Hurthle Cell Carcinoma

Background

Hürthle cell carcinoma of the thyroid gland is an unusual and relatively rare type of differentiated thyroid cancer. Hürthle cell cancer accounts for only about 3-10% of all differentiated thyroid cancers; therefore, few institutions have extensive experience with Hürthle cell neoplasms. According to the World Health Organization (WHO), these neoplasms are considered a variant of follicular carcinoma of the thyroid and are referred to as follicular carcinoma, oxyphilic type. See the image below.

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A monomorphous cell population of Hürthle cells arranged in loosely cohesive clusters and single cells. The cells are polyhedral and have abundant gra....

Some investigators believe that this condition is distinct from other follicular cell neoplasms. Hürthle cells are observed in both neoplastic and nonneoplastic conditions of the thyroid gland (eg, Hashimoto thyroiditis, nodular and toxic goiter).

Oncocytic cells in the thyroid are often called Hürthle cells, and oncocytic change is defined as cellular enlargement characterized by an abundant eosinophilic granular cytoplasm as a result of accumulation of altered mitochondria. This is a phenomenon of metaplasia that occurs in inflammatory disorders, such as thyroiditis, or other situations that result in cellular stress. The proliferation of oncocytes gives rise to hyperplastic and neoplastic nodules.^[1] The cytological features for Hürthle cell neoplasms are hypercellularity with a predominance of Hürthle cells (usually >75%), few or no lymphocytes, and scanty or absent colloid.

Hürthle cells were first described by Askanasy in 1898, in patients with Graves disease; however, these cells were mistakenly named for the German physiologist Karl Hürthle, who actually described the interfollicular C-cell.^[2] Hürthle cells are large and polygonal in shape, with indistinct cell borders. They have a large pleomorphic hyperchromatic nucleus, a prominent nucleolus, and intensely pink, fine, granular cytoplasm with hematoxylin-eosin staining.

Hürthle cells are also found in other tissues, such as the salivary gland, parathyroid gland, esophagus, pharynx, larynx, trachea, kidney, pituitary, and liver. Controversy exists about the origin of Hürthle cells, which generally are thought to derive from the follicular epithelium.

A Hürthle cell neoplasm is defined generally as an encapsulated thyroid lesion comprising at least 75% Hürthle cells. A benign neoplasm cannot be distinguished from a malignant neoplasm on the basis of cytologic analysis of fine-needle aspiration (FNA) biopsy. Features such as pleomorphism, anaplasia, hyperchromatism, and atypia are also observed in benign follicular adenomas; therefore, definitive differentiation of Hürthle cell carcinoma from Hürthle-cell adenoma is based on vascular invasion and/or capsular invasion, as well as on permanent histologic sections or extrathyroidal tumor spread and lymph node and systemic metastases.

In the literature, the incidence of malignancy in Hürthle-cell neoplasms is variable, ranging from 13-67%. Overall, only about 33% of Hürthle cell tumors demonstrate signs of that invasive growth that indicates malignancy and the possibility of metastasizing. On balance, Hürthle cell tumors may be considered to be more likely to metastasize than follicular tumors. The likelihood of nodal metastases is greater in Hürthle cell tumors than in follicular tumors; it is, however, not as great as with papillary tumors.

Permissive histologic interpretation may result in the designation of some non-neoplastic Hürthle cell lesions as malignant tumors. Obviously, this factor has a major impact in interpreting the natural history of this disease and adds to the controversy about the aggressiveness of Hürthle cell carcinoma. This leads to reported overall mortality rates ranging from 9-28%.

Tumor size is an important feature for biological behavior. A 1988 study found that a Hürthle tumor that is 4 cm or larger has an 80% chance of histologic evidence of malignancy.^[3] In another study by Pisanu et al,^[4] in a series of 23 patients, the mean tumor size was significantly greater for carcinomas than adenomas (3.1 cm vs 1.9 cm).

In another study done at Memorial Sloan-Kettering Cancer center,^[5] outcomes of 56 patients with Hürthle cell cancer were analyzed. In this study, recurrence was a significant predictor of tumor-related mortality, and the most significant predictor of outcome was extent of invasion. In addition, tumor size, extrathyroidal disease extension, and initial nodal or distant metastasis were found to be associated with an adverse outcome.^[6]

Hürthle cell cancer has the highest incidence of metastasis among the differentiated thyroid cancers. Metastatic disease is reported at the time of initial diagnosis in 10-20% of patients and in 34% of the patients overall. Metastasis usually occurs hematogenously, but lymph node metastasis is also not uncommon and typically involves the regional lymph nodes. Some studies suggest that lymph node metastases at initial diagnosis may not be an unfavorable prognostic factor.^[7] The lungs, bones, and central nervous system are the most prevalent sites of metastases.

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Pathophysiology

No widely accepted paradigm exists for the pathogenesis of follicular and Hürthle cell cancer of the thyroid. Some evidence suggests that a multistep adenoma-to-carcinoma pathway may be involved; however, this concept is not universally accepted. Many of the cells probably develop from preexisting adenomas, but a follicular carcinoma in situ is not recognized pathologically.

Progressive transformation through somatic mutations of genes that are important in growth control are involved in follicular thyroid cancer formation. Low iodide intake is a key environmental factor determining the relative incidence of follicular and papillary cancers. Most follicular adenomas and all follicular carcinomas are thought to have monoclonal origin.

Oncogene activation, particularly by mutation or translocation of the ras oncogene, is common in both follicular adenomas and follicular thyroid carcinomas (around 40%), supporting a role in early tumorigenesis. Such ras oncogene mutations are not specific for follicular tumors and also occur in papillary thyroid cancer (PTC). The ras oncogene is frequently involved in the pathogenesis of Hürthle cell tumors.

In papillary thyroid cancers and in many Hürthle cell tumors, RET rearrangements are found; these are not found in follicular tumors. Local spread may be found in RET-positive cases; RET-negative cases, as in follicular cancer cases, are more likely to spread through the bloodstream to distant metastatic sites.

An association also was found between overexpression of the p53 gene product and a subset of Hürthle cell carcinomas. Reduced immunoexpression of E-cadherin exists, with a trend to a diffuse cytoplasmic pattern, both in benign and malignant Hürthle cell tumors and in papillary, poorly differentiated, and undifferentiated thyroid carcinomas. Isolated studies indicate overexpression of the N-myc oncogene, tumor growth factor (TGF)-alpha, TGF-beta, insulinlike growth factor (IGF)-1, and somatostatin receptor in Hürthle cell carcinomas.

Cytogenetic abnormalities and evidence of genetic loss are more common in follicular thyroid cancer than in papillary thyroid cancer. These abnormalities occur in follicular adenomas, suggesting that cell cycle control, mitotic spindle formation, DNA repair, or more than one of these mechanisms may be impaired in these neoplasms, possibly at an earlier stage.

Activating mutations of genes encoding the thyrotropin receptor and the alpha subunit of the stimulatory G protein are also reported in some follicular carcinomas. These losses are associated particularly with chromosomes 3, 10, 11, and 17. The deletions and/or rearrangements involving the p (short) arm of chromosome 3 are the most common. Loss of a tumor suppressor on chromosome arm 3p has been postulated to be specific for follicular thyroid cancer and may be involved in adenoma-to-carcinoma progression.

Restriction fragment length polymorphism (RFLP) analysis demonstrates that unbalanced losses of genetic material are relatively common in Hürthle cell neoplasms. Loss of heterozygosity from the q (long) arm of chromosome 10 is also detected in oncocytic tumors. Evidence suggests that some Hürthle cell adenomas and carcinomas can express an RET/PTC gene arrangement, which is more unique to papillary thyroid carcinoma.

Because of this gene arrangement, another subclassification of Hürthle cell neoplasms has been proposed, namely the papillary variant of Hürthle cell cancer (ie, Hürthle cell papillary thyroid carcinoma), in addition to Hürthle cell cancer and adenoma. Clinically, tumors in this group tend to behave like papillary thyroid carcinoma; however, they are more indolent, with a propensity for lymph node metastasis rather than hematogenous spread. Maxwell et al reported that the Hürthle cell tumors with RET/PTC-positive gene arrangement have higher incidence of regional metastatic disease and more aggressive treatment has been recommended.^[8]

As reported by Asa, many Hürthle cell tumors, whether benign or malignant, show papillary change. This is a pseudopapillary phenomenon because Hürthle cell tumors have only scant stroma and may fall apart during manipulation, fixation, and processing. True oxyphilic, or Hürthle cell, papillary carcinoma has been reported to comprise 1%-11% of all papillary carcinomas. These tumors have a papillary architecture but are composed predominantly, or entirely, of Hürthle cells.^[1]

Mitochondrion-related alterations, such as mutations in mitochondrial DNA, are also described in Hürthle cell tumors. Defects of cytochrome c oxidase and the deletion of mitochondrial DNA occur frequently in Hürthle cell tumors and in Hürthle cells of Hashimoto thyroiditis. In one study, almost all Hürthle cells displayed a common deletion, somatic mitochondrial point mutations, or both.^[9] Activating gene mutations encoding the thyrotropin receptor and the alpha subunit of the stimulatory G protein are also reported in some follicular carcinomas.

DNA content profiles after flow cytometry are commonly abnormal. Hürthle cell neoplasms, including histologically benign tumors, are often aneuploid. This finding parallels with nuclear atypia and anisocytosis. The demonstration of aneuploidy may be a marker for a particularly aggressive clinical behavior compared with euploid tumors. In a recent Italian study, p27 and cyclin D3 proteins were found to be overexpressed in Hürthle cell carcinoma cell lines and clinical samples of thyroid cancer.^[10] The accumulation of p27 was found to be associated to the overexpression of cyclin D3 in Hürthle cell carcinoma of the thyroid.

A study analyzing genomic dissection of Hurthle cell carcinoma indicated that Hurthle cell carcinoma could be a unique type of malignancy. In this study, unsupervised hierarchical clustering of gene expression showed 3 groups of Hurthle cell tumors; Hurthle cell adenomas, minimally invasive Hurthle cell carcinoma, and widely invasive Hurthle cell carcinoma. These are clustered separately, with a marked difference between widely invasive Hurthle cell carcinoma and Hurthle cell adenoma. Molecular pathways that differentiate Hurthle cell adenomas from widely invasive Hurthle cell carcinomas included the PIK3CA-Akt-mTOR and Wnt/β -catenin pathways, potentially providing a rationale for new targets for the treatment of this type of thyroid carcinoma.^[11]

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Epidemiology

Frequency

United States

Hürthle cell carcinomas account for about 3%-10% of thyroid cancer cases. On the whole, thyroid cancer is uncommon, with an average age-adjusted annual incidence of fewer than 40 cases per 1 million population. However, while thyroid cancer accounts for only 0.74% of all cancers in men, it is the fifth most common cancer in woman, accounting for 5% of all new cancer cases, and is the most commonly diagnosed cancer in women 20 to 34 years of age.^[12]

Thyroid cancer is the most rapidly increasing cancer in the US, with rates rising by about 5% per year from 2004 to 2013, However, much of the increase has been attributed to increased detection because of more sensitive diagnostic procedures, and the magnitude of the increase appears to have slowed in recent years.^[12]

For thyroid cancers as a whole, in the United States for 2017, 56,870 new cases are projected; 42, 470 in females and 14,400 in males. The number of estimated deaths is 2010 (1090 in females and 920 in males).^[12]

International

Worldwide, thyroid cancer rates have been increasing over the past few decades.^[12] International frequency likely approximates that of the United States. In general, the annual incidence of thyroid cancer in various parts of the world is 0.5-10 cases per 100,000 population. As in the US, approximately 3%-10% of these cases are Hürthle cell carcinomas.

Mortality/Morbidity

Hürthle cell cancer reportedly behaves in a more aggressive fashion than other well-differentiated thyroid cancers, with a tendency to higher frequency of metastasis and a lower survival rate. This is truer for the lesions that are clearly demonstrated to be malignant and in patients who are considered to be at high risk based on such factors as age, tumor size, invasiveness, and the presence of metastasis. Widely invasive tumors behave more aggressively. Recurrent Hürthle cell carcinomas are considered to be incurable.

Ghossein et al at Memorial Sloan Kettering Cancer center reported that in encapsulated ("minimally invasive") Hürthle cell carcinomas, the extent of vascular invasion strongly correlated with recurrence. Presence of mitosis and a solid/trabecular tumor growth pattern also correlated with higher risk of recurrence.^[13]

Mortality rates vary in different series, based on the staging systems used, which consider the patient's age, tumor size, extrathyroidal tumor spread, pathologic classification of the neoplasm (Hürthle cell carcinoma versus adenoma), and the therapeutic approach.

Overall survival rates reportedly are similar or worse in patients with Hürthle cell carcinoma compared with rates for persons with follicular carcinoma. In a case series of Hürthle cell carcinoma, mortality rates at 5, 10, and 20 years were 8%, 18%, and 33%, respectively. Two other case series confirmed a 20-year cause-specific mortality rate of 20-35%. One study showed that when distant metastases were present, the 5-year mortality rate was 65%.^[14] Another study involving 33 patients showed that disease-free survival was 65% in 5 years and 40.5% in 10 years.^[15]

In a study of 108 patients with metastatic Hürthle cell thyroid carcinoma, Besic et al reported that sites of metastasis, in decreasing order of frequency, were lung, bone, mediastinum, kidney, and liver. Overall 10-year disease-specific survival was 60%. Median disease-specific survival after the diagnosis of metastatic disease was 72 months for patients with pulmonary metastases and 138 months for patients with metastases at other sites.^[16]

Morbidity depends on the behavior of the Hürthle cell carcinoma.

Race- and age-related demographics.

All races appear to be affected equally. The typical age range of patients presenting with this condition is 20-85 years. The mean age is usually 50-60 years, approximately 10 years older than the age associated with other types of differentiated thyroid cancers.

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History

The history in patients with a thyroid nodule or a known follicular or Hürthle cell neoplasm is neither sensitive nor specific for a diagnosis of malignancy. However, the following clinical features are more suggestive of malignancy:

• A palpable mass in the thyroid (most common clinical sign)
• Symptoms of pressure (eg, dysphagia, dyspnea, coughing, choking spells, hoarseness)
• Rapid growth or significant compressive symptoms
• Pain

Other features of Hürthle cell carcinoma are as follows:

• Hürthle cell carcinoma is more often multifocal and bilateral
• Lymph node metastasis and symptoms confined to metastatic sites can be the first clinical presentation in a subgroup of cases
• A history of head and neck external beam irradiation should alert the clinician to a possible malignancy; multifocal and bilateral disease is more common in such cases
• A family history of thyroid cancer and endocrinopathies can also be present
• Patients are usually euthyroid, but hyperthyroidism or hypothyroidism occurs in a small percentage of patients

Other benign thyroid and parathyroid disorders can be observed, as follows:

• Graves disease
• Colloid nodular disease
• Lymphocytic thyroiditis
• Thyroid hyperplasia
• Parathyroid adenoma
• Follicular adenomas

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Physical

The most common physical examination finding is a palpable single neck mass. (However, the contralateral lobe may harbor impalpable malignancy in such cases.) Less often, patients may have multiple palpable masses. Other findings on physical examination may include the following:

• Regional lymph nodes may sometimes be felt in the neck and locoregionally, although this is not as common as in papillary carcinoma
• The trachea can be compressed and deviated secondary to the mass effect of the tumor
• Hoarseness can occur if vocal cord involvement is present
• Horner syndrome can be present in patients with involvement of the cervical sympathetic ganglia
• If the tumor extends into the upper mediastinum behind the sternum, the superior mediastinal syndrome may ensue, with facial swelling, and dilated veins can be observed
• A hard, fixed thyroid nodule, cervical lymphadenopathy, and vocal cord paralysis are features that may indicate carcinoma
• Physical findings of metastases and pathologic bone fractures may also be found in long and flat bones
• Most patients with Hürthle cell cancer and Hürthle cell adenomas are euthyroid, but in rare cases, signs of thyrotoxicosis may be present; either massive tumor burden or functioning metastatic disease causes thyrotoxicosis

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Causes

Etiologic factors in Hürthle cell carcinomas include the following:

• Radiation to the neck
• Iodide deficiency
• Overexpression of the p53 oncogene
• Activating mutations of genes encoding the thyrotropin receptor and the alpha subunit of the stimulatory of G protein are reported in some follicular carcinomas
• Somatic mutations of genes important in growth control
• Oncogene activation, particularly by mutation or translocation of the ras oncogene
• Mitochondrion-related alterations (eg, mutations in mitochondrial DNA) also are described.

A study by Maximo et al linked somatic and germline mutation in GRIM-19 (a dual-function gene involved in mitochondrial metabolism and cell death) to Hürthle cell tumors of the thyroid. This is the first nuclear gene mutation described for a subgroup of Hürthle cell carcinomas.^[17]

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Laboratory Studies

A full set of thyroid function tests should be ordered, including the following:

• Thyroid-stimulating hormone (TSH)
• Thyroxine (T4)
• Triiodothyronine (T3)
• Free T4

In addition, the following antibody studies should be ordered:

• Antiperoxidase antibodies
• Antithyroglobulin antibodies

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Imaging Studies

Imaging study findings are as follows:

• Thyroid uptake and scan: Typical finding is an area of decreased uptake, which corresponds to the tumor
• Thyroid ultrasound: Ultrasound usually demonstrates a solid mass, as well as characterizes the solid/cystic nature of the lesion, and is also helpful in diagnosing enlarged lymph nodes in the neck
• MRI of the neck: MRI will provide more detailed information about the tumor and its relation to the other neck structures
• CT scan of the neck: CT scan provides more detailed information about the tumor and its relation to the other neck structures. CT scan is also helpful for assessment of calcifications
• Octreotide scintigraphy: This study can be considered for patients with metastatic Hürthle cell carcinoma because evidence suggests that some Hürthle cell neoplasms can express somatostatin receptors.

Positron emission tomography with ¹⁸F-2-fluoro-2-deoxy-D-glucose (18F-FDG PET) has been shown to be helpful in diagnosing metastatic disease in Hürthle cell carcinomas, particularly with tumors that have low iodine avidity. In a study by Pryma et al, 18F-FDG PET was shown to increase diagnostic accuracy over CT and radioactive iodine scan. In addition, in this study, intense 18F-FDG uptake in lesions were an indicator of poor prognosis.^[18]

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Fine-Needle Aspiration

Cytologic analysis of fine-needle aspiration (FNA) specimens can diagnose Hürthle cell neoplasm in most patients. However, FNA cannot differentiate Hürthle cell adenoma from Hürthle cell carcinoma, because it does not permit assessment of vascular and capsular invasion, which are the two main factors that differentiate carcinoma from adenoma.

In a study of 139 Hürthle cell lesions, Elliott et al found that the presence of all four of the following cytological features correctly identified Hürthle cell neopla in 86% of cases^[19] :

• Nonmacrofollicular architecture
• Absence of colloid
• Absence of inflammation
• Presence of transgressing blood vessels

MicroRNA expression array has identified novel diagnostic markers in FNA samples for conventional and oncocytic follicular thyroid carcinomas. In this study, novel miR-885-5p was strongly upregulated (>40 fold) in oncocytic follicular carcinomas compared with conventional follicular carcinomas, follicular adenomas, and hyperplastic nodules.^[20]

A test that measures the expression of 167 genes may help determine whether a cytologically indeterminate thyroid nodule is benign, and thus may be considered for more conservative treatment. In their study of 265 indeterminate nodules 1 cm or larger, Alexander et al reported that gene-expression classifier testing correctly identified 78 of 85 nodules as suspicious (92% sensitivity; 52% specificity). The negative predictive value of follicular neoplasm or lesion was 94%. Analysis of the aspirates with false-negative results showed that six of the seven had a paucity of thyroid follicular cells, suggesting insufficient sampling of the nodule.^[21]   

 In this study, 10 malignant Hurthle cell nodules were present, and 9 were correctly identified as malignant (90%). Twenty one were benign Hurthle-cell adenomas, and 17 of them were correctly identified (81%).^[21]

A study by Donatini et al concluded that the cellular proliferation index (Ki67) and GRIM-19, a protein involved in cell proliferation and apoptosis, are potential cytological markers of malignancy in Hürthle cell carcinoma. Compared with adenomas, carcinomas showed elevated Ki67 (p = 0.0004) and reduced expression of GRIM-19 (p = 0.005).^[22]     

Nevertheless, until more accurate methods to differentiate benign nodules from malignant ones are available, all patients with the cytologic diagnosis of a Hürthle cell tumor should proceed to surgery to ensure that the carcinomas are identified and managed appropria.  Additionally, as with any other thyroid neoplasm, one must take into account the tumor's size, calcification, echogenicity, and vascularity when considering whether to perform hemithyroidectomy or total thyroidectomy, or to choose observation.

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Histologic Findings

Common histological malignancy criteria, such as architectural distortion, cellular atypia, or pleomorphism, are encountered in both benign and malignant follicular adenomas; these histological criteria are not helpful while evaluating a thyroid mass.

The cytologic features for Hürthle cell neoplasms are hypercellularity, with a predominance of Hürthle cells usually above 75%, few or no lymphocytes, and scanty or absent colloid. Hürthle cells are large and polygonal in shape, with indistinct cell borders. They have a large pleomorphic hyperchromatic nucleus, a prominent nucleolus, and intensely pink fine granular cytoplasm with hematoxylin-eosin staining. See the image below.

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A monomorphous cell population of Hürthle cells arranged in loosely cohesive clusters and single cells. The cells are polyhedral and have abundant gra....

Papillary structures and intranuclear inclusions, features that are not ordinarily associated with Hürthle cell lesions, are occasionally noted. The electron microscopic examination of Hürthle cells in tumor formation is unique, revealing a large cytoplasm that is almost completely filled with mitochondria. This examination also reveals large lysosomelike dense bodies and dilated Golgi zones confined to the apical portion of the cytoplasm. Unusual richness of chromatin is clumped against the inner nuclear membrane and nuclei that are observed as round and dense, with separation of fibrillar and granular substances.

Histopathologic differentiation of Hürthle cell carcinoma from Hürthle cell adenoma is based on vascular and capsular invasion. Capsular invasion refers to tumor cell penetration of the capsule of the neoplasm. Vascular invasion is defined by the presence of tumor penetration of blood vessels within or outside of the capsule of the Hürthle cell lesion. Capsular invasion, vascular invasion, or both diagnose Hürthle cell carcinoma.

Benign diseases (eg, Hashimoto disease, nodular goiter, toxic goiter) usually have no encapsulation. Hürthle cell changes are part of an inflammatory process.

In a study by Volante et al, the role of galectin-3 and HBME-1 (an antimesothelial monoclonal antibody that recognizes an unknown antigen on microvilli of mesothelial cells) tumor markers, as well as the peroxisome proliferator-activated receptor (PPAR) gamma protein expression, were assessed in oncocytic Hürthle cell tumors, including Hürthle cell adenomas, Hürthle cell carcinomas, and an oncocytic variant of papillary carcinoma. In these 152 Hürthle cell tumors (50 Hürthle cell adenomas, 70 Hürthle cell carcinomas, and 32 oncocytic variant of papillary carcinoma), the sensitivity of galectin-3 was 95.1%, the sensitivity of HBME-1 was 53%, and a combination of galectin-3 and HBME-1 was high at 99%. However, the specificity for both markers was 88%, lower than for nononcocytic follicular tumors.^[23]

Interestingly, PPAR gamma protein overexpression was absent in all Hürthle cell adenomas tested and present in only 10% of Hürthle cell carcinomas, similar to other reports that confirm the low prevalence of PAX8-PPAR gamma translocations in Hürthle cell carcinomas.

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Staging

Different prognostic criteria and staging systems are used in differentiating thyroid cancer and Hürthle cell cancer. No uniformly accepted staging system and prognostic classification exists for Hürthle cell carcinoma.

The tumor, node, metastases (TNM) system is the most widely used staging system, as depicted in the image below. Most classification systems used in the evaluation of patients with Hürthle cell carcinoma consider such factors as tumor size, patient age, presence of metastases, and major capsular invasion (extensive capsular invasion in multiple sites). The other classification systems used for assessing Hürthle cell carcinoma are conducted with scoring systems, using the generally accepted prognostic factors, such as age, metastasis, extent of disease at operation, and size (AMES) and age, grade, extent, and size (AGES). See the image below.

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Tumor, lymph node, metastases (TNM) staging system for papillary and follicular thyroid carcinoma.

See Thyroid Cancer Staging for additional information.

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Medical Care

Surgical excision is the main treatment for patients with Hürthle cell carcinoma. Postoperative iodine-131 (¹³¹I) scanning is usually performed 4-6 weeks after surgery. No thyroid hormone treatment is administered to the patient in the interim. If uptake occurs in the thyroid bed or other sites, a treatment dose of ¹³¹I is administered, and another total body scan is obtained 4-7 days later.

Radioactive iodine-131 treatment

This treatment is usually administered if postoperative iodine scanning shows uptake, in the thyroid bed or elsewhere.

¹³¹I therapy is used after surgery for three reasons. First, radioactive iodide destroys any remaining normal thyroid tissue, thereby enhancing the sensitivity of subsequent ¹³¹I total-body scanning and increasing the specificity of measurements of serum thyroglobulin for the detection of persistent or recurrent disease. Second, ¹³¹I therapy may destroy occult microscopic carcinoma. Third, the use of a large amount of ¹³¹I allows for total-body scanning, which is a more sensitive test for detecting persistent carcinoma.

Compared with other thyroid carcinomas, Hürthle cell cancer has a lower avidity for ¹³¹I; therefore, treatment with radioactive iodide has limited efficacy. Reportedly, approximately 10% of metastases take up radioiodine, compared with 75% of metastases from follicular carcinoma; thus, radioactive iodide treatment, which is the most useful nonsurgical therapy for recurrent well-differentiated thyroid carcinoma, is not always useful in patients with Hürthle cell carcinoma. This causes difficulty in the treatment of recurrences. Nevertheless, radioactive iodide treatment is used for most patients with Hürthle cell cancers after total and near-total thyroidectomy and in the treatment of patients with recurrent and metastatic Hürthle cell carcinoma.

Jillard et al reported that post-thyroidectomy ¹³¹I therapy improves survival in patients with Hürthle cell carcinoma. In their review of 1909 cases, patients who received ¹³¹I (n=1162) had superior 5-year and 10-year survival compared with patients who did not (88.9 vs. 83.1% and 74.4 vs. 65.0%, respectively, p < 0.001). These authors conclude that their finding suggest that radioactive iodine therapy should be advocated for patients with  tumors >2 cm, and those with nodal and distant metastatic disease.^[24]

There is limited evidence in the literature that redifferentiation therapy with retinoic acid may restore ¹³¹I uptake in some thyroid carcinomas that have lost their capability for radioiodine concentration; however, the benefits of this approach remain uncertain.^{[25, 26]} Retinoic acid therapy also may be considered in patients with Hürthle cell carcinoma that does not take up radioactive iodide, although this is not yet a standard form of therapy.

Levothyroxine treatment

The growth of thyroid tumor cells is controlled by thyroid-stimulating hormone (TSH), and the inhibition of TSH secretion with levothyroxine (T4) lowers recurrence rates and improves survival; therefore, T4 should be administered to all patients with thyroid carcinoma, regardless of the extent of thyroid surgery and other treatments.

Levothyroxine treatment is started after the treatment dose of ¹³¹I is administered. The effective dose of T4 in adults is 2.2-2.8 mcg/kg; children require higher doses. The adequacy of therapy is monitored by measuring serum TSH about 8-12 weeks after the treatment begins. The initial goal is a serum TSH concentration of 0.1 µU/mL or less and a serum triiodothyronine concentration within the reference range. When these guidelines are followed, T4 therapy does not have deleterious effects on the heart or bone.

External radiotherapy

Hürthle cell carcinoma is considered a radiosensitive tumor. Radiation therapy may provide palliative relief from symptomatic metastases, control recurrent tumors, and prevent recurrence of advanced resected tumors.^{[27, 28]}

External radiotherapy to the neck and mediastinum is indicated only in patients in whom surgical excision is incomplete or impossible. This therapy can also be considered for tumors that do not take up ¹³¹I.

Chemotherapy

Chemotherapy for metastatic differentiated thyroid cancer is usually ineffective. However, some experimental trials have yielded promising results

Over the past decade, good progress has been made in understanding molecular mechanisms of thyroid cancer; accordingly, multiple medications are being developed to target various molecules involved in the development of differentiated thyroid cancer. These targets are present both in the tumor cell as well as at the vascular endothelial cells providing blood supply to the tumor. The drugs include multikinase inhibitors, selective kinase inhibitors, and combination therapies. Examples include sorafenib, gefitinib, axitinib, motesanib, sunitinib, and pazopanib. Sorafenib is approved by the US Food and Drug Administration (FDA) for advanced differentiated thyroid cancer.^[29]

Younes et al have studied antivascular therapy in mouse models with bone metastasis from follicular thyroid cancer.^{[30, 31]} In these studies, a novel dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGFR) was used alone and in combination with paclitaxel. These studies showed suppression of tumor growth, with promising outcomes.

A treatment algorithm can be viewed at the National Comprehensive Cancer Network’s Thyroid Carcinoma clinical practice guideline. See Thyroid Cancer Treatment Protocols for summarized information.

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Surgical Care

Surgery is the main treatment for patients with Hürthle cell carcinoma. Surgical treatment is aimed at removal of the entire cancer, thereby minimizing the risk of locally persistent or recurrent disease, providing adequate staging information, minimizing risk without compromise to optimal cancer management, improving efforts for postoperative adjunctive treatment (eg, radioactive iodide), and facilitating follow-up care.

Total thyroidectomy is usually recommended for patients with Hürthle cell carcinomas, whereas patients with Hürthle cell adenomas are generally treated with a thyroid lobectomy.

Although total thyroidectomy is generally considered the treatment of choice for Hürthle cell carcinoma, a lobectomy is usually performed first; if histologic sections show Hürthle cell carcinoma, as evidenced by vascular and/or capsular invasion, then a complete thyroidectomy is performed in a second surgery. In clinically high-risk cases and in some institutions, a total thyroidectomy is performed as the first surgery based on frozen section results. Unfortunately, the majority of series have insufficient numbers of patients to allow statistically valid conclusions regarding which of those approaches should become the standard.

Intraoperative frozen section examination of the thyroid gland has variable diagnostic value, based on institutional experience. This procedure requires processing of an average of 6-15 slides per patient, which is impractical in many institutions. Other limitations include the following:

• Sampling error
• Variable thickness
• Irregularity of the capsule
• Freezing artifact
• Difficulty in distinguishing capsular entrapment from invasion
• Freezing-induced distortion and collapse of the blood vessels.

Frozen section provides no additional value in most studies. However, in one study, the diagnosis of malignant follicular or Hürthle cell carcinoma was established correctly in 78% of cases, thereby permitting immediate definitive surgical management and eliminating the need for two-stage operations.^[32]

Standard surgical wound care is usually appropriate. Postoperative care includes careful monitoring for the following:

• Infection
• Hematoma
• Signs of recurrent laryngeal nerve injury (eg, hoarseness)
• Airway compromise
• Signs of hypoparathyroidism and hypocalcemia

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Consultations

Management of thyroid cancer is a team effort, and the following consultations should be obtained:

• Endocrinologist
• Surgeon
• Nuclear medicine specialist
• Pathologist
• Radiation oncologist

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Diet and Activity

No particular diet is recommended, but an iodide-free diet is recommended at least 1 week prior to scanning to minimize the interference. Activity may be performed as tolerated.

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Guidelines Summary

Guidelines Contributor: Kemp M Anderson Medical University of South Carolina College of Medicine

The following organizations have released guidelines for the diagnosis and/or management of thyroid cancer:

• American Thyroid Association (ATA)^[33]
• National Comprehensive Cancer Network (NCCN)^[34]
• American Association of Clinical Endocrinologists/Associazione Medici Endocrinologi/European Thyroid Association (AACE/AME/ETA^[35]  (diagnosis only)

Diagnosis

All the guidelines advocate ultrasound (US) evaluation of thyroid nodules along with measurement of serum thyroid-stimulating hormone (TSH) levels to determine whether a fine needle aspiration biopsy (FNAB) is indicated. A routine measurement of serum thyroglobulin (Tg) for the initial evaluation of thyroid nodules is not recommended because Tg levels are elevated in most benign thyroid conditions.^{[33, 34, 35]}

Although all the guidelines recommend FNAB as the procedure of choice in the evaluation of solid thyroid nodules, there is variance in the size of the nodule as an indication for FNAB.^{[33, 34, 35]} AACE/AME/ETA indications for FNAB according to size are as follows^[35] :

• Lesions ≥10 mm with high-risk US features
• Lesions ≥20 mm with intermediate-risk US features
• Lesions >20 mm with low-risk US features, but that are increasing in size or associated with a risk history and before thyroid surgery or minimally invasive ablation therapy

Other guidelines provide the following recommendations:

• >0.5 cm in diameter (ATA)^[33]
• ≥1 cm if suspicious sonographic features are present; ≥1.5 cm if no suspicious sonographic features are present (NCCN)^[34]

AACE/AME/ETA and NCCN suggest a serum calcitonin assay as an optional test,^{[34, 35]}  but the ATA guidelines make no recommendation on the routine measurement of serum calcitonin because of insufficient evidence. ^[33]  All three guidelines recommend radionuclide imaging in patients with a low TSH level.^{[33, 34, 35]}

Differentiated thyroid cancers arise from thyroid follicular epithelial cells and constitute 90% of all thyroid cancers. The subtypes and approximate frequencies of differentiated thyroid cancers are as follows:

• Papillary – 85%
• Follicular – 10%
• Hürthle or oxyphil – 5%

ATA guidelines state that FNAB provides the most economical and accurate methodology for diagnosing differentiated thyroid cancers. Due to potential false negatives or sampling error, it is recommended that FNAB procedures be performed under ultrasound (US) guidance. US guidance is particularly important for nodules located posteriorly and for those that are difficult to palpate. Additionally, certain features found on US examination are predictive for malignancy and may guide FNAB decision-making.^[33]  

Papillary thyroid cancer is characterized by the following US features:

• Solid or predominantly solid
• Hypo-echoic
• Microcalcifications (highly specific)
• Infiltrative irregular margins (common)
• Increased nodular vascularity

Follicular thyroid cancer is characterized by the following US features:

• Iso- to hyper-echoic
• Thick irregular halo

Benign US features are as follows:

• Purely cystic nodule
• Spongiform appearance (aggregation of multiple micro-cystic components >50% volume)

Malignancy risk

Cytological analysis of FNAB specimens is used to estimate malignancy risk. The most appropriate cytological classification of malignancy risk is the Bethesda system for thyroid cytopathology, which comprises the following categories^[36] :

• Malignant (risk 97-99%)
• Suspicious for malignancy (risk 60-75%)
• Follicular neoplasm or suspicious for follicular neoplasm (risk 15-30%)
• Atypia of undetermined significance or follicular lesion of undetermined significance (risk 5-15% based on repeated atypicals)
• Non-diagnostic or unsatisfactory (risk 1-4%)
• Benign (risk 0-3%)

For cytology “diagnostic of” or “suspicious for” papillary thyroid cancer, surgery is recommended.^[33]

If FNAB cytology is indeterminate, the use of molecular markers such as BRAF, RAS, RET/PTC, Pax8-PPARɣ, or galectin-3 may be considered to guide management.^[33]

An iodine-123 (¹²³I) thyroid scan may be considered if the cytology report documents a follicular neoplasm, especially if serum thyroid-stimulating hormone (TSH) is in the low-normal range^[33] . No radionuclide scan is needed for a reading of “suspicious for papillary carcinoma” or “Hürthle cell neoplasm”, as either lobectomy or total thyroidectomy is recommended depending on the nodule size and risk factors.^[33]

The NCCN recommends that FNAB should be the primary test for differentiated thyroid cancer. If FNAB reveals papillary carcinoma, follicular neoplasm, follicular lesion of undetermined significance, or Hürthle cell neoplasm, the following diagnostic recommendations should be undertaken (these are uniform for all differentiated thyroid carcinomas)^[34] :

• Thyroid and neck ultrasound (including central and lateral compartments) if not previously done
• Computed tomography (CT)/magnetic resonance imaging (MRI) for fixed, bulky, or substernal lesions (iodinated contrast optimal for cervical imaging)
• Consider evaluation of vocal cord mobility

• References

Treatment

The ATA does not have comprehensive guidelines for the treatment of follicular thyroid cancer (FTC) and Hürthle cell carcinoma as separate entities from papillary thyroid cancer; however, there are several individual recommendations that apply decision-making principles to these conditions.^[33]

The ATA recommends that if cytology readings report a follicular neoplasm, an ¹²³I thyroid scan may be considered, especially if serum thyroid-stimulating hormone (TSH) is in a low-normal range. If a concordant autonomously functioning nodule is not seen, lobectomy or total thyroidectomy should be considered.

If the cytology report indicates “Hürthle cell neoplasm” or “suspicious for papillary carcinoma”, the ATA recommends a lobectomy or thyroidectomy, depending on nodule size and other risk factors.

For patients with an isolated indeterminate (“follicular neoplasm” or “Hürthle cell neoplasm”) solitary nodule who prefer a more limited approach, the ATA recommends an initial lobectomy.

The ATA recommends a total thyroidectomy for patients with indeterminate nodules in any of the following situations:

• The tumor exceeds 4 cm
• Marked atypia is observed
• Biopsy result is reported as “suspicious for papillary carcinoma”
• The patient has a family history of thyroid carcinoma
• The patient has a history of radiation exposure

The ATA recommends that patients with indeterminate nodules who have bilateral nodular disease or who wish to avoid future surgery should undergo total or near-total thyroidectomy.^[33]

The treatment of choice for differentiated thyroid cancers is surgery, whenever possible, followed by radioiodine (¹³¹I) in selected patients and thyrotropin suppression in most patients, according to the National Comprehensive Cancer Network (NCCN) guidelines.^[5]

The NCCN guidelines recommend lobectomy plus isthmusectomy as the initial surgery for patients with follicular neoplasms and Hürthle cell carcinomas, with prompt completion of thyroidectomy if invasive cancer is found on the final histologic section. Therapeutic neck dissection of involved compartments is recommended for clinically apparent/biopsy-proven disease.

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.^[34]

Radioiodine Therapy

NCCN guidelines recommend radioiodine (¹³¹I) therapy if any of the following are present^[34] :

• Extrathyroidal extension
• Tumor >4 cm in diameter
• Postoperative unstimulated thyroglobulin (Tg) level >5-10 ng/mL

Radioiodine therapy is not recommended if all of the following are present^[34] :

• Classic papillary thyroid carcinoma (PTC)
• Primary tumor < 1 cm
• Intrathyroidal tumor
• Unifocal or multifocal tumor
• No detectable anti-Tg antibodies
• Postoperative unstimulated Tg< 1 ng/mL

Radioiodine therapy is selectively recommended if any of the following are present when the combination of clinical factors predicts a significant risk of recurrence:^[34]

• Primary tumor 1-4 cm
• High-risk histology
• Lymphovascular invasion
• Cervical lymph node metastases
• Macroscopic multifocality (one focus >1 cm)
• Presence of anti-Tg antibodies
• Postoperative unstimulated Tg < 5-10 ng/mL

The ATA recommends radioiodine therapy for all patients if any of the following are present:^[33]

• Distant metastases
• Extrathyroidal extension of the tumor regardless of tumor size
• Primary tumor size >4 cm even in the absence of other higher-risk features.

Radioiodine therapy is not recommended for patients with unifocal cancer < 1 cm without other higher- risk features; or for patients with multifocal cancer when all foci are < 1 cm in the absence of other higher-risk features.^[33]

Radioiodine therapy is also recommended for selected patients with 1-4 cm thyroid cancers confined to the thyroid who have documented lymph node metastases or other higher risk features, when the combination of age, tumor size, lymph node status, and individual histology predicts an intermediate to high risk of recurrence or death from thyroid cancer.^[33]

The ATA and NCCN guidelines recommend treatment with levothyroxine to suppress thyroid-stimulating hormone (TSH) levels. Degree of suppression is based on risk, as follows ^{[33, 34]} :

• Low-risk patients - Maintenance of the TSH at or slightly below the lower limit of normal (0.1 to 0.5 mU/L)
• Intermediate-risk patients - Initial TSH suppression to below 0.1 mU/L
• High-risk patients - Initial TSH suppression to below 0.1 mU/L

• References

Medication Summary

The goals of pharmacotherapy are to reduce morbidity, induce remission, and prevent complications. Thyroid hormone therapy is used to replace endogenous production after thyroidectomy and radioactive iodine therapy.

• References

Levothyroxine (Synthroid, Levoxyl)

• Dosing, Interactions, etc.

Clinical Context:  In active form, influences growth and maturation of tissues. Involved in normal growth, metabolism, and development. Children require treatment with higher doses than adults.

• References

Class Summary

Levothyroxine treatment is started after the treatment dose of¹³¹ I is administered.

• References

Further Outpatient Care

Outpatient care includes the following:

• Monitor for signs of hypothyroidism after surgical treatment
• Levothyroxine therapy should usually be started after the treatment dose of ¹³¹I is administered
• Monitor the patient for signs of hypocalcemia and measure calcium levels
• Before scanning, instruct the patient to avoid iodine-containing medications and iodine-rich foods; measure urinary iodine in doubtful cases
• In women of childbearing age, pregnancy must be ruled out
• Patients should be instructed carefully about radiation precautions prior to ¹³¹I treatment and should follow the instructions meticulously when sent home

Thyroxine treatment

The adequacy of therapy is monitored by measuring serum thyroid-stimulating hormone (TSH) approximately 8-12 weeks after treatment begins, with the initial goal being a serum TSH concentration of 0.1 µU/mL or less and a serum T3 concentration within the reference range.

In patients who are at low risk and considered cured, the dose of levothyroxine (T4) is decreased to maintain a low, but detectable, serum TSH concentration (0.1-0.5 µU/mL). In higher-risk patients, higher doses are continued, targeting a serum TSH concentration of 0.1 µU/mL or less.

Clinical and ultrasonographic examinations

Thyroid bed and lymph node areas should be examined routinely. Ultrasonography is recommended in patients at high risk for recurrent disease and in any patient with suspicious clinical findings. Palpable lymph nodes that are small, thin, or reduced in size after an interval of 3 months can be considered benign.

Thyroglobulin measurement

In the follow-up care of patients, thyroglobulin is used as a marker of residual disease, of disease recurrence, and as a prognostic factor. Thyroglobulin is produced only by normal or neoplastic thyroid follicular cells and should be undetectable in patients who have been treated with surgery and radioablation. Thyroglobulin concentrations as low as 1 ng/mL or even lower can be detected with current assays.

Antithyroglobulin antibodies, which are found in approximately 15% of patients with thyroid carcinoma, can produce artifactual alteration in thyroglobulin assay results. These antibodies should always be checked when serum thyroglobulin is measured.

Serum thyroglobulin concentrations were undetectable in a group of patients receiving T4 treatment who have isolated lymph node metastases; therefore, undetectable values do not rule out metastatic lymph node disease. If the patient is thought to have metastases, a lymph node biopsy may be performed.

Chest x-ray

Most patients with abnormal chest x-ray findings have detectable serum thyroglobulin concentrations; therefore, this study might not have an additional value in diagnosing metastatic disease. However, it still can have a limited diagnostic value in a subgroup of patients.

Iodine-131 total body scanning

If the serum thyroglobulin concentration becomes detectable in patients receiving T4, recombinant human thyrotropin (thyrotropin alfa; Thyrogen) should be administered or the T4 should be withdrawn, an¹³¹ I total-body scan should be obtained, and serum thyroglobulin should be measured. The uptake of ¹³¹I and the level of TSH concentration determine the accuracy of total body scanning. In patients whose T4 is withheld, the serum TSH concentration usually should be higher than 30 µU/mL when the total-body scan is performed.

Intramuscular injection of thyrotropin alfa is a promising alternative because T4 treatment does not need to be discontinued and the adverse effects are minimal. Thyroglobulin measurement and total body scanning after thyrotropin alfa administration is currently the standard of care in many institutions. For routine diagnostic scans, 2-5 mCi (74-185 mBq [millibecquerel]) of ¹³¹I is administered; higher doses may reduce the uptake of a subsequent therapeutic dose of ¹³¹I.

Scanning is performed to measure uptake, if any, 3 days after the thyrotropin alfa dose has been administered. In certain situations, uptake cannot be detected with diagnostic scans when 2-5 mCi of ¹³¹I is administered but may be detectable after the administration of 100 mCi. This is the rationale for administering 100 mCi (or more) of ¹³¹I in patients with elevated serum thyroglobulin concentrations (usually levels >10 ng/mL after T4 has been withdrawn). If this approach is taken, total-body scanning should be performed 4-7 days later.

If any uptake is detected on the ¹³¹I total-body scan or the serum thyroglobulin concentration rises above the previous level, ¹³¹I therapy should be administered or a positron emission tomography (PET) scan should be considered to localize the metastasis/recurrence.

In the absence of ¹³¹I uptake, a CT scan of the neck and lungs, bone scintigraphy, and scintigraphy using a less-specific tracer (eg, thallium, tetrofosmin, fluorodeoxyglucose) and particularly PET scan should be considered strongly in patients with Hürthle cell carcinoma who are known to have no or low uptake.

• References

Further Inpatient Care

Standard postsurgical care is usually adequate. Monitor patients for signs of infection or hematoma formation.

Clinically monitor patients for hypocalcemic signs and check calcium levels at least every 12-24 hours. If hypocalcemia is present, immediately treat the patient.

Monitor patient for signs of laryngeal nerve injury (eg, hoarseness, respiratory compromise).

If the patient is hospitalized for ¹³¹I treatment, administer antiemetics and adequate hydration. Follow effective radiation precautions.

Salivary dysfunction secondary to uptake in salivary glands can be managed with adequate hydration and sucking on candies.

• References

Deterrence/Prevention

No specific prevention is available, although avoidance of radioactive exposure and adequate iodide intake can be considered preventive measures.

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Complications

Surgical complications include laryngeal nerve injury and transient or permanent hypoparathyroidism. Other surgical complications are infection and hematoma. Surgical scars in the neck can be cosmetically disturbing in certain individuals.

Nonsurgical complications

Hypothyroidism can occur if replacement therapy is inadequate. Hyperthyroidism can occur if the patient is overtreated with levothyroxine.

Acute adverse effects include the following:

• Nausea or vomiting sialadenitis
• Radiation-induced effects
• Thyroiditis
• In metastatic cases, radiation-induced fibrosis of the lung when large doses of¹³¹ I (>150 mCi) are administered at short intervals
• Mild pancytopenia observed after repeated¹³¹ I therapy, particularly in patients with bone metastases who also have received external radiotherapy

Genetic defects and infertility may include the following:

• Transient reduction in spermatogenesis
• Transient ovarian failure
• Increased frequency of miscarriages

The risk of secondary carcinoma or leukemia increased only in patients who have received a high cumulative dose of¹³¹ I (>500 mCi) and those who also receive external radiation therapy

• References

Prognosis

Hürthle cell carcinomas behave in a more aggressive fashion than other well-differentiated thyroid cancers, as evidenced by a higher incidence of metastasis and a lower survival rate. Hürthle cell carcinomas produce thyroglobulin. In addition, most Hürthle cell carcinomas have decreased avidity for ¹³¹I; therefore, treatment with radioactive iodide has limited efficacy.

In some series, nuclear aneuploidy is present in as many as 90% of patients with Hürthle cell carcinoma; in some studies, this condition is shown to be associated with an adverse prognosis.

In a retrospective review of all patients treated with Hürthle cell carcinoma at their institution between 1946 and 2003 (62 patients in all), Mills et al found that independent predictors of disease-free survival were lymph node status (P = 0.008), presence of metastases at diagnosis (P = 0.005), and tumor stage (P = 0.009). These authors suggest that radical surgery may improve outcome; on multivariate analysis, extent of surgery (P< 0.001) was the only independent factor that affected cause-specific survival.^[37]

In a large retrospective study that analyzed the Surveillance, Epidemiology, and End Results (SEER) database from 1988-2009, 3311 patients with Hürthle cell cancer were identified and compared with 59,585 patients with other types of differentiated thyroid cancer. Overall disease-specific survival rates were lower for patients with Hürthle cell cancer (P< 0.001), indicating that Hürthle cell cancer has more aggressive behavior and compromises survival more than other types of differentiated thyroid cancer.^[38]

In a study of 239 patients with Hürthle cell cancer treated at a single institution from 1995 to 2014, Oluic et al reported 5-, 10-, and 20-year cancer-specific survival rates of 94.6%, 92.5%, and 87.4%, respectively. Involvement of both thyroid lobes and the need for reoperation due to local relapse were unfavorable independent prognostic factors, while total thyroidectomy as the primary procedure was a favorable predictive factor for cancer-specific survival.^[39]

• References

Patient Education

The need for life-long levothyroxine treatment should be explained to all patients. Radiation precautions should be explained clearly and in detail to patients who will be receiving radioactive iodine treatment. Women of childbearing age should be advised not to become pregnant for at least 1 year after treatment with¹³¹ I .

For patient education information, see the Thyroid and Metabolism Center, as well as Thyroid Problems.

• References