ANZ J. Surg.

2003;

73

: 1048–1051

REVIEW ARTICLE

REVIEW ARTICLE

INTRAPARATHYROID CYST: A TUMOUR OF BRANCHIAL ORIGIN AND A POSSIBLE PITFALL FOR TARGETED PARATHYROID SURGERY

J

ONATHAN

A

RMSTRONG

, E

MMANUELLE

L

ETEURTRE

AND

C

HARLES

P

ROYE

Service de Chirurgie Endocrinienne et d’Anatomopathologie, Lille University Hospital, Hôpital Huriez, Lille Cedex, France

Background:

Parathyroid cysts account for 0.5% of parathyroid pathologies. They usually contain sky-high levels of parathyroidhormone (PTH) but are not necessarily associated with primary hyperparathyroidism (PHPT). Their origin is subject to debate. Weprovide evidence for a branchial origin and illustrate some potential problems they pose for targeted parathyroid surgery.

Methods:

The present study is a single institution retrospective study of 1702 parathyroid and 10 021 thyroid operations per-formed over a period of 12 years (1990–2001). Twenty-three cases of parathyroid cyst were found: three palpable neck masses, fourcases associated with PHPT and 16 incidental findings at the time of thyroid surgery. Intracystic PTH measurements and immuno-staining of the lining wall of the cyst were obtained in 16 out of 23 and 18 out of 23 cases, respectively.

Results:

Intracystic PTH levels were elevated in 15 out of 16 cases (average 3877, range 36 000–23 pg/mL). The wall of the cyststained positively for epithelial cuboidal cell markers (CK +ve) and negatively for PTH (PTH –ve) in 18 out of 18 cases. In only onequarter of the cases associated with PHPT was the cyst the hypersecreting gland, nevertheless it contained less than the average PTHlevel (1440

vs

3877) and did not take up sestamibi. Results were conflicting in the other three cases. Histological studies on thepresent series suggest a branchial pouch origin.

Conclusion:

Despite containing high levels of PTH, parathyroid cysts are of branchial origin and when associated with PHPT are rarelyresponsible for the disease. Targeted parathyroid surgery should not rely only on ultrasound and intraparathyroid PTH measurements.

Key word: parathyroid cyst.

Abbreviations

: CK +ve, positive epithelial cell markers; PHPT, primary hyperparathyroidism; PTH, parathyroid hormone;PTH –ve, negative for parathyroid hormone; PTH +ve, positive for parathyroid hormone.

INTRODUCTION

Parathyroid cysts represent approximately 0.5–1% of all para-thyroid pathologies.

1

Their origin is the subject of debate. Our results of immuno-histochemical analysis suggest a branchial pouch origin for themajority of parathyroid cysts.

Typically their presentation is asymptomatic with most beingdetected through incidental findings at cervicotomy for thyroidor parathyroid pathology. However, they can present in a settingof primary hyperparathyroidism (PHPT). Thus, the questionarises whether or not they are responsible for this syndrome. It isthought that parathyroid cysts account for only 1% of all cases ofhyperparathyroidism

2,3

and less than 10% of parathyroid cysts areassociated with hyperparathyroidism.

There are numerous case reports in the literature documentingbizarre presentations of parathyroid cysts,

4

including compressivesymptoms with dysphagia, dyspnoea, stridor and hoarseness.

5

Parathyroid cysts can, in fact, arise in any site between the mandi-ble and the mediastinum.

6–8

Imaging studies, including ultrasound, computed tomographyor magnetic resonance imaging, might well reveal a cystic struc-ture in the region of a parathyroid locus and aid a preoperativediagnosis. Fine-needle aspiration has also assumed a position in

the overall management of cervical masses, and if clear, colourlesscystic fluid is withdrawn it should be sent for parathyroid hormone(PTH) level assays. Markedly supranormal levels of PTH arediagnostic.

5

Sestamibi studies in the context of hyperparathy-roidism might localize a functional adenomatous cystic lesion.

We undertook a retrospective study to clarify some of theseissues relating to presentation, diagnosis and management.

METHODS

Our retrospective study was performed on the Lille hospital (LilleCedex, France) series of 10 021 thyroid and 1702 parathyroidpatients who had undergone cervicotomy over a 12 year period.Using the hospital database and searching for ‘parathyroid cystpathology’ in their discharge letters 23 patients were identified.The patient details, age, sex, date of operation and circumstancesof cyst discovery were elucidated. Any associated hyperpara-thyroidism was noted and all the available details of adenomapathology, preoperative imagery, calcium, and PTH levels bothpre- and postoperatively were noted. The cyst’s dimensions,weight, aspirated volume and intracystic PTH levels weresearched for in the operation note and the pathology report. All thecyst pathology details were reviewed and a separate retrospectiveimmunohistochemical study was undertaken on the original path-ological material to search for epithelial and parathyroid markers.

RESULTS

The 23 patients retrieved over a 12-year period (Table 1) included21 women and two men. The average age at operation was45.5 years (

±

32.5 years).

J. Armstrong

MB BS, FRACS;

E. Leteurtre

MD;

C. Proye

MD, FRCS(Edin Hon).

Correspondence: Mr Jonathan Armstrong, Priory Thatch, Priory Green,Dunster, Somerset, TA 24 6RY, UK.Email: zoedog68@hotmail.com

Accepted for publication 2 June 2003.

PARATHYROID CYSTS 1049

Of the 23 patients, 22 had cysts that were in the inferior posi-tion, nine were left sided and 14 right sided.

We measured the cyst size in 14 cases. They ranged from2

×

2

×

2 mm to 50

×

50

×

60 mm. The average maximum diam-eter was 22.7 mm (

±

37.3 mm).Of the 23 cysts, eight parathyroid cysts had accurate documen-

tation of weight, varying from 10.6 mg to 1128 mg. The averageweight was 237 mg (

±

891 mg).An attempt at cyst aspiration to evaluate intracystic PTH levels

was made in 16 cases (Table 2). The PTH levels of the aspiratesvaried from 36 000 to <3. Median intracystic PTH level was 3877(

±

32 123). Within these cases, eight patients had accurate intra-operative aspiration of the cyst fluid volumes. These aspiratedvolumes ranged from two to 35 mL of fluid. The median volumewas 13.7 mL (

±

21.3).In terms of their presentation, the majority of cysts, 16 out of 23,

were noted as incidental findings at cervicotomy for thyroidpathology – either at hemithyroidectomy for a benign nodule orundergoing total thyroidectomy for multinodular goitre or dif-ferentiated thyroid cancer.

Three out of the 23 patients underwent neck exploration forpalpable neck masses, of uncertain preoperative origin, and ulti-mately revealed large parathyroid cystic lesions. Another fourunderwent cervicotomy for PHPT (patients A,B,C,D).

Patient A, a 65-year-old woman, underwent a formal cervic-otomy for PHPT; she had a preoperative calcium level of 130 mg/L,phosphorous 26 mg/L and PTH 229. No preoperative ultrasoundor sestamibi studies were performed for this patient. A parathyroidadenoma was discovered in the superior left position and removed.A parathyroid cyst was also then removed from the thymic pedicleon the left. Its dimensions were 14

×

10

×

8 mm and weight

285 mg. The two parathyroids on the right side were normal andleft

in situ

. The patient made an uneventful postoperative recoverywith normalization of biochemistry.

Patient B, a 75-year-old woman, with a preoperative diagnosisof hyperparathyroidism (calcium level 109 mg/L, phosphorous22 mg/L, PTH 83) had a preoperative neck ultrasound and sesta-mibi studies. The ultrasound showed a lesion at the left inferior

Table 1.

Subjects

Patient M/F Date of presentation

Age Discovery? Preoperative level Location Dimensions (mm) Calcium

(mg/L)Phosphorous

(mg/L)PTH

1 F 11/1990 22 TT-MNG 93 33 26 Inf left 2

×

2

×

22 F 1/1991 26 Palpable mass 92 36 48 Inf right 50

×

60

×

503 F 5/1991 59 TT-SN 90 24 31 Inf right –4 F 8/1992 69 TT-DTC 99 37 – Inf right –5(A) F 9/1992 65 PHPT 130 26 229 Inf left 14

×

10

×

86 F 4/1993 29 TT-MNG 96 37 – Inf right –7 F 2/1994 15 TT-SN 94 41 – Inf right –8 F 4/1994 35 TT-MNG 100 38 40 Inf right –9 M 5/1996 38 HT-SN 97 28 – Inf right –10 F 11/1996 28 TT-MNG 101 40 – Inf left 9

×

3

×

211 F 10/1998 52 TT-SN 90 31 – Inf left –12 F 7/1998 59 TT-SN 100 45 – Inf right –13 F 5/1999 47 TT-SN 96 30 – Inf right 12

×

8

×

614 F 5/1999 34 TT-MNG 99 27 – Inf right 40

×

30

×

3015 F 7/1999 49 TT-MNG 83 24 – Inf left 18

×

15

×

1016 F 3/2000 63 TT-DTC 102 34 66 Sup right 7

×

6

×

317(B) F 9/2000 75 PHPT 109 22 83 Inf left 40

×

12

×

1018 F 11/2000 35 Palpable mass 99 34 27 Inf left –19 F 11/2000 37 HT-SN 93 26 – Inf left 10

×

5

×

420 F 6/2001 48 TT-MNG 90 23 – Inf right 12

×

4

×

221 M 10/2001 21 Palpable mass 98 34 49 Inf left 55

×

20

×

1022(C) F 4/2002 62 PHPT 122 22 133 Inf right 9

×

5

×

523(D) F 6/2002 78 PHPT 107 26 62 Inf right 30

×

25

×

20

–, not recorded; HT-SN, hemithyroidectomy for a solitary nodule; Inf, inferior; PHPT, primary hyperparathyroidism; PTH, parathyroid hormone; TT-DTC,total thyroidectomy for differentiated thyroid cancer; TT-MNG, total thyroidectomy for multinodular goiter; TT-SN, total thyroidectomy for a solitary nodule.

Table 2.

Parathyroid hormone (PTH) levels

Patient Intracystic PTH

Hyperparathyroid Average = 1261 (range 3–2340)5 (A) –17 (B) 234022 (C) 323 (D) 1440

Non-hyperparathyroid Average = 4481 (range 60–36

000)1 9722 3663 5256 3167 3168 70009 23911 36

00014 20015 11

95018 10819 6021 209

–, not recorded.

1050 ARMSTRONG

ET AL

.

pole of the thyroid. However, the sestamibi study showed no areasof increased uptake. Our guidelines for minimally invasive uni-lateral parathyroid surgery are strict in that a minimal approach isonly undertaken when there is concordance between the ultra-sound and sestamibi studies. Because this was lacking here aformal open cervicotomy was undertaken. This revealed anadenoma in the superior right position and a large left-sidedintrathymic inferior parathyroid cyst, measuring 40

×

12

×

10 mm,weighing 240 mg and containing 3 mL of clear fluid with a meas-ured PTH of 2340. Both these parathyroids were removed. Theother two parathyroids were normal and left

in situ

. The patientunderwent a normal postoperative recovery with normalization ofbiochemistry. Patient B underlines the potential risk for failure of aminimally invasive approach relying on just an ultrasound pre-operatively. A left sided approach here would have revealed a largecystic and possibly adenomatous lesion in the thyrothymic liga-ment. The real right-sided adenoma could have been missed, espe-cially if intraoperative rapid PTH monitoring was not available.

Patient C was a 62-year-old woman with a calcium level of122 mg/L, phosphorous 22 mg/L and PTH 133. Ultrasoundrevealed a lesion of the upper left parathyroid. The sestamibirevealed three separate foci of uptake, superior left, and inferiorleft and right. For this reason an open procedure was performed.The adenoma was in fact in the superior left position and removed.A cystic parathyroid, of dimensions 9

×

5

×

5 mm, was alsoremoved from the inferior right position. Interestingly, intracysticaspiration in this instance revealed fluid with a PTH level of <3.The other two parathyroids were normal and the patient made afull recovery.

Patient D, a 78-year-old women, with a calcium level of107 mg/L, potassium 26 mg/L, PTH 62, had a preoperative ultra-sound revealing a cystic mass in the region of the inferior rightparathyroid on a background of a multinodular thyroid goitre.Sestamibi scanning was unable to localize a lesion and thus thispatient also underwent an open procedure. Intraoperatively a largecystic inferior right parathyroid adenoma was removed, whichmeasured 30

×

25

×

20 mm, weighed 1128 mg, and had a meas-ured intracystic PTH of 1440. The other parathyroids were normaland an uneventful recovery was made.

Preoperative ultrasound was also performed for the majority ofthe thyroid procedures undertaken (14/19). The ultrasound reportmade no mention of any anomalies in the region of the parathyroidcyst in nine out of 14 cases. In the remaining five cases who hada preoperative ultrasound, comment was made of a presumedintrathyroidal anomaly – either a cystic lesion or area of hetero-geneity. In one case a cystic lesion at the inferior left pole of thethyroid was thought to represent a congenital cyst. In no case was apreoperative diagnosis of parathyroid cyst made.

Immunohistochemical study of the parathyroid cyst wall

There are essentially four theories that have been put forward toexplain the occurrence of parathyroid cysts:

(1) They could be embryonic remnants of third or fourthbranchial pouch tissue.

9

(2) They could arise from the coalescence of parathyroid micro-cysts, which are often incidental findings on histological analysis.

(3) If they arise in the context of a functional parathyroidadenoma they might be the result of a central degeneration andliquefaction of the adenoma tissue.

(4) Alternatively, as in point three, they might be a form ofretention cyst caused by an accumulation of trapped secretions.

There is also one case report in the literature of four cases offamilial cystic parathyroid adenomatosis,

10

a rare but distinct here-ditary syndrome, which appears to have an association with PHPTand a form of mandibular tumour. We, therefore, undertook aimmunohistochemical review of the parathyroid cyst specimens toattempt to elucidate their possible embryological origin.

A total of 18 pathology specimens were able to be re-examined. Strikingly similar results were obtained in each case.The cyst wall lining itself was always of the same single-layer,cuboidal, simple epithelium. The wall of the cysts stained posi-tively for epithelial cell markers (CK +ve) and negatively forPTH (PTH –ve) in all 18 cases. The adjacent, but definitely sepa-rate, parathyroid tissue was both PTH +ve and CK +ve. (Fig. 1).

This confirmation of epithelial origin of the cyst would seem tolend weight to a branchial pouch origin for the cysts, rather thanthe theories of adenomatous cystic degeneration, or a coalescence

Fig. 1.

(a) Photomicrograph of a section of a parathyroid cyst, stained with positive epithelial cell markers (CK +ve), illustrating the epithelialnature of the cyst wall and also the epithelial nature of the abutting parathyroid tissue (magnification:

×

40). (b) Photomicrograph of the sameparathyroid cyst stained with an immunohistochemical marker for parathyroid hormone (PTH +ve), illustrating that only the parathyroid tissueis positively stained and not the cyst wall (magnification:

×

40).

PARATHYROID CYSTS 1051

of parathyroid microcysts with senescence. Other authors havealluded to this branchial origin and have also noted a form of sal-ivary heterotopia in close proximity to the parathyroid cyst wall.

9

They noted tissue consisting of normal-appearing salivary paren-chyma composed of acini, of serous type, with a myoepitheliallayer and ducts. In our series, however, no salivary-type tissuewas seen.

DISCUSSION

Our series of 23 parathyroid cysts is the largest reported in theliterature. It reveals an incidence of parathyroid cysts in 0.5% ofall cervicotomies performed for either parathyroid or thyroidpathology. The cysts are revealed most commonly in the 4thdecade. Furthermore, our series reports a 10–1 female predomi-nance, at odds with previous reports of male predominance.

5

The most common presentation is as an incidentaloma at cervi-cotomy for other pathology, either thyroid disease or primaryhyperparathyroidism caused by a parathyroid adenoma affectinganother gland. Rarely, (one in four in our series) the parathyroidcyst might be functional and present as a functional cysticadenoma requiring removal.

Preoperative ultrasound imagery is usually unhelpful in diag-nosis of the cysts. It can mistake the cyst for an intrathyroidal cystor nodule. If a cystic lesion is noted it should be aspirated and aPTH measurement taken of the aspirate – this will be diagnosticfor a parathyroid cyst.

It has been suggested that the levels of aspirated intraparathy-roidal PTH might be helpful in elucidating the functional status ofan individual parathyroid gland. If the parathyroid sampled hadan extremely elevated PTH level, this might indicate parathyroidadenoma pathology? There is certainly no supporting evidencefor this in our small series. Our group of four patients with par-athyroid cyst pathology and concomitant PHPT only includes onepatient (Patient D) with a functional cystic adenoma. In thispatient the intracystic PTH is 1440, well below the average intra-cystic PTH level (4481) in the control non-hyperparathyroidgroup of cyst patients (Table 2).

When viewing these data illustrating high levels of intracysticPTH and then correlating this with our anatamopathologicalfindings of an epithelial-type cyst lining distinctly separate fromthe neighbouring parathyroid tissue an obvious question arises –where is the PTH coming from if there are no parathyroid cells inthe cyst wall? Perhaps it is a transudative phenomenon across theintracellular junctions of the cyst wall. These junctions might notbe as ‘tight’ as imagined. It would also have been interesting tohave data on PTH degradation products within the aspirated cystfluid. The PTH in the cyst might be, to an extent, composed ofbreakdown products rather than the intact PTH molecule itself.

4

The intact PTH assays used do not detect only the intact (1–84)PTH molecule but also inactive fragments.

11,12

Using the Nicholsassay specific for the intact (1–84) molecule combined with a(53–84) PTH degradation product assay the ratios of intact anddegraded PTH would be evident.

In the setting of minimally invasive parathyroid surgery thereis the possibility that preoperative ultrasound could mistake thecyst for the adenoma and misdirect the surgeon. A strict adher-ence to a policy of concordance of ultrasound and sestamibilocalization should alleviate this error. With a unilateral mini-mally invasive approach, if a parathyroid cyst is noted it is morethan likely not the site of the adenoma and the other parathyroid

on the same side should be definitely verified. The use of rapidPTH measurements intraoperatively will confirm the appropriateadenoma removal. If rapid PTH measurements are unavailablewe suggest a conversion to an open formal cervicotomy to searchfor an adenoma elsewhere.

Should the parathyroid cyst always be removed? In the settingof an incidentaloma found at cervicotomy for thyroid pathologythe cyst can be simply aspirated and left

in situ

. This was per-formed in five of our patients with no evidence of cyst recurrenceor other parathyroid pathology at an average of follow up of105 months (

±

4.9 months).In the setting of hyperparathyroidism it seems prudent to

remove the parathyroid, which is cystic as well as the parathyroidadenoma. If left

in situ

and the patient were to develop recurrenthyperparathyroidism, a potentially reaccumulated cyst could wellconfuse imaging studies preoperatively. From our limited seriesthere is also no evidence of development of a hypoparathyroidstate postoperatively after a two gland removal in three patientswith an average follow up of 49 months (

±

46 months).In conclusion, parathyroid cysts are relatively rare and of epi-

thelial and probably branchial origin. Their presentation isusually that of an asymptomatic and incidental finding at cer-vicotomy. With targeted parathyroid surgery they can misleadpreoperative localization studies and if intraoperatively dis-covered are an indication for bilateral exploration.

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