PAPILLON COURSE on THYROID ULTRASOUND

Section 2 The nodular goiter

Part 2 The composition of the nodule

Manual

OPENING

The composition of a lesion refers to the lack or presence and the proportion of solid and cystic areas. If the cystic parts are below 50%, the nodule is classified as solid, if the cystic areas exceed 50%, then the nodule is cystic. The risk of malignancy is lower in cystic nodules,

however, it has limited relevance in the clinical practice except for pure and spongiform cysts. Cystic degeneration influences the presentation of the echogenicity of the solid part and makes the cytological pattern more difficult to evaluate.

SUBTYPES CYSTIC LESIONS

The different subtypes of cystic nodules are enlisted in Figure 1. The basis of the grouping is the amount and location of the solid portion within the cystic nodule.

The meaning of this grouping is that the malignancy rate and therefore the further management differs in the various subtypes.

Figure 1 Categorization of cystic lesions.

Central-type cystic lesion

This subtype is also cold as concentric. In this form, the solid part is located all along the inner wall of the cyst in a concentric position along the cyst wall. This is the typical appearance of follicular adenomas. The cause for the cystic changes is probably the decreased and insufficient vascular supply of the central areas of the solid part. Complex, multichambered cysts are a subtype of this category.

In this case, multiple cystic areas can be distinguished which are separated by fibrous septa. The risk of malignancy is significantly lower in central-type cyst compared with peripheral-type ones, and even lower in multichambered cystic nodules.

Peripheral-type cystic lesion

This subtype is also called as eccentric. The solid part is in contact with the cyst wall only at one part of the lesion the position of the solid part is eccentric. Although this subtype shares a significantly greater risk of malignancy, overwhelming majority of such lesions is also benign.

We can speculate that the cause of this form is the papillary growth, either benign or malignant. An acute rather than a blunt angle between the solid part and the cyst wall confers a higher risk of malignancy (7-9).

Spongiform-type cyst

Spongiform cysts are very rarely malignant, the cancer risk is < 1% (10). The literature is a bit confusing regarding the use of the term spongiform. Firstly, it is worth distinguishing the spongiform appearance from the spongiform nodule. Spongiform appearance (also known as 'honey-comb' or 'puff pastry') means an area which is composed of tiny cystic spaces separated by fibrous septa; this interpretation is uniform. On the other hand, there are differences in the use of spongiform nodules. Secondly, some authors (11) and the ETA-TIRADS restrict this term for nodules which are entirely composed of spongiform areas (12).

Others, including the AACE, ACR, ATA and Korean TIRADS define a nodule as spongiform if the microcystic areas > 50% of the nodule (13-17).

Moreover, the latter four TIRADS differ in whether the echogenicity of the solid part is taken into account in the determination. While Korean and in part the AACE TIRADS restrict the use of spongiform nodule only for isoechoic nodules, ACR and ATA TIRADS do not.

Kim et al. use three grades according to the extent of spongiform areas: <50% of the nodule (grade I), between 50% and 75% (grade II), and grade III, >75% (grade III). They have found 5 malignant nodules among 201 nodules presenting spongiform areas, 4 out of 101 grade I, 1 out of 45 grade II, while no out of 55 grade III nodules proved to be malignant (18).

Pure cyst

In all TIRADS pure cyst is defined as a nodule which has no solid part, ETA includes in the definition the lack of wall thickening, too.

True simple thyroid cysts lined by benign epithelial cells are rare. As an example, in one ultrasound study of 1985 patients with 3483 nodules larger than 10 mm, there were only seven completely cystic nodules (19).

There are several issues regarding purely cystic nodules. Firstly, small cystic lesions are indeed not nodules but dilated macrofollicles which are common and normal findings. Therefore, we do not agree with the ETA

TIRADS, which disregards the size of the lesion. It seems more realistic to maintain the term nodule for lesions > 1 cm. Secondly, an apparently cystic nodule might contain solid areas which cannot be revealed until the removal of cystic fluid (see case 1457). An opposite situation can occur when we see small solid-appearing portion at the wall of the cysts which thereafter we can completely remove during the aspiration (see case 2175). In such cases this solid-appearing mass was indeed either an optical artifact or a fibrin clot. These observations lead us to perform aspiration even in apparently purely cystic nodules > 10-15 mm, and to determine the type of cystic nodule only after the aspiration.

THE HANDLING OF CYSTIC NODULES IN TIRADS

Table 1 The main factors defining the categorization of cystic nodules in various TIRADS.
	AACE	ATA	ETA *	KOREAN *
Lowest possible category	All, if fluid component >80% No susp. sign and comet tail present Isoechoic spongiform	Pure cyst	Pure cyst Spongiform	Pure cyst Spongiform Comet tail present
The 2 most suspicious category	The presence of cystic degeneration has no influence on the categorization
* In these TIRADS the lowest category is the 'no nodule'.

Spongiform nodules are grouped among the possible lowest category in all (12,14,15,17) but the ATA TIRADS which puts this nodule into category 2 (16). On the other hand, ETA restricts the term spongiform for nodules which are composed entirely of spongiform areas, while the other 4 TIRADS define a nodule as spongiform if the microcystic areas > 50% (12).

Three TIRADS group only completely cystic nodules into the lowest category while AACE does so if fluid component >80% (14). This difference has practical relevance in such lesions presenting suspicious signs; these lesions are grouped among the most benign category or into the most suspicious category, AACE or ATA, ETA, Korean TIRADS, respectively (12,14,16,17).

The presence of comet tail artifact has no relevance in the ATA and ETA TIRADS (12,16). In contrast to them, all lesions presenting comet tail artifacts

are grouped among the most benign category in the event of Korean TIRADS (17). It emphasizes the correct interpretation of intranodular echogenic figures, which is not always possible. E.g. the ACR TIRADS enlist small comet-tail artifacts found within a solid portion into the same category as microcalcifications because these are difficult to differentiate (15).

The ACR system differs from the four other TIRADS (15). In complete or almost complete cysts the system does not deal with the solid part. The issue is that this guideline did not define 'almost' complete cysts. The other important and unique consideration in this system is the distinction between small (< 1mm) and large comet-tail artifacts. The latter is handled as a benign feature while the former, if found in solid part, is classified together with microcalcification as 'punctate echogenic foci' and is worth the highest possible points in this categorization. Considering the possibility of colloid crystals indeed or only apparently in solid part, this might lead to overestimation of colloid crystals.

PRACTICAL ISSUES IN CYSTIC NODULES

Cystic nodule or a normal finding?

We have already mentioned that most purely cystic lesions less than 1 cm in diameter are normal findings, they correspond to dilated macrofollicles.

Therefore, it seems reasonable to maintain the term nodule for those cystic lesions which are larger than 1 cm in diameter.

When to determine the subtype of a cystic nodule? Before or after the aspiration?

The aspiration of cystic content frequently alters both the subtype and the size and echogenicity of the solid part. It is well-known that the fluid amplifies the echo signal and therefore the solid part dorsal to the cystic content seems usually brighter, more echogenic than it is. The other influence of the cystic fluid is its compression effect on the solid part. After the relief of the compression, the solid part frequently becomes much larger than before aspiration. It is also not a rare finding that some parts of the solid part became visible only after the removal of the cystic fluid which can reveal that a seemingly peripheral-type cyst was indeed a central-type lesion. Based on these observations, both the subtype of the

cystic nodule and the real size and echogenicity of the solid part are better to determine after the aspiration.
If we determine the echogenicity before the aspiration, those areas of the solid part should be considered which are located not dorsal to the fluid. In contrast with solid nodules, in this case we cannot rely on the usual ultrasound characteristics, first of all on the echogenicity of the solid part which help us to classify the nodule for FNA. Therefore, FNA should be considered in cystic nodules which present a contiguous solid part larger than 1 cm, even if the lesion would not be a candidate for cytology.

The interpretation of usual suspicious signs in cystic nodules

There are two suspicious findings which rely exclusively on the solid part. These are the microcalcifications and the echogenicity. The former has similarly great relevance in the event of cystic nodules and microcalcification s consistently confer a higher risk of malignancy (7-9). The echogenicity of the solid part has less relevance in cystic compared with solid nodules. The cause for this is the worse evaluability of the echogenicity,

the amplification of the echo signal dorsal to cystic fluid. Kim et al. has found that 44% of mixed nodules had isoechoic solid part, a proportion which is much lower in solid nodules (9).
The other usual suspicious findings, i.e. irregular shape, irregular margins and increased vascularity of the solid part are also risk factors which are less robust in cystic compared with solid nodules (8-9).

The influence of cystic degeneration on cytology

Cystic degeneration frequently causes problems in the microscopical analysis and this is the most frequent cause of non-diagnostic cytological reports (20). There is a distinct subcategory in the Bethesda I group, the 'cystic fluid only' (21). In such cases the risk of malignancy is lower than in other forms of non-diagnostic cytologies. The ultrasound-guided aspiration of the solid part cannot fully resolve the issue. A solid part within a cystic fluid is similar to a sponge floating in a bath: the solid part is also impregnated with the fluid.

And because fluid is much easier to aspirate than solid cells, this frequently leads to non-diagnostic report. Cell block technique might have some role in such cases (22). Another issue is that the cystic fluid is an excellent substrate for cell proliferation. Smears prepared from cystic fluid are not infrequently very cellular which can mislead a less experienced cytopathologist (20). And a third problem, cystic degeneration often alters the appearance of the cells, cystically degenerated follicular cells are often difficult to judge.

ECHOGENIC FIGURES IN CYSTIC LESIONS

This topic, including differential diagnostics, is discussed in detail in a distinct chapter. Here, we only briefly describe the

ultrasound presentation of comet-tail artifact, and echogenic figures caused by back wall posterior enhancement.

Comet-tail artifacts or colloid crystals

These granular structures which have a dorsal narrowing tail are typically found in cystic cavities. The shape of the colloid crystal is usually round, however linear forms can be also observed. Although colloid crystals typically appear in the cystic part of a mixed solid-cystic lesion, we must be aware that comet-tail artifact might be located even within the solid part and the differentiation of bright granules in a solid lesion is the most important differential diagnostic issue regarding hyperechogenic figures.

Comet-tail artifact is generally held a protein-rich structure or a colloid crystal. Overwhelming majority of cystic nodules presenting comet-tail artifacts are benign (23-25).
The presentation of this figure is frequently non-typical because of the lack of the dorsal tail. From a practical point-of-view hyperechogenic granules within a cystic fluid are best held as colloid crystals even if they lack the dorsal tail. The issue is the appearance of non-typical forms within a solid nodule or within the solid part of a mixed nodule.

Posterior back wall enhancement

This bright granular or linear figure is seen exclusively in the dorsal wall and occasionally in the parenchyma just dorsal to a cystic area. The cause of this figure is the enhancement of US reflection. Spongiform and other mixed cystic solid nodules may exhibit bright reflectors on US imaging, caused by colloid crystals or posterior acoustic enhancement of the back wall of a microcystic area.

These may be confused with microcalcifications by less proficient sonographers (26).
In contrast with all other hyperechogenic figures this is not a real structure but only an optical artifact. (In the event of comet-tail artifact, the colloid crystal is a real figure, only the tail is the artifact.)

PARATHYROID CYST

There are various forms of cystic lesions in the neck located outside the thyroid. These are discussed in a distinct chapter. We emphasize here a very important phenomenon: the cystic degeneration of a neck lymph node in the event of papillary carcinoma is highly suggestive of metastasis. We focus here on the parathyroid cysts.

The four parathyroids are located dorsal and upper and dorsal and lower to the thyroid gland. However, neither an aberrant location of the thyroid nor the non-regular location of a parathyroid is an infrequent finding.

Therefore, the differentiation of a cystically degenerated thyroid from a parathyroid cyst is a difficult task. Beside the location of the lesion there is another feature, which might be of help. In contrast with thyroid nodules, parathyroid cysts are frequently almost entirely or entirely cystic. The distinction is of relatively low practical importance. A usually large cyst requires aspiration in order to decrease the size. The aspirated fluid of a typical parathyroid cyst is crystal clear (27). The wash-out parathormone level is very high, while the wash-out thyroglobulin is practically zero. A recurrent parathyroid cyst can be treated very successfully with ethanol.

CYSTIC DEGENERATION IN THE MOST FREQUENT TYPES OF THYROID CARCINOMAS

The malignancy risk is held lower in cystic compared with solid nodules, however the probability of malignancy of a cystic nodule differs widely (28-29). Some studies have shown very low incidence of malignancy in cystic nodules (0.5-3%) (30-32), whereas others have shown a similar incidence to that of sonographically solid nodules (33-35).

As it has been already discussed, certain types of cystic nodules share practically no risk of malignancy, these are the pure and spongiform type cysts. Cystic component is found in 13%-26% of all thyroid malignancies (36-37). Predominantly cystic nodules occur only in papillary carcinomas (36).

Papillary carcinoma

This is the type of carcinoma where cystic degeneration is frequently observed. 5% of PTC are predominantly cystic (36). The peripheral type is the one in which cancer occurs in practice. On the other hand, the judgement of the subtype is frequently hindered by the coexistence of macrocalcifications. The solid part of a cystically degenerated PTC is significantly more isoechoic compared with solid forms of PTC: almost half of the cystic nodules are proved to be iso/hyperechoic (9).

Similar to the primary focus, the lymph node metastases of PTC also present relatively frequent cystic changes. Wunderbaldinger et al. have found that in 14.9% of PTCs, the cystic lymph node metastasis was the initial manifestation of the disease. This emphasizes the importance of evaluation of the neck lymph nodes if we find thyroid nodule on ultrasound examination (38).

Follicular carcinoma

Similar to most ultrasound characteristics, the ultrasound presentation of follicular carcinoma is strikingly different from PTC. The presence of cystic degeneration proved to be the strongest negative predictor in the

diagnosis of FTC in one study, in which no FTC occurred in cystic nodules (39). While most FTCs are solid, a partially cystic component is more frequent (up to 18%) than in PTC (40-41).

Medullary carcinoma

This subtype of thyroid cancers very rarely undergoes cystic degeneration. There are only a few case reports in

the literature in which the authors have reported medullary carcinoma in cystic nodules (42).

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