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ORIGINAL ARTICLE
Year : 2018  |  Volume : 7  |  Issue : 2  |  Page : 69-74

Ectopic parathyroid adenoma: single-centre experience from India


1 Institute of Endocrinology, Diabetes, Thyroid and Osteoporosis Disorders, Bengaluru, Karnataka, India
2 Department of ENT, Sakra World Hospitals, Bengaluru, Karnataka, India
3 Department of Cardiothoracic and Vascular Surgery, Sakra World Hospitals, Bengaluru, Karnataka, India
4 Department of Nuclear Medicine, Health Care Global Hospitals, Bengaluru, Karnataka, India
5 Department of Laboratory Medicine and Pathology, Sakra World Hospitals, Bengaluru, Karnataka, India

Date of Web Publication26-Mar-2019

Correspondence Address:
C V Harinarayan
Director, Institute of Endocrinology, Diabetes, Thyroid and Osteoporosis Disorders, Bengaluru, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCSR.JCSR_39_18

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  Abstract 


Background: The commonest cause of primary hyperparathyroidism (PHPT) is hyperfunctional parathyroid adenoma (PA) (94%), parathyroid hyperplasia (<6%) and rarely parathyroid carcinoma (<1%). Excision of PA is a definitive cure with a success rate of 95%. Less than 15% have one or more hyperfunctioning glands in an ectopic location.
Methods: Between 2014 to 2017, seven of the 13 patients with PHPT, who had failed surgical and noninvasive localisation, were included in the study. Hybrid localisation technique positron emission tomography-Computed tomography (PET-CT) with tracer 11C-choline was used. Location of parathyroid adenoma was classified using Perrier classification, which uses, letters A-G to describe the exact location of the adenoma. A 50% drop in PTH levels as compared with pre-incision values was confirmed as a cure.
Results: The biochemical and hormonal profile of the 7 (54%) patients with ectopic PA are (mean±SD) serum calcium (mg/dL), 25OH-D (ng/dL) and PTH (pg/mL) 11.36 ± 0.82; 22.82 ± 8.57; 205 ± 105 respectively. Three of the seven had renal stones. In all, seven patients of PA were localised using PET-CT using tracer 11C-choline. The profile of PA were two type-G (intrathyroidal), one type-C (posterior mediastinum), two type-F (superior mediastinum), one of type D (mid region of posterior surface of thyroid parenchyma at the junction of recurrent laryngeal nerve and the middle thyroid vein) and one type B.
Conclusion: Ectopic PA is rare. In a biochemically and hormonally confirmed PHPT and in failed imaging localisation techniques/failed neck exploration one should look for ectopic PA. Newer hybrid techniques combined with newer tracer agents (PET-CT) will help in localization of PA. To the best of our knowledge this is the first report of series of ectopic PA from a single center from India.

Keywords: Ectopic parathyroid adenoma, Positron-emission tomography-computed tomography scan, Primary hyperparathyroidism


How to cite this article:
Harinarayan C V, Ashok H, Sadiq A, Prashant G R, Badanidiyur D, Gupta N, Rajani I, Sunil Kumar N K, Roohi S, Nandita G. Ectopic parathyroid adenoma: single-centre experience from India. J Clin Sci Res 2018;7:69-74

How to cite this URL:
Harinarayan C V, Ashok H, Sadiq A, Prashant G R, Badanidiyur D, Gupta N, Rajani I, Sunil Kumar N K, Roohi S, Nandita G. Ectopic parathyroid adenoma: single-centre experience from India. J Clin Sci Res [serial online] 2018 [cited 2019 Oct 14];7:69-74. Available from: http://www.jcsr.co.in/text.asp?2018/7/2/69/254981




  Introduction Top


The diagnosis of primary hyperparathyroidism (PHPT) is confirmed biochemically with elevated serum calcium and serum parathyroid hormone (PTH) levels. The most common cause is hyperfunctional parathyroid adenoma (PA) (94%), and the remaining is hyperplasia (<6%). Parathyroid carcinoma is rare (<1%).[1] Of the adenomas, 90% are solitary and 4% may be multiple.[1] The definitive cure of PHPT is excision of the pathological parathyroid with a success rate of 95%. In <15% of the cases, one or more hyperfunctioning glands are found in the ectopic location.[1] The location of PA is classified by Perrier et al.[2] For accurate and precise communication, between surgeons and specialists, which uses letters A-G to describe the exact location of the adenoma.[2] Ectopic parathyroid glands are most often derived from inferior glands, because of their long migration path, providing them with a higher probability of being ectopic from the angle of the mandible to the pericardium. They may be located in the mediastinum either anterior or posterior, in the thymus (intrathymic), in the tracheoesophageal groove and very rarely in the thyroid parenchyma.[3],[4] During embryogenesis, the superior and inferior parathyroid glands originate from the 4th and 3rd branchial clefts respectively and migrate caudally to their normal positions in relation to the thyroid gland. Any aberrancy during this descent may lead to the ectopic location of these glands.

Pre-operative localisation of the hyperfunctional PA is crucial for successful and minimally invasive parathyroidectomy. Pre-operative anatomical localisation of the parathyroid glands may be achieved by ultrasonography (USG), computed tomography (CT) and magnetic resonance imaging (MRI). Functional localisation modalities include dual-isotope imaging with or without Single-photon emission CT (SPECT)-CT using 99mTc-sestamibi (MIBI)/99m Tc-pertechnate.[5] Newer modalities of functional imaging are particularly relevant for patients with previously unsuccessful neck exploration or failed non-invasive localisation. Newer techniques such as hybrid localisation with newer tracer agents such as 11C-choline or 18F-fluorocholine or 14C methionine PET-CT and 4-dimensional (4D) CT are being explored with promising results.[6]

We present our cohort of patients with PA who were referred to us because of failed localisation by routine anatomical and functional imaging techniques. While there are many individual case reports of ectopic PA from India from different centres, our report represents a series of ectopic PA from a single centre.


  Material and Methods Top


Between 2014 and 2017, 13 patients presenting to the Institute of Endocrinology, Metabolism and Osteoporosis Disorders of this hospital for the evaluation of hypercalcemia were diagnosed to have PHPT. Of these, 7 (54%) of them had ectopic PAs. The diagnosis of PHPT was based on raised serum calcium with elevated parathormone levels. The presence of renal stones along with hypercalcemia and raised PTH strengthened the diagnosis of PHPT. All these patients, with failed non-invasive localisation, were referred for further evaluation. Previously, these patients had undergone USG of the neck and nuclear scan of the parathyroid which were negative.

Serum calcium, phosphorous, alkaline phosphatase, creatinine and albumin were analysed on UniCel DxE 860 (i) (Beckman coulter, Inc), 25OH vitamin D (25OH-D) and parathormone (PTH) levels were analysed using UniCel Dxl 600 Access immunoassay system (Beckman coulter, Inc.,) autoanalyser. Serum calcium levels >11 mg/dL and/or PTH levels >90 pg/mL were used to diagnose PHPT. Since all patients were referred for failed non-invasive localisation, their serum calcium and PTH levels before their visit to our centre were also considered for diagnosis (some were on treatment for hypercalcemia at the time of presentation to our centre). Results for continuous variables are presented as mean ± standard deviation (SD), while categorical variables are presented as absolute and relative (%) frequencies.

Since all the patients had failed non-invasive localisation, hybrid localisation with PET-CT and newer tracer agent 11C-Choline was used to localise the tumour. PA/hyperplasia show increased cell proliferation/metabolism and upregulation of choline kinase activity leading to enhanced choline uptake. Increased cell proliferation/metabolism in the adenoma or hyperplasia possibly leads to increased choline uptake which on phosphorylation by choline kinase gets trapped to form a major membrane phospholipid called phosphatidylcholine. Hence, upregulation of choline kinase activity leads to enhanced choline uptake. Based on this possible mechanism, 11C-Choline, a choline analogue is used for evaluation of PA.

11C Choline was synthesised, and 10–20 mCi of 11C Choline was injected intravenously. Immediate and 30-min delayed images were acquired with the views extending from the angle of mandible to the diaphragm. Images were assessed visually for abnormal localisation in the neck or mediastinum and reported accordingly.

Routinely intraoperative parathyroid hormone (ioPTH) testing is carried out to confirm cure and to alleviate re-exploration of the neck. A 50% drop in PTH levels as compared with pre-operative or pre-incision values is confirmed as cure (Wisconsin Index).[7]

PA thus excised was classified with letters A-G to describe the exact location of the adenoma as per classification of Perrier et al.[2] A PT gland originating from superior pedicle, lateral to recurrent laryngeal nerve and within the thyroid capsule is 'Type-A'. A gland in the tracheoesophageal groove and is in the same cross-sectional plane as a superior portion of the thyroid gland is 'Type-B'. 'Type C' Gland is posterior in the tracheoesophageal groove below the inferior pole of the thyroid gland. A gland in the mid-region of posterior surface of thyroid parenchyma at the junction of recurrent laryngeal nerve and the middle thyroid vein or the inferior thyroid artery is 'Type-D' gland. A gland close to inferior pole and lateral plane of thyroid parenchyma and anterior half of the trachea is 'Type-E' gland. A gland in the thyrothymic ligament or superior thymus or within the superior mediastinum is 'Type-F' gland. A gland truly intrathyroidal is 'Type-G' gland.


  Results Top


The biochemical and hormonal profile of the seven patients with ectopic PA are (mean ± SD) serum calcium 11.36 + 0.82 (mg/dl), 25OH D 22.82 + 8.57 (ng/dl) and PTH 205 + 105 (pg/ml) [Table 1]. About 43% (3/7) of the patients had renal stones at presentation.
Table 1: Pre- and post-operative biochemical and hormonal profile of patients with parathyroid adenoma along with localisation details

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USG was not able to localise the adenoma. Functional imaging by nuclear scan was positive only in 28.5% (2/7) of the patients. During the surgery, it turned out to be false positive localisation leading to failed neck exploration. In all, seven patients of PA were localised using PET-CT scans using tracer 11C-choline [Figure 1]. The profile of PA was two type-G, one type-C, two type-F, one each of type D and type B.
Figure 1: Patient 1. Prior MIBI scan did not show any abnormal uptake in the region of thyroid, neck or mediastinum. Increased 11C-choline concentration is seen in the right lobe of the thyroid gland, predominantly in the upper and lower poles-right intrathyroidal parathyroid adenomas (a). Patient 2 Prior MIBI scan did not show any abnormal uptake in the region of thyroid, neck or mediastinum. 11C-choline avid 6 mm intra-thyroid nodule in the lower pole region of the left lobe of thyroid-intrathyroidal parathyroid adenoma (b). Patient 3. Persistent elevated PTH in the postoperative period. 11C-choline concentration accumulation 1.8 cm × 1.1 cm soft-tissue lesion is seen in the right tracheoesophageal groove of the superior mediastinum at level of D2 vertebra (c). Patient 4. 1.3 cm × 1 cm11C-choline avid soft-tissue lesion seen in the anterior mediastinum behind the manubrium sternum just above angle of Louis – suggestive of parathyroid adenoma (d). Patient 6. Increased 11C-choline concentration 9 mm × 4 mm well-defined hypermetabolic soft tissue nodule inferior to the right lobe of thyroid – suggestive of parathyroid adenoma (e). Patient 7. 2.4 cm × 0.9 cm a discrete enhancing retropharyngeal soft tissue nodule and abutting the right lobe of thyroid with mild mass effect on the posterior wall of hypopharynx, likely representing of parathyroid adenoma (f)

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Hemithyroidectomy for excision of intrathyroidal PA was done for type-G adenoma. Routine surgical excision of PA was carried out for the remaining patients. In 5/7 patients the ioPTH levels fell by >50%. In patients, no 3 and 5 [Table 1], the ioPTH did not fall by 50%, who were positive by nuclear scan. In these patients, further evaluation by PET scan revealed an adenoma in the tracheoesophageal groove at D2 vertebrae. A 'targeted' Video-Assisted Thoracoscopic Surgical excision of the PA was performed under general anaesthesia using single lung ventilation with an endobronchial endoluminal blocker. In patient no 5, the nuclear scan showed an adenoma at right superior pole of the thyroid gland, and MRI revealed at the right inferior pole of the thyroid. At surgery, the ioPTH did not show a fall on the removal of the right superior adenoma. Later, the right inferior pole PT adenoma (documented by MRI before surgery) was removed, and there was a 50% fall of ioPTH.

All patients of PA showed predominant oxyphil cells with lesser proportions of clear cells [Figure 2]. Algorithm for localisation of parathyroid adenoma is shown in [Figure 3].
Figure 2: Photomicrograph showing thyroid with lymphocytic thyroiditis {arrow} with adjacent parathyroid adenoma (Asterisk) (H and E, ×40) (a). Photomicrograph showing parathyroid adenoma (Haematoxylin and eosin, ×400) (b). Photomicrograph showing parathyroid adenoma with oxyphil cells in microacinar pattern (arrow) (Hematoxylin and eosin, ×100) (c)

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Figure 3: Algorithm for localisation of parathyroid adenoma. PHPT = Primary hyperparathyroidism; SPECT = Single-photon emission computed tomography; SPECT-CT = Single photon emission computed tomography-computed tomography; MRI = Magnetic resonance imaging; 4D-CT = Four-dimensional computed tomography; PET-CT with 11C-choline = Positron emission tomography/computed tomography with 11C-choline

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  Discussion Top


Parathyroidectomy offers 95% cure for PHPT. In about 6%–16% of patients one or more hyperfunctioning glands are found in an ectopic location.[8]

Parathyroid surgery for PHPT has evolved tremendously in the past two decades. Imaging studies do not diagnose PHPT. Pre-operative localisation reduces the morbidity and operative time. Pre-operative localisation of PA can be done by various anatomical and functional imaging modalities. USG, the most common anatomical imaging, is of limited sensitivity for localisation of ectopic adenoma especially adenomas in the mediastinum and has difficulty in differentiating adenomas from lymph nodes and thyroid nodules. It is also operator dependent. Conventional computed tomography (CT) and MRI have a sensitivity of 55.4% and 77% respectively, with a benefit of high-resolution images.[9],[10],[11]

Major functional imaging available for evaluation of PAs is MIBI scintigraphy, SPECT, SPECT-CT, newer techniques such as positron emission tomography-CT (PET-CT) and 4DCT. SPECT is helpful in the differentiation of parathyroid from thyroid lesions and localisation of ectopic PAs.[12] SPECT when combined with CT improves the anatomical localisation of the lesion.

In biochemically and hormonally proven PHPT multiple scintigraphic studies can be used to localise the abnormal parathyroid glands. Unfortunately, a radiotracer specific for parathyroid glands does not currently exist. Thallium-201 is a cationic analogue of potassium which accumulates in both thyroid and parathyroid glands. Another tracer which accumulates only in thyroid like 123iodine or 99mTc-pertechnetate is used, and later, the thyroid image is subtracted. This method has many limitations of poor image quality, high patient radiation dose and technical problem of subtraction of images and patient motion between two scans.[12]

Currently, single radiopharmaceutical dual-phase method is used with differential washout rates of sestamibi for parathyroid and thyroid.[13] Sestamibi is retained for a longer time in parathyroid tissue, presumably due to mitochondria-rich oxyphil cells. The additional image of the chest is obtained to rule out ectopic PA in the upper mediastinum. SPECT and SPECT-CT are useful in localisation of ectopic parathyroid glands and to differentiate parathyroid from thyroid lesions.[12] In a meta-analysis, hybrid localisation with PET-CT with newer tracer agents such as[11] C-methionine is shown to have overall good sensitivity and positive predictive value.[6]

In our centre for the past 3 years, we encountered 13 patients with PHPT, out of which 7 (54%) were ectopic adenomas. This may be due to centre bias, as patients with failed non-invasive localisation are usually referred for evaluation. Of the seven patients with ectopic adenomas, two patients had false positive functional imaging by sestamibi, and five were negative in functional imaging by sestamibi studies. The two false positive cases accounted for failed neck exploration.

Sestamibi is a monovalent lipophilic cation which diffuses passively through the cell membrane because of electrochemical gradient and accumulates exclusively in the mitochondria of parathyroid lesions. The normal parathyroid tissue does not take up sestamibi. The mechanism of uptake in patients with PHPT is debatable and is presumed to be due to a high mitochondrial activity of oxyphil cells, leading to a longer retention time of sestamibi in nuclear scans.[13] Positive scans are biochemically associated with high serum calcium and pre-operative PTH levels, vitamin D deficiency and the use of calcium channel blocker. In our cohort of patients, the mean ± SD of serum calcium (mg/dL), 25OH-D (ng/dL) and PTH (pg/mL) of the cohort was 11.36 ± 0.82; 22.82 ± 8.57 and 205 ± 105, respectively. Erbil et al. reported that the rate of obtaining a positive sestamibi result increases by 10-fold if an adenoma weighs >600 mg and the oxyphil cell content is >20%.[14] In our series of patients, although the majority of the PA comprised of oxyphil cells, the size of the adenomas was not >900 mg on an average. P-glycoprotein (P-gp) expression is an important factor influencing the sestamibi uptake in PT adenoma. The accumulation of lipophilic cationic pharmaceutical (sestamibi) is prevented by P-gp coded on the multidrug resistance 1 gene, which functions as an ATP-dependent efflux pump.[15],[16] If there is P-gp expression, then the scan may be negative. In one of the studies, 71% of patients with strong P-gp membrane positivity had negative imaging, and 70% of patients with negative P-gp membrane expression had positive scans.[16] We could not study the P-gp expression in our patients, which could explain the negative nuclear scan despite being rich in oxyphil cells in histopathology. The accuracy of detection of multi-gland disease [Figure 3] is only 30% possibly due to preferential uptake of sestamibi by one abnormal parathyroid gland compared to others.[17]

Ectopic PA is rare, accounting for 6%–16% of patients with PHPT.[8] In a biochemically and hormonally confirmed PHPT (elevated serum calcium and PTH), when there is a failed localisation by routine anatomical and functional imaging techniques/failed neck exploration one should look for ectopic PA. Newer hybrid techniques combined with newer tracer agents (PET) will help in localisation of PA. To the best of our knowledge, this is the first report of a series of ectopic PA from a single centre from India, though there are lone case reports from our country.[18],[19],[20],[21]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Ruda JM, Hollenbeak CS, Stack BC Jr. A systematic review of the diagnosis and treatment of primary hyperparathyroidism from 1995 to 2003. Otolaryngol Head Neck Surg 2005;132:359-72.  Back to cited text no. 1
    
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Gouveia S, Rodrigues D, Barros L, Ribeiro C, Albuquerque A, Costa G, et al. Persistent primary hyperparathyroidism: An uncommon location for an ectopic gland – Case report and review. Arq Bras Endocrinol Metabol 2012;56:393-403.  Back to cited text no. 3
    
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McDermott VG, Fernandez RJ, Meakem TJ 3rd, Stolpen AH, Spritzer CE, Gefter WB, et al. Preoperative MR imaging in hyperparathyroidism: Results and factors affecting parathyroid detection. AJR Am J Roentgenol 1996;166:705-10.  Back to cited text no. 10
    
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Bhansali A, Masoodi SR, Bhadada S, Mittal BR, Behra A, Singh P, et al. Ultrasonography in detection of single and multiple abnormal parathyroid glands in primary hyperparathyroidism: Comparison with radionuclide scintigraphy and surgery. Clin Endocrinol (Oxf) 2006;65:340-5.  Back to cited text no. 11
    
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Palestro CJ, Tomas MB, Tronco GG. Radionuclide imaging of the parathyroid glands. Semin Nucl Med 2005;35:266-76.  Back to cited text no. 12
    
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Taillefer R, Boucher Y, Potvin C, Lambert R. Detection and localization of parathyroid adenomas in patients with hyperparathyroidism using a single radionuclide imaging procedure with technetium-99m-sestamibi (double-phase study) J Nucl Med 1992;33:1801-7.  Back to cited text no. 13
    
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Erbil Y, Kapran Y, Işsever H, Barbaros U, Adalet I, Dizdaroǧlu F, et al. The positive effect of adenoma weight and oxyphil cell content on preoperative localization with 99mTc-sestamibi scanning for primary hyperparathyroidism. Am J Surg 2008;195:34-9.  Back to cited text no. 14
    
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Piwnica-Worms D, Chiu ML, Budding M, Kronauge JF, Kramer RA, Croop JM, et al. Functional imaging of multidrug-resistant P-glycoprotein with an organotechnetium complex. Cancer Res 1993;53:977-84.  Back to cited text no. 15
    
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Gupta Y, Ahmed R, Happerfield L, Pinder SE, Balan KK, Wishart GC, et al. P-glycoprotein expression is associated with sestamibi washout in primary hyperparathyroidism. Br J Surg 2007;94:1491-5.  Back to cited text no. 16
    
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Haciyanli M, Lal G, Morita E, Duh QY, Kebebew E, Clark OH, et al. Accuracy of preoperative localization studies and intraoperative parathyroid hormone assay in patients with primary hyperparathyroidism and double adenoma. J Am Coll Surg 2003;197:739-46.  Back to cited text no. 17
    
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