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Imaging of the parathyroid glands
Imaging of the Parathyroid Glands Laurie A. Loevner Primary hyperparathyroidism resulting in hyperca!cemia is the most common presentation of parathyroid pathology and usually is related t o a parathyroid adenorda and, less commonly, to hyperplasia. Imaging of the I)arathyroid glands focuses on the detection of adenomas in patients with primary hyperparathyroidism. The role of imaging (as well as the m o d a l i t y used) for preoperative localization of the parathyroid glands continues to be
controversial. The embryology, anatomy, and physiologi/of the parathyroid glands are reviewed. The diagnostic utility of radiological imaging--inCluding ultrasonography, CT, MR imaging, and nuclear rscintigraphy---are discussed, particularly as it pertains to the evaluation of primary hyperparathyroidism. Copyright © 1996 by W,B. Saunders Company
HE PARATHYROID glands arise from the third and ,fourth branchial pouches. The upper or superior parathyroid glands arise from the fourth branchial pouch along with the lateral anlages of the thyroid gland. Because the upper parathyroid glands are related closely to the thyroid and have a minimal descent, their positions are relatively constant. Fewer than 2% of the superior parathyroid glands are ectopic in location. The lower or inferior parathyroid glands and thynius are derived from the third branchial pouch; in contrast to the upper glands, the lower glands descend a great distance with the thymic anlage. Therefore. the position of the inferior parathyroid glands is more variable because they may descend into the anterior mediastinum as far as the pericardium. The upper parathyroid glands usually are supplied by a branch of the superior thyroidal arteries, whereas the lower parathyroid glands are supplied by the inferior thyroidal arteries. Drainage from the glands is usually to thyroidal veins. The cervical sympathetic plexus innervates the parathyroid glands. The number of parathyroid glands ranges from two to six, although most individuals have four. ~ The most common anatomic location of the upper parathyroid glands is posterior to the middle one third of the thyroid (75% of the time). Most of the other upper parathyroid glands are located behind the upper or lower one third Of the thyroid, with approximately 7% found below the inferior thyroidal artery) The most common anatomic location of the lower parathyroid glands is lateral to the lower pole of the thyroid gland (50% of the time). The next most common location (15% of the time) encompasses an area 1 cm below the lower thyroid pole. The position of the remaining one third is variable along the thyrothymic tract, extending
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anywhere from the angle of the mandible to the lower anterior mediastinum. Intrathyroidal parathyroid glands are uncommon, being present in only 2% of cases. It is not possible with current imaging techniques to distinguish an intrathyroidal parathyroid adenoma from a primary thyroid lesion. 2-3 ENDOCRINOLOGY OF THE PARATHYROID GLANDS The parathyroid glands are composed of chief cells and oxyphil cells, both of which are embedded within fibrous and adipose tissue. The role of the oxyphi! cells is unknown: They appear around puberty and increase with age. Chief cells secrete parathormone (PTH), which regulates the concentration of calcium in interstitial fluids. The secretion of PTH, in turn, is regulated by serum calcium levels. Parathormone acts predominantly in three regions: (a) the skeleton to mobilize calcium into the plasma, (b) the kidneys to reduce calcium excretion, and (c) the gastrointestinal tract to increase calcium absorption. 4 Parathormone enhances the synthesis of 1,25-(OH)D3, which promotes the absorption of calcium by the intestines. In patients with elevated serum calcium concentrations, PTH should be suppressed. A normal PTH level encountered in the setting of hypercalcemia is referred to as hyperparathyroidism.
From the Department of Radiology, Neuroradiology Section, University of Pennsylvania Medical Center, Philadelphia, PA. Address reprint requests to Laurie A. Loevner, MD, Department of Radiology, Neuroradiology Section, University of Pennsylvania Medical Center, 3400 Spruce St, Philadelphia. PA 19104. Copyright © 1996 by W.B. Saunders Company 0887-2171/96/1706-000455.00/0
Seminars in Ultrasound, CT, andMRI, Vo117, No 6 (December), 1996: pp 563-575
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CLINICAL MANIFESTATIONS OF PARATHYROID DISEASE
Hyperparathyroidisrn Primary hyperparathyroidism is common, occurring in approximately i of every 700 adults. 5 It occurs secondary to hypersecretion of PTH, resulting in hypercalcemia. The causes of primary hyperparathyroidism include a single parathyroid adenoma (80% to 85% of cases), parathyroid hyperplasia (10% to 15%), multiple parathyroid adenomas (2% to 3%), and, rarely, parathyroid carcinomas (fewer than 1%). 3,6-8 Solitary adenomas vary widely in size, from less than 1 cm to several centimeters. Hyperplasia typically involves multiple parathyroid glands. The classic clinical features include bone pain related to osseous demineralization, abdominal pain secondary to renal calculi, and occasional psychiatric disturbances (Fig 1). The treatment of primary hyperparathyroidism is surgical excision of the abnormal parathyroid gland. Most surgeons perform bilateral neck explorations because very small lesions or hyperplasia may be overlooked with current imaging techniques. Although the need for preoperative radiological localization remains a topic of debate, some authors report fewer complications and shorter operating times when abnormal parathyroid glands are identified before surgery. 3,9,10 Nonetheless, there are certain situations in which imaging plays a very useful role. This includes the evaluation of high-risk surgical patients in whom imaging may permit the surgeon to resect the abnormal gland with only a unilateral neck exploration. Alternatively, percutaneous injection of absolute ethanol to ablate adenomas may be performed under ultrasound guidance in patients who are poor surgical candidates because of underlying medical illness.11,~2 Success of the treatment is monitored with serum calcium levels, which are followed until levels approach near normal values. Also, when hyperparathyroidism recurs after surgery, imaging is indicated because ectopic glands are prevalent in these patients. There are secondary and tertiary forms of hyperparathyroidism as well. Secondary hyperparathyroidiSm occurs in patients with longstanding renal failure, leading to changes in calcium metabolism, which in turn results in
enlargement of the parathyroid glands. In tertiary hyperparathyroidism, hypercalcemia occurs as a sequela of secondary hyperparathyroidism because of the autonomous Secretion of PTH from chronically overstimulated parathyroid glands.
Hypoparathyroidism Almost all cases of primary hypoparathyroidism are related to surgical removal of the parathyroid glands for management of primary hyperParathyroidism or inadvertent parathyroid resection during thyroidectomy for thyroid pathology. Idiopathic primary hypoparathyroidism is a disease of childhood. Imaging of the parathyroid glands in cases of hypoparathyroidism is limited to surveillance for congenital absence Of the glands, a study best achieved with scintigraphy. IMAGING OF THE PARATHYROID GLANDS
ParathyroidAdenoma Indications for preoperative localization of parathyroid adenomas remain a topic of debate. In addition, the choice of appropriate imaging modality also is debated in the literature. When imaging is used, options include ultras0nography, CT, MRI, and nuclear scintigraphy. Conventional catheter and digital Subtraction angiography, as well as selective parathyroid venography with sampling and measurement of PTH levels, are highly accurate in detecting parathyroid adenomas; however, their major drawbacks are their cost and invasiveness. At manY institutions with experienced parathyroid surgeons, preoperative localization of the glands with imaging is not performed because some studies have suggested that the morbidity, mortality, and operative time are not greatly affected by preoperative localization. 13-15 In addition, some investigators argue that the cost of imaging outweighs its benefit, a4,16 The surgical technique includes exploration of the perithyroidal region bilaterally with a particular emphasis on the inferior poles of the thyroid glands, where most parathyroid adenomas occur. In the hands of skilled surgeons, this procedure may be performed with a success rate of more than 90%. 3'14'17-19 When a parathyroid adenoma is not identified in the perithyroida! locati0nl the surgeon may explore the anterior
Fig 1. Patient with hyperparathyroidism who presented with diffuse bone pain. (A) Axial enhanced CT shows a hypodense mass just posterior to the inferior pole of the left lobe of the thyroid gland (a). At surgery, this mass was identified as a parathyroid adenoma separate from the thyroid. (B) Lateral plain film radiograph shows the classic "salt and pepper" skull. (C) Bone scan shows the increased activity in the calvarium and decreased activity in the kidneys that have been described in association with hyperparathyroidism.
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mediastinum, deep cervical space, and carotid sheath regions. Successful surgery in these cases is lower (less than 70%), and the surgical complication rate is higher.17 Arguments for performing preoperative imaging to localize the parathyroid glands include: (a) the need for only unilateral neck dissection when an adenoma is detected; (b) the identification of ectopic adenomas; (c) the detection of other head and neck masses (eg, thyroid lesions); and (d) a reduction in operating room time. 1°a9-21 In addition, the operative success rate improves from 90% to nearly 100% with preoperative imaging. = UItrasonography of the parathyroid glands typically is performed by an experienced sonographer, with a high-resolution linear array transducer (7.5 to 10 MHz). The patient is imaged in the supine position with the neck mildly hyperextended. The examination includes evaluation of the perithyroidal areas and the region of the carotid sheaths, extending from the angle of the mandible superiorly to the sternal notch inferiorly. The typical appearance of a parathyroid adenoma is that of a homogeneous, demarcated mass with an echogenicity less than that of the thyroid gland ls,23 (Fig 2B). Adenomas typically are solid but may have cystic components. In addition, adenomas may degenerate into cysts. Color Doppler ultrasonography may occasionally provide additional information that may help to distinguish thyroid from parathyroid lesions. Specifically, thyroid lesions tend to have some vascularity, whereas small parathyroid lesions more often lack Doppler signal. On occasion, larger parathyroid lesions may be vascular. 24 For adenomas located in the perithyroidal region, ultrasonography is an excellent imaging modality. Limitations predominantly center around the fact that ultrasonography is less accurate than other imaging modalities in identifying eetopic parathyroid adenomas. Evaluation of the anterior mediastinum is limited because of acoustic impedance by air and bone. In addition, adenomas dose to air-filled structures, such as the trachea or esophagus, may be obscured by scanning artifact. Ultrasonography identifies adenomas in 95% of glands heavier than 1 g.18 Investigators report a sensitivity of 50% to 70% and a specificity of
LAURIE A. LOEVNER
90% to 95% for adenomas in hyperplastic glands.6,7,1s,23,25 Cross-sectional techniques (CT and MR) allows imaging to be performed through the neck from the skull base through the anterior mediastinum, thus allowing detection of ectopic parathyroid adenomas (Fig 3). CT images should include thin sections (3 to 5 ram). Intravenous contrast must be used in CT both to distinguish blood vessels from adenomas and because up to 25% of parathyroid adenomas enhance. 23 Limitations of CT in detecting adenomas include scanning artifact and artifacts related to swallowing and breathing. Lymph nodes, tortuous vessels, and the esophagus may be mistaken for adenomas. Another drawback to CT is that the use of iodinated contrast prevents subsequent imaging with iodine-based radionuclides because of the uptake of contrast by the thyroid gland. Thus, it is necessary to wait 6 to 8 weeks before nuclear scintigraphy with iodinated agents may be performed accurately. 26Investigators have found that, in general, both the sensitivity and specificity of high-resolution CT are improved over those of ultrasound, being approximately 70% and 90%, respectively. 23,27 MRI, like CT, allows excellent evaluation of the mediastinum. This method offers superior soft tissue discrimination and is more sensitive than CT for identifying parathyroid adenomas. MRI should be performed on a high-field strength system using a surface coil. Accuracy can be improved and artifacts related to heart motion can be reduced by using electrocardiogram (ECG) gating. The administration of intravenous contrast (gadolinium) can help to increase lesion conspicuity. The appearance of adenomas on MRI is variable. 28 Usually, adenomas are of intermediate signal intensity compared with the thyroid gland and muscle, but of low signal intensity compared with fat on Tl-weighted images; they usually are hyperintense on T2-weighted images. They may enhance avidly after gadolinium administration (Figs 2C and 2D). Some lesions with high cellularity may be isointense or hyperintense on Tl-weighted images and isointense on T2-weighted images (Fig 4). It is uncommon for an adenoma to be hypointense on T2weighted images. Pitfalls in detection of parathyroid adenomas include confusion with cervical
Fig 2. A pitfall in ~mTc sestamibi scintigraphy is t h a t t h y r o i d lesions m a y concentrate sestamibi similar t o parathyroid adenomas. (A) This sestamibi scan obtained 1 hour after injection of radiotracer s h o w s increased activity over t h e right lobe of t h e t h y r o i d gland. (B) A transverse ultrasound image in t h e same patient s h o w s a w e l l - d e m a r c a t e d mass in t h e t h y r o i d (black arrows) t h a t w a s identified at surgery as a t h y r o i d adenoma, as w e l l as a rounded mass hypoechoic t o and posterior t o the t h y r o i d ; the latter w a s identified as a parathyroid adenoma ( w h i t e arrows). J, jugular vein; A, carotid artery. (C and D) Corresponding MRIs s h o w T2-hyperintensity in the t h y r o i d and parathyroid a d e n o m a s (C) as w e l l as e n h a n c e m e n t on postcontrast images (D) (arrows).
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Fig 3, Ectopic parathyroid adenoma. (A) Chest CT shows a small soft tissue mass in the anterior mediastinum (arrow). (B) A delayed image from a sestamibl scan shows increased uptake in the ectopic parathyroid adenoma (arrow),
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Fig 4. Parathyroid adenoma. (A) Axial Tl-weighted MRI shows a mass just posterior and inferior to the left lobe of the thyroid gland that is centrally hyperintense (*). {B) Axial T2-weighted image at the same level also shows the lesion to be hyperintense (*).
lymph nodes and large cervical ganglia as well as the multiplicity of ectopic sites. 28 Distinction between abnormal gland and vessel is less problematic with MR because of its ability to identify vascular structures (flow void) readily. MR has a reported accuracy of more than 90%. 29
Nuclear scintigraphy, used to identify parathyroid adenomas, may be performed with several radionuclides including thallium 201 (2mT1)/ technetium 99m (99mTC) pertechnetate subtraction scanning or 99mTc sestamibi subtraction imaging with iodine 123 (123I) or 99mTcpertech-
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netate. Because there are no radionuclides that are exclusively taken up by the parathyroid glands, subtraction techniques allow radionuclides that are concentrated in the thyroid gland (technetium and iodine) to be subtracted from those that accumulate in both thyroid and Parathyroid tissue (thallium and sestamibi). Thallium 201 is a potassium analog that is taken up by the thyroid as well as concentrated in parathyroid adenomas because of changes in potassium turnover. As a sole imaging agent, 2roT1 cannot distinguish a parathyroid adenoma from the thyroid gland. Thallium emits low2 energy photons and washes out of adenomas rapidly. Technetium has higher energy photons that penetrate the anterior neck and mediastin u m better. TeChnetium 99m is trapped in thyroid but not parathyroid tissue. When 2roT1 and 99mTc pertechnetate images are coregistered, computer-based subtraction techniques can remove the thyroid component, permitting identification of abnormal parathyroid tissue. Typically, 2 to 5 millicuries (mCi) of each tracer is administered intravenously, and either sequential or dual-isotope imaging is performed. The mediastinum should be included in the field of view to assess for possible ectopic adenomas. After thyroid subtraction, a perithyroidal parathyroid adenoma appears as a focus of increased thallium uptake (Fig 5). The major limitation of this examination is motion artifact, which may degrade the images, making superimposition of the images and subtraction unreliable, and interpretation difficult. The reported sensitivity and diagnostic accuracy of 2°lT1/99mTcsubtraction scintigraPhY varies, but each is approximately 80%. 3o Falsepositive examinations may result secondary to inflammatory conditions, lymphoma, and thyroid nodules. Size is an important factor in determining the sensitivity of subtraction scintigraphy. Specifically, lesions weighing less than 0.5 g rarely are visualized (the normal parathyroid gland weighs less than 700 mg). The histological content of the adenoma also influences sensitivity, with greater accuracy seen in lesions having a high Concentration of mitochondria. 3a Technetium-99m-sestamibi scintigraphy was introduced in the late 1980s.32 Technetium 99m sestamibi is a positively charged, lipid soluble,
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Fig 5. Parathyroid adenoma detected by 2°ITI/SSmTC pertechnetate subtraction imaging. Computer techniques allow technetium concentrated in the thyroid gland (A) to be subtracted from thallium, which accumulates both within (A) thyroid and parathyroid tissue (B). After thyroid subtraction, a perithyroidal parathyroid adenoma appears as a focus of increased thallium uptake (arrows) (C).
myocardial perfusion tracer. The mechanism for sestamibi uptake is poorly understood, but it may correspond to mitochondrial content in oxyphil cells, blood flow within adenomas, and/or potassium turnover. The intracellular distribution is determined by the negative transmembrane potential of cellular and mitochon-
drial membranes. Therefore, cells with a high mitochondrial content are believed to retain more of the positively charged tracer. Technetium 99m sestamibi can be used alone. taking advantage of rapid washout of the tracer from the thyroid gland and the avid retention in parathyroid lesions. Delayed images are all that
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is usually necessary for good localization. Images are obtained of the neck and chest immediately after injection of 10 to 30 mCi of radiotracer. Delayed images are obtained in the same sites approximately 2 to 4 hours after injection of the tracer. 33,34 Parathyroid adenomas are identified as loci of increased radiotracer uptake. Single-photon-emission CT (SPECT) can be combined with 99mTc sestamibi scintigraphy for more accurate adenoma localization. The accuracy of 99mTcsestamibi is better than that of 2°lT1/99mTc pertechnetate subtraction scintigraphy, with the accuracy Of Sestamibi ranging from 90% to 100% and the Specificity being consistently high. 34"39 The most recent data on sestamib! scintigraphy suggest that it surpasses all other imaging modalities--including ultrasound and CT--in both sensitivity and accuracy. Only a few studies have compared the accuracy of sestambi parathyroid scintigraphy with that of MRI. Some studies suggest that sestamibi is slightly more accurate than MR4°; however, other studies suggest that MR is better. 4~ Potential pitfalls in 99mTCsestambi scintigraphy include the occasional adenoma with rapid washout attributed to a low mitochondrial content, 42 poor conspicuity of lesions near the heart, and the occasional thyroid lesion or Hiirthle cell tumor that may retain 99mTcsestamibi. 43 The high rate of concomitant thyroid lesions (40% t ° 50%) in patients with parathyroid adenomas may lead to false-positive scintigraphy because thyroid lesions may concentrate sestamibi to the same degree as parathyroid adenomas2,18,38,39,44 (Fig 2). In addition, sestamibi uptake in thyroid cancers, as well as in nodal and distant metastases, has been reported.45,46
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occasion. The remainder of the adenomas are located in the deep cervical region. 2,15.47 A consensus in the literature is that imaging before reoperation is useful despite the cost. When preoperative imaging is performed, the success rate of surgery is approximately 80% to 90%, compared with 65% when imaging is not performed before reoperation. 8 In reoperations, the sensitivities of ultrasonography, CT. MRI. and scintigraphy are quite variable, z8.23-484° One of the major differences in imaging for detection of a parathyroid adenoma in patients who have failed prior surgery is that scar tissue in the operative bed in the perithyroidal region makes image interpretation, as well as anatomic detection at surgery, more difficult. As with cross-sectional imaging at initial surgery, lymphadenopathy may be mistaken for an adenoma. Because the incidence of false-positive examinations caused by lymphadenopathy is lowest with nuclear imaging,2 sestamibi scintigraphy as a single study is probably the most accurate and cost-effective means of detecting parathyroid adenomas. However. the increased surgical risk in cases of reoperation, including vocal cord paralysis15 and the distortion of anatomic landmarks related to prior surgery, causes many surgeons to feel that a functional scintigraphiC study combined with an anatomic cross-sectional examination (MR having a lower incidence of mistaking a lymph node for an adenoma compared with CT and ultrasoundz) is warranted. This combination of studies provides the most accurate means of detecting parathyroid tissue, despite its being a less costeffective approach. In general, MR in combination with sestamibi imaging allows accurate detection of parathyroid tissue, s°.51
Parathyroid Hyperplasia Reoperationfor Hyperparathyroidism In patients with recurrent hyperparathyroidism after surgery, reoperation shows abnormal parathyroid glands in the perithyroidal region in 30% to 75% of cases; these glands probably Correspond to parathyroids overlooked during initial surgery,z,15,17 Parathyroid adenomas also may be detected in the anterior mediastinum in 30% of cases and may be intrathyroidal on
Parathyroid hyperplasia accounts for hyperparathyroidism in up to 15% of patients and may be seen in multiple endocrine neoplasia (MEN) syndromes, most notably MEN-IIA. Parathyroid hyperplasia is difficult to evaluate with any imaging modality because of the small size of hyperp!astic glands. In addition, when there is a discrepancy in the size of the glands, the surgeon may conclude that a single parathy-
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roid adenoma is responsible for the hyperparathyroidism. The reported sensitivity for the detection of parathyroid hyperplasia is low, ranging from approximately 30% to 70% with cross-sectional imaging techniques. 6-s,23 More recently, 99mTcsestamibi has detected parathyroid hyperplasia in 50% to 75% of cases. 7,8,38,52
(Fig 6). Only invasion of the adjacent tissues or lymph node or distant metastases may help to distinguish a parathyroid carcinoma from an adenoma in the setting of hyperparathyroidism. Some parathyroid carcinomas may take up 99mTC sestamibi. 55
Parathyroid Carcinoma
Parathyroid Cyst
Parathyroid carcinoma is an unusual cause of hyperparathyroidism, accounting for fewer than 2% of all cases. However, hyperparathyroidism accounts for the Clinical presentation of approximately 85% of all parathyroid carcinomas. 1 There are no characteristic imaging features of parathyroid carcinomas that allow it to be readily distinguishable from a n adenoma or other soft tissue mass. Lymph node metastases may occur in up to one third of patients and distant metastases in approximately 25% of patients. Parathyroid carcinomas may also invade adjacent tissues including surrounding fat, cervical musculature, or the thyroid gland 53,54
Parathyroid cysts, like adenomas, most commonly arise in the region of the inferior pole of the thyroid gland. These cysts are rare in children. more common in women, and typically present in the fourth to fifth decades of life? On imaging, they usually are large and unilocular and have variable MR and CT characteristics depending on their protein content (Fig 7). They may be difficult to distinguish from cystic or necrotic lymph nodes or from cysts derived from other sources. Parathyroid cysts may be congenital, resulting from branchial pouch remnants, or they may be aquired (parathyroid adenomas may degenerate into cysts).
Fig 6. Parathyroid carcinoma. (A) A sof t tissue mass in the left paratrachea! region (M) has no features that distinguish it from an adenoma or other head and neck masses,
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Fig 7. Parathyroid cyst. (A) Axial Tl-weighted and (B) fat-saturated T2-weighted images show typical features of a cystic lesion (arrows), There is a myocutaneous flap in the right thyroidectomy bed (*),
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LAURIE A. LOEVNER REFERENCES
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36. Hindie E, Melliere D, Simon D, et al: Primary hyperparathyroidism: Is technetium 99m-sestamibi/iodine123 subtraction scanning the best procedure to locate enlarged glands before surgery? J Clin Endocrinol Metab 80:302-307, 1995 37. Khan A, Samtani S, Varma VM, et al: Preoperative parathyroid localization: Prospective evaluation of technetium-99m sestamibi. Otolaryngol Head Neck Surg 111:467472, 1994 38. O'Doherty MJ, Kettle AG, Wells P, et al: Parathyroid imaging with technetium-99m-sestamibi: Preoperative localization and tissue uptake studies. J Nucl Med 33:313-318, 1992 39. Oates E: Improved parathyroid scintigraphy with Tc-99m MIBI, a superior radiotracer. Appl Radiol 13:37-42, 1994 40. McBiles M, Lambert AT, Cote MG, Kim SY: Sestamibi parathyroid scintigraphy. Semin Nucl Med 25:221234, 1995 41. Nunerow LM, Morita ET, Clark OH, Higgins CB: Persistent/recurrent hyperparathyroidism: A comparison of sestamibi scintigraphy, MRI, and ultrasonography. J Magn Reson Imaging 5:702-708, 1995 42. Benard F, Lefebvre B, Beuvon F, et al: Rapid washout of technetium-99m-MIBI from a large parathyroid adenoma. J Nucl Med 36:241-243, 1995 43. Vattimo A, Bertelli P, Cintorino N, et al: Identification of Htirthle cell tumor by single-injection, double-phase scintigraphy with technetium-99m-sestamibi. J Nucl Med 36:778-782, 1995 44. Funari M, Campos Z, Gooding GA, et al: MRI and ultrasound detection of asymptomatic thyroid nodules in hyperparathyroidism. J Comput Assist Tomogr 16:615-619, 1992 45. Szybinski Z, Huszno B, Golkowski F, et al: Technetium 99m-methoxyisobutylisonitrile in early diagnosis of thyroid cancer. Endokrynol Po144:427-433, 1993
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46. Yen TC, Lin HD, Lee CH, et al: The role of technetium-99m sestamibi whole-body scans in diagnosing metastatic Htirthle cell carcinoma of the thyroid gland after total thyroidectomy: A comparison with iodine-131 and thallium-201 whole-body scans. Eur J Nucl Med 21:980-983, 1994 47. Rodriquez JM, Tezelman S, Siperstein AE, et al: Localization procedures in patients with persistent or recurrent hyperparathyroidism. Arch Surg 129:870-875, 1994 48. Hamilton R, Greenburg BM, Gefter W, et al: Successful localization of parathyroid adenomas by magnetic resonance imaging. Am J Surg 155:370-373, 1988 49. Peck WW, Higgins CB, Fisher MR, et al: Hyperparathyroidism: Comparison of MR imaging with radionuclide scanning. Radiology 163:415-420, 1987 50. Kang YS, Rosen K, Clark OH, et al: Localization of abnormal parathyroid glands of the mediastinum with MR imaging. Radiology 189:137-141, 1993 51. Weber CJ, Vansant J, Alazraki N, et al: Value of technetium-99m-sestamibi iodine-123 imaging in reoperative parathyroid surgery. Surgery 114:1011-1018, 1993 52. Lee VS, Wilkinson RH, Leight GS, et al: Hyperparathyroidism in high-risk surgical patients: Evaluation with double-phase technetium-99m sestamibi imaging. Radiology 197:627-633, 1995 53. Edmonson GR, Charboneau JW, James EM, et al: Parathyroid carcinoma: High-frequency sonographic features. Radiology 161:65-67, 1986 54. vanHeerden JA, Weiland LH, ReMine WH, et al: Cancer of the parathyroid gland. Arch Surg 114:475-479, 1979 55. Kitapci MT, Tastekin G, Turgut M, et al: Preoperative localization of parathyroid carcinoma using Tc-99m MIBI. Clin Nucl Med 18:217-219, 1993
controversial. The embryology, anatomy, and physiologi/of the parathyroid glands are reviewed. The diagnostic utility of radiological imaging--inCluding ultrasonography, CT, MR imaging, and nuclear rscintigraphy---are discussed, particularly as it pertains to the evaluation of primary hyperparathyroidism. Copyright © 1996 by W,B. Saunders Company
HE PARATHYROID glands arise from the third and ,fourth branchial pouches. The upper or superior parathyroid glands arise from the fourth branchial pouch along with the lateral anlages of the thyroid gland. Because the upper parathyroid glands are related closely to the thyroid and have a minimal descent, their positions are relatively constant. Fewer than 2% of the superior parathyroid glands are ectopic in location. The lower or inferior parathyroid glands and thynius are derived from the third branchial pouch; in contrast to the upper glands, the lower glands descend a great distance with the thymic anlage. Therefore. the position of the inferior parathyroid glands is more variable because they may descend into the anterior mediastinum as far as the pericardium. The upper parathyroid glands usually are supplied by a branch of the superior thyroidal arteries, whereas the lower parathyroid glands are supplied by the inferior thyroidal arteries. Drainage from the glands is usually to thyroidal veins. The cervical sympathetic plexus innervates the parathyroid glands. The number of parathyroid glands ranges from two to six, although most individuals have four. ~ The most common anatomic location of the upper parathyroid glands is posterior to the middle one third of the thyroid (75% of the time). Most of the other upper parathyroid glands are located behind the upper or lower one third Of the thyroid, with approximately 7% found below the inferior thyroidal artery) The most common anatomic location of the lower parathyroid glands is lateral to the lower pole of the thyroid gland (50% of the time). The next most common location (15% of the time) encompasses an area 1 cm below the lower thyroid pole. The position of the remaining one third is variable along the thyrothymic tract, extending
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anywhere from the angle of the mandible to the lower anterior mediastinum. Intrathyroidal parathyroid glands are uncommon, being present in only 2% of cases. It is not possible with current imaging techniques to distinguish an intrathyroidal parathyroid adenoma from a primary thyroid lesion. 2-3 ENDOCRINOLOGY OF THE PARATHYROID GLANDS The parathyroid glands are composed of chief cells and oxyphil cells, both of which are embedded within fibrous and adipose tissue. The role of the oxyphi! cells is unknown: They appear around puberty and increase with age. Chief cells secrete parathormone (PTH), which regulates the concentration of calcium in interstitial fluids. The secretion of PTH, in turn, is regulated by serum calcium levels. Parathormone acts predominantly in three regions: (a) the skeleton to mobilize calcium into the plasma, (b) the kidneys to reduce calcium excretion, and (c) the gastrointestinal tract to increase calcium absorption. 4 Parathormone enhances the synthesis of 1,25-(OH)D3, which promotes the absorption of calcium by the intestines. In patients with elevated serum calcium concentrations, PTH should be suppressed. A normal PTH level encountered in the setting of hypercalcemia is referred to as hyperparathyroidism.
From the Department of Radiology, Neuroradiology Section, University of Pennsylvania Medical Center, Philadelphia, PA. Address reprint requests to Laurie A. Loevner, MD, Department of Radiology, Neuroradiology Section, University of Pennsylvania Medical Center, 3400 Spruce St, Philadelphia. PA 19104. Copyright © 1996 by W.B. Saunders Company 0887-2171/96/1706-000455.00/0
Seminars in Ultrasound, CT, andMRI, Vo117, No 6 (December), 1996: pp 563-575
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CLINICAL MANIFESTATIONS OF PARATHYROID DISEASE
Hyperparathyroidisrn Primary hyperparathyroidism is common, occurring in approximately i of every 700 adults. 5 It occurs secondary to hypersecretion of PTH, resulting in hypercalcemia. The causes of primary hyperparathyroidism include a single parathyroid adenoma (80% to 85% of cases), parathyroid hyperplasia (10% to 15%), multiple parathyroid adenomas (2% to 3%), and, rarely, parathyroid carcinomas (fewer than 1%). 3,6-8 Solitary adenomas vary widely in size, from less than 1 cm to several centimeters. Hyperplasia typically involves multiple parathyroid glands. The classic clinical features include bone pain related to osseous demineralization, abdominal pain secondary to renal calculi, and occasional psychiatric disturbances (Fig 1). The treatment of primary hyperparathyroidism is surgical excision of the abnormal parathyroid gland. Most surgeons perform bilateral neck explorations because very small lesions or hyperplasia may be overlooked with current imaging techniques. Although the need for preoperative radiological localization remains a topic of debate, some authors report fewer complications and shorter operating times when abnormal parathyroid glands are identified before surgery. 3,9,10 Nonetheless, there are certain situations in which imaging plays a very useful role. This includes the evaluation of high-risk surgical patients in whom imaging may permit the surgeon to resect the abnormal gland with only a unilateral neck exploration. Alternatively, percutaneous injection of absolute ethanol to ablate adenomas may be performed under ultrasound guidance in patients who are poor surgical candidates because of underlying medical illness.11,~2 Success of the treatment is monitored with serum calcium levels, which are followed until levels approach near normal values. Also, when hyperparathyroidism recurs after surgery, imaging is indicated because ectopic glands are prevalent in these patients. There are secondary and tertiary forms of hyperparathyroidism as well. Secondary hyperparathyroidiSm occurs in patients with longstanding renal failure, leading to changes in calcium metabolism, which in turn results in
enlargement of the parathyroid glands. In tertiary hyperparathyroidism, hypercalcemia occurs as a sequela of secondary hyperparathyroidism because of the autonomous Secretion of PTH from chronically overstimulated parathyroid glands.
Hypoparathyroidism Almost all cases of primary hypoparathyroidism are related to surgical removal of the parathyroid glands for management of primary hyperParathyroidism or inadvertent parathyroid resection during thyroidectomy for thyroid pathology. Idiopathic primary hypoparathyroidism is a disease of childhood. Imaging of the parathyroid glands in cases of hypoparathyroidism is limited to surveillance for congenital absence Of the glands, a study best achieved with scintigraphy. IMAGING OF THE PARATHYROID GLANDS
ParathyroidAdenoma Indications for preoperative localization of parathyroid adenomas remain a topic of debate. In addition, the choice of appropriate imaging modality also is debated in the literature. When imaging is used, options include ultras0nography, CT, MRI, and nuclear scintigraphy. Conventional catheter and digital Subtraction angiography, as well as selective parathyroid venography with sampling and measurement of PTH levels, are highly accurate in detecting parathyroid adenomas; however, their major drawbacks are their cost and invasiveness. At manY institutions with experienced parathyroid surgeons, preoperative localization of the glands with imaging is not performed because some studies have suggested that the morbidity, mortality, and operative time are not greatly affected by preoperative localization. 13-15 In addition, some investigators argue that the cost of imaging outweighs its benefit, a4,16 The surgical technique includes exploration of the perithyroidal region bilaterally with a particular emphasis on the inferior poles of the thyroid glands, where most parathyroid adenomas occur. In the hands of skilled surgeons, this procedure may be performed with a success rate of more than 90%. 3'14'17-19 When a parathyroid adenoma is not identified in the perithyroida! locati0nl the surgeon may explore the anterior
Fig 1. Patient with hyperparathyroidism who presented with diffuse bone pain. (A) Axial enhanced CT shows a hypodense mass just posterior to the inferior pole of the left lobe of the thyroid gland (a). At surgery, this mass was identified as a parathyroid adenoma separate from the thyroid. (B) Lateral plain film radiograph shows the classic "salt and pepper" skull. (C) Bone scan shows the increased activity in the calvarium and decreased activity in the kidneys that have been described in association with hyperparathyroidism.
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mediastinum, deep cervical space, and carotid sheath regions. Successful surgery in these cases is lower (less than 70%), and the surgical complication rate is higher.17 Arguments for performing preoperative imaging to localize the parathyroid glands include: (a) the need for only unilateral neck dissection when an adenoma is detected; (b) the identification of ectopic adenomas; (c) the detection of other head and neck masses (eg, thyroid lesions); and (d) a reduction in operating room time. 1°a9-21 In addition, the operative success rate improves from 90% to nearly 100% with preoperative imaging. = UItrasonography of the parathyroid glands typically is performed by an experienced sonographer, with a high-resolution linear array transducer (7.5 to 10 MHz). The patient is imaged in the supine position with the neck mildly hyperextended. The examination includes evaluation of the perithyroidal areas and the region of the carotid sheaths, extending from the angle of the mandible superiorly to the sternal notch inferiorly. The typical appearance of a parathyroid adenoma is that of a homogeneous, demarcated mass with an echogenicity less than that of the thyroid gland ls,23 (Fig 2B). Adenomas typically are solid but may have cystic components. In addition, adenomas may degenerate into cysts. Color Doppler ultrasonography may occasionally provide additional information that may help to distinguish thyroid from parathyroid lesions. Specifically, thyroid lesions tend to have some vascularity, whereas small parathyroid lesions more often lack Doppler signal. On occasion, larger parathyroid lesions may be vascular. 24 For adenomas located in the perithyroidal region, ultrasonography is an excellent imaging modality. Limitations predominantly center around the fact that ultrasonography is less accurate than other imaging modalities in identifying eetopic parathyroid adenomas. Evaluation of the anterior mediastinum is limited because of acoustic impedance by air and bone. In addition, adenomas dose to air-filled structures, such as the trachea or esophagus, may be obscured by scanning artifact. Ultrasonography identifies adenomas in 95% of glands heavier than 1 g.18 Investigators report a sensitivity of 50% to 70% and a specificity of
LAURIE A. LOEVNER
90% to 95% for adenomas in hyperplastic glands.6,7,1s,23,25 Cross-sectional techniques (CT and MR) allows imaging to be performed through the neck from the skull base through the anterior mediastinum, thus allowing detection of ectopic parathyroid adenomas (Fig 3). CT images should include thin sections (3 to 5 ram). Intravenous contrast must be used in CT both to distinguish blood vessels from adenomas and because up to 25% of parathyroid adenomas enhance. 23 Limitations of CT in detecting adenomas include scanning artifact and artifacts related to swallowing and breathing. Lymph nodes, tortuous vessels, and the esophagus may be mistaken for adenomas. Another drawback to CT is that the use of iodinated contrast prevents subsequent imaging with iodine-based radionuclides because of the uptake of contrast by the thyroid gland. Thus, it is necessary to wait 6 to 8 weeks before nuclear scintigraphy with iodinated agents may be performed accurately. 26Investigators have found that, in general, both the sensitivity and specificity of high-resolution CT are improved over those of ultrasound, being approximately 70% and 90%, respectively. 23,27 MRI, like CT, allows excellent evaluation of the mediastinum. This method offers superior soft tissue discrimination and is more sensitive than CT for identifying parathyroid adenomas. MRI should be performed on a high-field strength system using a surface coil. Accuracy can be improved and artifacts related to heart motion can be reduced by using electrocardiogram (ECG) gating. The administration of intravenous contrast (gadolinium) can help to increase lesion conspicuity. The appearance of adenomas on MRI is variable. 28 Usually, adenomas are of intermediate signal intensity compared with the thyroid gland and muscle, but of low signal intensity compared with fat on Tl-weighted images; they usually are hyperintense on T2-weighted images. They may enhance avidly after gadolinium administration (Figs 2C and 2D). Some lesions with high cellularity may be isointense or hyperintense on Tl-weighted images and isointense on T2-weighted images (Fig 4). It is uncommon for an adenoma to be hypointense on T2weighted images. Pitfalls in detection of parathyroid adenomas include confusion with cervical
Fig 2. A pitfall in ~mTc sestamibi scintigraphy is t h a t t h y r o i d lesions m a y concentrate sestamibi similar t o parathyroid adenomas. (A) This sestamibi scan obtained 1 hour after injection of radiotracer s h o w s increased activity over t h e right lobe of t h e t h y r o i d gland. (B) A transverse ultrasound image in t h e same patient s h o w s a w e l l - d e m a r c a t e d mass in t h e t h y r o i d (black arrows) t h a t w a s identified at surgery as a t h y r o i d adenoma, as w e l l as a rounded mass hypoechoic t o and posterior t o the t h y r o i d ; the latter w a s identified as a parathyroid adenoma ( w h i t e arrows). J, jugular vein; A, carotid artery. (C and D) Corresponding MRIs s h o w T2-hyperintensity in the t h y r o i d and parathyroid a d e n o m a s (C) as w e l l as e n h a n c e m e n t on postcontrast images (D) (arrows).
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Fig 3, Ectopic parathyroid adenoma. (A) Chest CT shows a small soft tissue mass in the anterior mediastinum (arrow). (B) A delayed image from a sestamibl scan shows increased uptake in the ectopic parathyroid adenoma (arrow),
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Fig 4. Parathyroid adenoma. (A) Axial Tl-weighted MRI shows a mass just posterior and inferior to the left lobe of the thyroid gland that is centrally hyperintense (*). {B) Axial T2-weighted image at the same level also shows the lesion to be hyperintense (*).
lymph nodes and large cervical ganglia as well as the multiplicity of ectopic sites. 28 Distinction between abnormal gland and vessel is less problematic with MR because of its ability to identify vascular structures (flow void) readily. MR has a reported accuracy of more than 90%. 29
Nuclear scintigraphy, used to identify parathyroid adenomas, may be performed with several radionuclides including thallium 201 (2mT1)/ technetium 99m (99mTC) pertechnetate subtraction scanning or 99mTc sestamibi subtraction imaging with iodine 123 (123I) or 99mTcpertech-
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netate. Because there are no radionuclides that are exclusively taken up by the parathyroid glands, subtraction techniques allow radionuclides that are concentrated in the thyroid gland (technetium and iodine) to be subtracted from those that accumulate in both thyroid and Parathyroid tissue (thallium and sestamibi). Thallium 201 is a potassium analog that is taken up by the thyroid as well as concentrated in parathyroid adenomas because of changes in potassium turnover. As a sole imaging agent, 2roT1 cannot distinguish a parathyroid adenoma from the thyroid gland. Thallium emits low2 energy photons and washes out of adenomas rapidly. Technetium has higher energy photons that penetrate the anterior neck and mediastin u m better. TeChnetium 99m is trapped in thyroid but not parathyroid tissue. When 2roT1 and 99mTc pertechnetate images are coregistered, computer-based subtraction techniques can remove the thyroid component, permitting identification of abnormal parathyroid tissue. Typically, 2 to 5 millicuries (mCi) of each tracer is administered intravenously, and either sequential or dual-isotope imaging is performed. The mediastinum should be included in the field of view to assess for possible ectopic adenomas. After thyroid subtraction, a perithyroidal parathyroid adenoma appears as a focus of increased thallium uptake (Fig 5). The major limitation of this examination is motion artifact, which may degrade the images, making superimposition of the images and subtraction unreliable, and interpretation difficult. The reported sensitivity and diagnostic accuracy of 2°lT1/99mTcsubtraction scintigraPhY varies, but each is approximately 80%. 3o Falsepositive examinations may result secondary to inflammatory conditions, lymphoma, and thyroid nodules. Size is an important factor in determining the sensitivity of subtraction scintigraphy. Specifically, lesions weighing less than 0.5 g rarely are visualized (the normal parathyroid gland weighs less than 700 mg). The histological content of the adenoma also influences sensitivity, with greater accuracy seen in lesions having a high Concentration of mitochondria. 3a Technetium-99m-sestamibi scintigraphy was introduced in the late 1980s.32 Technetium 99m sestamibi is a positively charged, lipid soluble,
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Fig 5. Parathyroid adenoma detected by 2°ITI/SSmTC pertechnetate subtraction imaging. Computer techniques allow technetium concentrated in the thyroid gland (A) to be subtracted from thallium, which accumulates both within (A) thyroid and parathyroid tissue (B). After thyroid subtraction, a perithyroidal parathyroid adenoma appears as a focus of increased thallium uptake (arrows) (C).
myocardial perfusion tracer. The mechanism for sestamibi uptake is poorly understood, but it may correspond to mitochondrial content in oxyphil cells, blood flow within adenomas, and/or potassium turnover. The intracellular distribution is determined by the negative transmembrane potential of cellular and mitochon-
drial membranes. Therefore, cells with a high mitochondrial content are believed to retain more of the positively charged tracer. Technetium 99m sestamibi can be used alone. taking advantage of rapid washout of the tracer from the thyroid gland and the avid retention in parathyroid lesions. Delayed images are all that
IMAGING OF THE PARATHYROID GLANDS
is usually necessary for good localization. Images are obtained of the neck and chest immediately after injection of 10 to 30 mCi of radiotracer. Delayed images are obtained in the same sites approximately 2 to 4 hours after injection of the tracer. 33,34 Parathyroid adenomas are identified as loci of increased radiotracer uptake. Single-photon-emission CT (SPECT) can be combined with 99mTc sestamibi scintigraphy for more accurate adenoma localization. The accuracy of 99mTcsestamibi is better than that of 2°lT1/99mTc pertechnetate subtraction scintigraphy, with the accuracy Of Sestamibi ranging from 90% to 100% and the Specificity being consistently high. 34"39 The most recent data on sestamib! scintigraphy suggest that it surpasses all other imaging modalities--including ultrasound and CT--in both sensitivity and accuracy. Only a few studies have compared the accuracy of sestambi parathyroid scintigraphy with that of MRI. Some studies suggest that sestamibi is slightly more accurate than MR4°; however, other studies suggest that MR is better. 4~ Potential pitfalls in 99mTCsestambi scintigraphy include the occasional adenoma with rapid washout attributed to a low mitochondrial content, 42 poor conspicuity of lesions near the heart, and the occasional thyroid lesion or Hiirthle cell tumor that may retain 99mTcsestamibi. 43 The high rate of concomitant thyroid lesions (40% t ° 50%) in patients with parathyroid adenomas may lead to false-positive scintigraphy because thyroid lesions may concentrate sestamibi to the same degree as parathyroid adenomas2,18,38,39,44 (Fig 2). In addition, sestamibi uptake in thyroid cancers, as well as in nodal and distant metastases, has been reported.45,46
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occasion. The remainder of the adenomas are located in the deep cervical region. 2,15.47 A consensus in the literature is that imaging before reoperation is useful despite the cost. When preoperative imaging is performed, the success rate of surgery is approximately 80% to 90%, compared with 65% when imaging is not performed before reoperation. 8 In reoperations, the sensitivities of ultrasonography, CT. MRI. and scintigraphy are quite variable, z8.23-484° One of the major differences in imaging for detection of a parathyroid adenoma in patients who have failed prior surgery is that scar tissue in the operative bed in the perithyroidal region makes image interpretation, as well as anatomic detection at surgery, more difficult. As with cross-sectional imaging at initial surgery, lymphadenopathy may be mistaken for an adenoma. Because the incidence of false-positive examinations caused by lymphadenopathy is lowest with nuclear imaging,2 sestamibi scintigraphy as a single study is probably the most accurate and cost-effective means of detecting parathyroid adenomas. However. the increased surgical risk in cases of reoperation, including vocal cord paralysis15 and the distortion of anatomic landmarks related to prior surgery, causes many surgeons to feel that a functional scintigraphiC study combined with an anatomic cross-sectional examination (MR having a lower incidence of mistaking a lymph node for an adenoma compared with CT and ultrasoundz) is warranted. This combination of studies provides the most accurate means of detecting parathyroid tissue, despite its being a less costeffective approach. In general, MR in combination with sestamibi imaging allows accurate detection of parathyroid tissue, s°.51
Parathyroid Hyperplasia Reoperationfor Hyperparathyroidism In patients with recurrent hyperparathyroidism after surgery, reoperation shows abnormal parathyroid glands in the perithyroidal region in 30% to 75% of cases; these glands probably Correspond to parathyroids overlooked during initial surgery,z,15,17 Parathyroid adenomas also may be detected in the anterior mediastinum in 30% of cases and may be intrathyroidal on
Parathyroid hyperplasia accounts for hyperparathyroidism in up to 15% of patients and may be seen in multiple endocrine neoplasia (MEN) syndromes, most notably MEN-IIA. Parathyroid hyperplasia is difficult to evaluate with any imaging modality because of the small size of hyperp!astic glands. In addition, when there is a discrepancy in the size of the glands, the surgeon may conclude that a single parathy-
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roid adenoma is responsible for the hyperparathyroidism. The reported sensitivity for the detection of parathyroid hyperplasia is low, ranging from approximately 30% to 70% with cross-sectional imaging techniques. 6-s,23 More recently, 99mTcsestamibi has detected parathyroid hyperplasia in 50% to 75% of cases. 7,8,38,52
(Fig 6). Only invasion of the adjacent tissues or lymph node or distant metastases may help to distinguish a parathyroid carcinoma from an adenoma in the setting of hyperparathyroidism. Some parathyroid carcinomas may take up 99mTC sestamibi. 55
Parathyroid Carcinoma
Parathyroid Cyst
Parathyroid carcinoma is an unusual cause of hyperparathyroidism, accounting for fewer than 2% of all cases. However, hyperparathyroidism accounts for the Clinical presentation of approximately 85% of all parathyroid carcinomas. 1 There are no characteristic imaging features of parathyroid carcinomas that allow it to be readily distinguishable from a n adenoma or other soft tissue mass. Lymph node metastases may occur in up to one third of patients and distant metastases in approximately 25% of patients. Parathyroid carcinomas may also invade adjacent tissues including surrounding fat, cervical musculature, or the thyroid gland 53,54
Parathyroid cysts, like adenomas, most commonly arise in the region of the inferior pole of the thyroid gland. These cysts are rare in children. more common in women, and typically present in the fourth to fifth decades of life? On imaging, they usually are large and unilocular and have variable MR and CT characteristics depending on their protein content (Fig 7). They may be difficult to distinguish from cystic or necrotic lymph nodes or from cysts derived from other sources. Parathyroid cysts may be congenital, resulting from branchial pouch remnants, or they may be aquired (parathyroid adenomas may degenerate into cysts).
Fig 6. Parathyroid carcinoma. (A) A sof t tissue mass in the left paratrachea! region (M) has no features that distinguish it from an adenoma or other head and neck masses,
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Fig 7. Parathyroid cyst. (A) Axial Tl-weighted and (B) fat-saturated T2-weighted images show typical features of a cystic lesion (arrows), There is a myocutaneous flap in the right thyroidectomy bed (*),
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LAURIE A. LOEVNER REFERENCES
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