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Thyroid carcinomas develop from the two cell types present in the thyroid gland. The endodermally derived follicular cell, responsible for producing thyroid hormone, gives rise to papillary, follicular, and anaplastic carcinomas. Parafollicular cells, also called C cells, which are neuroendocrine thyroid cells that are responsible for producing calcitonin, give rise to medullary thyroid carcinomas (MTCs). Papillary and follicular thyroid cancers are known collectively as differentiated thyroid cancers (DTCs).
Thyroid lymphomas develop from intrathyroidal lymphoid tissue, whereas sarcomas likely arise from connective tissue in the thyroid gland.
Thyroid cancer is one of the few head and neck cancers in the United States whose incidence is increasing, and the incidence-based mortality continues to rise. Overdiagnosis of small, indolent papillary thyroid carcinomas may contribute to some, but not all, of the increase. A rise in obesity, a decrease in smoking prevalence, and reproductive factors may also contribute to the increased incidence. Future research may elucidate other driving forces.
Papillary carcinomas account for 80% of thyroid malignancies, and follicular carcinomas, for 10%. Hürthle cell carcinoma is a variant of follicular carcinoma and makes up 2-3% of all thyroid malignancies. MTCs account for 2-3%; anaplastic carcinomas (1-2%), primary thyroid lymphomas, and primary thyroid sarcomas are rare. [1]
These include the following:
Heat intolerance and palpitations suggest an autonomously functioning nodule, which is typically benign.
Laboratory testing
When a thyroid nodule is found, thyroid function tests should be obtained to determine the functional status of the nodule. An autonomously functioning (ie, hyperfunctioning), or “hot,” nodule, is less likely to be malignant.
Imaging
Solitary thyroid nodules should be evaluated with neck ultrasonography, the gold standard for diagnosing thyroid disease. In addition to evaluating thyroid nodules within the thyroid parenchyma, neck ultrasonography must include the lateral neck regions in order to evaluate for cervical lymphadenopathy, which may imply metastasis.
Fine-needle aspiration biopsy
Fine-needle aspiration biopsy (FNAB) is an essential diagnostic tool in evaluating thyroid nodules and is typically performed under ultrasonographic guidance. However, not all thyroid nodules visualized on ultrasonography warrant further investigation with FNAB, and indeed, the indications for FNAB have become more stringent to balance the risk of potential malignancy with the risk of unnecessary procedures and over-treatment.
This includes the following:
With the establishment of only a few modifiable risk factors for thyroid cancer, speculation remains regarding the specific environmental factors associated with the disease’s rising incidence. Nonetheless, new data exists concerning exposures that may be linked to the development of thyroid cancers, as reported by several large, well-designed epidemiologic studies. Research has consistently pointed to obesity as a risk factor, while in contrast, smoking has been associated with a decrease in thyroid cancer risk.
Because thyroid cancer arises most often in women, reproductive issues are considered suspect in its development, but a strong correlation has been conclusively demonstrated in only a few studies to date. Using the Harvard Nurses’ Health Study II cohort, a report indicated that a significant link exists between increased thyroid cancer risk and a later age at the time of first birth, a later age at menopause, and a higher number of reproductive years. Conversely, according to the study, thyroid cancer risk is reduced in association with a longer duration of oral contraceptive use. [2]
While it is unlikely that the significance of any of the above factors is enough by itself to account for the large increase in thyroid cancer, the greater rate may have resulted from these (and possibly other, as-yet-unidentified risk factors) working tandem with overdiagnosis.
Kitahara and Sosa report that increased opportunities for detecting and diagnosing small, indolent thyroid cancers seem to explain some, but not all, thyroid cancer incidence patterns. The investigators also posit that a substantial proportion of thyroid cancer diagnoses (>40% in the United States) could be attributable to environmental factors, such as obesity and cigarette smoking, which is in agreement with a Cancer article by Goldenberg. [2, 3]
Radiation exposure significantly increases the risk for malignancies arising from thyroid follicular cells, particularly papillary thyroid carcinoma. This finding was observed in children exposed to radiation after the nuclear bombings in Hiroshima and Nagasaki during World War II. Additional evidence was gathered after atomic bombs were tested in the Marshall Islands, after the accident at the Chernobyl nuclear power plant, and in patients who received therapeutic low-dose radiation therapy for benign disorders (eg, acne, adenotonsillar hypertrophy, ringworm). However, low-dose radiation exposure from imaging studies has not been found to have a tumorigenic effect.
The two main risk factors for developing radiation-induced thyroid cancer are the radiation dose delivered to the thyroid gland and the age at exposure. The risk rises in persons exposed to a mean dose of over 0.05-0.1 Gy (50-100 mGy). Of greater importance during childhood, the risk is reduced with increased age at exposure, thus being low in adulthood. Following radiation exposure, thyroid cancer has a minimum latency period of 5-15 years before it appears.
A study by Le et al indicated that among patients in the Veterans Health Administration (VHA) system with thyroid cancer, the percentage of those with self-reported exposure to the herbicide Agent Orange (used during the Vietnam War) is significantly higher than in the general VHA population. The study included 19,592 patients diagnosed with thyroid cancer. [4]
Low dietary intake of iodine does not increase the incidence of thyroid cancers overall. However, populations with low dietary iodine intake have a high proportion of follicular and anaplastic carcinomas.
The National Cancer Institute (NCI) estimated that thyroid cancers accounted for approximately 2.3% of all new cancer diagnoses in the United States in 2022, based on data from the Surveillance, Epidemiology, and End Results (SEER) program. [5] The American Cancer Society (ACS) estimated that 43,800 new cases of thyroid cancer were diagnosed in 2022.
The US incidence of thyroid cancer has more than tripled since the late 20th century, growing from nearly 5.0 new cases per 100,000 persons in 1975 to 15.5 new cases per 100,000 persons per year in the period between 2014 and 2018. [6, 7] This is primarily due to a rise in the incidence of papillary thyroid carcinoma. Although the increased thyroid cancer incidence is well documented, the underlying cause remains controversial. It was previously speculated that the increase was due to the overdiagnosis of small, clinically insignificant papillary thyroid carcinomas, owing to the increasing availability of ultrasonography and fine-needle aspiration biopsy (FNAB). However, extensive, well-structured studies have provided evidence of an actual increase in incidence and incidence-based mortality. [8, 9] Research has also shown that thyroid cancers of all sizes have increased, not solely small, indolent tumors. [10, 11]
The incidence of thyroid cancer is three times higher in women than in men.
The incidence of thyroid cancer peaks in the third and fourth decades of life.
Patients with thyroid cancers generally have a favorable prognosis compared with those with many other solid tumors. The SEER database reports the 5-year relative survival rate for all types of thyroid cancer from 2012-2018 to be 98.4%. [5] Still, the ACS estimated that about 2230 deaths from thyroid cancer occurred in the United States in 2022. [1] Contemporary treatment of patients with a thyroid malignancy requires a multidisciplinary approach involving an endocrinologist, a thyroid surgeon, a nuclear radiologist, and, on occasion, medical and radiation oncologists.
Labarge et al utilized the SEER database to evaluate the incidence-based mortality from thyroid cancer. They demonstrated that between 1987 and 2017, the overall annual percent change in the thyroid cancer mortality rate was 0.61%, suggesting a statistically significant increase in mortality. [12]
The growth of a nodule may suggest malignancy. Rapid growth is an ominous sign.
Malignant thyroid nodules are usually painless. Sudden onset of pain is more strongly associated with benign disease, such as hemorrhage into a benign cyst or subacute viral thyroiditis, than with malignancy.
New-onset hoarseness is an ominous sign and suggests the involvement of the recurrent laryngeal nerve and vocal fold paralysis. Dysphagia may be a sign of impingement of the digestive tract. Heat intolerance and palpitations suggest an autonomously functioning nodule, which is typically benign.
Medullary carcinoma is most often sporadic but can occur as part of multiple endocrine neoplasia (MEN) 2A or 2B syndrome and familial MTC (FMTC) syndrome.
Thyroid carcinoma most commonly manifests as a painless, palpable, solitary thyroid nodule, with the vast majority of such lesions discovered incidentally. Patients or physicians discover most of these nodules during routine neck palpation or an unrelated imaging study. Palpable thyroid nodules are present in approximately 4-7% of the general population; most represent benign nodular disease. High-resolution ultrasonography reportedly depicts thyroid nodules in 19-67% of randomly selected individuals. An estimated 5% of solitary thyroid nodules are malignant. Palpable and nonpalpable nodules of similar size have the same risk of malignancy.
Physical examination should include a thorough head and neck examination with careful attention to the thyroid gland, cervical soft tissues, and indirect laryngoscopy. Solitary thyroid nodules can vary from soft to hard. Hard, fixed nodules are more suggestive of malignancy than supple, mobile nodules are. Thyroid carcinoma is usually non-tender to palpation. Concurrent lateral cervical masses are highly suggestive of regional lymph node metastases. Vocal fold paralysis identified on direct laryngoscopy implies recurrent laryngeal nerve involvement.
The patient’s age at presentation is important because solitary nodules are more suspicious for malignancy at age extremes. In addition, thyroid nodules are associated with an increased rate of malignancy in males and those who have been exposed to radiation at a younger age.
The key to the workup of a solitary thyroid nodule is differentiation of malignant from benign disease and, thus, determination of which patients require intervention and which ones may be monitored serially. History taking, physical examination, laboratory evaluation, and FNAB are the mainstays of thyroid nodule assessment.
When the history and physical exam demonstrate a thyroid nodule or if a thyroid nodule is found incidentally on imaging, thyroid function tests should be obtained to determine the functional status of the nodule. If the thyroid-stimulating hormone (TSH) level is low, this suggests suppression by an autonomously functioning (ie, hyperfunctioning), or “hot,” nodule, which is less likely to be malignant.
Solitary thyroid nodules should be evaluated with neck ultrasonography, the gold standard for diagnosing thyroid disease. In addition to evaluating thyroid nodules within the thyroid parenchyma, neck ultrasonography must include the lateral neck regions in order to evaluate for cervical lymphadenopathy, which may imply metastasis. Computed tomography (CT) scanning or magnetic resonance imaging (MRI) is not routinely performed in the workup of a solitary thyroid nodule. However, they may be helpful later during preoperative planning to evaluate for extension of large or recurrent thyroid masses into the soft tissue of the neck, trachea, or esophagus or to assess metastases to the cervical lymph nodes.
Radioiodine imaging was used in the past to determine the functional status of a nodule. Nonfunctioning nodules do not take up radiolabeled iodine-123 (123I) and appear as cold spots in the thyroid (cold nodules), [13] while hyperfunctioning nodules take up radioiodine and appear as hot spots (hot nodules). Warm nodules appear similar to the surrounding normal thyroid tissue. Unfortunately, carcinoma cannot be excluded based on radioiodine scans, so these are usually not helpful in the routine evaluation of thyroid nodules.
The information gleaned from a thyroid and lateral neck ultrasonographic exam will guide whether a nodule should be further evaluated with FNAB. These biopsies are an essential diagnostic tool in evaluating thyroid nodules and are typically performed under ultrasonographic guidance. However, not all thyroid nodules visualized on ultrasonography warrant further investigation with FNAB, and indeed, the indications for FNAB have become more stringent to balance the risk of potential malignancy with the risk of unnecessary procedures and over-treatment.
Historically, lesion size and clinical history (rapid growth, family history, etc) drove clinicians to recommend FNAB. Presently, the indications for FNAB place more weight on the thyroid nodule’s ultrasonographic characteristics. For example, nodules that are solid or mixed cystic-solid (as opposed to simple cysts); that have microcalcifications; that have hypoechoic, irregular borders; or that are taller than they are wide are associated with a higher risk of malignancy. [14, 15, 16] The table below summarizes thyroid ultrasonographic characteristics [17] :
American Thyroid Association and American College of Radiology guidelines
Several published guidelines exist for delineating which thyroid nodules should undergo FNAB. The two most prominent are the 2015 American Thyroid Association (ATA) guidelines and the American College of Radiology’s Thyroid Imaging Reporting and Data System (TI-RADS) guidelines. Both sets of guidelines stratify nodules into categories with an associated risk of malignancy and apply a size cutoff for which an FNAB is indicated in each category. However, the size cutoffs for FNAB are slightly higher in the TI-RADS guidelines than in the 2015 ATA guidelines. Therefore, following the TI-RADS guidelines results in fewer FNABs and a higher specificity for detecting thyroid cancer, while the 2015 ATA guidelines have a higher sensitivity.
The 2015 ATA guidelines assess the ultrasonographic characteristics of thyroid nodules and stratify them into categories based on risk of malignancy (ROM), as follows [14] :
The American College of Radiology’s TI-RADS system risk stratifies thyroid nodules into categories with associated size cutoffs for FNAB [15] :
The table below, published in Goldenberg’s Head & Neck Endocrine Surgery: A Comprehensive Textbook, Surgical, and Video Atlas, compares the difference in size cutoffs between the 2015 ATA guidelines and the TI-RADS guidelines. [17]
FNAB is inexpensive and easy to perform, and it causes few complications. Successful diagnosis by the cytologist depends on an accurate sampling of the nodule and specimen cellularity. For this reason, several authors recommend performing at least three aspirations to ensure specimen adequacy and minimize false-negative results. Ultrasonographic guidance can help to increase the accuracy of FNAB. Danese et al reported increased false-negative rates with palpation FNAB compared with ultrasonographically guided FNAB. [18]
Bethesda classification system
Through cytologic analysis of FNAB specimens, the Bethesda classification system, second edition, is used to estimate the malignancy risk of thyroid nodules. In this system, nodules are classified into one of the following categories:
Role of molecular testing
The management of Bethesda category I, II, V, and VI nodules is relatively straightforward:
Bethesda categories III and IV represent a gray zone. Historically, nodules in these categories were treated with a diagnostic lobectomy, whereby the pathology would confirm or exclude the presence of malignancy. However, molecular testing of FNAB specimens can now reveal the malignant potential of these nodules, revolutionizing their management.
A 2021 review by Hanba et al comments on the role of genetic testing in assessing an indeterminate FNAB. They report that molecular testing is an increasingly employed adjunct procedure in determining the risk of malignancy for indeterminate thyroid nodules, providing a way to avoid unnecessary surgical risks to a patient. Molecular testing results provide the surgeon with information about any mutations or translocations that may be present within the nodule and are typically accompanied by a likelihood-of-malignancy percentage. These metrics can help to guide discussions with patients about managing their thyroid nodules. Other considerations can be taken into account as well. For example, for patients who have a low risk tolerance or who are unlikely to return for regular active surveillance, even a low reported risk of malignancy may be enough to cause the surgeon and patient to opt for surgery. [19]
Several molecular tests exist, including the University of Pittsburgh’s ThyroSeq test, Veracyte’s Afirma Genomic Sequencing Classifier (GSC) model, and Interpace Biosciences’ ThyGeNEXT and ThyraMIR tests.
The ATA and National Comprehensive Cancer Network (NCCN) support the use of molecular testing, which became the standard of practice for managing indeterminate (Bethesda III) thyroid nodules after the first decade of the 21st century. [19]
Indeed, follicular thyroid carcinoma cannot be distinguished from a benign follicular adenoma on FNAB alone because the characteristics that define follicular carcinoma—capsular invasion/extrathyroidal extension or hematogenous invasion—cannot be determined based on an FNAB specimen. Thus, FNAB specimens with follicular architecture (Bethesda III or IV) are routinely sent for molecular testing to help guide decision-making.
Skaugen et al published a study investigating the utility of molecular testing in nodules considered suspicious for malignancy (Bethesda V) on FNAB. They determined that ThyroSeq had a sensitivity of 89.6% and a specificity of 77% in predicting malignancy in such lesions. There may be a role for molecular testing of Bethesda V nodules, [20] but at this time the standard of care for these remains surgical resection.
Malignant diagnoses (Bethesda VI) require surgical intervention. Papillary thyroid carcinoma and MTC are often positively identified based on FNAB results alone and do not require molecular testing. In patients with these carcinomas, definitive surgical planning can be undertaken at the outset. Some controversy exists regarding the extent of thyroidectomy for a particular pathologic diagnosis (ie, whether total thyroidectomy, subtotal thyroidectomy, or lobectomy). Each such diagnosis and the corresponding extent of thyroidectomy are discussed below.
Clinical features
Well-differentiated thyroid carcinomas include papillary carcinoma and follicular carcinoma. Papillary carcinoma is a slow-growing tumor arising from follicular cells, or thyrocytes. Thyrocytes produce thyroxine (T4) and thyroglobulin. In addition, the cells are TSH-sensitive and take up iodine. This feature has diagnostic value, as well as therapeutic benefit for managing residual disease and recurrences after surgical excision.
Papillary carcinoma is the most common thyroid malignancy, representing approximately 80% of such cancers. Women develop papillary cancer three times more frequently than men do, and the mean age at presentation is 30-40 years.
Cases can occur sporadically or familially and can arise alone or (rarely) be associated with Gardner syndrome (familial adenomatous polyposis). As noted above, radiation exposure, especially during childhood, is associated with the development of papillary thyroid carcinoma. Tumors typically appear after a latency period of about 10-20 years.
Pathology
On gross pathologic examination, papillary carcinomas are often whitish, invasive neoplasms with ill-defined margins. Under microscopy, the tumors are seen to be unencapsulated lesions; they characteristically have papillae consisting of neoplastic epithelium overlying fibrovascular stalks. (Very differentiated tumors can have a complex arborizing pattern.) Nuclei have an empty ground-glass appearance with characteristic nuclear grooves, pseudoinclusions, and irregularities of chromatin distribution.
Another histologic feature is the presence of psammoma bodies, which occur in 50% of papillary carcinomas. Psammoma bodies are calcific concretions that have a circular, laminated appearance and are found in the stroma of the tumor. In addition, many papillary carcinomas contain areas that show a follicular growth pattern. However, when the nuclear features in follicular areas are the same as those in papillary areas, the tumor behaves like a classic papillary carcinoma and should be designated as such. (See the images below.)
There are several variants of papillary thyroid carcinoma, including tall cell, columnar, hobnail, trabecular, clear cell, insular, diffuse sclerosing, and cribriform-morular subtypes, that are generally understood to be more aggressive than classic papillary thyroid carcinoma. (See the images below.) Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a new entity formerly known as a noninvasive encapsulated follicular variant of papillary thyroid carcinoma. NIFTP is considered an indolent, premalignant diagnosis and is no longer referred to as a “cancer.”
Risk stratification and prognostic factors
The 2015 ATA guidelines recommend a risk-directed approach to the treatment of papillary thyroid cancer, with three tiers: low, intermediate, and high risk. [14] Recurrence rates are less than 1% in the lowest tier and more than 50% in the highest tier. Features of papillary thyroid cancer that is considered to be high risk include the following:
Local invasion
Tumors can grow directly through the thyroid capsule to invade surrounding structures. Growth into the trachea can occur, producing hemoptysis, and extensive involvement can cause airway obstruction. The recurrent laryngeal nerve can become involved because of its proximity in the tracheoesophageal groove, with invasion of this nerve often causing patients to present with a hoarse, breathy voice. However, the absence of hoarseness or vocal fold dysfunction does not rule out the possibility of recurrent laryngeal nerve invasion. A multi-institutional study reported that less than 50% of patients in whom invasion of the nerve was found intraoperatively actually presented preoperatively with vocal fold paralysis complaints. [21] Patients may also present with dysphagia due to upper aerodigestive tract compression.
Regional metastatic disease
Another common feature of papillary carcinoma is its propensity to spread to the cervical lymph nodes. The most frequent site of lymph node involvement is the central compartment (level 6), located medial to the carotid sheaths on both sides and with extension from the hyoid bone superiorly to the sternal notch inferiorly. The jugular lymph node chains (levels 2-4) are the next most common sites of cervical node involvement. Lymph nodes in the posterior triangle of the neck (level 5) may also develop metastases.
Various risk factors, including younger age, male sex, multifocality, tumor size, lymphatic and vascular invasion, and gross extrathyroidal extension, are positively correlated with regional lymph node metastasis. [22, 23, 24] Further, such metastasis correlates with increased rates of recurrence. Specifically, a lymph node ratio (ratio of positive lymph nodes to total lymph nodes resected and examined) of greater than 0.3 has been significantly associated with nodal recurrence. [25]
Metastasis to a Delphian (prelaryngeal) lymph node is an ominous sign and is correlated with central neck lymph node metastasis. Delphian lymph node metastases have also been correlated with high-risk features such as younger age, male sex, bilaterality of tumor, capsular invasion, extrathyroidal extension, lymphovascular invasion, multifocality, and tumor size greater than 1 cm. [23]
Distant metastatic disease
Approximately 5-10% of patients with papillary thyroid carcinoma develop distant metastases, typically affecting the lungs and bone.
Papillary thyroid microcarcinoma
Considered to be T1 lesions, papillary thyroid microcarcinomas (PTMCs) are 1 cm or less in diameter. Up to 50% of all DTC diagnoses are PTMCs, with increased detection rates leading to a greater known incidence. Having an excellent prognosis, the disease-specific mortality rate for these carcinomas is under 1%. Historically, hemithyroidectomy or even total thyroidectomy has been used to treat PTMC.
However, an active surveillance program initiated in Japan was designed to manage these indolent, possibly clinically insignificant microcarcinomas non-operatively; with initial evaluation through routine follow-up and imaging, these lesions were monitored for changes in features or size. PTMCs are reasonably managed through active surveillance (active monitoring), with follow-up every 6-12 months, a strategy that has been adopted not only in Japan but in the United States as well. Nonetheless, one or more high-risk features in a PTMC may warrant hemithyroidectomy or total thyroidectomy. [17]
Surgical treatment
For patients in whom active surveillance is not appropriate, the treatment for papillary thyroid carcinoma and follicular carcinoma (discussed separately below) is surgical excision whenever possible. Historically, near-total thyroidectomy, in which all apparent thyroid tissue is surgically removed, has been the mainstay procedure. However, with improved stratification of patients into prognostic groups (low, intermediate, and high risk), as outlined above, surgeons have proposed thyroid lobectomy with isthmusectomy alone as definitive treatment for patients at low risk for recurrent or metastatic disease. Studies suggest that the extent of surgery is not necessarily associated with better overall survival for well-differentiated papillary carcinomas that are up to 4 cm in size and are unifocal, clinically node negative (cN0), and without distant metastasis (cM0).
Guidelines from the NCCN state that surgical management with thyroid lobectomy is acceptable when the following criteria are met: no prior radiation, no distant metastases, no cervical lymph node metastases, and no extrathyroidal extension.
The guidelines recommend total thyroidectomy for patients with biopsy-proven papillary thyroid carcinoma in whom the following criteria are met: T3 or larger, clinically node-positive (cN1) disease, metastatic (M1) disease, an aggressive subtype, significant radiation exposure, significant family history, or coexistent thyroid disease. [26]
After deciding to perform a hemithyroidectomy or total thyroidectomy, the surgeon will decide whether to also carry out a central or lateral neck dissection. As stated previously, preoperative thyroid ultrasonography should include the central compartment and the lateral neck. Therapeutic neck dissection (central or lateral) should be performed with lymph nodes removed en bloc if there is preoperative evidence of suspicious lymphadenopathy.
Historically, many surgeons routinely favored performing an elective central neck dissection (ie, with no clinical evidence of lymph node metastasis) when performing a thyroidectomy. However, studies have been changing the landscape. A randomized, controlled trial concluded that elective central neck dissection does not improve oncologic outcomes at 5 years, even when micrometastases are present in the resected central lymph node specimens. [27] A meta-analysis by Alsubaie et al reported that in terms of the rate of structural locoregional recurrence in patients with clinically N0 papillary thyroid carcinoma, the results of total thyroidectomy plus elective central neck dissection did not significantly differ from total thyroidectomy alone. [28] Many surgeons now advocate reserving elective central neck dissection for patients with tumors with high-risk features rather than performing it on a routine basis.
Clinical features
Follicular carcinoma is the second most common thyroid malignancy, representing about 10% of thyroid cancers. It makes up a greater portion of thyroid cancers in regions where dietary intake of iodine is low. Like papillary carcinoma, follicular carcinoma occurs three times more frequently in women than men. Patients with follicular carcinoma are typically older than those with papillary carcinoma, with the mean age range at diagnosis being late in the fourth to sixth decades.
As with papillary carcinomas, follicular carcinomas arise from the follicular cells of the thyroid. The neoplastic cells are TSH sensitive as well, taking up iodine and producing thyroglobulin—a feature that is exploited diagnostically and therapeutically.
Follicular carcinomas may be linked to RAS mutations, RET/PTC mutations, or TSH-receptor mutations. Moreover, PAX8-PPARγ1, a gene rearrangement, exists in both follicular adenomas and carcinomas. [17]
Pathology
On gross pathology, the tumors appear as round, encapsulated, light brown neoplasms. Fibrosis, hemorrhage, and cystic changes are found in the lesions. Under microscopy, the tumors contain neoplastic follicular cells, which can have a solid, trabecular, or follicular growth pattern (that usually produces microfollicles). The follicular cells in these tumors do not have characteristic nuclear features like papillary carcinoma cells do.
Follicular carcinomas are differentiated from benign follicular adenomas by tumor capsular invasion and/or vascular invasion. (See the images below.) For this reason, differentiating follicular adenomas from follicular carcinomas was historically challenging by FNAB alone. However, molecular testing of FNAB specimens has allowed surgeons to determine the risk of malignancy.
Prognostic features
Prognostic factors and more concerning features for follicular carcinoma, which mirror those listed above for papillary thyroid carcinoma, are as follows:
When intrathyroidal encapsulated tumors have minor capsular or vascular invasion (< 4 foci) or five or less metastatic lymph nodes, with the foci of metastases being under 0.2 cm, the ATA considers them to be at low risk for recurrence. Intermediate risk of recurrence is defined by vascular invasion, minimal extrathyroidal extension, or greater than five metastatic lymph nodes (0.2-0.3 cm). A high risk of recurrence is defined by macroscopic extrathyroidal extension, extensive vascular invasion (>4 foci), incomplete tumor resection, distant metastases, or metastatic lymph nodes greater than 3 cm. [14]
Local invasion
Local invasion can occur as it does with papillary carcinoma, with the same presenting features.
Regional and distant metastatic disease [
In contrast to papillary carcinomas, cervical metastases from follicular carcinomas are uncommon. However, the rate of distant metastasis is significantly increased (approximately 20%). Lung and bone are the most common sites.
Surgical treatment
Total thyroidectomy is recommended if the tumor diameter is over 4 cm, if radiographic evidence or intraoperative findings point to extrathyroidal extension, if distant metastases are found at the time of surgery, or if, should the cancer be found at permanent pathology, the patient opts for avoidance of a completion thyroidectomy by undergoing total thyroidectomy. Otherwise, it is advised that the initial surgery for follicular neoplasia be lobectomy plus isthmusectomy. [26] If intermediate or high-risk disease is found on pathology for a lobectomy, a completion thyroidectomy, with or without central neck dissection (and with or without radioactive iodine therapy), should be considered.
Because differentiated thyroid tissue and well-differentiated thyroid carcinomas are TSH sensitive and because they take up iodine, radioiodine preferentially targets residual normal or malignant tissue after thyroidectomy. Therefore, radioiodine can be given in diagnostic doses to detect residual normal or neoplastic tissue in the body and in therapeutic doses to ablate this tissue. Radioiodine scanning and ablation have become commonplace after thyroidectomy, for diagnosing and treating residual thyroid tissue, as well as regional and distant metastases from well-differentiated thyroid carcinomas. However, pretherapeutic iodine-uptake scanning is controversial because of its cost and concerns about 131I-induced tumor stunning, which may decrease the effectiveness of radioiodine treatment.
After thyroidectomy, patients are given thyroid replacement therapy with T4 (Synthroid) or triiodothyronine (T3, Cytomel). To subsequently detect residual thyroid tissue or metastases, the following steps are taken, with 131I or 123I scanning performed when the patient is in a hypothyroid state:
If a treatment dose of 131I has been required, diagnostic thyroid scanning is subsequently repeated while the patient is in a hypothyroid state. If the diagnostic scan is positive, an additional therapeutic dose is given. This process is repeated until the diagnostic scan is negative.
A promising development for follow-up thyroid scanning has been the use of recombinant human TSH, as opposed to the withdrawal of T4 to increase autogenous TSH levels. This approach avoids the discomfort of having to discontinue thyroid replacement therapy for these scans.
After thyroidectomy and radioiodine ablation, patients with well-differentiated thyroid carcinoma are maintained on thyroid suppression, usually monotherapy with levothyroxine (LT4). With TSH able to promote the remaining DTC cells’ growth, LT4 should initially be administered at a dosage high enough to suppress thyrotropin.
After surgery and radioiodine therapy, patients are regularly monitored every 6-12 months with serial imaging (ultrasonography or computed tomography [CT] scanning) and serum thyroglobulin measurements. Historically, thyroglobulin levels were thought to be a way to monitor disease recurrence, though this remains somewhat unproven and is not superior to surveillance with physical examination and neck ultrasonography. [29] The idea is that thyroglobulin is a marker of tumor recurrence because well-differentiated thyroid cancers synthesize thyroglobulin. However, it is a useful tool only after total thyroid ablation. Serum thyroglobulin is measured at the time of follow-up thyroid scanning, during the withdrawal of thyroid hormone or the administration of recombinant TSH. Serum antithyroglobulin antibodies are measured in addition to thyroglobulin because their presence invalidates the assay. Thyroglobulin antibody levels should be obtained with each thyroglobulin measurement. Rising thyroglobulin level after thyroid ablation suggests recurrence.
Recurrences are best treated with surgical excision if the disease is clinically evident and surgically accessible. Nonlocalized recurrences detected on the basis of elevated thyroglobulin levels are treated with 131I. On occasion, recurrent tumors do not concentrate iodine. Positron emission tomography (PET) scanning may be helpful in localizing disease in such circumstances.
When surgical excision of recurrent disease is not feasible, external-beam radiation therapy may be useful. Alternatively, as reported above, radioiodine may be useful. If refractory to radioiodine, pharmacologic treatments such as vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors may be beneficial. Chemotherapy, usually with doxorubicin, is reserved for tumors that do not respond to other treatments and for palliative care.
The prognosis in radioiodine‐refractory DTC is considered poor. In many cases, the disease is controlled using the VEGFR inhibitors sorafenib and lenvatinib. Nonetheless, treatment resistance and disease progression may still occur. [30]
Sorafenib (Nexavar) was approved for radioiodine-refractory DTC by the US Food and Drug Administration (FDA) in November 2013. In a study of 417 patients with the refractory disease, treatment with sorafenib, an orally active inhibitor of VEGFR1-3 and Raf kinases, significantly improved progression-free survival (10.8 months) compared with placebo (5.8 months). [31, 32, 33] The rate of stable disease for 6 months or longer was 42% in the sorafenib group and 33% in the placebo group.
Lenvatinib (Lenvima) was approved for refractory DTC in February 2015, based on the SELECT phase-3 trial. Compared with patients on placebo, those taking lenvatinib showed significant improvements in progression-free survival (median period of 18.3 months, compared with 3.6 months with placebo). [34, 35]
Cabozantinib (Cabometyx) was approved by the FDA in September of 2021 for the treatment of patients with locally advanced or metastatic DTC that has progressed subsequent to previous VEGFR-targeted therapy and who are ineligible to receive or are refractory to radioactive iodine. Approval was based on the COSMIC-311 trial, which was a randomized, double-blind, placebo-controlled, multicenter clinical trial that showed that patients treated with cabozantinib had a significant reduction in the risk of disease progression or death compared with placebo patients. A median progression-free survival of 11.0 months was observed in the cabozantinib arm, compared with 1.9 months in the placebo arm. [36, 30]
Several clinical trials have evaluated the use of other tyrosine kinase and VEGFR receptor inhibitors, including dabrafenib, trametinib, and anlotinib, though these are not FDA approved at this time. [37, 38]
Hürthle cell carcinoma, also known as oncocytic carcinoma, is a rare thyroid malignancy that is often considered to be a more aggressive variant of follicular carcinoma. Hürthle cell carcinoma has unique biologic features. About 75-100% of the tumor is composed of Hürthle cells, which are also known as oxyphilic, oncocytic, Askanazy, or large cells. These are large polygonal follicular cells that contain abundant granular acidophilic cytoplasm. Hürthle cells can also be found in a variety of benign thyroid conditions, such as Hashimoto thyroiditis, Graves disease, multinodular goiter, and Hürthle cell adenomas.
Hürthle cell carcinomas account for 2-3% of all thyroid malignancies. They occur more commonly in women than in men and typically manifest in the fifth decade of life. The clinical presentation is similar to that of other thyroid malignancies.
An association commonly exists between Hürthle cell carcinoma and either RAS mutations or PAX8/PPARγ gene rearrangements, although these also occur in benign Hürthle cell adenomas. In addition, there is a potential link between mutations in p53 or PI3 kinase genes and more aggressive Hürthle cell carcinoma. The RET/PTC oncogene has a connection with Hürthle cell carcinoma as well. [17]
On pathologic examination, Hürthle cell carcinoma, like follicular carcinoma, is differentiated from Hürthle cell adenoma by the presence of capsular invasion, vascular invasion, or both. On gross evaluation, Hürthle cell carcinomas appear brown and solid, and most have an appreciable capsule. Under microscopy, the tumors have a solid or trabecular growth pattern of large, granular, polygonal Hürthle cells.
Because Hürthle cell carcinoma is defined by capsular or vascular invasion, FNAB specimens alone cannot classify a tumor as malignant or benign. Therefore, when FNAB results suggest a Hürthle cell neoplasm, the specimen should be sent for molecular testing. A positive molecular test (RET/PTC-positive) or a diagnostic lobectomy is required to make the diagnosis.
An aggressive approach to pathology-proven Hürthle cell carcinomas using lobectomy and isthmusectomy is advocated by most surgeons, with subsequent completion thyroidectomy. This approach also includes confirmation made via the final pathologic result, and neck dissection employed for positive malignant adenopathy. Older patients, individuals with tumors larger than 4 cm, or patients with biopsy-proven lymphatic metastases may undergo total thyroidectomy and neck dissection during the initial operation. [26]
Postoperatively, because Hürthle cell carcinomas do not take up iodine and are not TSH sensitive, thyroid suppression and radioiodine therapy have little value. Moreover, since these carcinomas tend to be non–iodine avid, negative iodine scans cannot rule out persistence/recurrence of Hürthle cell carcinomas. Therefore, fluorodeoxyglucose-PET (FDG-PET) imaging is indicated in the presence of high thyroglobulin and/or high-risk pathology. [39]
Hürthle cell carcinoma is considered a radiosensitive tumor; thus, external-beam radiation therapy can be used to treat metastatic disease or control recurrent tumors.
Hürthle cell carcinoma behaves aggressively, and patients with the condition should be monitored closely for recurrent and metastatic disease. The overall 5-year survival rate is 50-60%. The extent of vascular invasion is strongly correlated with recurrence. Matsuura et al reported that in a retrospective study of 111 patients with Hürthle cell carcinoma, widely invasive tumors and encapsulated, angioinvasive tumors with extensive vascular invasion were significantly associated with recurrence when compared with tumors considered to be minimally invasive or that were encapsulated, angioinvasive lesions with focal invasion. [40]
MTC represents approximately 2-3% of all thyroid malignancies, with a slight female preponderance. Tumors arise from the parafollicular C cells of the thyroid gland. C cells are neural-crest derivatives and produce calcitonin. About 75-80% of MTCs develop sporadically, and 20-25% occur familially. While sporadic disease typically presents in the fifth through seventh decade of life, inherited forms of MTC tend to present before then. [39] Familial cases are commonly multifocal throughout the thyroid gland, whereas sporadic cases are usually not multifocal.
Patients may present with clinical evidence of MTC, or, if they are from a family with a familial MTC (FMTC) syndrome, they may present before MTC develops. New germline mutations can also occur; although patients with such mutations present with MTC without a positive family history, they are at risk for passing an FMTC syndrome on to their offspring.
The FMTC syndromes consist of multiple endocrine neoplasia type 2A (MEN 2A), MEN 2B, and FMTC. MEN 2A is a combination of MTC, pheochromocytoma (in 50% of patients), and hyperparathyroidism (in 10-20% of patients). MEN 2B consists of MTC, pheochromocytoma (in 50% of patients), marfanoid habitus, and ganglioneuromatosis. FMTC consists of MTC alone.
MTC in MEN 2B has the most aggressive biologic features. In this situation, MTC usually develops by the age of 10 years, and it has a high propensity for rapid growth and metastasis. MTC in MEN 2A can appear in the first or second decade of life, and it almost always develops by the third or fourth decade. [39] MTC in FMTC usually develops during adulthood.
Sporadic cases typically manifest with painless solitary thyroid nodules, like other thyroid malignancies do. Likewise, symptoms of pain, dysphagia, and hoarseness can develop with local invasion. The workup and diagnosis are similar to those of other thyroid carcinomas, employing neck ultrasonography, including the central and lateral neck, and FNAB.
Inheritance of all familial forms of MTC and MEN2 is in an autosomal dominant fashion. [39] Genetic testing is now the mainstay in the diagnosis of the FMTC syndromes. RET proto-oncogene mutations (on chromosome arm 10q) have been discovered in each of the MTC syndromes. The RET proto-oncogene is a receptor tyrosine kinase whose exact function and role in these syndromes has not been elucidated. Patients with MEN 2A have germline RET mutations resulting in substitutions of conserved cysteine residues in exons 10 and 11. All patients with MEN 2B have a germline mutation resulting in a threonine-for-methionine substitution in codon 918 of exon 16. Mutations are described in exons 13 and 14 in patients with FMTC.
Genetic screening with sensitive polymerase chain reaction (PCR) assays for germline RET mutations is routinely performed in at-risk patients. That means that children of parents known to have MEN or FMTC are tested for RET mutations to guide therapy and future genetic counseling. In addition, patients presenting with sporadic MTC should undergo RET mutational analysis to rule out new spontaneous germline mutations and prompt the testing of offspring for similar mutations.
Because MTC cells produce calcitonin, elevated serum calcitonin levels are diagnostic for MTC. Although routine measurement of serum calcitonin has low yield in managing the solitary thyroid nodule because of the uncommon nature of MTCs, it is useful in the surveillance of patients with a history of MTC and in managing familial forms. Plasma calcitonin levels are commonly increased before clinical evidence of MTC appears. Although this finding was once the mainstay for diagnosing familial forms of MTC, results from genetic testing have largely supplanted it. Plasma calcitonin testing is now used for the early detection of MTC in patients already known to be at risk for MTC because of their family history and genetic results, although it is most commonly employed as a tumor marker to identify residual and metastatic disease after thyroidectomy for MTC.
If MTC is suspected, the preoperative workup generally includes, in addition to serum calcitonin, serum carcinoembryonic antigen (CEA) level, screening for hyperparathyroidism, and urinary and/or plasma fractionated metanephrines and catecholamines (to eliminate the possibility of pheochromocytoma). To avoid intraoperative hypertensive crisis, resection of pheochromocytoma should occur before that of the MTC. [39]
RNA sequencing to identify MTC on FNAB specimens is a newer topic in the literature. A large multi-institutional study evaluated the clinical performance of the Afirma RNA-sequencing MTC classifier in identifying MTC in FNAB specimens. Blind testing was carried out on 211 preoperative specimens, with the classifier demonstrating 100% sensitivity and 100% specificity in identifying MTC. There may be a role for Afirma’s RNA-sequencing MTC classifier in facilitating an MTC-specific preoperative evaluation and treatment in the future. [41]
On gross examination, MTCs are fairly well circumscribed, although they are unencapsulated. They are typically tannish pink and often contain yellow granular regions, which represent focal calcification. Most tumors arise in the middle and upper third of the thyroid lobes, commensurate with the location of the parafollicular C cells in the thyroid gland. Sporadic tumors are unilateral, and inherited forms usually involve both thyroid lobes.
MTCs can have a varied microscopic appearance. The tumors typically have a lobular, trabecular, insular, or sheetlike growth pattern. Some tumors have a fibrotic character. Malignant cells may appear round, polygonal, or spindle shaped. The cytoplasm is eosinophilic and finely granular. In the stroma, characteristic deposits of amyloid are commonly observed. This amyloid has typical green birefringence on Congo red staining, a feature unique to MTC among thyroid malignancies. Immunohistochemical stains for calcitonin and CEA are microscopically useful for differentiating MTC from other tumors.
A unique feature in familial cases of MTC is the finding of C-cell hyperplasia, which can help in distinguishing familial cases from sporadic ones. C-cell hyperplasia is considered a precursor to MTC and is usually adjacent to its foci.
The primary treatment for MTC is extensive and meticulous surgical resection. Both sporadic MTCs and FMTCs are treated with total thyroidectomy and central compartment lymph node dissection (level 6). Metastasis to the cervical lymph nodes is common in patients with MTC, particularly those with familial forms who have multicentricity and bilaterality of the primary tumor. Lymph node metastases can occur in more than 50% of patients.
Both before and at the time of surgery, the lateral jugular lymphatics should carefully be palpated for evidence of metastatic disease. Selective lateral lymph node neck dissection is performed when metastases are clinically evident and may be considered electively. Prophylactic thyroidectomy and central compartment lymph node dissection are performed in children with MEN2A and MEN2B syndrome.
After receiving treatment for MTC, patients are monitored via measurement of serum calcitonin and serum CEA levels. Patients with elevated levels of either of these are evaluated for recurrent disease. Calcitonin/CEA doubling time is a measure used to indicate prognosis after treatment of MTC. Calcitonin doubling times of greater than 2 years are associated with improved prognosis, while calcitonin doubling times of less than 6 months are associated with poor prognosis.
Nigam et al reported that, similarly, in patients with high-grade MTC, calcitonin doubling times were significantly faster in comparison with those of patients with low-grade MTC (8.5 months vs 38.4 months, respectively). High-grade tumors are associated with a risk for poor disease-specific outcomes as well as for structural recurrence. [42]
Neck, abdominal, and pelvic CT scanning or MRI may be used to detect disease if metastasis or recurrence is suspected. Ultrasonography may be useful to localize cervical disease. In addition, radionuclide studies and PET scans can be performed to localize recurrences.
Radiation therapy is used in an adjuvant setting in some centers and can be employed to treat patients with surgically inoperable recurrences and metastases. Because MTC does not concentrate iodine, radioiodine therapy has no role in follow-up care or treatment.
A variety of chemotherapeutic regimens have been used to treat metastatic disease, although MTC is relatively insensitive to chemotherapy. However, partial responses have been obtained. To date, the most effective chemotherapeutic combination is dacarbazine, vincristine, and cyclophosphamide. [43]
Vandetanib (Caprelsa) and cabozantinib (Cometriq) are tyrosine kinase inhibitors approved by the FDA for progressive, metastatic MTC. These agents target various tyrosine kinases, including MET, RET, and VEGFR-2. Subsequently, selpercatinib (Retevmo) and pralsetinib (Gavreto) were approved by the FDA for advanced or metastatic RET-mutant MTC in adults and children aged 12 years or older. [44, 45]
The overall prognosis for patients with MTC is worse than that for patients with well-differentiated carcinoma. The survival rate for patients with small localized MTC at 5 and 10 years is approximately 99%. For regional disease, a decrease to 92% and 71% is seen at 5 and 10 years, respectively. The 5- and 10-year survival drops drastically to 37% and 21%, respectively, with metastatic MTC. Young age, small primary tumor, low stage of disease, and completeness of initial resection improve survival. Patients with MEN 2B have a prognosis substantially worse than that of patients with MEN 2A, though the prognosis for both groups has improved with early diagnosis and intervention. [46, 47]
Clinical features
Anaplastic thyroid carcinoma (ATC) is one of the least common thyroid carcinomas, accounting for 1-2% of all thyroid cancers. However, it has the most aggressive biologic behavior of all thyroid malignancies and one of the worst survival rates of all malignancies in general. ATCs affect more women than men, with presentation typically in the sixth or seventh decade of life, later than for other thyroid malignancies. [48]
ATC manifests as a rapidly growing thyroid mass, in contrast to well-differentiated carcinomas, which are comparatively slow growing. Patients commonly present with symptoms associated with local invasion, with hoarseness and dyspnea resulting from the involvement of the recurrent laryngeal nerve and airway. [49]
Physical examination reveals a firm thyroid mass or masses that are most often larger than 5 cm at presentation. About 30% of patients have vocal fold paralysis, and cervical metastases are palpable on examination in 40% of patients. At least one half of patients already have distant metastases at the time of diagnosis. The most common sites of involvement are the lungs, bones, and brain. [50]
Diagnosis
FNAB should be performed. When considering a diagnosis of ATC, BRAF V600E mutation should be expeditiously assessed via immunohistochemistry, with molecular testing employed for confirmation. In addition, the ATA recommends obtaining a panel of routine immunohistochemical markers for evaluation of suspected ATC, including pan-cytokeratins, thyroglobulin, thyroid-transcription factor 1, BRAF V600E, PAX8, Ki67 index, chromogranin, calcitonin, CEA, p53, and CD45. Immunohistochemical markers consistent with, but not necessarily specific for, ATC include PAX8, a high Ki67 proliferation index (>30%), BRAF mutation, and loss of p53 tumor suppressor function. [51] Egan et al reported that CSPG4 expression is also significantly elevated in ATC. [52]
Molecular profiling should also be performed when ATC is being diagnosed, to aid targeted therapy–related decisions. ATC can be associated with various mutations, including in BRAF, RAS, EIF1AX, PI3K/AKT, TP53, TERT, PTEN, CDKN2A, CDKN2B, ATN, RB1, NF1, and ALK fusion proteins, as well as DNA mismatch repair genes. FDA-approved, mutation-specific therapies now exist to treat ATC that has some of these mutations. [51]
In addition, FDG PET/CT whole-body scanning should be obtained at the time of diagnosis. CT scans of the neck, chest, abdomen, and pelvis, with contrast, or MRI scans of these areas are acceptable if PET scanning is unavailable. Brain MRI is recommended if the patient has symptoms concerning for brain metastasis (neurologic symptoms, headache), given the high rate of distant metastases at time of diagnosis. Laryngoscopy should be performed to assess the status of the recurrent laryngeal nerves and airway. [51]
Pathology
On gross examination, ATC is a large and invasive tumor. Areas of focal necrosis and hemorrhage may be present throughout the lesion, giving it a highly variable appearance. The tumor often extends through the capsule of the thyroid gland itself. Areas of well-differentiated thyroid carcinoma are often found concomitantly, with ATC believed to arise from a preexisting well-differentiated thyroid carcinoma.
On microscopic evaluation, squamoid, spindle cell, and giant cell variants of ATC are observed. All three histologic variants show high mitotic activity, large foci of necrosis, and notable infiltration. Immunohistochemical stains are often positive for low–molecular-weight keratins and are occasionally positive for thyroglobulin. Regarding their ultrastructure, the neoplasms have epithelial features (eg, desmosomes, tight junctions) that are helpful in differentiating them from sarcomas. Small cell carcinomas, which usually represent lymphomas, may be confused with ATC.
Surgical treatment
The progression of disease is rapid, and, despite treatment efforts, most patients die from local airway obstruction or complications of pulmonary metastases within 1 year. Total thyroidectomy is performed when ATC is considered operable. Neck dissection is carried out when there is preoperative or intra-operative evidence of cervical metastases. Complete excision is often impossible because many patients present with clinically significant local extension. Cricothyrotomy or tracheotomy may be needed in cases with airway compromise caused by tracheal invasion or obstruction.
Non-operative therapies
Chemotherapy and radiation therapy are administered in combination. Postoperative external-beam irradiation effectively improves local control; this may also be used as primary treatment in unresectable cases. Chemotherapy (most commonly doxorubicin) is added for palliation.
Anti-cancer therapy has been revolutionized by immuno-oncologic treatments. High-throughput sequencing has paved the way for targeted therapies by revealing the molecular alterations of ATC. In addition, enthusiasm followed the approval of therapy combining the BRAF protein inhibitor dabrafenib with the mitogen-activated extracellular signal–regulated kinase (MEK) inhibitor trametinib, for use in patients with unresectable or metastatic BRAF V600E–positive ATC. In May 2018, dabrafenib used in combination with trametinib became the first FDA-approved treatment for locally advanced or metastatic ATC with BRAF V600E mutation, in patients with no satisfactory alternatives for locoregional therapy. Approval came following a nine-cohort, multicenter, nonrandomized, open-label trial involving patients with BRAF V600E mutation–positive cancer. Investigators found that 57% of patients with ATC experienced a partial response to the treatment, and 4% had a complete response. Sixty-four percent of the patients who responded suffered no significant tumor growths for at least 6 months. [53, 54]
Several institutions are investigating other pharmacologic treatments. Hatashima et al reported outcomes of a case series of 13 patients with locally advanced or metastatic, unresectable ATC who received immune checkpoint inhibitor therapy (pembrolizumab or nivolumab). The investigators reported a median progression-free survival of 1.9 months, a median overall survival of 4.4 months, and a 1-year survival rate of 38%. They concluded that in the future, immune checkpoint inhibition may provide an effective treatment option for ATC. [55]
Prognosis
ATC is poorly responsive to multimodality therapy, and median survival is 5-6 months; the 1-year survival rate is 20%. [51] Young age, unilateral tumors, small tumors (< 4 cm), absence of local invasion of the surrounding tissue, and a lack of cervical metastases are relatively favorable prognostic indicators, so that patients with these features may have slightly prolonged survival. Long-term survival should prompt a reconsideration of the diagnosis of ATC; in such cases, the original tumor is usually found to be a variant of MTC or thyroid lymphoma. Given the overall poor prognosis for ATC, the treatment team should work to aid the control of pain and symptoms via the inclusion of palliative care at every stage of patient management, with psychosocial issues addressed as well. Hospice care should be utilized when appropriate. [51]
Clinical features
Primary lymphomas of the thyroid gland are rare. Most thyroid lymphomas are non-Hodgkin B-cell tumors, with the next most common histologic type being low-grade malignant lymphomas of mucosa-associated lymphoid tissue (MALT). Hodgkin lymphoma, Burkitt cell lymphoma, and T-cell lymphoma have also been reported.
The incidence of primary thyroid lymphoma peaks in the sixth decade of life, and most diagnoses are made in patients aged 50-80 years. Women are more commonly affected than men, with a female-to-male ratio of 4:1. This tumor is highly associated with chronic lymphocytic thyroiditis (Hashimoto thyroiditis). Indeed, almost all patients with primary thyroid lymphoma have either a clinical history or histologic evidence of chronic lymphocytic thyroiditis, the risk of primary thyroid lymphoma being 70-fold greater in patients with chronic lymphocytic thyroiditis compared with the general population.
Diagnosis is based on the patient’s clinical presentation, with a positive tissue diagnosis. FNAB may be useful for diagnosing thyroid lymphoma, but it is considered less reliable with this lesion than with other thyroid malignancies. Tumor cells are positive for leukocyte-common antigen and for B- or T-cell markers, depending on the type of tumor.
Staging of thyroid lymphomas is important for therapeutic and prognostic purposes. Staging involves CT scanning of the brain, neck, chest, abdomen, and pelvis, as well as bone marrow biopsy.
Treatment and prognosis
For early stage, intrathyroidal MALT lymphomas, consideration can be given to single-modality therapy, using surgery or radiation alone. Also, though uncommon, surgery can be used for the purpose of diagnostic biopsy when FNA is nondiagnostic. Surgical excision should not be performed if local infiltration into surrounding tissues is evident. Stage IIE lymphomas are treated with a combination of chemotherapy and radiation therapy. Doxorubicin or CHOP (cyclophosphamide, hydroxydaunomycin, Oncovin [vincristine], prednisone) is the commonly used chemotherapeutic regimen.
Most thyroid lymphomas are stage IE, which have a 5-year survival rate of up to 85%. Spread beyond the thyroid gland reduces the 5-year survival rate to about 64%. [56] Lymphomas at higher stages have a worse prognosis.
Sarcomas arising in the thyroid gland are uncommon. They are aggressive tumors that most likely develop from stromal or vascular tissue in the gland. Malignancies that appear to be sarcomas should be differentiated from ATCs, which can appear sarcomatous.
The treatment for thyroid sarcomas is total thyroidectomy. Radiation therapy may be used in an adjunctive setting. Most sarcomas are unresponsive to chemotherapy. Recurrence is common, as with sarcomas arising in other sites in the body, and the patient’s overall prognosis is poor.
Thyroid surgery is performed to diagnose or treat thyroid disease. The extent of surgery ranges from isthmusectomy alone (for small nodules truly localized to the isthmus) to lobectomy, subtotal thyroidectomy, total thyroidectomy, or extended thyroidectomy. Radioiodine studies performed after total thyroidectomy usually show residual normal thyroid tissue despite surgery.
The principles of thyroid surgery are accurate execution of the planned excision, avoidance of injury to the recurrent laryngeal nerve, avoidance of injury to or devascularization of the parathyroid glands, and meticulous hemostasis.
Vocal fold mobility should always be determined before thyroid surgery. If lobectomy is planned, discuss the potential need for completion thyroidectomy with the patient.
Positioning of the patient is important. Place the patient in a supine position with his or her neck extended by using a shoulder roll. Plan a horizontal incision in a natural skin crease to contour the curvature of the neck. The location should overlie the thyroid gland, evenly extending between the anterior aspect of the sternocleidomastoid muscles on both sides.
Elevate skin flaps superiorly and inferiorly in a subplatysmal plane. (Platysma is often absent in the midline.) Ligate the anterior jugular veins only if they directly limit exposure. Separate the sternohyoid and sternothyroid muscles in the median raphe, and retract them laterally to expose the cricoid cartilage and thyroid isthmus.
In the anterior region, dissect the strap muscles off the face of the thyroid lobe (bilaterally for total thyroidectomy). Supracapsular dissection is continued until the superior pole and its vascular pedicle are isolated. The superior pole vessels are divided and ligated. During superior dissection, remember the nearby location of the external branch of the superior laryngeal nerve, which innervates the cricothyroid muscle. Ligation of the superior-pole vessels tight to the thyroid in this area avoids inadvertent injury to this nerve. The dissection continues laterally with division of the middle thyroid vein. The thyroid lobe is gradually medialized. Careful blunt dissection is performed to identify the recurrent laryngeal nerve in the tracheoesophageal groove.
The American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) created a task force to generate a consensus statement on neural monitoring. The 2022 statement strongly recommends the use of neural monitoring of the recurrent and superior laryngeal nerves in thyroid surgery. [57] Moreover, research has indicated that compared with intermittent intraoperative nerve monitoring in thyroid surgery, the risk for early postoperative vocal fold palsy is lowered 1.8 fold, and for permanent palsy, 29.4 fold, through continuous intraoperative nerve monitoring, although this technique has not yet been uniformly adopted in practice. [58]
After the recurrent nerve is identified, carefully follow the nerve superiorly toward the larynx. The nerve passes close to the Berry ligament. After the nerve is thoroughly identified in this region, divide the ligament to release the thyroid gland. The authors advocate that if, intraoperatively, the recurrent laryngeal nerve is injured on one side or there is loss of the neural monitoring signal, the surgeon may, if clinically appropriate, consider performing only an ipsilateral lobectomy, on the injured side, with assessment of the patient’s vocal fold function postoperatively. The surgeon could at a later time consider proceeding to total thyroidectomy if the benefits outweighs the risks.
Keep the location of the parathyroid glands in mind during lateral dissection. Avoid disturbing the glands and vasculature as much as possible. Dissection close to the thyroid capsule minimizes this risk. If possible, ligate the inferior thyroid artery only after the vessels to the inferior parathyroid glands branch.
If only lobectomy is planned, divide the thyroid isthmus in the midline. Ligate the final soft tissue attachments, and remove and label the lobe. Examine the specimen for parathyroid tissue. If a parathyroid gland is inadvertently removed, reimplant it in the sternocleidomastoid muscle after slicing it into small pieces, marking the implantation area with a surgical tie or clip. Send the specimen to the pathology laboratory.
When total thyroidectomy is performed, the surgeon may elect not to divide the thyroid isthmus in the midline but rather to perform lateral dissection bilaterally. Identify the recurrent laryngeal nerve, and manage the inferior and superior vascular pedicles similarly. Remove the gland in one piece, label it, and send it for pathologic analysis.
Irrigate the wound, and achieve meticulous hemostasis. The decision to place a drain often depends on the surgeon’s judgment. If a drain is used, place it into the wound and bring it out laterally through the incision or through a separate stab incision. Reapproximate the sternothyroid and sternohyoid, and carefully close the platysma and skin in layers.
Manage pain as needed. If a surgical drain is placed, the drain should remain in place until its output has sufficiently diminished.
Measure ionized calcium postoperatively; hypocalcemia may occur in patients who have undergone total thyroidectomy and may require calcium and vitamin D supplementation. Many institutions start patients on calcium carbonate supplementation postoperatively after total thyroidectomy. Hypocalcemia may present with perioral paresthesias or paresthesias of the hands. In a patient with hypocalcemia, tapping on the preauricular region overlying the trunk of the facial nerve may cause ipsilateral contraction of the face (Chvostek sign).
If the recurrent laryngeal nerve is damaged intraoperatively, there is some data to suggest that postoperative nimodipine and steroids may shorten the nerve’s time to recovery. [59]
Overview
What is the clinical background of thyroid cancer?
What is the prevalence of thyroid cancer in the US?
What causes thyroid cancer?
What is thyroid cancer?
What are the signs and symptoms of thyroid cancer?
What is included in the physical exam of suspected thyroid cancer?
What is the role of fine-needle aspiration biopsy (FNAB) in the diagnosis of thyroid cancer?
What is the role of lab testing in the diagnosis of thyroid cancer?
What is the role of imaging studies in the diagnosis of thyroid cancer?
What is are the ATA guidelines for preoperative imaging for thyroid cancer surgery?
How is thyroid cancer treated?
How is differentiated thyroid cancer treated?
What are the ATA treatment guidelines for recurrent differentiated thyroid cancer?
How is Hürthle cell carcinoma thyroid cancer treated?
How is medullary thyroid carcinomas (MTC) treated?
How is anaplastic thyroid carcinoma treated?
What is included in postsurgical management of thyroid cancer?
Which clinical history findings are characteristic of thyroid cancer?
What is included in the physical exam for thyroid cancer?
Which physical findings are characteristic of thyroid cancer?
Which tests are included in the evaluation of solitary thyroid nodules for thyroid cancer?
What are the ATA guidelines on preoperative imaging for thyroid cancer surgery?
What is the role of fine-needle aspiration biopsy (FNAB) in the evaluation of thyroid cancer?
How are the results fine-needle aspiration biopsy (FNAB) used in the diagnosis and treatment of thyroid cancer?
What are the possible complications of FNAB for the diagnosis of thyroid cancer?
What is the role of lab testing in the diagnosis of thyroid cancer?
What is the role of imaging studies in the diagnosis of thyroid cancer?
What are the ATA treatment guidelines for differentiated thyroid cancer?
What is papillary carcinoma in patients with thyroid cancer?
What is the pathology of papillary carcinoma in patients with thyroid cancer?
How does papillary carcinoma progress in patients with thyroid cancer and how is it treated?
What is follicular carcinoma in patients with thyroid cancer?
What is the pathology of follicular carcinoma in patients with thyroid cancer?
How does follicular carcinoma progress in patients with thyroid cancer?
What is the role of surgery in the treatment of well-differentiated thyroid cancer?
What is included in the management of the neck in patients with thyroid cancer?
What is the role of postoperative radioiodine scanning and ablation in the treatment of thyroid cancer?
What is the role of thyroid suppression in the treatment of thyroid cancer?
What is included in long-term monitoring of thyroid cancer?
What is the role of pharmacologic therapy in the treatment of thyroid cancer?
How is recurrent thyroid cancer treated?
What is the prognosis of thyroid cancer?
What is Hürthle cell carcinoma in patients with thyroid cancer?
How is Hürthle cell carcinoma treated in patients with thyroid cancer?
What is the prognosis of Hürthle cell carcinoma?
What is the pathology of Hürthle cell carcinoma in patients with thyroid cancer?
What is medullary thyroid carcinoma (MTC)?
What are the signs and symptoms of medullary thyroid carcinoma (MTC)?
What is the role of genetic testing in the diagnosis of medullary thyroid carcinomas (MTC)?
What is the role of biochemical testing in the diagnosis of medullary thyroid carcinoma (MTC)?
What is the pathology of medullary thyroid carcinoma (MTC)?
How is medullary thyroid carcinoma (MTC) treated?
When is prophylactic thyroidectomy indicated in the treatment of thyroid cancer?
What is included in long-term monitoring of medullary thyroid carcinoma (MTC)?
What is the prognosis of medullary thyroid carcinoma (MTC)?
What is anaplastic thyroid carcinoma?
What is the pathology of anaplastic thyroid carcinoma?
How is anaplastic thyroid carcinoma treated?
What is the prognosis of anaplastic thyroid carcinoma?
What is primary thyroid lymphoma?
How is primary thyroid lymphoma treated?
What is the prognosis of primary thyroid lymphoma?
What is sarcoma of the thyroid gland and how is it treated?
What is the role of surgery in the treatment of thyroid cancer?
When is thyroid lobectomy indicated for the treatment of thyroid cancer?
When is total thyroidectomy indicated in the treatment of thyroid cancer?
What is included in the preoperative planning of thyroidectomy for thyroid cancer?
How is thyroidectomy performed for thyroid cancer?
What is included in the postoperative care following thyroidectomy for thyroid cancer?
Which findings on ultrasound are characteristic of follicular thyroid cancer?
Which organizations have released guidelines for the diagnosis and management of thyroid cancer?
What are the diagnostic guidelines for thyroid cancer?
What are the ATA guidelines for the use of FNAB in the diagnosis of thyroid cancer?
What are the NCCN guidelines for the use of FNAB in the diagnosis of thyroid cancer?
What are the AACE/ACE/AME guidelines for the use of FNAB in the diagnosis of thyroid cancer?
What are ATA diagnostic guidelines for differentiated thyroid cancer?
Which findings on ultrasound are characteristic of papillary thyroid cancer?
Which findings on ultrasound are characteristic of benign thyroid nodules?
What is the Bethesda system for assessing malignancy risk in thyroid cancer?
What are the NCCN guidelines for assessing malignancy risk in thyroid cancer?
What are the ATA diagnostic guidelines for medullary thyroid carcinoma?
What are the NCCN diagnostic guidelines for medullary thyroid carcinoma?
What are the NCCN treatment guidelines for differentiated thyroid cancers?
What are the NCCN treatment guidelines for papillary thyroid carcinoma?
What are the ATA treatment guidelines for papillary thyroid carcinoma?
What are the ATA treatment guidelines for follicular thyroid cancer and Hürthle cell carcinoma?
What are the NCCN treatment guidelines for follicular thyroid cancer and Hürthle cell carcinoma?
What is the role of radioiodine therapy in the management of thyroid cancer?
What are the guidelines for use of radioiodine therapy to treat thyroid cancer?
What are the guidelines for use of levothyroxine in the treatment of thyroid cancer?
What are the NCCN treatment guidelines for medullary thyroid carcinoma (MTC)?
What are the guidelines for the treatment for anaplastic thyroid cancer, and what are the guidelines from the Japan Association of Endocrine Surgeons?
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David Goldenberg, MD, FACS Professor and Chair, Department of Otolaryngology-Head and Neck Surgery, Penn State Hershey Medical Center and Penn State College of Medicine; Vice President, Otolaryngology-Head and Neck Surgery Services, Penn State Health
David Goldenberg, MD, FACS is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, American Head and Neck Society, American Thyroid Association, Association of Academic Departments of Otolaryngology-Head and Neck Surgery, Penn State Cancer Institute, Pennsylvania Academy of Otolaryngology-Head and Neck Surgery, The Triological Society
Disclosure: Nothing to disclose.
Alyssa K Givens, MD Resident Physician, Department of Otolaryngology-Head and Neck Surgery, Penn State Milton S Hershey Medical Center
Alyssa K Givens, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Nader Sadeghi, MD, FRCSC Professor and Chairman, Department of Otolaryngology-Head and Neck Surgery, McGill University Faculty of Medicine; Chief Otolaryngologist, MUHC; Director, McGill Head and Neck Cancer Program, Royal Victoria Hospital, Canada
Nader Sadeghi, MD, FRCSC is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American Head and Neck Society, American Thyroid Association, Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.
Arlen D Meyers, MD, MBA Emeritus Professor of Otolaryngology, Dentistry, and Engineering, University of Colorado School of Medicine
Arlen D Meyers, MD, MBA is a member of the following medical societies: American Academy of Facial Plastic and Reconstructive Surgery, American Academy of Otolaryngology-Head and Neck Surgery, American Head and Neck Society
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Cerescan; Neosoma; MI10;<br/>Received income in an amount equal to or greater than $250 from: Neosoma; Cyberionix (CYBX)<br/>Received ownership interest from Cerescan for consulting for: Neosoma, MI10 advisor.
Michael M Johns, MD Director of USC Voice Center, Division Director of Laryngology, Professor, USC Tina and Rick Caruso Department of Otolaryngology-Head and Neck Surgery, Keck School of Medicine of the University of Southern California
Michael M Johns, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Otolaryngology-Head and Neck Surgery, American Bronchoesophagological Association, Phi Beta Kappa, Voice Foundation
Disclosure: Nothing to disclose.
Pramod K Sharma, MD Consulting Staff, Ear, Nose and Throat Center
Pramod K Sharma, MD is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American College of Surgeons, American Head and Neck Society, The Triological Society, American Medical Association, American Rhinologic Society, Society of University Otolaryngologists-Head and Neck Surgeons, Utah Medical Association
Disclosure: Nothing to disclose.
Samia Nawaz, MBBS, MD Associate Professor, Department of Pathology, University of Colorado Health Science Center
Samia Nawaz, MBBS, MD is a member of the following medical societies: American Society for Clinical Pathology, American Society of Cytopathology, International Academy of Pathology
Disclosure: Nothing to disclose.
Kemp M Anderson, MD Resident Physician, Department of Surgery, Keck School of Medicine of the University of Southern California
Kemp M Anderson, MD is a member of the following medical societies: Gold Humanism Honor Society
Disclosure: Nothing to disclose.