Approach Considerations
Current guidelines from the National Comprehensive Cancer Network recommend that patients with thyroid nodules undergo measurement of thyroid-stimulating hormone (TSH) and ultrasound of the thyroid and central neck; ultrasound of the lateral neck may be considered. Patients with thyroid nodules and a low TSH level should have radioiodine imaging: if this study reveals an autonomously functioning (“hot”) nodule, the patient should be evaluated for thyrotoxicosis. [1]
Patients with hypofunctional nodules, and those with a normal or elevated TSH level, should be considered for fine-needle aspiration biopsy (FNAB), based on clinical and sonographic features. A cytologist could experience difficulty in distinguishing some benign cellular adenomas from their malignant counterparts (ie, follicular and Hürthle cell adenomas from carcinomas). On final pathologic assessment, approximately 15-40% of FNAB samples with a cytologic diagnosis of “suspicious for follicular neoplasm” prove to be malignant. [1]
A prognostic indicator of significant value may be RAS genotyping by polymerase chain reaction (PCR), which may help in the clinical and histologic reassessment of these tumors. In thyroid nodules with otherwise indeterminate cytology, the presence of RAS mutation may potentially alters initial surgical management, as it indicates a markedly elevated increased risk for cancer (∼85%). [21]
Determining the serum level of carcinoembryonic antigen (CEA) may be helpful; the reference value is less than 3 ng/dL. However, the implications of CEA elevation are not specific because CEA levels are elevated in several cancers, and many healthy people may have small amounts of CEA, especially pregnant women and heavy smokers.
Imaging Studies
Ultrasonography is the first imaging study that must be performed in any patient with suspected thyroid malignancy.
Ultrasonography is noninvasive and inexpensive, and it represents the most sensitive procedure for identifying thyroid lesions and determining the diameter of a nodule (2-3 mm). Ultrasonography is also useful to localize lesions when a nodule is difficult to palpate or is located deeply.
A study by Xing et al demonstrates that the strain ratio measurement of thyroid lesions, which is a fast standardized method for analyzing stiffness inside examined areas, can be used as an additional tool with B-mode ultrasonography and helps increase the diagnostic performance of the examination. [22]
Ultrasonography can determine whether a lesion is solid or cystic and can detect the presence of calcifications. The rate of accuracy of ultrasonography in categorizing nodules as solid, cystic, or mixed is near 90%.
Ultrasonography may direct a fine-needle aspiration biopsy (FNAB).
Disadvantages of thyroid ultrasonography are that the test cannot distinguish benign nodules from malignant nodules, and it cannot be used to identify true cystic lesions.
Pulsed and power Doppler ultrasonography may provide important information about the vascular pattern and the velocimetric parameters. [23] Such information can be useful preoperatively to differentiate malignant from benign thyroid lesions.
Prior to the introduction of FNAB, thyroid scintigraphy (or thyroid scanning) performed with technetium Tc 99m pertechnetate (99mTc) or radioactive iodine (I-131 or I-123) was the initial diagnostic procedure of choice in thyroid evaluation.
Thyroid scanning is not as sensitive or specific as FNAB in distinguishing benign nodules from malignant nodules.
The scintigraphy procedure performed with 99mTc has a high error rate because although 99mTc is trapped in the thyroid, as iodide is, it is not organified there. 99mTc has a short half-life and cannot be used to determine functionality of a thyroid nodule.
Radioactive iodine is trapped and organified in the thyroid and can be used to determine functionality of a thyroid nodule. Iodine-containing compounds and seafood interfere with any tests that use radioactive iodine. Scintigraphic images of the thyroid are acquired 20-40 minutes after IV administration of radionuclide. In more than 90% of cases, clearly benign nodules appear as hot because they are hyperfunctioning and have a high uptake of radionuclide and, physiologically, of iodine. Malignant nodules usually appear as cold nodules because they are not functioning.
Thyroid scanning is helpful and specific in localizing the tumor preoperatively and identifying residual thyroid tissue immediately postoperatively. It also is used to follow-up for tumor recurrence or metastasis. Thyroid scanning could be useful in diagnosing thyroid tumors in patients with benign lesions (by FNAB) or solid lesions (by ultrasonography).
Integrated imaging, using 18F-FDG and coregistered total body PET and CT scan, seems to be effective in improving diagnostic accuracy in patients with iodine-negative differentiated thyroid carcinoma, allowing precise localization of the tumor tissue. [24] In addition, image fusion by integrated PET/CT offers more information than side-by-side interpretation of single images obtained separately with CT and PET.
Chest radiography, CT scanning, and MRI usually are not used in the initial workup of a thyroid nodule, except in patients with clear metastatic disease at presentation. These tests are second-level diagnostic tools and are useful in preoperative patient assessment.
Other Tests
Perform indirect or fiberoptic laryngoscopy to evaluate airway and vocal cord mobility and to have preoperative documentation of any unrelated abnormalities.
Histologic Findings
On gross examination, FTC appears encapsulated and solitary and is often found in necrotic and/or hemorrhagic areas, as depicted in the images below.
Follicular thyroid carcinoma. Surgical specimen of a large goiter. Total thyroidectomy was performed because of the presence of a solid nodule in the right lobe (note the size of the thyroid lobe at left of the screen).
Follicular thyroid carcinoma. The right lobe of the thyroid was sectioned and reveals a large solid nodule with necrotic and hemorrhagic areas. Histologic diagnosis is follicular thyroid carcinoma.
Histologically, the lesion may be encapsulated and may demonstrate well-defined follicles containing colloid, making its distinction from follicular adenoma difficult. Examples of FTC are shown in the images below.
Follicular thyroid carcinoma. Histologic pattern of a mildly differentiated follicular thyroid carcinoma (250 X). Image courtesy of Professor Pantaleo Bufo at University of Foggia, Italy.
Follicular thyroid carcinoma. Histologic pattern of a rare lymph node metastasis of follicular thyroid carcinoma (140 X). Image courtesy of Professor Pantaleo Bufo at University of Foggia, Italy.
Follicular thyroid carcinoma. Histologic pattern of a rare lymph node metastasis of follicular thyroid carcinoma (250 X). Image courtesy of Professor Pantaleo Bufo at University of Foggia, Italy.
See the list below:
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Histologic and cellular patterns of endocrine tumors do not allow diagnosis of carcinoma; therefore, this diagnosis is made by finding pseudocapsule and/or blood vessel invasion, not by cellular morphology.
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High magnification of the abortive follicles may demonstrate atypia of the follicular epithelium and intervening stroma.
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Thyrocytes are large and show an abnormal nuclear/cytoplasmic ratio with several mitoses.
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Presence of colloid-rich follicles lined by flattened follicular cells that are occasionally accompanied by several histiocytes is maintained in a benign lesion.
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Definitive diagnosis is often not possible with samples obtained from FNAB because accurate distinction between benign and malignant lesions cannot be made.
Because of the well-known role of the RAS-RAF-MEK-MAP kinase pathway in thyroid carcinogenesis, n-RAS expression may be evaluated to differentiate follicular and papillary cancer of the thyroid.
Staging
The accurate assessment of the proliferative grade and the extent of invasion have high prognostic value and are mandatory in every specimen.
The staging of well-differentiated thyroid cancers is related to age for the first and second stages but not for the third and fourth stages.
In patients younger than 45 years, staging is as follows:
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Stage I: Any T, any N, M0 (Cancer is in the thyroid only.)
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Stage II: Any T, any N, M1 (Cancer has spread to distant organs.)
In patients older than 45 years, staging is as follows:
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Stage I: T1, N0, M0 (Cancer is in the thyroid only, in one or both lobes.)
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Stage II: T2, N0, M0 and T3, N0, M0 (Cancer is in the thyroid only and is larger than 1.5 cm.)
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Stage III: T4, N0, M0 and any T, N1, M0 (Cancer has spread outside the thyroid but not outside of the neck.)
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Stage IV: Any T, any N, M1 (Cancer has spread to other parts of the body.)
See Thyroid Cancer Staging for more information.
American Thyroid Association staging
The American Thyroid Association (ATA) has published guidelines for estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation. The guidelines provide initial risk estimates and re-stratification based on response to initial therapy. [25]
For initial risk estimates, patients are considered at low risk if all of the following are present:
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No local or distant metastases
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All macroscopic tumor has been resected
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No invasion of locoregional tissues
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Tumor does not have aggressive histology (eg, tall cell, insular, columnar cell carcinoma, Hürthle cell carcinoma, FTC)
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No vascular invasion
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No 131I uptake outside the thyroid bed on the post-treatment scan, if done
Patients are considered at intermediate risk if any of the following is present:
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Microscopic invasion into the perithyroidal soft tissues
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Cervical lymph node metastases or 131I uptake outside the thyroid bed on the post-treatment scan done after thyroid remnant ablation
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Tumor with aggressive histology or vascular invasion (eg, tall cell, insular, columnar cell carcinoma, Hürthle cell carcinoma, FTC)
Patients are considered at high risk if any of the following is present:
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Macroscopic tumor invasion
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Incomplete tumor resection with gross residual disease
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Distant metastases
The ATA guidelines define response to initial therapy (6–24 months after radioactive iodine ablation) as excellent if all the following are present:
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Suppressed and stimulated Tg < 1 ng/mL
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No evidence of disease on neck ultrasound (US)
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Negative cross-sectional and/or nuclear medicine imaging (if performed)
Response is defined as acceptable if any of the following are present:
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Suppressed Tg < 1 ng/mL and stimulated Tg ≥ 1 and < 10 ng/mL
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Neck US with nonspecific changes or stable sub-centimeter lymph nodes
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Cross-sectional and/or nuclear medicine imaging with nonspecific changes, although not completely normal
Response is defined as incomplete if any of the following are present:
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Suppressed Tg ≥ 1 ng/mL or stimulated Tg ≥ 10 ng/mL
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Rising Tg values
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Persistent or newly identified disease on cross-sectional and/or nuclear medicine imaging
A comparison study in 98 patients with FTC concluded that the ATA staging system predicts recurrence rate and survival better than TNM staging. Hazard ratios were 4.67 with ATA staging versus 1.26 for TNM staging. [26]
Thyroid Studies
Perform complete assessment of thyroid function in any patient with thyroid lumps. In addition to TSH, measure thyroxine, triiodothyronine, and serum levels of thyroglobulin, calcium, and calcitonin.
Levels above the reference range of thyroxine (T4; reference range, 4.5-12.5 mcg/dL), triiodothyronine (T3; reference range, 100-200 ng/dL), and TSH (reference range, 0.2-4.7 mIU/dL) may indicate thyroid cancer. Available studies are not specific for FTC.
TSH suppression test
Thyroid cancer is autonomous and does not require TSH for growth, whereas benign thyroid lesions do. Therefore, when exogenous thyroid hormone feeds back to the pituitary to decrease the production of TSH, thyroid nodules that continue to enlarge are likely to be malignant. However, consider that 15-20% of malignant nodules are suppressible.
Preoperatively, the test is useful for patients with nontoxic solitary benign nodules and for women with repeated inconclusive test results. Postoperatively, the test also is useful in follow-up of FTC cases.
Fine-Needle Aspiration Biopsy
Fine-needle aspiration biopsy (FNAB) is considered the best first-line diagnostic procedure for a thyroid nodule; it is a safe and minimally invasive test. It is the required procedure for the diagnostic evaluation of the classic solitary thyroid nodule.
Local anesthesia is administered at the puncture site, and a 21G or 23G aspiration biopsy needle is guided into the mass. The nodule is held with the fingers of the left hand while a needle is introduced through the skin into the nodule with the right hand.
After aspiration, the material is placed on a glass slide, fixed with alcohol-acetone, and stained according to the technique of Papanicolaou.
Accuracy of FNAB is better than that of any other test for uninodular lesions. Sensitivity of the procedure is near 80%, specificity is near 100%, and errors can be diminished using ultrasound guidance. False-negative and false-positive results occur less than 6% of the time.
A cytologist could experience difficulty in distinguishing some benign cellular adenomas from their malignant counterparts (ie, follicular and Hürthle cell adenomas from carcinomas).
Thyroid biopsy could be performed using the classic Tru-Cut or Vim-Silverman needles, but FNAB is preferable. Patients comply best with FNAB.
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Follicular thyroid carcinoma. Surgical specimen of a large goiter. Total thyroidectomy was performed because of the presence of a solid nodule in the right lobe (note the size of the thyroid lobe at left of the screen).
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Follicular thyroid carcinoma. The right lobe of the thyroid was sectioned and reveals a large solid nodule with necrotic and hemorrhagic areas. Histologic diagnosis is follicular thyroid carcinoma.
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Follicular thyroid carcinoma. Histologic pattern of a mildly differentiated follicular thyroid carcinoma (250 X). Image courtesy of Professor Pantaleo Bufo at University of Foggia, Italy.
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Follicular thyroid carcinoma. Histologic pattern of a rare lymph node metastasis of follicular thyroid carcinoma (140 X). Image courtesy of Professor Pantaleo Bufo at University of Foggia, Italy.
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Follicular thyroid carcinoma. Histologic pattern of a rare lymph node metastasis of follicular thyroid carcinoma (250 X). Image courtesy of Professor Pantaleo Bufo at University of Foggia, Italy.
