Imaging techniques for identifying parathyroid tumors

EMERGING Imaging Techniques for Identifying Parathyroid Tumors Gary G. Winzelberg

Recent advances in imaging techniques, including high-resolution sonography, parathyroid scintigraphy, computerized tomography, magnetic resonance imaging, venography and venous sampling, arteriography, and fine-needle aspiration biopsy, have made it possible consistently to identify parathyroid glands enlarged owing to adenoma formation, diffuse hyperplasia, or carcinoma. Whereas the routine use of these techniques in the previously unoperated patient with suspected hypevparathyroidism is debated, most experts would agree to their utility in patients with prior negative neck exploration in whom elevated serum calcium and parathyroid hormone persist.

The routine use of automated techniques to measure serum calcium levels and the widespread use of refined methods to measure biologically active parathyroid hormone have made disease states of the parathyroid glands a common endocrinologic problem (Heath et al. 1980). Whereas solitary parathyroid adenomas account for the vast majority of the abnormalities, diffuse parathyroid hyperplasia, parathyroid cysts, and parathyroid carcinoma are part of the spectrum of the diseases. Because of the low sensitivity and specificity of early radiologic techniques to identify enlarged parathyroid glands, historically most parathyroid surgery was performed without preoperative localization techniques. Although skilled endocrine surgeons boast success rates of ~95% in identifying abnormal parathyroid glands, the large number of second and third operations for persistently elevated calcium levels after failure of primary parathyroid exploration suggests that less skilled surgeons have less impressive results in identifying diseased parathyroids (Satava et al. 1975; Wang 1977; Saxe and Brennan 1982; Clark et Gary G. Winzelberg is at the Division of Nuclear Imaging, Shadyside Hospital, 5230 Centre Avenue, Pittsburgh, PA 15232, USA.

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al. 1985). The development of sophisticated cross-sectional imaging techniques has now made it possible to identify preoperatively the abnormal gland or glands in a significant number of patients and make the surgeon’s job shorter and less tedious. While the routine use of these imaging techniques for the previously unoperated-upon patient with suspected parathyroid anomalies is still somewhat controversial, these techniques are used routinely in those patients with initially unsuccessful parathyroid exploration (Winzelberg 1987; Miller et al. 1987a and b). Whereas most of these techniques provide indirect evidence for localization of the enlarged parathyroid gland, fine-needle aspiration biopsy techniques (Solbiati et al. 1983), which allow cytologic tcsting and improvements in assays for immunoreactive parathymeasuring roid hormone from the aspirated samples, have enabled positive preoperative localization, which is of ultimate concern for a second or third parathyroid exploration.

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Embryologic and Anatomic Considerations

The paired superior and inferior parathyroid glands arise from the fourth and

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TECHNIQUES third branchial pouches, respectively. In the normal state each gland weighs ~40 mg and on average measures 5 x 3 x 1 mm. The superior glands are reasonably constant in position and most often lie posterior to the cricothyroid junction, behind the upper pole of the thyroid or in the retropharyngeal and/or retroesophageal space (Wang 1976). When one or more of these glands enlarge, they are displaced inferiorly and may lie in the superior posterior mediastinum. The paired inferior parathyroid glands migrate with the thymus during embryonic development and have a much more varied range of location. Most commonly, they are located anteriorly, in the lateral posterior surface of the lower pole of the thyroid, in the thymic tongue remnant or lateral to the lower pole of the thyroid. When the inferior gland migrates into the mediastinum, it is usually anterior in position and supplied by a vascular pedicle of the inferior thyroidal artery. Hyperfunctioning supernumerary (fifth) glands have been reported and should be suspected when four normal glands are found and the patient has persistently elevated serum calcium and parathyroid hormone levels. These supernumeraries are frequently found in the thymic remnant in the neck or in the mediastinum in association with the thymus. A complete understanding of the developmental factors is mandatory for both the imaging specialist and surgeon caring for the patients with abnormal parathyroids.

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Parathyroid

Ultrasonography

High-resolution real-time ultrasonography has had considerable success in identifying enlarged parathyroid glands in patients with suspected parathyroid tumors (Scheible et al. 1981; van Heerden et al. 1982; Simeone et al. 1981; Reading et al. 1982). Technologic advances in ultrasound design that allow for a l- to 2-mm tissue resolution, along with a skilled sonographer, are requisites in achieving the ultimate success in sonography. Attention to details such as patient positioning during scanning is most important to optimize ultra-

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sound results. Optimal scanning is performed with the patient’s neck in a hyperextended position to bring low-lying parathyroid tumors that may be obscured by the clavicle or manubrium into the ultrasonic field of view. Unfortunately, the retrotracheal, retroesophageal, supraclavicular, and mediastinal areas cannot be adequately assessed with ultrasound because of the lack of an acoustical window to scan through. The typical ultrasound appearance of a solitary adenoma is a discrete area that is less echogenic (hypoechoic) than surrounding thyroid tissue. It usually has a discrete border, is separate, but may be contiguous with the thyroid and can vary in shape from being oval, round, crescentic, sausage-shaped, or bilobed. Often, the posteriorly located gland abuts against the posterior aspect of the thyroid, and it is difficult to know with certainty if the mass is extra- or intrathyroidal. In patients with diffuse parathyroid hyperplasia, multiple enlarged glands may be identified, but it is rare to see all four enlarged glands. In patients with underlying thyroid abnormalities such as multinodular goiters or thyroiditis, or with prior thyroid resection with distortion of normal anatomy, ultrasonography is more difficult and a skilled sonographer is necessary to maximize scan results. Protruding thyroid nodules or enlarged and inflamed lymph nodes can mimic enlarged parathyroid glands and reduce the specificity of scan results. In general, the sensitivity of ultrasonography for identifying adenomas is directly related to the size of the adenomas. Most false-negative tests occur with minimally enlarged glands weighing ~250 mg or with adenomas that are positioned within the mediastinum retrotracheally or in the retroesophageal space. In several large series, the sensitivity of ultrasonography for identifying adenomas in patients without prior neck exploration varied from 70% to 88%, with a specificity of 90%-94%. Van Heerden et al. (1982), using high-resolution sonography to preoperatively assess 100 consecutive patients with suspected primary hyperparathyroidism, had an overall sensitivity of 76%. The sensitivity was 96% with adenomas weighing >lOOO mg and 44% in those weighing ~250 mg. In their study, surgical success rate was not affected by scan results. Others have demonstrated that correct preoperative localization of en-

336

I(‘, 1990,

larged parathyroid

glands prior to sur-

gery can reduce the duration of surgery (Brewer et al. 1983), but to date ultrasonography has not been documented to decrease complications or the need for second neck explorations, although no specific study to answer these questions has been reported.

Results of ultrasonography in patients with suspected parathyroid tumors and negative initial neck explorations has been addressed by several authors. In one large series of 60 consecutive patients with recurrent or persistent hypercalcemia after initial negative neck exploration for abnormal parathyroids, ultrasonography showed a sensitivity of 82% and a specificity of 86% for identifying parathyroid tumors when mediastinal glands were excluded (Reading et al. 1985). Since the identification of a nodule or mass is only indirect evidence for a parathyroid tumor, and since many patients with initially negative neckexplorations have concomitant thyroid disease or altered natural anatomy, some authors have used ultrasonography to guide fineneedle aspiration biopsy of suspected parathyroid tumors (Solbiati et al. 1983). In one series of 42 patients, ultrasonography-guided fine-needle aspiration biopsy of 52 suspected tumors yielded cytologic evidence for parathyroid tumor in 31 and thyroid tissue in 14, and was nondiagnostic in seven. Since reoperation can be technically difficult owing to altered anatomy and loss of venous or soft tissue landmarks with concomitant scar tissue present, some authors have successfully used intraoperative ultrasonography to help identify parathyroid tumors not readily apparent with dissection and palpation (Miller et al. 1987b).

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Computed

Tomography

Initial studies using first- and secondgeneration computed tomography (CT)

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scanners yielded relatively poor sensitivities in identifying parathyroid adenomas in the neck, while having some success in the mediastinum. Refinements in CT technology that enable faster scanning times to reduce motion artifact along with bolus techniques of contrast injection, proper patient positioning with adequate neck extension, and thin overlying CT sections to the thyroid bed have significantly increased the sensitivity of CT in identifying abnormal parathyroid glands. On CT, enlarged parathyroid glands appear as discrete soft-tissue masses near or adjacent to the thyroid that show enhancement following intravenous contrast. Occasionally, an adenoma may have a cystic component. Pure parathyroid cysts do occur but generally are not endocrinely active and not associated with increased calcium or parathyroid hormone (PTH) levels. In patients with diffuse parathyroid hyperplasia, multiple enlarged glands can be identified. In one large series utilizing the above-described CT refinements along with a specially designed head harness to insure maximal neck extension, bolus contrast injection, and dynamic CT scanning, CT had a sensitivity of 70% for identifying cervical adenomas as compared to 65% for highresolution sonography (Stark et al. 1983). Sensitivity of CT appeared to be more dependent upon the size of the parathyroid gland than position. Thus, CT appears to be better suited to assess retropharyngeal, retrotracheal, and anterior, posterior, or superior mediastinal adenomas (Doppman et al. 1982). More recently, CT has also been used as a guide for fine-needle aspiration biopsy with tissue samples being assayed for immunoreactive PTH to confirm parathyroid tissue.

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Venography

and Venous Sampling

Venous sampling from the paired superior, middle, and inferior thyroid veins, which form a venous plexus around the thyroid, has been helpful in identifying parathyroid adenomas by identifying regional elevation of immunoreactive PTH that usually occurs on the side of the adenoma when the samples are compared to surrounding superior vena cava or inferior vena cava PTH levels (Reitz et al. 1969; Doppman et al. 1976). When ectopic glands are suspected, it is neces-

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Angiography

Because

enlarged

parathyroid

glands

are usually well vascularized, angiographic techniques have been successful in identifying

parathyroid

adenomas.

These are invasive procedures requiring a skilled angiographer and in general are not performed as a screening survey but are usually reserved for patients with initial negative exploration in whom a second exploration is planned. At our hospital, it is usually the last imaging procedure performed prior to neck exploration when other noninvasive examinations have been nondiagnostic. We usually perform venography and venous sampling first so that we can tailor the angiographic study to reduce its duration and minimize the contrast load. Angiographically, parathyroid adenomas appear as focal vascular tumors that may have an enlarged feeding vessel. Unfortunately, the angiographic appearance is nonspecific, as a vascular thyroid adenoma may have a similar appearance. The inferior thyroid artery, a branch of the thyrocervical trunk, supplies most nonectopic enlarged parathyroid adenomas. Selective injection of the superior thyroid artery (a branch of the

a

b Figure 1. A 64-year-old woman with an elevated serum calcium of 11.1 mg/dL and elevated PTH levels. (a) Anterior 20’Tl parathyroid scan (I&) shows increased uptake (black (IWOW)over scan (openm~otv) the lower pole of the left thyroid. 9”mTc scan (middle) is normal. Subtraction confirms thallium-avid left inferior parathyroid adenoma. (b) High-resolution parathyroid sonogram confirms 3 x 2-cm hypoechoic soft tissue mass in this area that is separate from the thyroid. At surgery, a 3-g left inferior parathyroid adenoma was found.

sary to sample the vertebral and thymic veins as well. Usually, venography is performed at the time of venous sampling to identify normal veins and to mark and identify aberrant venous structures carefully. Meticulous attention to detail at the time of the venous sampling is necessary to insure that the specific site of the origin of the venous sample is identified. Early work using venous sampling techniques located the general site of the enlarged parathyroid gland in 21 of 33 patients (Powell et al. 1972). In a recent series from the NIH in a series of patients with initial negative

neck exploration, venous sampling techniques had the highest sensitivity (80%) for identifying parathyroid adenomas when compared to intraoperative sonography (78%), selective angiography (60%), and digital subtraction angiography (49%) (Miller et al. 1987b). In our institution, we usually perform venous sampling and venography as an outpatient procedure. After the PTH levels are available and compared with the venogram, the general site of the adenoma is identified, and angiography is then performed prior to parathyroid reexploration.

external carotid artery) and the internal mammary artery may also be necessary to evaluate completely patients with suspected aberrant or ectopic parathyroid adenomas. Because blood vessels that supply the cervical spinal cord (branches of the costocervical trunk) can be confused with vessels that supply the inferior thyroid artery, a skilled angiographer is necessary to minimize any potential neurologic damage (Miller et al. 1987b). Recent advances in angiographic techniques, including the use of digital subtraction angiography to help enhance angiographic imaging, have been helpful as a further refinement to parathyroid angiography. Recent work at the NIH suggests that superselective arterial digital subtraction angiography appears to be as sensitive as conventional angiography for preoperative parathyroid localization in the neck and may be more sensitive for localization of mediastinal glands (Miller et al. 1989).

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Magnetic

Magnetic

Resonance

imaging (MRI) has used to identify enlarged parathyroid glands without ion-

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resonance

Imaging

successfully

tracer

TL2”

l-c-

and the poorer

mechanisms for ‘“‘Tl uptake in parathyroid adenomas is unclear, but appears to be directly related to the vascularity and cellularity of the enlarged glands. Since the normal thyroid tissue is vascular and surrounds parathyroid tissue, it is necessary to use a second radiopharmaccutical that is only extracted by the thyroid so that thyroid background activity can be removed, leaving abnormal “‘Tl uptake in parathyroid tissue. With computerized subtraction techniques, it

a

b Figure 2. A 42-year-old man with a mildly elevated serum calcium level of 10.8 mg/dL and *“‘TI scan (left) shows homogeneous activity in minimally elevated PTH. (a) Parathyroid can the 99”TcOJ scan (middle) is normal. Only on the subtraction image (vighf) thyroid. abnormal activity inferior to the lower pole of the left thyroid be identified (UWOW). (b) Highresolution parathyroid sonogram demonstrated a 1.5 x 1-cm bilobed hypoechoic extrathyroidal soft tissue mass that is located in the same position. At surgery, a bilobed 750.mg left inferior parathyroid adenoma was found.

izing radiation. In a recent prospective study utilizing a 1.5Tesla superconducting MRI system with a high-resolution surface coil, 22 patients with hyperparathyroidism were primary studied (Kneeland et al. 1987). The sensitivity and specificity of MRI to identify parathyroid adenomas was 74% and 88%, respectively, and was similar to CT, ultrasound, and scintigraphy results in the same patient sample. In another series of 28 patients with recurrent hyperparathyroidism after initial negative neck exploration in whom surgical results were available after second surgery, MRI located the abnormal parathyroid 75% of the time prospectively and 89% of the time retrospectively. These results were similar to those of

338

by the adcnoma

imaging properties of the tracer. Intcrest in parathyroid scintigraphy was revived after Ferlin et al. (1983) demon“‘Tl, a widely used strated that radiopharmaceutical to measure regional myocardial blood flow, accumulates in parathyroid tumors. The precise

scintigraphy but better than those of ultrasonography (Auffermann et al. 1988). The magnetic resonance signal intensity of parathyroid adenoma varies, depending upon the degree of cellularity, fibrosis, and hemorrhage present in the adenoma. The most common appearance is low signal on T-l spine echo scans and increased signal on T-2 weighted scans. Because of the relative high cost of MRI, at most centers MRI is not one of the initial screening techniques used to identify parathyroid adenomas.

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Scintigraphy

Early attempts to image parathyroid adenomas with selenomethionine-75 were suboptimal because of poor uptake of

is possible to image parathyroid tissue in and around the thyroid and mediastinum. Areas of parathyroid enlargement superior, inferior, medial, and lateral to the thyroid are in general easier to image than parathyroid enlargement posterior to the parathyroid gland (Figures 1 and 2). Multiple reports of large series have reported good results with ‘“‘Tli 99mT~ subtraction techniques yielding sensitivities of 75%-85% and specificities of 80%-90% in patients without prior neck exploration (Winzelberg et al. 1985; Fcrlin et al. 1983; MacFarlane ct al. 1984; Okerlund et al. 1984). The scnsitivity of the scan in general is directly related to the size of the adcnoma, with in adenomas sensitivities of -70% weighing 500 mg. Lower sensitivities and specificities have been reported in patients with recurrent or persistent hypercalccmia after initial negative neck exploration and in patients with diffuse parathyroid hyperplasia. Scintigraphy has also been helpful in identifying patients with ectopic glands in the neck and mediastinum. Several modifications of Ferlin’s initial technique to identify parathproid adenomas have been used to simplify image acquisition and optimize the physical properties of the radiopharmaceutical used in the examination and include the injection of 201Tl first and obtaining mediastinal views (Winzelberg and Hydovitz 1985). Other authors have used oblique views and color-coded image processing to help improve the imaging techniques (Okerlund et al. 1984) (Figure 3). As these procedures have become

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similar sensitivity and specificity of diagnostic accuracy. Currently, both of these techniques appear to be the first choice for the preoperative localization of parathyroid adenomas before surgery in patients who have not had previous surgery.

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Parathyroid localization techniques are currently indicated before second surgery in patients with a firm diagnosis of hyperparathyroidism (based on biochemical criteria) who have had previously unsuccessful exploratory surgery of the neck. In patients with histories of previous neck or thyroid surgery or with significant medical problems with associated high anesthesia risks, preoperative localization studies can also be used to guide surgical exploration so that the duration of surgery and risk for complications during surgery will be reduced. In these subsets of patients, the sensitivity for noninvasive

a

b Figure 3. A 50-year-old asymptomatic woman with a serum calcium of 11 mg/dL and mildly elevated midregion PTH. (a) Parathyroid “‘Tl scan in anterior and oblique views show a small area of increased tracer just below the left thyroid lobe. The anterior yymTcthyroid scan was normal. Only on the subraction views is the abnormal uptake (awoll~) clearly seen. It is best visualized where the thallium image was normalized to the y9mT~ images and direct ultrasound confirmed a left inferior parathyroid subtraction performed. (b) A high-resolution adenoma that was confirmed surgically

accepted in the preoperative localization ofparathyroid abnormalities, many series have documented utility of parathyroid scintigraphy for identifying parathyroid adenomas. A significant number of false-positive examinations can occur. “‘Tl accumulation in the neck and mediastinum has been found in patients with metastatic cancers and lymph nodes, small cell and adenocarcinoma of the lung, ovarian cancer, lymphoma, Hodgkin’s disease, and sarcoidosis and can cause false-positive results (Winzelberg et al. 1987) (Figure 4). Additionally, discordant “‘Tl uptake and lack of y9mT~uptake occurs in many types of thyroid disease such as Hashi-

TEM SeprerrzhrulOctoht,r

Summary

R

moto’s thyroiditis, thyroid adenomas, and thyroid carcinomas and can cause false-positive parathyroid examinations. Focal goitrous change can also cause increased areas of “‘Tl uptake and have diminished areas of 99mT~ uptake that on subtraction scintigraphy can lead to false-positive results. In general, the sensitivity and specificity of scintigraphy is reduced in patients with underlying thyroid disease. Although 20’Tl/ 99mT~ subtraction scintigraphy has the advantage of being able to image the mediastinum and retrotracheal and retroesophageal areas, prospective studies that have compared this technique with high-resolution sonography have shown

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imaging appears to be significantly lower than for patients who have had no previous surgery (Miller et al. 1987a and b). CT in these patients may have a greater sensitivity than ultrasonography or scintigraphy. Ultrasonic or CTguided biopsy with either cytologic examination or tissue assay may enable definite preoperative localization. The precise sequencing of invasive procedures in patients with previously unsuccessful parathyroid explorations in general should be determined by the clinical factors and not by the sensitivity of the test. Additionally, the variation that exists in hospitals regarding the skills of various imaging specialists may also dictate precise sequencing of imaging tests. In patients who have not had previous surgery, high-resolution realtime sonography and/or 201T1/99mT~subtraction scintigraphy appears to be the initial imaging method of choice for the preoperative localization of enlarged parathyroid glands. If these tests are nondiagnostic, CT scan of the neck and mediastinum followed by MRI would appear to be the next logical sequence. Although it has been documented that some preoperative localization techniques have decreased the time of parathyroid surgery, no large series of patients has yet been evaluated to assess whether anv noninvasive technique is clearly beneficial in preventing negative

339

The USC of high-resolution ultrasound to locate parathyroid tumors during reoperations for primary hyperparathyroidism. World J Surg 1987; 11:579. Kneeland JB, Krusbsack AJ, Lawson TL, ct al.: Enlarged parathyroid glands: high resolution local coil MR imaging. Radiology 1987; 162:143. MacFarlane SD, Manelin LG, Taft DA, Ryan JA Jr, Frcdlung PN: Localization of abnormal parathyroid glands using thallium201. Am J Surg 1984; 148:7. Miller DL, Doppman JL, Shawker TH, et al.: Localization of parathyroid adenomas in patients who have undergone surgery. 1. Non invasive imaging methods. Radiology 1987a; 162:133. Miller DL, Doppman JL, Krudy AG, et al.: Localization of parathyroid adenomas in patients who have undergone surgery. II. Invasive procedures. Radiology 1987b; 162:138. Miller DL, Chang R, Doppman JL, Norton JA: Localization of parathyroid adenomas: supcrselective arterial DSA versus superselective conventional angiography. Radiology 1989; 170:1003. Okerlund MD, Sheldon K, Corpuz S, et al.: A new method with high sensitivity and specificity for localization of abnormal parathyroid glands. Ann Surg 1984; 200:38 1.

b scan in a patient with hypercalcemia and Figure 4. (a) Parathyroid 20’T1/9y”‘Tcsubtraction elevated serum parathyroid hormone levels. Mediastinal views show small focal area of increased 20’T1 uptake (awow) in superior mediastinum. The rest of the scan was normal. (b) CT scan of mediastinum confirms 2-cm mass (awot~) in superior mediastinum that at surgery proved to be an ectopically located 1500-mg parathyroid adenoma. From Winzclberg (1987), with permission

initial neck explorations or reducing the potential complications of parathyroid exploration. Clearly, a skilled surgeon will be successful in achieving cures in up to 90% of these patients during exploration, whereas less skilled surgeons doing infrequent surgery will have less favorable

results.

References Aufferman W, Gooding GAW, Okerlund MD, et al.: Diagnosis of recurrent hyperparathyroidism comparison of MR imaging and other imaging techniques. AJR 1988; 150:1027. Brewer WH, Walsh JW, Newsome HH: Impact of sonography on surgery for primary hyperparathyroidism. Am J Surg 1983; 145:270.

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Powell D, Shimkin PM, Doppman JL, et al.: Primary hyperparathyroidism: prcoperative tumor localization and differentiation between adcnoma and hyperplasia N Engl J Med 1972; 286:1169. Reading CC, Charboncau JW. James EM, et al.: High-resolution parathyroid sonography. AJR 1982; 139:539. Reading CC, Charboneau JW, James EM, et al.: Postoperative parathyroid high-frequency sonography: evaluation of persistent or recurrent hypcrparathyroidism. AJR 1985; 144:399. Reitz RE, Pollard JJ, Wang CA, et al.: Localization of parathyroid adenomas by selective venous catheterization and radioimmunoassay. N Engl J Med 1969; 281:348. Satava RM, Beahrs OH, Scholz DA: Success rate of cervical exploration for hyperparathyroidism. Arch Surg 1975; IlO:625. Saxe AW, Brennan MF: Reoperative parathyroid surgery for primary hyperparathyroidism caused by multiple-gland disease: total parathyroidectomy and autotransplantation with cryopreserved tissue. Surgery 1982; 91:616. Scheible W, Deutsch AL, Leopold GR: Parathyroid adenoma: accuracy of preoperative localization by high-resolution real-time sonography. JCU 1981; 9325. Simeone JF, Mueller PR, Ferrucci JT, et al.: High resolution real-time sonography of the parathyroid. Radiology 1981; 141:745. Solbiati L, Montali G, Croce F, Bellotti Giangrande A, Ravetto C: Parathyroid

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