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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 Hrthle cell adenomas from
carcinomas). On final pathologic assessment, only about 20% of patients
with an FNAB cytologic diagnosis of suspicious for follicular neoplasm will
prove to have a follicular thyroid carcinoma.[1]
A prognostic indicator of significant value may be ras genotyping by
polymerase chain reaction (PCR) technique, which may help in the clinical
and histologic reassessment of these tumors.
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. [15]
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. [16] 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 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. [17] 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.

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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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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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.
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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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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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.
View Media Gallery
See the list below:
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.
High magnification of the abortive follicles may demonstrate atypia of
the follicular epithelium and intervening stroma.
Thyrocytes are large and show an abnormal nuclear/cytoplasmic ratio
with several mitoses.
Presence of colloid-rich follicles lined by flattened follicular cells that
are occasionally accompanied by several histiocytes is maintained in a
benign lesion.
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 grading 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 related for the third and fourth stages.
In patients younger than 45 years, staging is as follows:
Stage I: Any T, any N, M0 (Cancer is in the thyroid only.)
Stage II: Any T, any N, M1 (Cancer has spread to distant organs.)
In patients older than 45 years, staging is as follows:
Stage I: T1, N0, M0 (Cancer is in the thyroid only and may be found in
one or both lobes.)
Stage II: T2, N0, M0 and T3, N0, M0 (Cancer is in the thyroid only and
is larger than 1.5 cm.)
Stage III: T4, N0, M0 and any T, N1, M0 (Cancer has spread outside
the thyroid but not outside of the neck.)
Stage IV: Any T, any N, M1 (Cancer has spread to other parts of the
body.)
See Thyroid Cancer Staging for more information.
A comparison study in 98 patients with follicular thyroid carcinoma
concluded that the American Thyroid Association (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. [18]
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 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
Hrthle 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.

Approach Considerations
The initial treatment for cancer of the thyroid is surgical. The exact nature
of the surgical procedure to be performed depends for the most part on the
extent of the local disease. A consensus approach might be to perform a
total thyroidectomy if the primary tumor is larger than 1 cm in diameter or if
there is extrathyroidal involvement or distant metastases. Clinically evident
lymphadenopathy should be removed with a neck dissection. If the primary
tumor is less than 1 cm in diameter, a unilateral lobectomy might be
considered.
Current National Comprehensive Cancer Network (NCCN) guidelines
recommend lobectomy plus isthmusectomy as the initial surgery for
patients with follicular neoplasms, with prompt completion of thyroidectomy
if invasive follicular thyroid carcinoma (FTC) is found on the final histologic
section. Therapeutic neck dissection of involved compartments is
recommended for clinically apparent/biopsy-proven disease. [1]
The NCCN recommends total thyroidectomy as the initial procedure only if
invasive cancer or metastatic disease is apparent at the time or surgery, or
if the patient wishes to avoid a second, completion thyroidectomy should
the pathologic review reveal cancer. [1]
About 4-6 weeks after surgical thyroid removal, patients must have
radioiodine to detect and destroy any metastasis and any residual tissue in
the thyroid. Administer therapy until no further radioiodine uptake is noted.
Patients take thyroid replacement therapy (ie, L-thyroxine [L-T4]) for life.
This entails taking 2.5-3.5 mcg/kg of L-T4 every day. The thyroxine is given
in the dose necessary to inhibit thyrotropin to a value of 0.1-0.5 mU/L. This
treatment plan is generally successful. However, a 10-year recurrence rate
of 20-30% may be seen in older patients, in patients with primary tumors
greater than 4 cm in diameter, and in patients where tumor has spread
beyond the thyroid boundaries and where lymph node involvement is
widespread. Once metastatic thyroid cancer becomes resistant to
radioiodine, the 10-year survival is less than 15%.
A number of indications for external beam radiation therapy (EBRT) apply
to the management of FTC.
If all gross disease cannot be resected, or if residual disease is not avid for
radioactive iodine, EBRT is often employed for locally advanced disease.
Similarly, radiation therapy is indicated for unresectable disease extending
into adjacent structures, such as the trachea, esophagus, great vessels,
mediastinum, and/or connective tissue. In this situation, radiation therapy
doses of 6000-6500 cGy are typically used. Following radiation therapy for
unresectable disease, the patient should undergo radioactive iodine (I-131)
scanning. If uptake is detected, a dose of I-131 should be administered.
EBRT increases the local-regional control of the residual disease for patients with
locally advanced differentiated thyroid carcinoma. [19] EBRT also may be used after
resection of recurrent FTC that is no longer avid for radioactive iodine.
In the postoperative setting, radiation therapy doses of 5000-6000 cGy are
commonly delivered to the tumor bed to reduce the risk of local-regional recurrence.
Careful treatment planning (typically with multiple radiation therapy fields) should be
employed to minimize the risks of radiation therapy complications.
Finally, a palliative course of radiation therapy is useful to relieve pain from bone
metastases.
Chemotherapy with cisplatin or doxorubicin has limited efficacy, producing
occasional objective responses (generally for short durations). Because of the high
toxicity of cisplatin and doxorubicin, chemotherapy may be considered in
symptomatic patients with recurrent or progressive disease. It could improve quality
of life in patients with bone metastases. No standard protocol exists for
chemotherapy of metastatic FTC.
FTC is a highly vascular lesion. In patients with bone metastases who experience
severe pain that does not respond to palliative radiation, arterial embolization of the
tumor might be considered.
The possible involvement of angiogenesis in the progression of metastatic thyroid
carcinoma has suggested a role for the multikinase inhibitor sunitinib, which may
inhibit angiogenesis. A phase II trial in 23 patients with advanced differentiated
thyroid cancer who had received at least one course of radioactive iodine treatment
demonstrated that sunitinib exhibits significant anti-tumor activity. Of the 23 patients,
six (26%) achieved a partial response and 13 (57%) had stab

urgery is the definitive management of thyroid cancer, and various types of


operations may be performed.
Lobectomy with isthmectomy
This represents the minimal operation for a potentially malignant thyroid nodule.
A study of 889 thyroid cancer patients who underwent either total thyroidectomy or
thyroid lobectomy showed similarly high rates of survival among both
groups. [21]Patients younger than 40 years who have FTC nodules that are less than
1 cm in size, well defined, minimally invasive, and isolated may be treated with
hemithyroidectomy and isthmectomy.
Subtotal thyroidectomy (near-total thyroidectomy)
Subtotal thyroidectomy is preferable if it is feasible, since it carries a lower incidence
of complications (eg, hypoparathyroidism, superior and/or recurrent laryngeal nerve
injury).
Moreover, total thyroidectomy does not improve the long-term prognosis.
Total thyroidectomy (removal of all thyroid tissue, with preservation of the
contralateral parathyroid glands)
Approximately 10% of patients who have had total thyroidectomy demonstrate
cancer in the contralateral lobe. Therefore, residual thyroid tissue has the potential to
dedifferentiate to anaplastic cancer.
Perform total thyroidectomy in patients who are older than 40 years with FTC and in
any patient with bilateral disease; furthermore, recommend total thyroidectomy to
anyone with a thyroid nodule and a history of irradiation.
Some studies show lower recurrence rates and increased survival rates in patients
who have undergone total thyroidectomy. This surgical procedure also facilitates
earlier detection and treatment of recurrent or metastatic carcinoma. This surgical
option is mandatory in patients with FTC ascertained by postoperative histologic
studies (ie, if a very well-differentiated tumor is discovered) after a one-side
lobectomy, with or without isthmectomy.

When the primary tumor has spread outside the thyroid and involves adjacent vital
organs, such as the larynx, trachea, or esophagus, preserve these organs at the first
surgical approach. However, the surrounding soft tissues, including muscles and
involved areas of the trachea and/or esophagus, may be sacrificed whenever they
are involved directly in the differentiated thyroid carcinoma and their local resection
is easily feasible. Surgical resection of one or more brain metastases may prolong
survival from 4 to 22 months.
Minimally invasive techniques
During the last decade, a number of minimally invasive endoscopic approaches have
been proposed for the treatment of thyroid carcinoma, but these techniques may be
applied only to a small number of casesthose classified as 'low risk' carcinomas
according to the AGES and AMES classifications.
Robotic-assisted thyroidectomy
A study by Lee et al found that the application of robot technology to endoscopic
thyroidectomy may overcome the limitations of conventional surgery. [22]

The most useful drugs for postsurgical treatment of FTC are L-thyroxine (L-
T4) and radioiodine. Antineoplastic drugs such as cisplatin and doxorubicin
may be useful for palliation in patients with metastases.
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