PAPILLON COURSE on THYROID ULTRASOUND

Section 2 The nodular goiter

Part 7 Extrathyroidal spread

Manual

 

OPENING

Extrathyroidal extension (ETE) is a controversial topic. While this is one of the very few characteristics which can be compared to a biological standard, the usefulness is substantially hindered by several circumstances. At first, we should bear in mind the normal anatomy of the thyroid, the lack of a complete fibrous capsule surrounding the organ. The second issue is that in contrast with most malignant conditions of the human body, the ETE does not mean itself a worse prognosis in all forms. The third issue is the high interobserver variation and the far-from-ideal sensitivity of ultrasound (US) in detection of ETE.

We must realize that US signs of ETE is used in two different senses.

Firstly, these signs may suggest ETE. Secondly, these signs are useful to predict the cancer irrespectively of spreading extrathyroidal or not. In the latter case, these signs are similar to microcalcification, irregular border or shape and deep hypoechogenicity. The guidelines differ as to which of these signs are used.

From a very important point-of-view, ETE is the most important US characteristics, the only one which influences even the staging of a thyroid cancer. We must be aware that this influence might be extremely large and exceedingly beyond the scope of thyroid US examination.

 

THE IMPORTANCE OF EXTRATHYROIDAL SPREAD IN THE NEWEST TNM CLASSIFICATION SYSTEM

One of the most important changes in the 8th edition of TNM staging is the removal of the minor ETE from the definition of T3 disease in the event of differentiated thyroid cancer, if ETE was detected only on histological examination (1) which leads to downstaging a significant number of patients from stage III to either stage I or stage II disease. Minor ETE does influence neither the T category, nor the staging of the tumor.

In essence the new TNM staging differentiates four grades of ETE (see Table 1). Essentially, except for cases with distant metastasis, the T2, T3 and T4 categories are defined exclusively by the presence of ETE. In the event of clinical staging the role of ETE has a bit lower but very important relevance. Be aware that a T4 tumor (i.e. a tumor with the possible largest gross ETE) without distant metastasis belongs to stage I group which means that the 10-year disease free survival is 98-100%.

Table 1 The role of extrathyroidal extension in 8th edition of TNM staging system.

Recognition
T-status
Stage
< 55 years old *
≥ 55 years old**
Minor
Only on histopathology
No influence
I or II*
I-IV
Gross extrathyroidal extension into strap muscles
Gross
T3b
II-IV
Gross extrathyroidal extension into subcutaneous tissue, larynx, trachea, esophagus, recurrent laryngeal nerve
Gross
T4a
III-IV
Gross extrathyroidal extension into prevertebral fascia, encasing major vessels
Gross
T4b
IV

* Depends exclusively on the lack or presence of distant metastasis, stage I or stage II, respectively.

** Depends on other histopathological findings, i.e. T-status.

 

HISTOPATHOLOGICAL ASSESSMENT OF EXTRATHYROIDAL GROWTH

The details are far beyond the scope of this work. We give a short summary of the issues of histopathological evaluation and highly recommend immersing in detail, e.g. to read the excellent work of Turk and coworkers (2).

The most basic thing about normal thyroid anatomy is that the thyroid lacks a complete fibrous capsule. The gland is instead surrounded by a partial fibroadipose pseudocapsule of variable thickness, usually continuous with intraglandular fibrous septa that delineate parenchymal lobules (2). Given the composition of this pseudocapsule, the presence of carcinoma in adipose or fibrous tissue beyond thyroid parenchyma does not necessarily indicate ETE. Additionally, adipose tissue metaplasia of the interfollicular stroma sometimes occurs), further complicating the relevance of adipose tissue in the assessment of ETE (3). Due to the normal anatomical situation, i.e. to the association between the so-called Soemmerring's muscle and the isthmus and pyramidal lobe, involvement of skeletal muscle around these locations may not be diagnostic of ETE. Skeletal muscle fibers or bundles other than Soemmerring's muscle can be seen within the thyroid gland parenchyma, as are nerves and thick-walled blood vessels (4).

There are four types or degrees of ETE (see Table 1). Sue et al have investigated minimal ETE and have demonstrated that in terms of ETE, the overall agreement was only slight among thyroid pathologists. These authors have examined the diagnostic agreement among 11 expert

pathologists regarding the involvement of four anatomical structures by microscopical analysis of 69 thyroid tumors. The kappa values have been 0.03, 0.10, 0.20 and 0.46, perithyroidal thick-walled vessel, nerve, fat and skeletal muscle involvement, respectively.

This resulted in a 0.16 kappa value regarding the presence of minimal ETE (Su-2016). One of the causes for these very low kappa values was that the experts used different histological criteria to establish the different types of ETE. As a consequence, the reported frequency of ETE varies from 5% to 45% (3, 5-16).

In fact, 3 out of 4 types of ETE are defined not by microscopical analysis but by analysis of gross specimen. As described in the current version of the CAP Thyroid Carcinoma Protocol, this requirement warrants review of gross, intraoperative, and radiologic findings (2). This criterion underscores the importance of adequate dissection technique and thorough macroscopic evaluation, enhancing the importance of the prosector's role. Notably, neither the AJCC manual nor the explicative notes provided by the CAP offer guidance regarding the scenario in which microscopically extensive ETE is not appreciated grossly. Accordingly, macroscopic examination of thyroid cancer resection specimens by an experienced prosector (if not an attending pathologist) may be necessary and is recommended. This more stringent definition also elevates the importance of intraoperative, and radiologic correlation and incorporates review of these findings into the pathologist's workflow.

 

THE ROLE AND LIMITATIONS OF ULTRASOUND AND OTHER RADIOLOGIC TECHNIQUES IN DETECTING EXTRATHYROIDAL GROWTH

We have demonstrated the very importance of ETE in staging and therefore in the prognosis of thyroid malignancies. We must realize a very controversial situation. Current staging system places a huge amount of responsibility on the ultrasonographer's shoulders, while on the one hand a lot of investigators are not aware of it, and on the other hand to accomplish this task, there is a lack of professional justification.
None of the current endocrinological guidelines recognizes this huge responsibility of thyroid US in tumor staging (17-21). In fact, three of the guidelines out of the five TIRADS systems had incorporated the ultrasound signs of ETE into their scoring systems (17-19) while two guidelines suggest FNA even if subcentimeter nodules if US is suspicious for ETE (17,21).

So, it would be of great importance if we would be able to detect ETE on US examination. Unfortunately, we cannot meet this goal. US has a very limited ability to judge ETE and is unable to determine the extent of an existing ETE. We can rely on the borders of the nodule and that of the thyroid. Many circumstances hinder the exact determination of the borders. One of the most important factors is the similarity of the echogenicity of the malignant nodule and the neighboring anatomical structure. In the event of tumors in the ventral part of the lobe we have to consider that most malignant nodules are hypoechoic, and a similarly hypoechoic strap muscle runs in most cases just on the ventral border of the thyroid. In tumors located in the dorsal part, the main issue is that this part of the thyroid is worse to visualize simply because of physical reasons. The medial part of the thyroid is adjacent to the trachea where the visualization is the worst because the cartilage of the trachea hinders the spread of US wave.

Nevertheless, in certain cases the situation makes it possible to consider

ETE. First, ETE can be excluded in nodules which are covered by thyroid tissue all along the borders. It means that the specificity of ETE in sono-histological comparison could be very high. Regarding not the exclusion, but the detection of ETE we can rely on the surface of the nodule which is at the edge of the thyroid. If it the edge of the nodule protrudes and is beyond the surface of the thyroid, ETE can be considered. In certain cases, we can rely on another sign. The thyroid can be covered by connective tissue, which appears as a thin echogenic line on the ventral surface of the lobe. If this line is broken by the nodule, ETE can be considered again. The issue is that this echogenic line if at all exists, is not infrequently discontinuous. Let me remind you that the thyroid gland lacks a complete fibrous capsule (3).

The two other radiologic modalities which might be used for detection of ETE are the CT and MRI. The first concern is that these are not included in the usual evaluation process of a nodular goiter' patient. The second problem is that these techniques are not better than US for ETE. We present a comparison of diagnostic performance of US and MRI based on the data of Kim et al. in Table 2 (22). This data proves that neither of the techniques is able to detect ETE with high enough accuracy. It is worth focusing on gross ETE because minimal ETE does not influence the prognosis of patients. Similar results were found in the event of CT (23). In a series of 299 consecutively registered patients with pathologically proven PTC who underwent preoperative CT and US, US was more accurate than CT in predicting ETE and multifocal bilobar disease (p<0.05). The accuracy of staging was better overall with US (p<0.01), and US had greater sensitivity than CT at predicting lateral compartment metastases (p=0.041). It means that the concern affecting US and MRI as a basis for a postoperative pathological staging, is also present in the event of CT (24).

Table 2 Diagnostic performance of ultrasound and magnetic resonance imaging in the prediction of extrathyroidal extension.

 

Modality

Sensitivity (%)

Specificity (%)

PPV (%)

NPV (%)

Accuracy (%)

Minimal degree of extrathyroidal extension

 US

80.1

70.4

86.3

59.6

77.3

 MRI

64.7

84.9

90.6

50.0

70.4

Gross extrathyroidal extension

 US

78.5

79.5

46.8

94.1

79.3

 MRI

89.2

76.8

47.1

96.8

79.1


 See reference of Kim et al. (22).

The work of Kim et al. has proven that US and MRI have a very limited potential defining the degree of ETE (see Table 3) (22).

Table 3 The role of ultrasound and magnetic resonance imaging (MRI) in the prediction of direct invasion of thyroid cancer.

Structure invaded

Diagnostic tool

Sensitivity (%)

Specificity (%)

PPV (%)

NPV (%)

Accuracy (%)

Trachea

 

Ultrasound

63.6

85.1

42.4

93.1

82.0

 

MRI

59.0

82.6

37.1

92.1

79.1

Esophagus

 

Ultrasound

35.7

96.3

50.0

93.5

90.6

 

MRI

57.1

92.5

44.4

95.4

89.2

Major vessels

 

Ultrasound

35.7

97.7

62.5

93.6

92.0

 

MRI

42.8

96.2

54.5

94.2

91.2

Recurrent laryngeal nerve

 

Ultrasound

50.0

97.2

20.0

99.3

96.6

 

MRI

50.0

95.9

14.2

99.2

95.3

The less than 50% positive predictive value of radiological assessment means that if we would rely on the radiologic reports following the suggestion of the newest TNM, than more than half of the cases would be

falsely diagnosed as presenting ETE; this misinterpretation would lead to overtreatment, false judgement of prognosis. Following the newest TNM would cause immeasurable harm to huge number of the patients.

 

HOW TO JUDGE THE EXTRATHYROIDAL EXTENSION?

As we have mentioned earlier the strap muscle is not a homogeneous tissue and is composed of three different components: There are different suggestions in the literature regarding ETE. Basically, there are two features which can raise the possibility of ETE, the first is integrity of the capsule (in fact the pseudocapsule) and the second is the location (the contour) of the tumor (see Table 4). Rim et al. have distinguished three types of the continuity of the capsule, it can be continuous, discontinuous or invisible. The last two were more prevalent in ETE than non-ETE (25). The other is the location of the tumor, i.e. the relation between surface of the nodule and the surface of the thyroid. Kwak et al. have reported that more than 25% of tumor perimeter contact with the adjacent capsule was the most accurate measurement for predicting ETE if the lesion was smaller than 10 mm (26). Choi et al. also used the criterion of more than 25% tumor abutment with the thyroid capsule for T3, and they reported that the accuracy for determining ETE was 70.2% (27). However, Park et al. used a criterion of more than 50% tumor abutment with the thyroid capsule for T3, and they reported that the accuracy for determining ETE

was 74.5% (28). Gweon et al. used the criterion of more than 25% tumor perimeter abutment with the thyroid capsule or focal abruption of the thyroid capsule by a tumor as T3 on both 2D and 3D sonography (29). They have found an overall accuracy of 60.8% and 66.2% in predicting ETE, 2D and 3D US, respectively.

Rim et al. distinguished three types of tumor contour: it can be covered by normal parenchyma, or it can be abutting or bulging. In the latter two cases ETE was more prevalent than non-ETE (25). There are no data in the literature on which we could even assume that US would be able to discriminate between stage III and stage IV tumors.

The main issue is that although abutting or bulging contours have a very good sensitivity but have a poor specificity, i.e. great proportion of benign lesions have also abutting or bulging contours. It seems to be self-evident that a nodule covered entirely by normal thyroid parenchyma cannot present ETE.

 

Table 4 Ultrasound sings suggesting extrathyroidal spread according to Rim et al. (25).
Integrity of pseudocapsule
  • Continuous
  • Discontinuous
  • Invisible
Contour of the tumor
  • Covered by normal parenchyma
  • Abutting
  • Bulging

 

ACCURACY OF THE JUDGEMENT OF EXTRATHYROIDAL SPREAD

There are very limited number on this issue. The interobserver agreement of 3 reviewers was fair (kappa=0.33) for 2D sonography and moderate for 3D sonography (kappa = 0.46) in one study, which used still images for comparison. Using real time videos is much closer to the real-world situation, and it is not surprising that the interobserver agreement was lower, the kappa value was 0.28 (30).

One thing is the agreement, the other is the reality. In this study which involved 7 experienced investigators, only 48.1% of cases presenting ETE were detected by the ultrasonographers, moreover the positive predictive value of US proved to be only 39.8% (30).

 

DESCRIPTION OF AN AMBIGUOUS AND DANGEREOUS SITUATION AND A POSSIBLE RESOLUTION

In the sections discussed so far, we examined the suitability of US for ETE prediction. We now investigate whether the US signs of ETE can be predict thyroid cancer - regardless of the presence or absence of ETE. US signs of ETE may be useful predicting thyroid cancer because PTC is preferentially located at the edge of the thyroid, either in the upper pole (32) of the lobe or in the isthmus (33). It seems to be a reasonable assumption that the location and the potential ETE are linked. But I underline here again, that the US signs of ETE for the prediction of cancer is not influenced by the real occurrence of ETE in TIRADS scoring.

There are two main issues. Studies in the literature almost exclusively focus on the prediction of ETE and not on the prediction of cancer. This is very disturbing because e.g. the three American TIRADS use US signs of ETE for prediction of cancer when they involve these signs into generating TIRADS score. To the best of my knowledges, there is only one study in the literature which focused on the diagnostic performance of US signs of ETE in predicting thyroid cancer, namely medullary cancer. This study has found that the US signs of ETE have a similar diagnostic value to other suspicious US characteristics (34).

The second issue is that it is not clear and not described in the literature and in the guidelines which US signs or which combination of US signs should be taken into account that we say that the nodule shows sign of ETE. It seems to be reasonable that only abutting nodules with non-continuous nodules fulfill the criteria of suspicion.

Basically, three TIRADS involve ETE in the categorization of thyroid

nodules (see Table 5). In the TIRADS of the American Thyroid Association (18) and in the collaborative TIRADS of the American Association of Clinical Endocrinologists (AACE), American College of Endocrinology (ACE) and Associazione Medici Endocrinologi (AME) (17) the presence of ETE automatically puts the lesion into the most suspicious category. The AACE guideline has an important consideration; in contrast with other suspicious features, AACE suggests FNA even in subcentimeter nodules in the event of suspicion of ETE: 'Due to the nonnegligible prevalence of extracapsular extension in subcentimetric tumors (35), suspicious (high-risk) lesions <10 mm should receive FNA for early diagnosis and treatment when subcapsular (especially if associated with capsular abutment)' (AACE). In the system of the American Clinical Radiologist ETE is worth 3 points (19), which following the logic of this system means that the lesion belongs either to the most or the most suspicious but one subgroup.

In contrast with the former systems, neither the TIRADS of the Korean Society of Radiologist (21) nor that of the European Thyroid Association (20) takes ETE into account in generating a score mainly because the US-based diagnostic criteria for ETE is somewhat subjective and has not been established yet. The handling of ETE might cause some confusions by using the KSTR TIRADS: on the one hand, the system does not involve this feature into generating the score and therefore indication of FNA based on the score and the size of the nodule. On the other hand, the Korean guideline takes ETE most seriously, because it suggests FNA even in the suspicion of ETE, moreover, in contrast with all other features, irrespectively of nodule' size (21).

Table 5 The role of extrathyroidal extension in the most important TIRADS systems.

Type of TIRADS
Echogenicity of the nodule
Extrathyroidal extension present
AACE
Irrelevant
3
ACR
4 or 5
ATA
Non-hypoechoic
Non-classifiable
 
Hypoechoic
5
European
Irrelevant
No influence on TIRADS score
Korean
Irrelevant
No influence on TIRADS score
The TIRADS of the European Thyroid Association is although more consistent but seem to be less realistic: this system describes the presentation of ETE and the concerns about its usefulness but does not suggest FNA in the event of ETE (20).

 

EXTRATHYROIDAL EXTENSION IN THE MOST FREQUENT THYROID CANCERS

As in most US characteristics, papillary thyroid carcinoma is in the frontline. The data of Youngwirth et al. (31) who have analyzed the National Cancer Database (1998-2012) regarding the presence of ETE are presented in Table 6.

The ratio of follicular cancery present with ETE is less than half compared with papillary or medullary carcinomas (31). The latter two displays ETE in similar proportions. 

Table 6 The occurrence of minimal and extensive extrathyroidal extension in the most frequent thyroid carcinomas.

Type of carcinoma
All cases (N)
No ETE (N) (%)
Minimal ETE (N) (%)
Extensive ETE (N) (%)
Papillary
225,872
195,096 (86.4)
21,438 (9.5)
9,338 (4.1)
Follicular
10,729
10,186 (94.9)
276 (2.6)
267 (2.5)
Hürthle-cell
4,585
4,195 (91.5)
193 (4.2)
197 (4.3)
Medullary
3,415
3,001 (87.9)
242 (7.1)
172 (5.0)

ETE means extrathyroidal extension.
Data from Youngwirth et al. (31).

 

TO SUMMARIZE

US is a valuable tool to rule out ETE and can raise the suspicion of ETE with a weak positive predictive value. However, US is not able to verify ETE with high enough accuracy and is unable to discriminate between minimal and gross ETE and is unable to determine the degree of gross ETE.

We should bear in mind that based on the failure (or on the possibility of misinterpretation) of the newest TNM classification, our US report might have a huge consequence on the further therapy of patients, therefore a

US finding on a suspected ETE should be formulated with a high degree of restraint.

In the case of mere suspicion of ETE, FNA must be performed irrespectively of other clinical and US characteristics and irrespectively of TIRADS categorization. The key to raise the suspicion of ETE are discontinuation of the pseudocapsule, the abutment and the bulging of the contour. These signs are frequently observed not only in carcinomas without ETE but are common findings in benign thyroid lesion.

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