisafea. This approach is clearly illustrated in the Mayo Clinicseries22 in which, until 1970, 1000 parathyroid explora-tions were performed and only 12 required a sternotomy,an incidence of 1.2%. At the Massachusetts General Hos-pital,45 21 % of cases of primary hyperparathyroidism in-volved ectopically placed parathyroid adenomas. Almostall of these, however, could be removed through a neckincision. Thus, do nol fusIl lo do a slernolomy as part ofthe first operation.

Reoperation for Persistent or RecurrentHyperparathyroidism

Before reoperating, a number of factors that should beconsidered46:

l. Be certain that the patient has primary hyperparathy-roidism and not some other hypercalcemic state.

2. Be certain that the severity of the hyperparathyroidstate warrants the risk of reoperative surgery.

3. Be certain that the patient does not have familial hy-pocalciuric hypercalcemia. If so, do not reoperate. Suchpatients are cured ofhypercalcemia only by total para-thyroidectomy and they usually have few complica-tions of their disease state.

4. CarefulIy read the previous operative note and pa-thology report and understand how many normal orabnormal parathyroid glands on each side were iden-tified histologicalIy and how many of them were re-moved. Review the pathologic slides if at alI possible.Is ibis a case of a missing adenoma, incompletelytreated hyperplasia, or even a recurrence of a carci-noma?

5. Use localization studies extensively.

Strategy and Technique

Reoperations of the neck are more difficult because ofthe scarring, changes in anatomy, and loss oftissue planesthat occur as a result of the first exploration, whether itwas for a thyroid or a parathyroid disorder.46-48.54 Fre-quently, for example, the strap muscles will be denselyadherent to the anterior surface ofthe thyroid lobes, mak-ing entry into the usual anatomic planes more difficult.Furthermore, the recurrent laryngeal nerve is in greaterjeopardy beca use it mar be encased in scar tissue, butespecially beca use it might líe immediately beneath thestrap muscles ifthe thyroid lobe was previously removed.Always evaluate vocal cord function preoperatively insuch cases. Finally, because one's knowledge ofhow many

fourth cannot be located, the surgeon should assesswhether an upper or a lower parathyroid giand on thatsirle is missing.

Very frequently, it is an adenoma of the upper para-thyroid giand that is overlooked. This mar be found pos-terior to the esophagus, or it often falls clown along theesophagus joto the posterior-superior mediastinum. Themistake in this situation is that the dissection was notcarried out deeply enough, back to the prevertebral fasciaof the neck. When this is done near the upper pole of thethyroid, a finger can be inserted safely behind the inferiorthyroid artery and posterior to the recurrent laryngealnerve. In many instances, an adenoma is palpable besideor behind the esophagus, and this giand can be pulled upand easily removed.

If the missing giand is the lower parathyroid giand, asmuch ofthe thymus as possible should be pulled up jotothe neck and resected, because the inferior adenoma oftenis found within the thymus. If the adenoma still cannotbe found, the dissection should be carried up in a cephaladdirection to the hyoid bone, where occasionally an "un-descended" lower parathyroid adenoma is found anteriorto the carotid artery bifurcation. Ifthis is still nonreward-ing, the carotid sheath should be opened from the levelof the clavicle upward. Occasionally, a parathyroid ade-noma will be found, which cannot be palpated, becauseit is flattened out like a pan cake. The area of the necklateral to the jugular vein also should be explored, for wehave identified two patients who had a parathyroid ade-noma in this unusuallocation.29 Finally, the thyroid lobeon the sirle of the missing gland should be carefully pal-pated. Any lump within the thyroid should be excised,for this might represent an intrathyroidal parathyroid ad-enoma. Even if no lump is present, a "blind" subtotalresection of the thyroid lobe on the sirle of the missinggiand should be performed. Sometimes a non palpableparathyroid adenoma will emerge. Others use a thyroi-dotomy and incise the lower pole of the thyroid ratherthan resecting it.

Rem.ember that even if four normal glands are foundin the neck, the surgeon should search all ofthese ectopicsites for a fifth giand that is adenomatous. Similarly, iffour hyperplastic giands are found, these same sites shouldbe explored beca use supemumerary glands mar bepresento

Only rarely should a stemotomy and formal medias-tinal dissection be done as part of the first exploration.This procedure is probably indicated only if the patientis extremely ill from hypercalcemia that cannot be ade-quately managed medically. The reasons for this approachare several. First ofall, rarely the diagnosis ofhyperpara-thyroidism might be in error. Second, occasionally hy-percalcemia regresses or is eliminated by the first neckexploration, despite the fact that no abnormal parathyroid

314 KAPLAN, YASHIRO, ANO SAL TI

viable parathyroid glands remain in the neck after thefirst exploration is often limited, the chance of creatingpermanent hypoparathyroidism after removal of one ormore abnormal parathyroid gIands found at re-explora-tion is increased.

Usually there is not a rush to reoperate, and it is betterto allow some time to pass to permit the wound to heal,to re-evaluate the diagnosis, to perform localization test-ing, and to assess the findings of the previous operation.The location ofparathyroid adenomas that were removedby Wang48 at reoperation are shown in Figure 11.

When reoperating, we almost always explore the neckagain first, unless an adenoma is localized to the medias-tinum or to another ectopic site preoperatively. When anexperienced parathyroid surgeon did the initial operationand was "certain" that the lesion was not in the neck, itis much more likely to be found in an unusuallocation.

The prior transverse neck incision is used and subpla-tysmal flaps are elevated. The strap muscles are often ad-herent to the thyroid lobes; hence, instead of separatingthem in the midline, it is often easier to use a "lateralapproach, as described by Fiend,"26 and to dissect thevertical plane between the sternocleidomastoid muscleand the strap muscles (Fig. 12). Not infrequently, this

Ann. Sur¡.. April1992

l& rI (r/' Strap muscle midline

Sternomastoid m.bei(1g freed up

"/

~/, //""",,~'--f~---=~--

Une of skin incision

AG. 12. During reoperative parathyroid operations, the strap musclesare often fixed to the surface of the thyroid lobes, making their usualmobilization difficult. Hence, rather than dissecting the midline, it isoften easier to enter the plane between the strap muscles and the ster-nocleidomastoid muscle, an area that is oft~n unscarred and allows easyaccess to the recurrent laryngeal nerve and to the parathyroid glands.Adapted from Kaplan}6

plan e is totally unscarred, and by retracting the carotidsheath laterally and the thyroid gland medially, a "fresh"aTea containing the recurrent laryngeal nerve and para-thyroid glands sometimes will be entered. If this aTea isscarred, the dissection should be started as low in the neckas possible, because this region is often untouched. Qncethe recurrent nerve is identified, it can be safely followedin a cephalad direction. Ifthe adenoma was not localizedbeforehand, a bilateral neck exploration mar be necessaryif it can be done safely. In the case of either positive 10-calization or retrospective determination of the sirle ofthe neck ofthe missing gland, the cervical dissection mightbe started there initially and might be unilateral if an ad.enoma is found or if the dissection is technically verydifficult.

One ofthe most rewarding maneuvers, one that shouldbe done early, is to look for an upper parathyroid glandthat has fallen down into the posterior superior medias-tinum. Introduce one's finger downward behind the in-feriQr thyroid artery along the esophagus into the posteriormediastinum as far as one can reach. Often the missingadenoma can be palpated here before it can be seen. Thisis the aTea in which many missing adenomas are foundbecause the initial dissection was not carried out deepenough. -

If this is unsuccessful, all of the sités already describedunder the heading The Search for Ectopic ParathyroidGlands should be explored.38 This involves pulling upand removing the thymus on each sirle into the neck,

Surgery for Parathyroid Cancer

Parathyroid cancer accounts for less than 1% of casesof primary HPT at the University of Chicago MedicalCenter and elsewhere, but has been reported to occur inup to 6% of cases in other series. so A carcinoma often

presents as a "sticky," adherent gJand at operation. Oftena thick, dense, fibrotic, whitish capsule is presento

If recognized or suspected intraoperatively, one shouldnot enter its capsule, for local seeding oftumor is a com-mon occurrence. The gland should be removed widely,taking the ipsilateral thyroid lobe with it. Ipsilaterallymphnades should be dissected in the central compartm~ntand perhaps in the lateral neck as well, for nodal spreadcan occur. Distant spread occurs to the lungs, bone, brain,and elsewhere. If hypercalcemia recurs after any parathy-roidectomy for parathyroid carcinoma, metastases shouldbe aggressively localized and resected,s I because there is

no good therapy other than surgical excision. In general,death occurs from unrelenting hyperparathyroidism withall ofthe complications ofthis disorder, rather than fromtumor spread itself.

Results oC Parath~Toidectomy Cor PrimaryHyperparathyroidism

There is no question that the results of parathyroid-ectomy for primary hyperparathyroidism relate to the ex-perience of the operator. In a recent report from Scan-dinavia,52 this is clearly shown. In centers that specializein endocrine surgery, 90% of patients were normocal-cemic, with mean follow-up of 4.4 years after their initialparathyroidectomy-6% were hypercalcemic and 4% werehypocalcemic. In contrast, in a general Scandinavian sur-vey of all hospitals done at roughly the same time andwith similar follow-up, 76% of patients were normocal-cemic. In hospitals in which less than 10 operations forprimary hyperparathyroidism were done each year, only70% were normocalcemic at follow-up-15% had persis-tent or recurrent hyperparathyroidism and 14% had per-manent hypoparathyroidism.

In a number of other studies from centers that haveconsiderable experience in parathyroid surgery, approx-imately 95% of patients or more can be rendered nor-mocalcemic by the initial operation!3.27.53 At the Uni-versity of Chicago, for example, ayer 97% of the last 300patients who had their initial exploration at our Institutionwere normocalcemic, 1 month or longer after operation.Recurrent hyperparathyroidism occurs infrequently innonfamilial cases,18.23 but remains a problem in familialhyperparathyroidism and in others with the MEN-I syn-drome.23 In experienced hands, the complication rate islow in these initial operations. Permanent recurrent la-ryngeal nerve injuries occurred in less than 1 %.18,52 Per-

dissecting as high in the neck as the hyoid bone, removinga part of one or both thyroid lobes, and opening and ex-ploring the carotid sheath afeas and even lateral to thecarotid sheath. A careful neck re-exploration done in thismanner will almost always yield the missing adenoma orthe elusive hyperplastic gland or glands that remain.

Before the operation, consent should be obtained for apossible sternotomy, if that is your plan. Either a partialsternotomy to the third intercostal space or a completesternotomy can be performed. First, the thymus and sur-rounding fat pads should be palpated. On several occa-sions, we were able to fee" a mass, which proved to be themissing adenoma, and only a partial thymectomy wasnecessary. Otherwise, the entire thymus should be re-moved. If the parathyroid gland is not found therein, aposterior dissection then should be performed. Lesionshave been found between the aorta and pulmonary ar-tery, in the middle mediastinum,28 and even, very rarely,in an intrapericardial location.22 Needless to say, thesedissections can be very long and tedious.

When an adenoma is found in the neck or chest, itshould be totally removed. If at least one additional nor-mal gland remains viable after the first operation, the pa-tient will be normocalcemic with normal postoperativeparathyroid function. This fact stresses the importance ofno! removing normal parathyroid glands during an un-successful initial operation.

If hyperplastic glands are identified at reoperation, asubtotal parathyroidectomy can be performed. Othersprefer a total parathyroidectomy, arguing that if recur-rence were to occur in a remnant that is left, this wouldnecessitate a third neck operation. If total parathyroid-ectomy is used, or after removal of an adenoma whenone thinks that no other parathyroid tissue remains, onehas the option of either immediately autotransplantingsome of the abnormal parathyroid to the arm after con-firming that it is not a carcinoma,41 or else cryopreservingthe tissue and waiting to see whether or not hypocalcemiaoccurs postoperatively.4o If permanent hypoparathyroid-ism occurs, a subsequent autotransplant to the arm wouldbe employed.

Either of these approaches has advantages and disad-vantages. In our hands, cryopreservation has not beendeveloped to the extent described by Wells et al.4o andBrennan et al.49 Furthermore, reimplantation of tissuethat has been cryopreserved is not always successful.Hence we would be more likely to use immediate auto-transplantation ifit were thought to be necessary, but onlyif we believed strongly that all other parathyroid tissuehad been removed from the patient. The long-term prev-alence of recurrent hyperparathyroidism when part of anadenoma or of a hyperplastic gland is used as an auto-transplant to the arm remains a fruitful afea for study.

316 KAPLAN, y ASHIRO, AND SAL TI Ann. SUf!.. April 1992

variant of hypercalcemia: clinical and biochemical features intifteen kindreds. Medicine 1981; 60:397.

17. Ronni-Sivula H, Sivula A. Long-term effect of surgical treatmenton the symptoms ofprimary hyperparathyroidism. Ann Clin Res1985; 17:144-147.

18. Lafferty FW, Hubay CA. Primary hyperparathyroidism. A re~1ewofthe long-term surgical and non-surgical morbidities as a basisfor a rationaI approach to treatment. Arch Intem Med 1989; 149:789-796.

19. Scholz DA, Purnell DC. Asymptomatic primary h)'perparath)TOid-ism. Mayo Oin Proc 1981; 56:473.

20. Kaplan RA, Snyder WH, Steward A. Metabolic effects of parathy-roidectomy in asymptomatic primary hyperparath)TOidism. J OinEndrocrinol Metab 1976; 42:415.

21. Gilmour JR. The embryology ofthe parathyroid giands. the thymusand certain associated rudiments. J Pathol 1937; 45:507.

22. Scholz DA, Purnell DC, Woolner LB, Clagett OT. Mediastinal hy-perfunctioningparathyroid tumors. Ann Surg 1973; 178(2):173-178.

23. Clark OH, Hunt TR, Way L W, et al. ReculTent hyperparathyroidism.Ann Surg 1976; 184:391-402.

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25. Sedgwick CE, Cady B. Embryology and developmental abnormal-ities. Chapter 2. In Sedgwick, Cady, eds. Surgery ofthe Thyroidand Parathyroid Glands. Philadelphia: WB Saunders, 1980; pp6-18.

26. Kaplan EL. Thyroid and parathyroid. Chapter 38. In Schwartz SI,oo. Principies ofSurgery, 5th Edition. New York: McGraw-Hill,1989;pp 1613-1685.

27. Bruining HA. Operative strategy for primary hyperparath)TOidism.Chapter II.In Kap]an EL, ed. Surgery ofthe Thyroid and Para-thyroid G]ands. Edinburgh: Churchill Livingstone, 1983; pp 158-167.

28. Curley IR, Wheeler MH, Thompson NW, Grant CS. The challengeofthe middle mediastinal parathyroid. World J Surg 1988; 12:818-824.

29. Udekwu AO, Kaplan EL, Wu TC, Arganini M. Ectopic parath)TOidadenoma of the lateral triang]e of the neck: report of two cases.Surgery 1987; 101:114'-118.

30. Cope O, Keynes WM, Roth SI, Castelman B. Primary chief-cellhyperplasia ofthe parathyroid giands: a new entity in the surgeryofhyperparathyroidism. Ann Surg 1958; 148:375.

31. Edis AJ, Beahrs OH, van Heerden JA, Akwari OE. 'Conservative'versus 'Liberal' approach to parathyroid neck exploration. Surgery1977; 82:466.

32. Cusumano RJ, Mahadevia P, Silver CEo Intraoperative histo]ogicevaIuation in exp]oration ofthe parathyroid giands. Surg GynecolObstet 1989; 169:506-510.

33. Roth SI. Pathology ofthe parathyroids in hyperparath)TOidism: dis-cussion ofrecent advances in the anatomy and pathology oftheparathyroid giands. Arch Patho11962; 73:495.

34. Roth SI, Gallagher MJ. The rapid identitication of 'normal' para-thyroid giands by the presente of intracellu]ar fato Am Pathol1976; 84:521-528.

35. Brothers TE, Thompson NW. Surgical treatment of primary hy-perparathyroidism in elderly patients. Acta Chir Scand ] 987; ] 53:175-178.

36. Prinz RA, Pa]oyan E, Lawrence AM, et al. Radiation-associatedhyperparathyroidism: a new syndrome? Surgery 1977; 82:296-302.

37. Tisell L-E, Hansson G, Lindberg S, Ragnhult l. Occurrence ofpre-vious neck radiotherapy among patients with associated non-medullary thyroid carcinoma and parathyroid adenoma or hy-perplasia. Acta Chir Scand 1978; 144:l-ll.

38. Levin KE, Clark OH. The reasons for failure in parathyroid oper-ations. Arch Surg 1989; ]24:911-914.

39. Paloyan D, Pick]eman JR. Hyperparathyroidism today. Surg OinNorth Am 1973; 53:21].

40. Wells SA Jr, Gunnells CJ, Gutman RA, et al. The successful trans-plantation of frozen tissue in mano Surgery 1977; 81 :86.

41. Edis AJ, Linos DA, Kao PC. Parathyroid autotransplantation at the

manent hypoparathyroidism has been reported to be 2%or less in a number of series, but is higher in others.18Finally, the operative mortality rate is consistently far lessthan 1%.18

Reoperations for persistent or recurrent hyperparathy-roidism are more difficult and have a greater potential forhypoparathyroidism, for recurrent nerve injuries, and forfailure.46 Using advanced localization studies, however,up to 90% of these tumors may be found and corrected,in the best of series. 38

Thus, the results of parathyroid surgery for primaryhyperparathyroidism in the 1990s are excellent when doneby experienced surgeons. As stated by Malmaeus and co-workers,52 "These findings strongly advocate specialtraining and interest in parathyroid surgery in arder toensure success."

AcknowledgmentsThe authors thank Ms. Noreen Fulton and Ms. Kim Maddy for aiding

in the preparation ofthis manuscript.

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