Jack Baskin , MD, FACEDirector, Florida Thyroid and Endocrine Clinic

Originally printed in:
» US Endocrine Review 2005 - September 2005

Reference Section a report by Jack Baskin, MD, FACE Director, Florida Thyroid and Endocrine Clinic Ultrasound of the Endocrine Neck B USINESS BRIEFING: US ENDOCRINE REVIEW 2005 1 Over the past decade, ultrasound has become an essential part of the examination of thyroid and parathyroid patients. Sonography has been integrated with the history and physical exam and other tests (especially needle biopsy) to provide valuable information that has improved patient care.Advances in technology and engineering, including high-resolution phased-array transducers, color flow, and power Doppler, have provided much more detail and information regarding thyroid and neck morphology, making diagnosis more accurate. This capability has expanded the use of ultrasound and resulted in the development of new ultrasound applications for both the diagnosis and therapy of thyroid and parathyroid disorders. Ultrasound guidance for needle biopsy of thyroid nodules has become routine. It is now being used to confirm the ultrasound diagnosis of parathyroid adenoma by measuring parathyroid hormone obtained with the needle placed in the lesion under ultrasound guidance. Likewise, non-palpable lymph nodes in the neck discovered by ultrasound and suspected of having metastatic carcinoma can be easily biopsied using ultrasound. The material can be submitted for both cytology and thyroglobulin (Tg) to confirm the diagnosis replacing more expensive imaging. Using these same ultrasound guidance techniques, several groups of investigators have developed methods of therapeutic ablation of tissue by chemical or physical means.This has resulted in an alternative to surgery for certain thyroid, parathyroid, and lymph node lesions.

Although high-resolution realtime ultrasound has been available since the early 1980s, it did not make a significant impact in the diagnosis and management of thyroid disease until the mid 1990s. Initially, an ultrasound of the thyroid entailed referring the patient to a radiology department where the ultrasound was performed by a sonographer who took spot films that were interpreted by the radiologist for the clinician.This delay in diagnosis and increased cost of going to another specialist deterred the application of ultrasound to the study of thyroid disorders. Furthermore, the separation of the realtime procedure from the clinician’s physical examination resulted in loss of information and hampered the appreciation of subtle changes that have proven valuable in treating thyroid patients.

Advances in ultrasound engineering and electronic technology in the 1990s make modern ultrasound more user-friendly.These advances coincide with a marked reduction in equipment cost that allows clinicians who treat thyroid patients to have access to a machine dedicated to thyroid ultrasound. The performance of realtime ultrasound by the examining physician who has taken a history, performed a physical examination, and anticipated what may be seen on ultrasound imaging prevents loss of information and allows the ultrasound findings to be integrated with the patients’ clinical palpation findings.The recent introduction of small linear phased-array transducers greatly facilitates ultrasound-guided fine-needle aspiration (UG FNA) biopsy, which decreases the number of inadequate biopsies.The increased convenience and the decreased cost of thyroid ultrasound by not having to refer the patient out to another level of specialty care make thyroid ultrasound an essential part of the examination of the thyroid patient.

Thyroid Ultrasound Realtime ultrasound has proven to be the most sensitive test to detect thyroid nodules. It can recognize nodules that are missed on physical examination,radioiodine scan, computed tomography (CT), or magnetic resonance imaging (MRI). Initially, ultrasound of the thyroid was used primarily to identify and locate nodules within the thyroid. This was practiced following the Chernobyl nuclear accident when ultrasound screening of children detected hundreds of cases of early thyroid cancer and allowed surgical cure. Ultrasound has also been used to identify aberrant anatomy, such as hemiagenesis of the thyroid, and to measure thyroid volume. In children, the thyroid volume correlates with iodine content in the diet and urinary iodine.Thus, it provides a quick and efficient method to identify iodine-deficient areas of the world allowing treatment of endemic goiter.

The primary concern when a patient presents with a thyroid nodule is whether the nodule is benign or malignant.Various ultrasound characteristics of thyroid nodules have proven to have predictive diagnostic value in determining which nodules are malignant and which are not (see Table 1). Among these characteristics of Jack Baskin, MD, FACE, is Director of the Florida Thyroid and Endocrine Clinic. He is also a Founding Member and Past-President of the American Association of Clinical Endocrinologists. Dr Baskin is Editor of Thyroid Ultrasound and Ultrasound-Guided FNA Biopsy, and has published numerous peer- reviewed manuscripts and book chapters. He also currently teaches a three-day course each month on the clinical applications of thyroid and parathyroid ultrasound. In 2000, when he was President of the American College of Endocrinology, he founded Endocrine University—a one-week training program for all second year endocrine fellows in the US.

2 B USINESS BRIEFING: US ENDOCRINE REVIEW 2005 Reference Section thyroid nodules are echogenecity,regularity of the border or margin around the nodule, presence and type of calcifications, vascular pattern using power Doppler, shape of the nodule, and the presence or absence of enlarged adjacent lymph nodes. The most reliable ultrasound finding that indicates benignity is the presence of a comet tail sign.This artifact caused by the refraction of sound waves by colloid in complex/cystic nodules is pathognomonic of a benign lesion. However, care is needed to differentiate this comet tail artifact from microcalcifications that are highly suspicious of malignancy. Ultrasound also allows observation of changes in thyroid nodules over time that often helps in making the decision regarding surgery. For example, a nodule that is decreasing in size is unlikely to be malignant or require surgical intervention, while a nodule that is increasing in size while on thyroid- stimulating hormone (TSH) suppression needs re- evaluation.An initial ultrasound examination performed on a patient who presents with a morphologic abnormality of the thyroid often directs what further tests are needed.

UG FNA Biopsy of Thyroid Nodules Ultrasound alone is not specific enough and cannot be relied upon to diagnose malignancy. FNA has been the standard diagnostic test for evaluating malignancy in a thyroid nodule, but it has limitations. FNA cannot differentiate between follicular adenoma and follicular carcinoma and up to 20% of FNA biopsies yield inadequate material for diagnosis. Ultrasound and FNA compliment each other and, when used together, enhance diagnostic capability.

Many investigators have shown that combining ultrasound and FNA into a single procedure, UG FNA, decreases the number of inadequate specimens to less than 5%. This technique assures precise placement of the needle tip in the target and avoids biopsy of the surrounding normal tissue, which may yield a false negative diagnosis. It prevents puncturing the trachea, common carotid artery, and internal jugular vein, and it often enables avoiding passing the needle through the sternocleiodomastoid muscle, thus markedly reducing the discomfort to the patient. UG FNA is indicated for the biopsy of complex or cystic nodules in order to obtain material from the mural or solid component of the nodule and assure adequate cytology. In solid nodules the best cytology material is usually obtained from the periphery of the nodule rather than the center; this is particularly true if there is any central necrosis. In heterogeneous nodules, the biopsy should be taken from the hypoechoic area of the nodule.

When performing FNA of a multinodular goiter, ultrasound is useful in selecting the most suspicious nodule(s) for biopsy by evaluating the nodule’s characteristics. If lymphadenopathy accompanies a thyroid nodule, UG FNA of the lymph node may be more useful than biopsy of the nodule. Sometimes, an irregular thyroid surface is misdiagnosed as a thyroid nodule, and an ultrasound examination can avoid having to perform an FNA. Pseudonodules are often seen in Hashimoto disease, which is easily recognized with ultrasound.

Ultrasound guidance permits biopsy of nodules that were not previously amenable to FNA biopsy. These include many small nodules that are less than 1.5cm and non-palpable nodules such as those located posterior in the thyroid or in the upper mediastinum. Even large nodules may not be palpable in obese or large muscular individuals or in the elderly patient with kyphosis, especially when placed in the supine position.UG FNA permits proper placement of the needle in these patients. Indeed, UG FNA allows tissue sampling of virtually all nodules 0.5cm or greater in size.

Because micronodules (nodules 0.5–1cm) are so common in the population, the question arises when to perform UG FNA.A nodule this size seldom presents a threat to life and they are so numerous that routine biopsy of all such nodules is not practical or cost- effective. However, several investigators have shown that the incidence of malignancy in small non-palpable nodules is the same as in palpable nodules. In addition, others have shown that cancers that present less than 1.5cm in size are often as aggressive as larger cancers.

Some judgment is required in deciding which micronodules require FNA. Patients who received external radiation during childhood and those with a Table 1:Thyroid Nodule Characteristics Benign Malignant Echogenecity Hyperechoic Hypoechoic or heterogeneous Margins Smooth border or halo Irregular border or invasion Colloid Comet tail sign Calcifications Periferic (eggshell) Microcalcifications Vascularity Peripheral Intranodular Shape Flattened Rounded Lymphadenopathy Absent Present Cyst Thin-walled Thick-walled Table 2: Indications for UG FNA of Thyroid Micronodules (0.5—1cm) Family history of medullary or papillary thyroid cancer History of radiation to head or neck during childhood Micronodule in remaining lobe after hemithyroidectomy for thyroid cancer Hypoechoic micronodule with one or more of the following ultrasound findings: Blurred margins Intranodular vascularity Taller than wide Microcalcifications Ultrasound of the Endocrine Neck B USINESS BRIEFING: US ENDOCRINE REVIEW 2005 3 family history of thyroid cancer (medullary or papillary) should have their micronodules biopsied. The occurrence of a nodule >0.5cm in a patient who had only a hemithyroidectomy for thyroid cancer also requires an UG FNA. Recently, ultrasound criteria have been established to help identify which micronodules are most likely to be malignant and therefore need UG FNA.These include hypoechogenecity, accompanied by one or more of the following: • blurred margins; • microcalcifications; • intranodular vascularity; or • nodules that appear taller than wide on transverse view.

Most other nodules 1cm or less in size can safely be observed over a period of time using ultrasound, and FNA can be avoided if there is no increase in size (see Table 2).

There is general agreement that a repeat biopsy performed because of inadequate material should always be done using ultrasound guidance. Realtime ultrasound guidance has refined the FNA biopsy technique by decreasing the number of inadequate specimens, and increasing specificity and sensitivity.

Aside from being cost-effective, well tolerated, and quick, UG FNA has emerged as the most accurate method of evaluating thyroid nodules. This improvement in diagnostic accuracy has resulted in making UG FNA the standard method of conducting all FNA in many thyroid clinics.

Ultrasound Surveillance of Post-operative Thyroid Cancer Ultrasound has assumed a primary role in the management of patients who have been treated for thyroid cancer. In spite of better surgical techniques, the widespread acceptance of total and near-total thyroidectomy, and the increasing use of radioiodine, the mortality rate from well differentiated thyroid cancer has changed very little over the past 30 years. Because of its propensity to occur at any age, even in the very young, and to recur many years later, thyroid cancer must be monitored for the lifetime of the patient. Surveillance of these patients in a cost-effective manner has been a challenge. Until the 1990s the only diagnostic tool available was a 131I whole body scan (WBS) conducted after withdrawing the patient from their thyroid hormone replacement. The sensitivity of a WBS in the early detection of residual, recurrent, or metastatic thyroid cancer is poor.This is apparent from the many patients who have increased thyroglobulin (Tg) but negative diagnostic scans that are treated with 131I and have positive post-treatment scans.In addition,the dose of 131I used for WBS can stun the uptake of iodine in metastatic lesions and interfere with the subsequent treatment dose of 131I.The expense,poor sensitivity,and risk of stunning with a WBS make it an unsatisfactory test with which to follow patients with thyroid cancer. In the last decade, several new probes have been developed that aid in the early detection of recurrent thyroid cancer.These include: • sensitive, reliable, reproducible Tg assays that biochemically detect early cancer recurrence; • development of recombinant TSH (rhTSH) that allows scanning and Tg stimulation without thyroid hormone withdrawal; and • high-resolution ultrasound of the post-operative neck to identify early lymph node recurrence.

Using these new tools, especially Tg after rhTSH stimulation and neck ultrasound combined with UG FNA of suspicious lymph nodes, has greatly improved sensitivity of cancer surveillance. Hopefully, their use will result in lower mortality from thyroid cancer.

Physical examination of the neck of a patient who has undergone a thyroidectomy for thyroid cancer is seldom helpful in the early detection of a recurrence.The scar tissue following surgery combined with the propensity of metastatic lymph nodes to lie deep in the neck beneath the sternocleidomastoid muscle make palpation of enlarged lymph nodes in the neck difficult. Even lymph nodes several centimeters in diameter are often not palpable. High-resolution ultrasound has solved this problem by proving to be a very sensitive method to find and locate early recurrent cancer and lymph node metastasis. Because most thyroid cancer metastasizes to the neck, it is rare for thyroid cancer to spread elsewhere without neck lymph node involvement.Therefore, neck ultrasound has proven very helpful in locating early recurrent disease even before serum Tg is elevated. It is also valuable in following patients with positive anti-Tg antibodies (anti-TgAB).

Some ultrasound findings may suggest a lymph node is malignant (see Table 3). Because the sonographic features of malignant lymph nodes are not always present and there is overlap in the ultrasound appearance of benign and malignant lymph nodes, biopsy of suspicious lesions is essential for a definitive diagnosis. Lymph nodes with a height >0.5cm and a height/width ratio >0.5 that do not have a hilar line must have a UG FNA.

UG FNA of a suspicious lymph node in the neck is carried out in the same manner as a UG FNA of a thyroid nodule with aspirate slides prepared and sent for cytology interpretation. Lymph node cytology is sometimes difficult to interpret. However, thyroid cancer metastases contain Tg, which can be measured and used as a tissue 4 B USINESS BRIEFING: US ENDOCRINE REVIEW 2005 Reference Section marker. The biopsy needle is washed with 1cc normal saline and the washout sent for Tg assay.A normal saline control is also sent for Tg assay. Most patients are on thyroid hormone suppression, therefore serum Tg is usually low or non-detectable, and the material in the needle is diluted approximately 100-fold, so finding a Tg >10 in the needle washout is positive for malignancy.

Because the intracellular Tg is not exposed to circulating anti-TgAB, a positive test for anti-TgAB in the serum does not interfere with measurement of Tg obtained from lymph nodes as it does with serum Tg. Either a positive cytology report or finding Tg present in the needle washout confirms that the lymph node is malignant.

Parathyroid Ultrasound Normal parathyroid glands are small and generally not visualized by ultrasound. Enlarged parathyroid glands (adenomas or hyperplasia) as well as parathyroid cysts can usually be seen unless they are located behind the trachea, the esophagus, or in the mediastinum.Typically, a parathyroid adenoma is hypoechoic,homogenous,and has an oval or elongated shape. In the transverse view, the parathyroid glands are generally posterior medial to the carotid artery. In the longitudinal view, the superior parathyroid glands frequently lie along the posterior border of the mid portion of the thyroid separated by an echogenic line while the inferior parathyroid glands lie at the lower pole of the thyroid or in the first portion of the thyro-thymic ligament. Gentle pressure on the trachea using the transducer often makes the adenoma ‘pop out’ from its retrotrachael position, especially the inferior glands. Color flow Doppler will often demonstrate a pulsating feeder artery entering the hilum and increased arterial vascularization of the parenchyma compared with a lymph node or thyroid nodule. Occasionally, an intrathyroidal parathyroid will be mistaken for a thyroid nodule.

Endocrinologists and surgeons have underutilized parathyroid ultrasound. Ultrasound should be the initial imaging procedure for patients with hyperparathyroidism. By using high-resolution ultrasound along with patience, practice, and enthusiasm, approximately 80% of parathyroid adenomas can be identified.The benefits of localizing the adenoma prior to surgery are obvious. Sometimes, ultrasound cannot absolutely differentiate a parathyroid adenoma from an enlarged lymph node or a thyroid nodule; therefore the correct diagnosis may need to be confirmed by UG FNA and submitting the needle ‘washout’ for parathormone (PTH) analysis. Like measuring Tg from needles used to biopsy lymph nodes, the needle is flushed with 1cc normal saline and submitted for PTH analysis (UG FNA PTH) along with a normal saline control. Measuring PTH in the needle washout is qualitative rather than quantitative, but levels >1000pg/ml are typical in parathyroid adenomas. In clinical practice this has been found to be more accurate than parathyroid cytology.The sensitivity and specificity of parathyroid ultrasound with UG FNA are as good as a sestamibi scan at a fraction of the cost.

UG Percutaneous Ethanol Injection In addition to diagnostic ultrasound, therapeutic ultrasound techniques using chemical or physical methods to ablate tissue are being developed. Of the ultrasound-directed tissue ablative methods tried, percutaneous ethanol injection (PEI) is the most widely utilized. It has become the most cost-effective treatment for cystic thyroid nodules. PEI should be considered for cystic or complex (>50% fluid) nodules that have been aspirated, had a satisfactory negative FNA biopsy, and recurred. All but a small portion of the fluid is slowly drained, and, without removing the needle, 95% ethanol (EtOH) is slowly injected into the cyst. EtOH causes tissue damage resulting in coagulation necrosis, vascular thrombosis, and hemorrhage. This is replaced by granulation tissue, which then scars and retracts the walls of the cyst causing shrinkage over a period of several months.

During the aspiration of the fluid the tip of the needle is constantly repositioned in the center of the cyst to avoid puncturing the posterior wall. The volume of ethanol injected is approximately half of the volume of fluid extracted being careful to avoid excessive pressure.The only side effect is transient local pain in some patients. No permanent vocal cord palsy or other side effects have been reported. PEI provides a safe, cost-effective, curative alternative to surgery in the treatment of benign thyroid cysts.

Summary Realtime ultrasound of the neck coupled with UG FNA biopsy is a powerful new tool in diagnosing and managing patients with thyroid and parathyroid disorders. The ultrasound instrument is as helpful in examining these patients as the stethoscope is in examining patients who have a heart murmur. As with the stethoscope, ultrasound must be incorporated into the physical examination and performed by the examining physician in order to reach its full potential.a73 Table 3: Neck Lymph Node Characteristics Benign Malignant Long/Short Axis <0.5 >0.5 Hilar Line Present Absent Jugular Deviation Absent Present Microcalcifications Absent Present Cystic Necrosis Absent Present Vascularity Central Chaotic Ultrasound of the Endocrine Neck B USINESS BRIEFING: US ENDOCRINE REVIEW 2005 5 References 1. Baskin H,“Thyroid ultrasonography-a review”, Endocrine Practice (1997);3: pp. 153–157.

2. Thyroid Ultrasound and Ultrasound-Guided FNA Biopsy, Baskin H (ed), Boston: Kluwer Academic Publishers. (2000); pp. 103–123.

3. Papini E, Guglielmi R, Bianchini A, Crescenzi A,Taccogna O, Nardi F,“Risk of malignancy in nonpalpable thyroid nodules: Predictive value of ultrasound and color-doppler features”, J. Clin. Endo. Metab. (2002);87: pp. 1,941–1,946.

4. Kim E, Park C S, Chung W Y, Oh K K, Kim D I, Lee J T et al., “New sonographic criteria for recommending fine-needle aspiration biopsy of nonpalpable solid nodules of the thyroid”, AJR (2002);178: pp. 687–691.

5. Frasoldati A, Presenti M, Gallo M, Coroggio A, Salvo D,Valcavi R,“Diagnosis of neck recurrences in patients with differentiated thyroid carcinoma”, Cancer (2003);97: pp. 90–96.

6. Baskin H, Advances in Molecular and Cellular Endocrinology,Vol. 4 – Thyroid Neoplasms, Elsevier Publishers, New York, Ed: Haugen, B. Chapter 3; (2005); pp. 35–48.

7. Marqusee E, Benson C B, Frates M C, Doubilet P M, Larson R, Cibas E M et al., “Usefulness of ultrasonography in the management of nodular thyroid disease”, Ann. Int. Med. (2000);133: pp. 696–700.

8. Baskin H,“Ultrasound-guidance fine needle aspiration biopsy of thyroid nodules and multinodular goiter”, Endocrine Practice (2004);10: pp. 242–245.

9. Baskin H,“Detection of recurrent papillary thyroid carcinoma by thyroglobulin assessment in the needle washout after fine-needle aspiration of suspicious lymph nodes”, Thyroid (2004);14: pp. 959–963.

10. Baskin H,“New Applications of thyroid and parathyroid ultrasound”, Minerva Endocrinologica (2004);29: pp. 195–206.