Eur. Radiol. (2001) 11: 24112424 DOI 10.

1007/s00330-001-1163-7

U LT R A S O U N D *

Luigi Solbiati Valeria Osti Luca Cova Massimo Tonolini

Ultrasound of thyroid, parathyroid glands and neck lymph nodes

Published online: 25 October 2001  Springer-Verlag 2001 * Categorical Course ECR 2002

L. Solbiati ( ) V. Osti L. Cova M. Tonolini Department of Radiology, General Hospital of Busto Arsizio, Piazzale Solaro, 3, 21052 Busto Arsizio (VA), Italy E-mail: lusolbia@tin.it Phone: +39-03 31-69 94 78 Fax: +39-03 31-32 62 52

Abstract In the past 15 years highfrequency B-mode sonography and colourpower Doppler have become the most important and most widely employed imaging modalities for the study of the neck, in particular for thyroid gland, parathyroids and lymph nodes. Sonography allows not only the detection but often also the characterization of the diseases of these organs, distinguishing benign from malignant lesions with high sensitivity and specificity, which could be further improved by the employ of ultrasound contrast agents and harmonic imaging. Although no single sonographic criterion is specific for benign or malignant nature of the lesions, the combination of different signs can

be markedly helpful to speed up the diagnostic process. Fine-needle aspiration biopsy (FNAB) remains the most accurate modality for the definitive assessment of thyroid gland nodules and of any doubtful case of nodal disease. In association with clinical findings and serum levels of parathormone, FNAB has specificity close to 100 % for the characterization of parathyroid adenomas. A combined approach with sonography and FNAB is generally highly effective. Keywords Thyroid gland Parathyroid glands Lymph nodes Ultrasonography Power Doppler Colour Doppler

Thyroid gland
In the past 15 years high-frequency B-mode sonography and colour-power Doppler have become the most important and most widely employed imaging modalities for the study of the thyroid gland. This is due to many reasons: the favourable anatomical location of the gland, the highest degree of vascularity (both macroand microvascularization detectable with colour Doppler) in normal subjects among all the superficially located normal structures of the body and the extremely high incidence of thyroid abnormalities, either nodular or diffuse, most of which are benign diseases requiring periodical sonographic follow-up. When the thyroid gland is approached with sonography, the first relevant parameter to study is the size of the gland, which is not always easily assessable with

palpation due to, for example, physical limitations and surgical scars. The size of the normal thyroid gland varies according to the morphotype of subjects, reaching 78 cm in length with only 0.71.0 cm as thickness in thin subjects, whereas in obese patients the length is usually less than 5 cm, but the normal anteroposterior diameter can reach 2 cm. Being volumetric studies of thyroid lobes easily performable only with 3D ultrasound (not yet widely available), thus far thickness is considered the simplest among the most reliable indexes of thyroid size: when it is larger than 2 cm, enlargement can be confidently diagnosed [1, 2, 3]. The normal thyroid parenchyma has a characteristically homogeneous ultrasound appearance which is more echogenic than the adjacent strap muscle and well distinguishable from the many relevant adjacent structures, i.e. trachea, esophagus, nerves, large blood vessels.

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in countries (like most southern European countries) with high prevalence of thyroid goitrous disease sonography is capable of detecting small, non-palpable thyroid nodules (benign in over 90 % of cases) in a large amount of the population, in order to speed up the diagnostic work-up, sonographic criteria have to be employed to select the suspected lesions to undergo fineneedle aspiration biopsy (FNAB) [7]. On the contrary, in countries such as those of North America where thyroid goiter is generally sporadic, free-hand FNAB is usually performed as first assessment after the detection of a palpable thyroid nodule and sonography is performed only when FNAB is not diagnostic or when a preoperative map of the thyroid gland is needed [8]. Nodular diseases In the investigation of thyroid nodular diseases, sonography has five major applications: 1. Detection of thyroid nodules 2. Differentiation of hyperplasia/goiter from all other thyroid nodular diseases 3. Preoperative determination of the extent of known thyroid malignancy 4. Detection of residual, recurrent or metastatic carcinoma 5. Guidance to FNAB for non-palpable nodules
Fig. 1 a, b Multinodularity does not exclude malignancy. a Multiple nodules with different echogenicity (isoechoic, mixed, cystic with dense fluid) in benign goiter. b Two contiguous hypoechoic nodules with microcalcifications and irregular margins: multifocal papillary carcinoma

Thyroid pathologies are classifiable into two groups, nodular and diffuse diseases. All thyroid diffuse diseases (with the exception of the extremely rare diffuse primary lymphoma) and approximately 9092 % of nodular pathologies are benign [4]. Actually, thyroid cancer is rare, accounting for less than 1 % of all malignant neoplasms [5]. Sonography is significantly more sensitive than clinical palpation in identifying thyroid nodules [6] and in detecting multinodularity when single nodules are clinically diagnosed. Studies comparing clinical palpation with thyroid imaging show a prevalence of 1350 % for the detection of thyroid incidentalomas [7, 8]. In recent years, high-resolution sonography has confirmed the pathological statement that multinodularity does not necessarily mean benign disease or does not exclude malignancy (Fig. 1) [4, 6], being the rare thyroid malignancies often found in association with one or more benign nodules, both in the same and in the opposite thyroid lobe. Since

As for detection and characterization, each thyroid nodule has to be studied paying attention to its level of echogenicity compared with the normal parenchyma, the presence of calcifications or cystic changes, the pattern of margins, the presence of peripheral echo-poor halo and the amount and distribution of blood supply [3, 9, 10, 11]. Hyperplasia is the most common pathology of thyroid gland, accounting for 8085 % of all thyroid nodules, and is more common in women [12]. It may be familial, due to iodine deficiency, to compensatory hypertrophy or secondary to hypoplasia of one lobe or partial thyroidectomy. When single or multiple hyperplastic nodules lead to a global enlargement of the gland, the term goiter (either single or multinodular) is properly used. Patients with hyperplasia/goiter are frequently asymptomatic but may occasionally present with compressive symptoms or rapidly enlarging mass, usually indicating spontaneous haemorrhagic changes within the nodule(s). Hyperplasia may have a diffuse or nodular pattern. Diffuse hyperplasia results in the enlargement of one or both lobes, with lateral or posterior deviation of the great vessels and/or the trachea, but never with infiltration of their walls. Mono- or multinodular hyperplasia is usually seen as single or multiple discrete nodules, varying greatly in number and size, separated

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2a

2b

2d

2c

3
Fig. 2 ad Four different examples of thyroid nodular hyperplasias with typical features of benign nature: a isoechoic with thin regular halo and small internal cystic change, b isoechoic with peripheral vascularity and wide internal fluid-filled area, c cystic with multiple comet-tail artefacts due to colloid substance and d isoechoic, markedly hypovascular within a highly vascularized thyroid parenchyma Fig. 3 Thyroid adenoma with characteristic arrangement of the blood supply: peripheral vascularity with spoke-and-wheel appearance of the blood vessels towards the centre of the mass

by normal parenchyma. They are mostly isoechoic (Fig. 2) and hyperechoic with well-defined margins. The very unusual hypoechoic nodular hyperplasias (5 %) are due to sponge-like multilocular lesions filled with colloid substance. Cystic changes are present in 6070 % of cases, due to either haemorrhages (Fig. 2) or colloid substance collections: in this latter circumstance, typical comet tail artefacts are seen within the nodules (Fig. 2). Macro-calcifications are present in 2025 % of goitrous nodules, usually with greater incidence in elderly patients or old nodules, representing the final pathological evolution of these lesions. The calcifications of goitrous nodules are typically curvilinear, annular or dys-

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Fig. 4 Hyperfunctioning thyroid nodule seen as a hypervascularized nodule on colour Doppler and b lesion with high uptake on isotope scintigraphy Fig. 5 a, b Papillary carcinoma with typical features: a hypoechogenicity, microcalcifications and b hypervascularity with chaotic arrangement

4a

4b

5a

5b

morphic and seen as large, densely calcified areas with posterior shadowing [4]. As clearly demonstrated by pathological studies, hyperplasticgoitrous nodules are usually less vascularized than normal thyroid parenchyma, with the exception of rapidly growing hyperplastic lesions in young patients. As a consequence, on colourpower Doppler these nodules usually appear poorly vascularized, with prevalent perilesional blood supply (Fig. 3). Unfortunately, with the increasing sensitivity to slow blood flows of modern power-colour Doppler technology, a great amount of hyperplastic/goitrous nodules currently show also intralesional flow signals. Therefore, the sign of exclusively perilesional blood flow signals on colour Doppler is markedly decreasing its relevance as character of benign nature. Non-goitrous nodules include mostly adenomas and carcinomas. Adenomas represent only 510 % of all nodular diseases of the thyroid and are more common in women [5]. Thyroid adenomas may be either hypoechoic, isoechoic (like most follicular adenomas) or hyperechoic. Characteristically, they usually show a thick and smooth peripheral echo-poor halo, likely representing fibrous capsule and peripheral blood supply of the tumour. Even more typically, from the periphery blood vessels move to the centre of the lesion, with a relatively regular

spoke-and-wheel arrangement which is clearly visible with colour Doppler (Fig. 4). Hyperfunctioning thyroid nodules may pathologically be either hyperplastic nodules or adenomas. In this latter circumstance, hypervascularity (Fig. 5) and typical blood supply arrangement allow for a highly reliable recognition of the hyperfunctioning lesion within the thyroid parenchyma, with reported sensitivity of 96 % and specificity of 75 % [13]. Malignant neoplasms of the thyroid gland are quite rare (23 cases per 100,000 individuals). Papillary carcinoma is the most common malignancy of the thyroid gland (6070 % of all thyroid malignancies) [14]. It affects women more often than males and is prevalent in patients under 20 and above 70 years of age. Slow growth and good prognosis are common features of this neoplasm, the reported 20year survival rate being as high as 90 % [15]. On ultrasound papillary carcinoma appears as a predominantly hypoechoic nodule, mostly solid, even if in 2030 % of cases cystic changes with detectable blood supply within intracystic septa may be seen (cystic-papillary carcinoma; Fig. 6). Intralesional punctate calcifications (microcalcifications), are characteristically present in 8590 % of these tumours and are highly reliable for the sonographic diagnosis of papillary carci-

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7
Fig. 6 Cysticpapillary carcinoma with microcalcifications and blood vessels in the solid portion of the mass Fig. 7 Thyroid mass with aspecific sonographic features: isoechogenicity, no microcalcifications, perilesional and internal blood supply. The histological diagnosis is follicular carcinoma

noma (or, much more rarely, of medullary carcinoma; Fig. 6). With high-frequency ultrasound, they appear highly echogenic but typically do not exhibit posterior shadowing. Pathologically, they represent calcified psammoma bodies, which are a typical landmark of this disease. On colour-power Doppler, hypervascularity with chaotic arrangement of blood vessels, related to arteriovenous shunts and tortuosity of vessel course, is commonly seen (90 % of cases; Fig. 6) [15, 16]. The major route of spread of papillary carcinoma is through the lymphatics of the neck and therefore laterocervical and/or recurrent adenopathies are either often associated with the primary tumour at initial diagnosis (approximately 50 % of cases) [17, 18, 19] or may develop after thyroidectomy. These nodes often reproduce the

appearance of the primary tumour, showing microcalcifications, cystic changes or chaotic hypervascularity (Fig. 7). Follicular carcinomas account for 515 % of thyroid cancers, with higher incidence in older patients [1]. In most cases they develop from pre-existing adenomas [16, 20]. Follicular carcinomas are associated with hyperplastic/adenomatous thyroid nodules in 6070 % of cases. The most significant pathological criteria for the diagnosis of follicular carcinoma are invasion of the capsule and vascular invasion. Minimally invasive follicular carcinomas, with capsular infiltration but no vascular invasion, have a low mortality rate (3 %). Frankly invasive follicular carcinomas, with invasion of vascular supply and thyroid parenchyma, metastasize in 5080 % of cases and have high mortality rate (50 %). Both histotypes spread via the blood to bone, lung, brain and liver [12]. On ultrasound follicular carcinomas are predominantly solid, homogeneous, mostly hyperechoic or isoechoic (Fig. 8). Thick irregular capsule, tortuous perinodular and intranodular blood vessels and signs of extracapsular spread are sonographic signs suggesting the diagnosis of malignant lesion (Fig. 8) [16]; however, even FNAB cannot be diagnostic in most cases, being capsular and vascular invasions signs detectable only with histology of surgical specimens. Anaplastic carcinomas represent 510 % of all thyroid cancers, occur mostly in elderly people and are highly aggressive, with 5-year mortality rate of more than 95 % [14]. They typically present as rapidly enlarging masses extending beyond the gland and invading adjacent structures. Frequent association with papillary or follicular carcinomas has been reported [1]. With sonography, anaplastic carcinomas are diffusely hypoechoic, with areas of necrosis in 78 % of cases, dense amorphous calcifications in 58 % and nodal or distant metastases in 80 % [7, 21]. Furthermore, even more diagnostically useful, sonographic signs of this cancer are marked irregularities of the boundaries and the early invasion of thyroid gland capsule, with infiltration of adjacent structures (Fig. 9). Medullary carcinomas account for only 5 % of all thyroid malignancies. In 20 % of the cases they may be familial, occurring in association with the multiple endocrine neoplasia (MEN IIA) syndrome. Slow growth and spread via the lymphatics to nearby lymph nodes are characteristic features. Medullary carcinomas are multicentric and/or bilateral in approximately 90 % of the familial cases. Prognosis is considered to be generally worse than that for follicular cancer. The sonographic appearance of medullary carcinoma is similar to that of papillary carcinoma: hypoechogenicity, irregular margins, microcalcifications (histologically representing calcified deposits of amyloid), hypervascularity with irregular arrangement of blood vessels)

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9a

9b
be assigned to all the most important sonographic signs of thyroid nodules. These data are summarized in Table 1. In recent years several papers in the international literature have reported data concerning the reliability of sonography (B-mode and colour/power Doppler) in the differentiation of benign vs malignant thyroid nodules, employing the sonographic features described above. Sensitivity rates ranged from 63 to 87 %, specificity from 61 to 95 % and overall accuracy from 80 to 94 % [8, 24, 25]. In the near future, contrast-enhanced sonographic studies using microbubbles could further improve the diagnostic capabilities of sonography. Thus far, preliminary experiences with the first generation, galactose-based contrast agent seem to provide useful data for the differentiation of benign vs malignant nodules through the analysis of the time-intensity curves correlating the variation of signal intensities during the contrast transit time [26]. Even though no sonographic feature is pathognomonic for malignancy, the high rates of sensitivity and specificity reported account for the current major role of sonography among all imaging modalities in thyroid nodular lesions. Its use is likely to be complementary, rather than alternative, to FNAB which is the most effective method for diagnosing malignancy in a thyroid nodule. The FNAB is reported to have sensitivity ranges of 6598 % specificity of 72100 %, false-negative rates of 111 % and false-positive rates of 18 % [27, 28]. In our opinion, in patients presenting with one or more palpable thyroid nodules, the initial imaging modality to be performed should be chosen on the basis of laboratory tests: if the blood levels of TSH are either normal or increased, sonography (including colour/ power Doppler) has to be the first imaging test. If no sonographic signs suggesting malignancy are detected and no clinical data of possible malignancy (e.g. rapid growth, hard consistency, history of neck radiotherapy treatment) are reported, no further assessment is needed and only a 6- to 12-month sonographic follow-up study is advisable. If even a low probability of malignancy is sonographically suspected, FNAB is the mandatory further assessment. On the contrary, if TSH lev-

Fig. 8 Large anaplastic carcinoma with irregular margins, posterior extracapsular growth and infiltration of the laryngeal recurrent nerve (arrow) Fig. 9 a, b Patient with family history of multiple endocrine neoplasia II A. a In the left lobe of the thyroid gland, there is a large hypoechoic nodule with thick halo and scattered microcalcifications. Pathological diagnosis: medullary carcinoma. b On the right side, typical parathyroid adenoma (oval, hypoechoic, with regular margins) is seen caudally to the thyroid lobe

and frequent association with metastatic lymphadenopathies are the most distinctive features [12, 22]. Thyroid primary lymphoma is rare (4 % of all thyroid malignancies), mostly of the non-Hodgkin's type and usually affects elderly females. The typical sign is a rapidly growing mass which may cause symptoms of obstruction such as dyspnea and dysphagia. In 7080 % of cases, thyroid lymphoma arises from a pre-existing chronic thyroiditis with subclinical or overt hypothyroidism [23]. Prognosis is highly variable and depends on the stage of the disease. The 5-year survival rate may range from nearly 90 % in early-stage cases to less than 5 % in advanced, disseminated disease. Sonographically, thyroid lymphoma appears as a hypoechoic, lobulated, nearly avascular mass. Large areas of cystic necrosis may occur, as well as encasement of large blood vessels of the neck. The adjacent thyroid parenchyma may be heterogeneous due to associated chronic thyroiditis [23]. Once a thyroid nodule has been detected with sonography the fundamental problem is to determine whether it is benign or malignant. For this purpose, all the different sonographic signs described above (echogenicity, margins, peripheral halo, amount and arrangement of vascularity, microcalcifications, invasion of adjacent structures) have to be singularly analysed and combined with clinical data in order to differentiate purely benign nodules from lesions requiring cytological assessment by FNAB, being suspected of malignancy. According to our experience and the literature, rates of likelihood of benign or malignant nature can

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Table 1 Likelihood of benign or malignant nature assigned to the most important sonographic signs of thyroid nodules. (Modified from [3]) Feature Internal contents Purely cystic content Cystic with thin septa Mixed solid and cystic Comet-tail artefact Echogenicity Hyperechoic Isoechoic Hypoechoic Halo Thin regular halo Thick irregular halo Margin Well defined Poorly defined Calcification Eggshell calcifications Coarse calcifications Microcalcifications Doppler Peripheral flow pattern Internal flow pattern Benign ++++ ++++ +++ ++++ ++++ +++ ++ ++++ ++ +++ + ++++ +++ + +++ ++ Malignant + ++ + + ++ +++ ++ +++ ++ +++ + + ++++ + +++ Fig. 10 Graves-Basedow disease with peak systolic velocities of approximately 85 cm/s

+ rare probability (< 1 %); ++ low probability (< 15 %); +++ intermediate probability (1684 %); ++++ high probability (> 85 %)

els are increased, with a reasonable likelihood of thyroid hyperfunction, isotope scintigraphy has to be the initial imaging test, with the essential aim of differentiating between diffusely hyperfunctioning thyroid gland and hot nodules. As for the increasingly frequent issue of nonpalpable nodules incidentally detected by sonography, three different criteria (even though with possible overlapping in some instances) may be followed in the diagnostic workup: 1. Size: according to this parameter, all nodules exceeding 1.0 cm in maximum diameter should be punctured, irrespective of physical and sonographic features, whereas lesions under 1.0 cm should be only followed on time. 2. Clinicalsonographic features: patients with history of neck irradiation or familial history of MEN disease and patients presenting with cervical adenopathies with sonographic appearance consistent with malignancy and thyroid nodule(s) of any size must undergo ultrasound-guided FNAB of both thyroid nodule(s) and adenopathies. 3. Purely sonographic features: nonpalpable nodules showing sonographic features highly suspected for malignancy should always undergo ultrasound-guided FNAB [5].

In conclusion, a combined approach with sonography and FNA in patients with questionable thyroid nodules is generally highly effective. In fact, the extremely low probability to develop thyroid malignancies during a 6year follow-up period in patients with benign FNA has been already reported. Consequently, the possibility of missing a malignancy in a patient in whom both sonography and FNAB do not yield malignant features is actually very small [29]. Diffuse diseases Several thyroid diseases are characterized by diffuse rather than focal involvement: acute suppurative thyroiditis; subacute granulomatous or De Quervain's thyroiditis, and chronic lymphocytic thyroiditis, called Hashimoto' s disease in its goitrous form [35]; colloid diffuse goiter and Graves' disease, the commonest cause of thyrotoxicosis. Diagnosis of these conditions is usually made on the basis of clinical and laboratory findings and, on occasion, by FNAB, with a very limited role of sonography. In hyperplasia with hyperfunction (Graves' disease) the gland contours are lobulated and the size is increased, with usually prompt response to effective medical treatment: size reduction is a useful indicator of therapeutic success. The echotexture may be more inhomogeneous than in diffuse goiter, mainly because of the presence of numerous large intraparenchymal vessels. Furthermore, especially in young patients, the parenchyma may be diffusely hypoechoic either due to the extensive lymphocytic infiltration or to the predominantly cellular content of the parenchyma, almost lacking of colloid substance. Colour flow Doppler and spectrum analysis confirm the hypervascular pattern

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Fig. 11 a, b Chronic lymphocytic thyroiditis. a Severe disease, with pseudolobules, fibrous septa, irregular margins and very low level of echoes. b Occult disease with hypoechoic micronodules and mild irregularities of margins

that Ralls called thyroid inferno: intrathyroid arteries present turbulent blood flow with arterovenous shunts and the highest peak systolic velocities found in thyroid diseases (50120 cm/s), due to a flow rate usually exceeding 70 cm/s (Fig. 10). There are at present no demonstrations of correlation among degree of thyroid hyperfunction assessed on the laboratory parameters, extent of hypervascularization and flow-velocity values. On the contrary, in Graves' disease it has been demonstrated that the features of hypoechoic thyroid parenchyma and high flow in the thyroid artery and glandular parenchyma prior to starting medical therapy are highly specific for the prediction of relapse of hyperthyroidism at the end of the treatment [30]. In the course of medical treatment of Graves' disease, a significant decrease in flow velocities of the inferior and superior thyroid arteries is usually recorded. It is generally directly proportional to the decrease of the free fractions of thyroid hormones. Subacute granulomatous (or De Quervain's) thyroiditis is a self-limiting viral disease, usually preceded by infection of the upper airways. In the initial stage, transient hyperthyroidism due to massive follicular rupture has been reported. Subsequently, moderate and transient hypothyroidism may occur, related to slowly

progressive functional normalization. In the majority of cases subacute thyroiditis responds well to medical therapy with complete recovery of thyroid function within a few weeks. Histologically, interstitial oedema and cellular exudation with destruction of follicular cells are the predominant phenomena. Although subacute thyroiditis is easily diagnosed clinically, sonographic findings are pathognomonic [31]. In the initial stage the affected segments of the thyroid appear enlarged, with ill-defined, irregular margins and markedly hypoechoic structure with high acoustic absorption. With colour Doppler vascularization appears normal or, more commonly, reduced owing to the diffuse oedema of the gland. As the disease evolves, recovery of the normal thyroid structure may take pseudonodular form, involving asynchronously the various pathological foci. Occasionally, hypoechoic areas increase in size on follow-up examinations, requiring further medical treatment; therefore, the main roles of sonography in subacute thyroiditis are to assess the evolution of the disease and the timing of medical therapy and to detect early possible recurrences. Chronic autoimmune thyroiditis is more frequent in women (9:1) and in patients with other autoimmune pathologies. Thyrotoxicosis may be the initial clinical presentation, related to excessive hormonal release stimulated by antibodies (hashitoxicosis). Following this phase, hypothyroidism slowly develops, together with the progression of histological changes, consisting of lymphocytic infiltration and fibrosis. The typical sonographic features are increase in size, lobulated margins, fibrotic septa (pseudolobulated appearance) [32] and particularly micronodulation [33], namely the dissemination in the whole thyroid parenchyma of hypoechoic rounded spots, commonly 16.5 mm in size (Fig. 11). Histologically, they represent lobules of thyroid parenchyma with massive infiltration of lymphocytes and plasma cells, surrounded by a hyperechoic ring of fibrous strands. Micronodulation is a highly sensitive sign of chronic thyroiditis, with a positive predictive value of 94.7 % [33]. With colour Doppler marked intraparenchymal hypervascularity, chiefly arterial, is mostly detected, especially inside the hyperechoic septa. This pattern does not differ significantly from the thyroid inferno described in Graves' disease, but in chronic thyroiditis blood flow velocities mostly remain within normal limits, both before and following medical treatment. The end stage of chronic thyroiditis is the atrophic form: the thyroid gland is small, with ill-defined margins and heterogeneous texture due to progressive increase of fibrosis. Blood flow signals are completely absent. A quite peculiar, though not exceptional, finding is the coexistence of thyroid nodules, benign or malignant, with chronic lymphocytic thyroiditis. Cytology is often needed to achieve the final diagnosis [34].

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12 a

12 b

13

14 a

14 b
Fig. 12 a, b Parathyroid hyperplasias in secondary hyperparathyroidism. a Transverse scan of the thyroid gland: large hypoechoic parathyroid hyperplasia on the right side and small lesion on the left side. Both lesions are located posteriorly to the thyroid lobes and show peripheral capsule. b Longitudinal scan of the thyroid lobe with two small, rounded, hypoechoic and capsulated parathyroid hyperplasias Fig. 13 Primary hyperparathyroidism. Large hypervascular parathyroid adenoma with both internal and perilesional blood flow signals Fig. 14 a, b Cystic parathyroid tumours. a Highly echogenic parathyroid adenoma with wide cystic changes and perilesional blood flow signals. b Anechoic parathyroid cyst with perilesional blood supply

In summary, sonography plays a minor role in the diagnosis and management of diffuse thyroid diseases, although some sonographic features are nearly pathognomonic of definite diseases. Sonography can be useful in diagnosing subclinical forms of diffuse disease, in determining the coexistence of nodular lesions and thyroiditis, and in monitoring changes in textural and vascular patterns during medical treatment.

Parathyroid glands
Normal parathyroid glands are not detectable with any imaging modality, due to small size and structural pattern similar to that of the adjacent thyroid parenchyma; however, when there is biochemical evidence of hyperparathyroidism (HPT), high-frequency sonography is commonly used to detect abnormal parathyroid glands, being a highly accurate non-invasive procedure for this purpose. Primary hyperparathyroidism is now recognized as a common endocrine disease, especially in patients over 50 years old. The three main aetiologies are: adenoma

Painless (silent) thyroiditis has the typical histological and sonographic (hypoechogenicity, micronodulation and fibrosis) pattern of chronic autoimmune thyroiditis, but clinical symptoms may be completely absent in most cases (Fig. 11). Usually the detection is occasional during sonographic studies of the neck performed for different purposes. Slow progression to hypothyroidism is a common finding.

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(almost always limited to a single gland); hyperplasia (which involves all four glands); and carcinoma. Adenoma is the most common cause of HPT (80 % of cases) [35]. The preoperative localization of parathyroid tumour(s) is highly recommended, since it allows for a remarkable shortening of operative time, especially when surgery is complicated by, for example, anatomical peculiarities and abnormal locations of the glands. In addition, preoperative localization reduces the risk of damaging the laryngeal nerve and normal parathyroids [4, 36, 37]. Secondary hyperparathyroidism is usually a response to chronic hypocalcaemia in uraemic patients. Since surgery is advisable only in advanced cases, ultrasound examination may help the clinical management of these patients, monitoring size and structure changes during medical treatment, but may also help the surgical management, facilitating the detection of enlarged supernumerary parathyroid glands or glands in atypical positions [38]. Parathyroid adenomas and hyperplasias have usually oval or oblong shape, with longitudinal diameter ranging from 7 to 15 mm. The smallest adenomas can be minimally enlarged glands that appear virtually normal during surgery but are found to be hypercellular on pathological examination Occasionally, the largest adenomas may have tubular shape and exceed 45 cm in longitudinal size. They are mostly homogeneously solid, markedly more hypoechoic than the adjacent thyroid tissue. This characteristic hypoechogenicity is due to the uniform hypercellularity of the gland, which leaves few interfaces for reflecting sound. Parathyroid lesions are separated from thyroid tissue by an echogenic plane, representing the capsule [35]. Most adenomas and hyperplasias are hypervascular on colour Doppler, with prominent diastolic flow (Fig. 12). In 1520 % there are variations in the echotexture of parathyroid tumours. Occasionally, the level of echogenicity can be similar to that of thyroid parenchyma, increasing the difficulties for the sonographic differential diagnosis; approximately 2 % have internal cystic components that are due to cystic degeneration (Fig. 13). More rarely, purely cystic adenomas may be found (Fig. 13). Solitary parathyroid cyst, more frequent in women, occur below the level of the inferior thyroid margin in 95 % of cases; 65 % of them involve the inferior parathyroid glands. The cystic fluid has high levels of parahormone. Calcifications are rare in adenomas and more common in carcinomas and hyperplasias due to secondary HPT, because of the long duration of these diseases. Preoperative serum calcium levels are usually higher in patients with larger adenomas. When multiple parathyroid tumours (either adenomas or hyperplasias) are present in the same patient, they have the same sonographic and gross appearance as single parathyroid tu-

mours; however, the glands may be inconsistently and asymmetrically enlarged, and the diagnosis of multiple gland disease often is difficult to make sonographically. The appearance may be misinterpreted as solitary adenomatous disease, or the diagnosis may be missed altogether if the glandular enlargement is minimal. In most cases, parathyroid carcinomas are indistinguishable sonographically from large benign adenomas. Gross evidence of invasion of adjacent structures, such as vessels or muscles, is the only reliable preoperative sonographic criterion for diagnosis of malignancy, but this is an uncommon finding (Fig. 14) [1, 4]. Furthermore, benign lesions are mobile when patient swallows, whereas malignant lesions may be fixed [35]. Parathyroid glands have an extreme variability of number and location in normal subjects. Most subjects have four glands which are located posteriorly to the upper and lower poles of the thyroid gland; however, in as many as 25 % of normal subjects more than four glands are present [39, 40]. When parathyroid tumours are ectopically located, the sonographic detection may be more difficult: intrathyroidal glands (1 % of cases) mimic thyroid nodules, being hypoechoic with well-defined margins. Retrotracheal glands are hardly detectable because of the acoustic shadowing from the trachea. Finally, the undescended glands, situated along the course of the common carotid artery or the recurrent laryngeal nerve, are similar to laterocervical lymph nodes [35]. False-positive sonographic diagnoses may be due to prominent blood vessels, oesophagus, longus colli muscle, thyroid nodules and enlarged cervical lymph nodes, whereas false-negative results are caused by minimally enlarged adenomas, adenomas obscured by enlarged thyroid goiters, and ectopic adenomas. The sensitivity of ultrasound for the parathyroid adenoma localization in primary HPT ranges between 70 and 80 % [1, 41, 42, 43]. Specificity may be improved with ultrasound using FNAB. Sonography also permits the reliable differentiation of parathyroid adenomas from other pathological structures such as thyroid nodules or cervical lymph nodes [44, 45, 46]. In persistent or recurrent hyperparathyroidism, the reported sensitivity of ultrasound ranges between 36 and 63 % [43, 44]. Ultrasound augmented by FNAB and PTH assay can lead to a specificity approaching 100 % [47, 48]. In conclusion, pre-operative localization of the parathyroid glands is useful for the following purposes: 1. To identify one abnormal parathyroid gland: this allows for unilateral neck exploration, thus reducing operative time and surgical complications. 2. To localize parathyroid tumours in post-operative either persistent or recurrent HPT: the complication rate at re-operation is relatively high and the success rate decreased [36, 46].

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Fig. 15 Parathyroid carcinoma with non-specific sonographic features: mild hypoechogenicity and irregular margins

Fig. 16 Schematic representation of cervical lymph nodes grouped in six levels. Level VII is located in the upper mediastinum

3. In case of negative results with ultrasound, to aid in the differential diagnosis of hypercalcaemia which can be related to causes other than HPT.

Neck lymph nodes

In the normal adult neck there may be up to 300 lymph nodes, ranging in size from 3 mm to 3 cm. Lymph nodes are small, oval or reniform bodies lying along the course of lymphatic vessels. When a node undergoes antigenic stimulation, it reacts with an increase in size and vascularity [4]. Many pathologies of the head and neck region present as palpable lymph nodes, most of which are superficially located. Using high-frequency ultrasound, multiple nodes in all areas of the neck can be detected and their morphology and vascularity can be thoroughly assessed; however, due to the different echotexture and size, it is more difficult to detect benign innocent than malignant lymph nodes. Neck lymph nodes can be classified according to their anatomical location: submental; submandibular; parotid; facial; deep cervical; spinal accessory; transverse cervical; retropharyngeal; occipital; and mastoid [4, 49, 50]. A further topographic classification, performed by AJCC [51], is based on 7 levels, usually employed in order to plan surgical interventions. Level I includes submental and submandibolar nodes; levels II, III and IV include deep cervical chain, the nodes deep to the sternocleidomastoid muscle and the upper spinal accessory chain. Level V includes the transverse cervical chain; level VI the anterior cervical nodes and level VII nodes in the superior mediastinum (Fig. 15). Once lymph nodes are detected, it is mandatory to define whether they are benign or malignant. For this purpose, eight parameters should be evaluated: size; shape; echogenic hilum; level of echogenicity; necrosis;

extracapsular spread; characteristics of vascularity; and calcifications. Normal lymph nodes are formed by an outer cortex with lymphoid follicles and an inner medulla with lymphatic sinuses, connective tissue and blood vessels. Reactive nodes are sonographically indistinguishable from normal nodes. Most inflammatory diseases, except for granulomatous infections such as tuberculosis, involve lymph nodes diffusely and homogeneously, generally preserving their normal oval shape (Fig. 16). On the contrary, the neoplastic infiltration of lymph nodes occurs primarily in the cortex; therefore, malignant nodes tend to have a greater transverse diameter, with a rounded, asymmetrical morphology of the node (Fig. 16). The long-to-short-axis ratio (L/S ratio) can be employed for the distinction between benign (L/S > 2.0) and malignant nodes (L/S < 2.0) [52, 53, 54, 55, 56]. The centrally located, thick and regular echogenic hilum is a common feature of normal lymph nodes. Malignant nodes have thin hilum, because of the peripheral neoplastic infiltration: often the hilum is eccentric (or completely lacking), with associated eccentric cortical widening (Fig. 17) [56]. As for the echotexture of the cortex, lymphomatous nodes have thickened, uniformly hypoechoic cortex, whereas metastatic nodes show a more echogenic and heterogeneous cortex. In patients with known primary cancer, the presence of necrosis in a lymph node is a highly probable sign of malignancy: it may appear as a true cystic area or a hyperechoic zone (coagulative necrosis; Fig. 18). Cystic necrosis is also often identified in tuberculous nodes, commonly located in the spinal accessory chain and in the supraclavicular region. They tend to be clumped together, with associated inflamed surrounding interstitium [56]. Whenever cystic necrosis is detected in a node, aspiration biopsies for both cytology and microbiology studies should be performed.

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Fig. 17 a, b Hyperplastic lymph node of the neck with elongated shape. a Central hilum, and b central hilar blood supply Fig. 18 Rounded hypoechoic adenopathy with eccentric thin hilum Fig. 19 Typical metastatic adenopathy: rounded, isoechoic, with multiple poles of vascular supply, both perilesional and intralesional Fig. 20 a Rounded hypoechoic tuberculous nodes with macrocalcifications and poor (mostly perilesional) vascular supply. b Lymphomatous node (Hodgkin's disease) with poor vascularity. Blood vessels show predominantly hilar and regular arrangement

17 a

17 b

18

19

20 a

20 b

Normal lymph nodes have smooth margins. In malignant transformation nodes have rounded and welldefined margins. With advancing malignancy, margins become less defined and sharp, due to possible extracapsular spread. The patterns of vascularity and their changes are very important in distinguishing between benign and malignant nodes. Histopathological studies have shown that arteries and veins enter the node at the hilum and spread in bundles which course longitudinally with the long axis of the node. Capillaries arising from these hilar and medullary vessels feed the nodal cortex [57, 58]. Hilar flow with central vascular pattern is seen in most (98 %) benign nodes. On the contrary, most malignant nodes (78 %) show aberrant vessels with curved course entering from the nodal capsule, in addition to hilar

vessels (mixed capsularhilar vascularity; Fig. 19, 20) [59]. The amount of extrahilar vessels is higher in metastatic nodes than in lymphomatous nodes, which is likely due to different angiogenesis. Malignant nodes have pulsatility index (PI) and resistive index (RI) higher than benign nodes; cut-off values are 1.3 for PI and 0.72 for RI [59, 60, 61]. Three-dimensional sonography can be helpful in detecting more easily abnormal vasculature, especially subcapsular and intranodal tortuous vessels [62]. No single sonographic criterion is absolutely specific for benign or malignant nature; however, rounded shape, absence of hilum, irregular or spiculated outline, coagulative or cystic necrosis, and chaotic capsular blood flow pattern are signs highly suspicious for malignancy, especially when they coexist in the same node.

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For any doubtful case, the most reliable diagnostic modality is ultrasound-guided FNAB, which is reported to

have accuracy of 8990 %, sensitivity of 7678 % and specificity of 98100 % [4, 63].

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