Differentiated Thyroid Cancer of Follicular Cell Origin

The minimal test for determining the diagnosis of a thyroid nodule is fine-needle aspiration cytology with or without ultrasonography. Use of these two tests enables one to discriminate benign from malignant thyroid tumors in about 85% of patients. The remaining 15% of thyroid malignancies are follicular cancer, Hiirthle cell cancer, and some follicular variants of papillary thyroid cancer. Various imaging techniques are used for detecting regional and/or distant metastasis and identifying local invasion of adjacent structures.

Ultrasonography for Papillary Cancer

Since the advent of high-resolution ultrasonography, it is sometimes possible to establish the diagnosis of papillary cancer with only ultrasonography, and fine-needle aspiration cytology is used to confirm the diagnosis.1"4 Papillary cancer is most frequently thyroid cancer (=80%). The presence of calcification, irregular shape, absence of a halo and hypo-echogenicity, and local invasion suggest it is a malignant nodule. Calcification is identified as multiple, small hyper-echogenic spots in a hypoechogenic area (Figs. 16-1 and 16-2). They are usually due to superimposed psammoma bodies. Larger papillary thyroid cancers often degenerate, and complex cyst formation is common. These partially cystic areas are usually located at the peripheral part of the tumor (Fig. 16-3). A protrusion of solid tumor into the cyst can frequently be seen. Lymph node metastases or recurrence in lymph nodes is also identified with ultrasonography. Lymph nodes greater than 9 mm in diameter, those with a longitudinal-transverse diameter ratio of less than 2.0, and those with a round configuration are likely to contain metastatic cancer (Fig. 16-4).5"7 When one or more suspicious nodes are identified by ultrasonography, fine-needle aspiration cytology is usually recommended for confirmation of diagnosis. Ultrasonography is an accurate and sensitive localization test for diagnosing cervical metastases, but unfortunately it is not useful for identifying metastases in the retroclavicular area and mediastinum. Thus, when serum thyroglobulin levels are increased, other localization tests are necessary, such as magnetic resonance imaging (MRI) or radioiodine whole-body scanning (WBS), the latter for the patient who has previously had a total or near-total thyroidectomy. The search for enlarged lymph node metastases in the neck has become easier because of ultrasonography; however, microscopic metastases are also present in about 80% of patients with papillary thyroid cancer who have no evident cervical metastases on clinical examination.8,9 These small metastases may or may not be visualized with ultrasonography.10 In patients with papillary thyroid cancer, the importance of nodal metastasis on survival is controversial. Some studies suggest that the presence of clinically evident lymph node metastases in patients with papillary and follicular cancer has an adverse effect on survival.11"16 Extracapsular invasion of nodal metastases of thyroid cancer is associated with a poorer survival rate in patients with papillary microcarci-noma.17 Other studies suggest that lymph node metastases are associated with increased recurrence rate, but survival is not affected.18 21 Since cervical lymph node is the most frequent site for recurrent tumor, ultrasonography of the neck is helpful for the management of patients with papillary thyroid cancer.

Radioiodine Scintigraphy

Iodine 131 (131I) is a favored scanning agent for following patients after total or near-total thyroidectomy for thyroid cancer of follicular cell origin because 131I can be used therapeutically. Many studies have examined the sensitivity and specificity of a low dose (370 MBq, or lower) and high dose of 131I (2.9 GBq, 80 mCi, or more) for the detection of disease.22"34 The sensitivity ranges from 40% to 84% depending on the dose of 131I, the age of the patient, tumor differentiation, and tumor location. The specificity is high and the range is narrow, from 90% to 100% (Fig. 16-5). The sensitivity for detecting lung metastases is reported to vary from 42% to 60%, and for bone metastasis it varies from

FIGURE 16-1. Papillary cancer. A and B, Many small hyperechoic spots are seen in the hypoechoic region.

54% to 60%.2635 The sensitivity for detecting lymph node metastasis is only about 22%26; luckily, ultrasonography, computed tomography (CT), MRI, Tc 99m sestamibi, and thallium can usually detect cervical lymph node metastases. The sensitivity may change depending on the definition of tumor presence. Serum thyroglobulin levels, 201T1 scan, neck ultrasonography, l8F-2-fluoro-2-deoxy-D-glucose positronemission tomography (FDG-PET), or Tc 99m sestamibi are often used alone or in combination to document the presence and site of persistent or recurrent disease.

123I is a pure lower energy (159-keV) gamma emitter, whereas 13'I is a high-energy (364-keV) gamma and beta emitter. 123I has better resolution imaging properties than 13II because l23I does not emit beta particles; therefore, a larger dose of 123I can be administered with a lower risk of stunning, which reduces subsequent therapeutic efficacy.36 Image quality after radioiodine administration is good in terms of resolution and low background at 24 hours. The recommended dose of ,23I is 56 MBq; there is little incremental advantage of sensitivity after scanning using larger doses. The concordance with l31I is almost identical with post-therapy scan.37 38 The overall sensitivity of 123I is 93% when compared with 131I.

Scintigraphy with Alternative Nucleotides

THALLIUM 201 CHLORIDE

Thallium 201 (201T1) was first used in the early 1980s for detecting metastases from both well-differentiated thyroid cancer and recurrent medullary cancer in 1980s.39"44 It accumulates in the tumor and gives a positive image by contrasting with the negative image by radioiodine and remains in the tumor longer than it does in normal thyroid (Fig. 16-6). Tc 99m sestamibi became available around 1987, and many investigators compared the results of 20IT1 scintigraphy to Tc 99m sestamibi. Although these two imaging isotopes gave comparable results, Tc 99m sestamibi results were slightly better and clearer than those with 20'T1 in patients with differentiated thyroid cancer.45-46 For patients with medullary cancer 99mTc(V)-dimercaptosuccinic acid (Tc 99m DMSA) appeared to be somewhat more accurate than 201T1 for routine clinical use 47 20IT1 imaging is most useful after total or near-total thyroidectomy and 131I ablative therapy in patients with rising or elevated serum thyroglobulin levels. In addition, about 10% of hypothyroid patients with verified thyroid cancer and positive 201T1 scan have a low serum thyroglobulin level.48-49 20IT1 imaging has an additional advantage in that it can be done in the patients who are

FIGURE 16-2. Papillary cancer. Arrow 1, right carotid artery; arrow 2, primary tumor; arrow 3, trachea; arrow 4, esophagus; and arrow 5, left carotid artery.

FIGURE 16-3. Papillary thyroid cancer with cystic degeneration.

receiving thyroid hormone. Discontinuation of thyroid hormone medication stimulates increased thyroid-stimulating hormone (TSH) secretion, which can stimulate thyroid tumor uptake of radioiodine and tumor growth. Imaging with 201T1 also requires only one visit, in contrast with scanning with 13II using human recombinant TSH, which requires several visits. The sensitivities reported for 20IT1 vary depending on the dose of 20IT1 and the timing of imaging after injection of the isotope. When imaging is done 15 to 20 minutes after injection, sensitivities ranging from 74% to 94% have been reported.23'27-50 Reported specificities range from 84% to 97%.27-49

In a large retrospective series including 326 patients, 20IT1 scintigraphy demonstrated abnormal findings in 39 patients who had negative l3lI studies.27 Among these patients, 26 were confirmed histologically and 5 radiologically, and 8 had no definite confirmation. The sensitivity was 94% and the specificity was 98%. There is a large discordance between 20'T1 and 13'I studies in patients with remaining normal thyroid tissue, because the sensitivity of 20IT1 is poor when normal thyroid remains, whereas l3lI uptake is high in this tissue.51 After ablation with l3lI, 201T1 has a sensitivity of 94% and a specificity of 96%.23 The sensitivity of 20IT1 is equivalent or superior to low-dose 1311 but less sensitive than high-dose l3lI. 20IT1 is particularly useful in the setting of a negative l31I scan in a patient with an elevated serum thyroglobulin level.28-49

20IT1 scanning is helpful for detecting cervicomediastinal nodal metastases but is not accurate for detecting a normal thyroid remnant or pulmonary metastasis. Overall, 201T1 is the most commonly used radioactive pharmaceuticals for patients with thyroid cancer, other than l3lI.

TECHNETIUM 99M SESTAMIBI

Scanning with Tc 99m sestamibi in thyroid cancer patients has been compared to radioiodine,27 with 20IT1,45 with Tc 99m terrofosmin, and with MRI.52 Tc 99m sestamibi, like 201T1, does not require discontinuing thyroid hormone and requires only one visit. This is an advantage of Tc 99m sestamibi over 13II. Imaging with noniodine radiopharmaceuticals is independent of TSH stimulation, but TSH stimulation improve the quality of images.

Contemporary gamma cameras are optimized for imaging at the emission energy of 99mTc (140 keV) rather than much higher emission energies of l3lI (364 keV) or the lower emission energy of 201T1 (69 to 81 keV). Tc 99m sestamibi has the advantage of the availability of a kit-based radiopharmaceutical with same-day imaging. The other advantage of Tc 99m sestamibi over 20IT1 is a short physical half-life of 6 hours, whereas 201T1 has a physical half-life of 73 hours. Therefore, Tc 99m sestamibi can be administered in a larger dose (20 to 25 mCi), resulting in better images and lower radiation exposure to the patient.

Invasion of Papillary Cancer to Adjacent Organs

Involvement of the recurrent laryngeal nerve by tumor cannot be determined preoperatively unless vocal cord palsy is evident on direct laryngoscopy. However, the size and position of the primary tumor provide some information. Among our 3148 patients with papillary thyroid cancer larger than 10 mm in maximum dimension, there was a direct correlation between adhesion/invasion of the recurrent laryngeal nerve. Thus, involvement occurred in 9.2% of tumors 10 to 14 mm, 17.3% of tumors 15 to 24 mm, and 33.0% of tumor more than 25 mm in maximum diameter. Using the same size criteria, as determined by frozen section, invasion/adhesion occurred within the esophagus in 2.7%, 9.2%, and 21.4%, respectively. CT, MRI, conventional esophagography, and esophagoscopy may help predict the

FIGURE 16-4. Lymph node metastasis with calcification (A) and with cystic degeneration (B).

FIGURE 16-5. Lung metastases. A, With conventional chest radiograph, no metastases were seen. B, With high-dose l3lI scintigraphy, extensive metastases were shown. C, With helical CT, multiple small shadows of metastases were seen in one patient.

presence of invasion of thyroid cancer into the esophagus; however, these modalities are insufficient for a precise diagnosis and determination of exact dep'.h of invasion. Recently, endoscopic ultrasonography was reported to be superior to MRI and esophogography in terms of accuracy and specificity regarding esophageal invasion.53 Invasion of the trachea is also difficult to determine preoperatively. Using the same size criteria, adhesion/invasion to the trachea was observed in 17%, 29%, and 40%, respectively; however, when the tumor was close to Berry's ligament, it was hard to differentiate. These figures therefore could be an overestimation. Tumor size is a well-known predictor of tumor behavior.54,55 MRI helps determine extent of tracheal invasion. Characteristic findings include a soft tissue signal in the tracheal cartilage, intraluminal mass, and degree of tumor circumference around the trachea abutting 180 degrees or more.54 An anterior part of the trachea is most likely to be invaded by thyroid cancer in primary cases; however, in cases of recurrence, invasion can occur in any part of the trachea. Endoscopic documentation of

Thyroid Scan Thallium
FIGURE 16-6. Thallium scan, showing early image (A) and delayed image (B). The arrow in B indicates tumor localization.

laryngotracheal invasion was recently reported. The major findings included mucous membrane swelling, dilated capillaries, localized reddening, localized swelling, edema, and erosion (Fig. 16-7). Intraluminal tumor is rare.56 When these findings are present, resection of a part of the trachea followed by end-to-end anastomosis or partial resection with preservation of the recurrent laryngeal nerve is recommended rather than shaving the tumor off the surface of the trachea.57,58

Follow-Up of Patients Who Lost Differentiation Markers

Although the serum thyroglobulin level is the most sensitive and useful marker for follow-up of patients with differentiated thyroid cancer, especially in patients after total thyroidectomy, in some patients serum basal thyroglobulin levels are not increased and fail to increase when TSH levels are increased. Thyroglobulin in this small group does not

FIGURE 16-7. A, Stage 1 thyroid cancer that extended through the capsule of the thyroid gland and abutted the external perichondrium.

B, Stage 2 thyroid cancer that invaded between the rings of cartilage or destroyed the cartilage.

C, Stage 3 thyroid cancer that extended through the cartilage or between the cartilaginous plates into the lamina propria of the tracheal mucosa.

D, Stage 4 thyroid cancer that extended through the entire thickness of and expanded the tracheal mucosa.

FIGURE 16-7. A, Stage 1 thyroid cancer that extended through the capsule of the thyroid gland and abutted the external perichondrium.

B, Stage 2 thyroid cancer that invaded between the rings of cartilage or destroyed the cartilage.

C, Stage 3 thyroid cancer that extended through the cartilage or between the cartilaginous plates into the lamina propria of the tracheal mucosa.

D, Stage 4 thyroid cancer that extended through the entire thickness of and expanded the tracheal mucosa.

serve as a useful marker for recurrence. Some thyroid cancers also dedifferentiate, particularly with advanced disease and age. 131I ablation is less effective in these patients.7 45'48'52'59 61 Since the most common site of recurrence is in the neck lymph nodes, ultrasonography would be selected first for local disease and 201T1 or Tc 99m sestamibi for WBS. For lung metastases with small miliary foci, helical CT is better than WBS. External-beam radiation can be helpful for treatment of high-risk patients with persistent or recurrent disease. Redifferentiation with retinoic acid and other agents may be helpful.62

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