The Diagnosis of Thyroid Cancer
C. Reiners
4.1
Prevalence/Risk Assessment
The prevalence of thyroid nodules depends on iodine supply. In North America, the incidence of thyroid nodules detected by palpation is estimated to be 0.1%
per year, with a prevalence of between 4% and 7% in the general population.
Thyroid nodules are more common in women, with advancing age, in areas of iodine deficiency, and after exposure to external radiation [30].
According to a recent meta-analysis [35], the prevalence of thyroid nodules diagnosed by ultrasonography ranges between 20% and 70%, whereas the prevalence of abnormal findings detected by thyroid scintigraphy ranges be- tween 30% and 40%. The relatively large variability of the prevalence of thyroid nodules detected by ultrasonography is due at least partially to the different equipment used. In the most recent studies applying 7.5–10 MHz ultrasound scanners, a prevalence of 40–70% has been revealed. By autopsy, thyroid nod- ules in patients with clinically normal thyroids are found in 30–50%. The risk of malignancy in asymptomatic nodules found in non-irradiated glands ranges between 0.4% and 13% (mean ± SD: 3.9±4.1%). The risk is higher in females (females:males=1.75:1) [35].
According to a study performed in Italy, thyroid nodules in children and ado- lescents below age of 20 years were malignant in 10% of cases, whereas the rate of malignancy with 5% was considerably lower in adults [1]. The most important risk factor for thyroid cancer is exposure to ionizing irradiation. In patients with thyroid nodules who have been irradiated during childhood or adolescence, the prevalence of thyroid cancer ranges between 30% and 50% [14].
4.2
Findings/Symptoms
Thyroid cancer frequently does not present with clinical symptoms. In a study of 835 patients who had been operated on for nodular goiter [37], 31% also had thyroid cancer (tumors with a diameter of less than 10 mm, which were clini- cally occult in 46% of those patients).
A study of 1.116 patients with thyroid cancer from an iodine-deficient area [29]
showed that the leading symptom of thyroid cancer was an intra-thyroidal soli-
4
tary nodule in 40% of the patients. Cervical lymph node enlargement as an initial symptom has been found more frequently in males (21%) than in females (10%). In patients younger than 40 years of age lymph node enlargements were three times more frequent than in patients older than 50 years. In patients aged 60 years and above, higher tumor stages (T3 and T4) have been found more frequently (42%) than in patients younger than 40 years (25%). Clinical symptoms such as hoarse- ness due to paresis of the laryngeal nerve were very rare, at 0.6%, and distant metastases were also found infrequently (0.8%) as initial sign of thyroid cancer.
During childhood 2.6% of the patients had been irradiated for different benign diseases. Scintigraphically cold nodules were detected in 55% of the patients.
The question of the prevalence of thyroid cancer in patients with hyperthy- roidism and scintigraphically hot nodules has been frequently discussed. A study performed on the same patient material [19] showed that in only 2.6% of the patients being operated on for thyrotoxicosis occult thyroid cancers were prevalent (2% of the patients with Graves’ disease and 4% of the patients with functional autonomy).
The clinical signs and symptoms of thyroid cancer have very recently been evaluated in a German Patient Care Evaluation Study of thyroid cancer (PCES) and compared to a PCES Study from the USA [17]. In 4% of the German patients previous exposure to radioiodine was found; the frequency of radiation exposure in USA patients, at 4.5%, was comparable. A considerable difference could be do- cumented concerning the prevalence of goiter: in 81% of the German patients thyroid enlargement was found, against only 45% of USA patients. A nodule could be palpated in 77% of the German and 75% of the USA patients. Dyspha- gia, neck pain, hoarseness and stridor could be documented in 26%, 8%, 5%
and 11% of German patients as compared to 12%, 6%; 8% and 4% of the USA patients, respectively. An enlargement of neck lymph nodes was much more fre- quent in patients from the USA than in those from Germany (27% vs 7%).
4.3
Ultrasonography
Ultrasonography is the modality most often used for thyroid imaging. It is relatively cheap, easily accessible, rapidly performed and has the advantage of no exposure to ionizing radiation. It allows determination of the volume of the thyroid and the size of nodules, the echo structure (diffuse, uni- or multinodular), echogenicity (iso-, hyper- or hypo-echogenic) and the evaluation of adjacent neck structures. Today ultrasound scanners with high-frequency transducers (7.5–10 MHz) are recom- mended. They allow even very small (2–3 mm) thyroid lesions to be imaged [15].
The typical sign of malignancy is – in more than 90% of cases – a hypo- echogenic solid lesion. In contrast, malignancy is very rarely found in iso- or hyper-echogenic lesions [36].
Several studies have been designed in order to evaluate whether additional
criteria determinable by high-frequency ultrasound – such as the appearance of
the margins (halo-sign), cystic degeneration or calcification – can be used in the
differentiation of benign from malignant thyroid nodules. The general finding
has been that there is no ultrasound pattern, alone or in combination with other techniques, that may be considered specific for thyroid cancer [15, 25]. The only reliable indicators of malignancy were invasive growth into surrounding struc- tures (Fig. 4.1), metastases to cervical lymph nodes or both [15]. In contrast, thyroid cancer may be excluded in iso- or hyper-echogenic nodules with a prob- ability of more than 90%. In the future, three-dimensional ultrasound may help to delineate thyroid nodules more precisely (Fig. 4.2).
For more than 10 years, the speed and direction of blood flow in thyroid lesions have been investigated by the color-Doppler and – more recently – the power-Doppler mode. The perfusion pattern may be delineated more clearly by means of ultrasound contrast media. However, no study has shown a specific pattern for malignancy [15, 18]. In a recent study by Rago et al. [25], intra-nodu- lar blood flow was found to be increased in 67% of malignant and 50% of benign thyroid nodules (Fig. 4.3). However, Hegedues and Karstrup argue that at least 60–70% of cold solitary nodules can be classified as benign colloid nodules with a minimal risk of overlooking malignancy (<1%) on the basis of conventional sonography and ultrasound-guided fine-needle biopsy [15].
4.4
Scintigraphy
Scintigraphy is not a rival method to ultrasound, but complements the mor- phological information of sonography with the functional scintigraphic image, which shows the regional metabolic activity of the thyroid gland. Today Tc-
Fig. 4.1. Conventional 2D-sonography (trans- verse section) of a pap- illary thyroid cancer with irregular contours and deformation of the thyroid capsule
99m-pertechnetate is used routinely for thyroid scintigraphy. For specific in- dications (e.g., recurrences or metastases of differentiated thyroid cancer after surgery)
131I-NaI is the radiopharmaceutical of choice. For imaging the thyroid, a gamma-camera with a high-resolution collimator is necessary [10].
The typical scintigraphic sign of malignancy is a cold nodule (Fig. 4.3). Börner et al. published as early as 1965 a detailed study of scintigraphic investigations in 2,237 thyroid patients [3]. It was shown that the frequency of cold nodules increased from 21% in patients aged 15–16 years up to 44% in patients over the age of 65 years. In patients younger than 35 years, malignancy was rare in case of hypo-functionality.
In contrast, thyroid cancer was histologically verified in 11% of cold nodules of pa- tients aged 45–65 years and 25% in patients above the age of 65 years.
For follow-up of differentiated thyroid cancer, different scintigraphic proce- dures with a number of more or less specific radiopharmaceuticals may be used [7, 32]. The most relevant procedure is whole body scanning with diagnostic or therapeutic activities of
131I NaI, frequently showing regional or distant me- tastases that have not been detected by other imaging procedures. The role of whole-body scintigraphy with Tl-201 chloride and Tc-99m-MIBI or -tetrofosmin in the follow-up of patients with differentiated thyroid cancer after surgery and/or radioiodine therapy is well established (especially in tumors taking up no radioiodine) [21, 23, 31]. Most recently, positron emission tomography (PET) with F-18-FDG has shown to be a promising imaging procedure especially in patients with negative radioiodine scans [12].
With respect to primary diagnosis of thyroid cancer, Tl-201, Tc-99m-MIBI and F-18-FDG have been proposed as imaging agents to determine the sus-
Fig. 4.3. 3D-display of color-Doppler ultrasound of a benign follicular ade- noma: nonspecifically increased intra-nodular blood flow
Fig. 4.2. 3D-ultrasound slices of a patient with papillary thyroid cancer in the left thyroid lobe: 3D-cube (upper left), longitudinal slice (upper right), horizontal slice (lower left) and transversal slice (lower right)
pected malignancy of thyroid nodules [2, 20, 32]. Kresnick et al. [20] conclude that MIBI accumulation and retention is not specific for thyroid malignancy.
In combination with all other findings, a positive MIBI scan would appear to indicate an adenoma rather than a malignant tumor. This statement can be extended to the attempts to qualify malignancy of a thyroid nodule pre-opera- tively by scintigraphy with Tl-201 or PET with F-18-FDG.
In the past, X-ray fluorescence scintigraphy [27], which allows measurement of the stable iodine content of the thyroid and thyroidal nodules has been used to differentiate between benign and malignant lesions. However, a low iodine content, described as typical for thyroid cancer, has proved to be not specific enough for diagnosis [24].
To summarize, the clinical impact of routine thyroid scintigraphy with Tc- 99m-pertechnetate has to be seen in combination with the results of ultrasono- graphy (Table 4.1).
In patients (especially of young age) with a rapidly growing nodule, however, fine-needle aspiration biopsy (FNA) is indicated in any case and histological ve- rification is frequently necessary.
4.5
Fine-Needle Aspiration Biopsy
According to the PCES Study [17] ultrasonography is performed in Germany before surgery in 78%, scintigraphy in 77% and FNA in 27% of patients with thyroid nodules. The corresponding figures in the USA are 39%, 40% and 43%
respectively [17]. This comparison shows that FNA seems to have higher diag- nostic impact in the United States. However, due to the high prevalence of goiter in Germany (81% vs 45% in the USA), the use of FNA in Germany is mostly restricted to differential diagnosis of the clinically most suspicious solitary thyroid nodules.
Table 4.1. Indications for fine-needle aspiration biopsy (FNA) of the thyroid with respect to the results of sonography and scintigraphy [28]
Sonography Scintigraphy Presumptive FNA
diagnosis
Iso-echogenic/hyper-echogenic Hot Autonomy Relative indication Cold Regressive nodule Relative indication Hypo-echogenic/complex Hot Autonomy Relative indication Follicular adenoma Relative indication Cold Malignoma Absolute indication
Thyroiditis Absolute indication
Hemorrhage Absolute indication
Echo-free Cold Cyst Relative indication
Particularly in regions with endemic iodine deficiency, patients have to be selected for FNA. As shown in Table 4.1 sonography and scintigraphy can ef- ficiently be used for selection. FNA is mandatory in patients with hypo-echo- genic and scintigraphically cold nodules. Today disposable cannulas (no. 17 or no. 16; gauge 25–23, respectively) are used. By using such small cannulas, side effects such as hemorrhage (1 per 1000) or infections (1 per 4000) are rare [8].
Today ultrasound is usually used to guide the puncture needle during biopsy. A comparison of nine studies published since 1994, each including more than 100 cases, shows that the diagnostic accuracy can be improved by ultrasound guid- ance. The median sensitivity and specificity increased after introduction of ul- trasound guidance from 89% and 69%, respectively, to 97% and 83% (Table 4.2).
Table 4.2. Diagnostic validity of fine needle aspiration biopsy (FNA) of the thyroid: Data from the literature
Author, year Method n Insuffi- Sensiti- Specifi- Accu- PV+ PV–
cient mate- vity (%) city (%) racy (%) (%) (%)
rial (%)
Cochand- US guided 132 4 79 84 83 54 95
Priollet [8]
Takashima Palpation 34 19 88 90 88 95 75 [34] guided
US guided 99 4 96 91 94 96 91
Carpi [6]
<1 mm US guided 39 3 97 34 67 – –
1–1.9 mm US guided 52 0 90 52 66 – –
2–3 mm US guided 32 0 94 70 77 – –
>3 mm US guided 35 9 88 76 80 – –
García-Mayor Palpation 403 16 94 61 72 54 95 [11] guided
Hatada [13] Palpation 94 30 45 51 48 – – guided
US guided 72 17 62 74 68 – –
Danese [9] Palpation 522 9 92 69 73 37 98 guided
US guided 535 4 97 71 76 44 99
Carmeci [5] Palpation 370 16 89 69 – – – guided
US guided 127 7 100 100 – – –
Cáp [4] Palpation 516 8 90 79 81 51 97
guided (25%
US guided)
Mikosch [22] US guided 718 5 88 79 80 34 98 PV+/PV–: Positive/negative predictive value; US: ultrasound
In addition, the median frequency of biopsies with insufficient material could be reduced by a factor of approximately 2 from 18% to 7% (Table 4.2). However, to date no generally acknowledged criteria for definition of an adequate biopsy smear have been approved. Usually, 5–6 groups of 10 well-preserved follicular cells each have been suggested [33].
Today the traditional classification of cytopathological smears of the thyroid according to Papanicolaou is obsolete. According to recent recommendations from the American Papanicolaou Society for Cytopathology [33] the classifica- tion should consider benign (non-neoplastic lesions), suspicious (follicular or oncocytic lesions of high cellularity) and malignant findings.
Usually the diagnosis of papillary thyroid cancer (Fig. 4.5) is not difficult, since cell-rich formations of thyroid cells organized in monolayered sheets and forming papillary clusters showing psammoma bodies, enlarged nuclei with “ground-glass” appearance containing chromatin and large and irregu- lar nucleoli, nuclear grooves and cytoplasmic inclusions are considered to be typical [33]. However, in cases of cell-rich smears with a monomorphic or rarely pleomorphic population of epithelial cells, frequently grouped in micro-follicu- lar clusters, distinction of a well-differentiated follicular thyroid cancer from a benign follicular adenoma is not possible (Fig. 4.5). The frequency of such findings, often judged as “follicular neoplasia”, ranges between 5% and 20% [4, 8, 9, 11, 22]. In cases of “follicular neoplasia” the histological verification of the suspicious cytological finding is mandatory.
A study from Spain has shown that, since the introduction of palpation- guided FNA, the frequency of patients requiring prophylactic “surgery” has decreased from 90% to 47% and the frequency of malignancy in the surgical specimens has increased from 15% to 33% [11]. Recently, Carmeci et al. [5] from Stanford University, California, USA showed that ultrasound guidance of FNA
Fig. 4.4. Thyroid scan with Tc-99m-pertech- netate of a patient with papillary thyroid cancer showing a cold nodule in the lower quadrant of the left lobe
leads to a considerable improvement compared to palpation-guided FNA: the cancer yield at surgery increased from 40% to 59%.
To summarize, ultrasound-guided FNA is highly recommended for differential diagnosis of especially solitary solid thyroid nodules of poor echogenicity sho- wing decreased uptake on the scan.
4.6
Additional Diagnostic Procedures
In patients with large or multi-nodular goiters, an X-ray of the neck is useful to disclose deviation of the trachea or restriction of its lumen. For a detailed study of mediastinal involvement, CT or MRI is preferable. Particularly in cases of large invasive thyroid cancers with involvement of the sternum, MRI is highly recommended before surgery. However, CT and MRT do not allow benign and malignant thyroid lesions to be differentiated. It has to be taken into account that use of iodine-containing contrast media for CT is contraindicated in cases of suspected thyroid malignancies, as diagnostic or therapeutic applications of radioiodine may be hampered for several weeks.
Fig. 4.5. Cytology smears of fine needle aspiration biopsies (May-Grün- wald-Giemsa staining) of papillary thyroid carci- noma (left) and follicular neoplasia later histologi- cally verified as benign follicular adenoma (right) (with permission of Prof.
Dr. R. Schäffer, Institute of Pathology, University of Gießen, Germany)
Determinations of the thyroid-specific tumor marker thyroglobulin are usu- ally not very informative in cases of suspected malignancy preoperatively, since relatively high thyroglobulin levels, up to 500 ng/ml, may be observed in pa- tients with benign cold nodules (i.e., follicular adenoma or oncocytic adenoma).
However, it has been shown that serum thyroglobulin preoperatively exceeds 500 ng/ml in 72% of patients with follicular and 56% of patients with oncocytic thyroid cancer [16]. Especially in a patient with metastases of cancer of un- known primary a high thyroglobulin level may be indicative for differentiated thyroid cancer even in the case of no large abnormalities in thyroid imaging.
The potential of thyroglobulin as a tumor marker, however, is used most effec- tively after removal of the thyroid by surgery and radioiodine therapy.
However, routine determinations of serum calcitonin have been advocated for screening of sporadic medullary thyroid cancer in patients with thyroid nodules [26]. Prospective studies revealed a prevalence of medullary cancer in 0.6–1.3%
of all patients with nodular goiter [26]. Since this surprisingly high prevalence of a rare disease may be caused by a selection bias, routine determinations of serum calcitonin, which are costly, seem to be unjustified. In patients with sus- picious findings, however (i.e., nodules with calcifications, enlarged neck lymph nodes), calcitonin in serum may be determined in addition to FNA.
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