January 17, 2007

Hurthle Cell Carcinoma

Synonyms and related keywords: Hürthle cell carcinoma; Hurthle cell carcinoma; Ashkenazi cells; oncocytic tumors; oncocytoma; oxyphil tumor; follicular carcinoma, oxyphilic type; differentiated thyroid cancer; Hürthle cell neoplasms; follicular carcinoma of the thyroid; follicular cell neoplasms; oncocytic cells; Hashimoto thyroiditis; Hashimoto's thyroiditis; nodular goiter; toxic goiter; thyroid gland


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.

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 (Asa, 2004).

The cytological features for Hürthle cell neoplasms are hypercellularity with a predominance of Hürthle cells (usually more than 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. Hürthle cells also are 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 consisting of at least 75% of Hürthle cells. Distinguishing a benign neoplasm from a malignant neoplasm based on cytologic analysis of fine-needle aspiration (FNA) biopsy is not possible. Features such as pleomorphism, anaplasia, hyperchromatism, and atypia also are observed in benign follicular adenomas; therefore, a definitive way to differentiate 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.

Incidence of malignancy in patients with Hürthle cell neoplasms reported in the literature is variable. Reports show that malignancy occurring in these patients is 13-67%. Some lesions considered malignant could be a reflection of permissive histologic interpretation, which may lead to the inclusion of nonneoplastic Hürthle cell lesions with 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. In a study, a Hürthle tumor that is 4 cm or larger has an 80% chance of histologic evidence of malignancy (Bronner, 1988).

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. Metastatic disease usually is hematogenous, but lymph node metastasis also is not uncommon and more frequently involves the regional lymph nodes. Some studies arguably show that lymph node metastases at initial diagnosis may not be an unfavorable prognostic factor. The lungs, bones, and central nervous system are the most prevalent sites of metastases.

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 pathogenesis may be present; 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 frequently is involved in the pathogenesis of Hürthle cell tumors.

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 PTC. 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 also are 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 also is 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, Hürthle cell neoplasms supposedly have another subclassification, namely the papillary variant of Hürthle cell cancer (ie, Hürthle cell PTC), in addition to Hürthle cell cancer and adenoma. Clinically, this group of tumors tends to behave like PTC; however, they are more indolent, with a propensity for lymph node metastasis rather than hematogenous spread.

As reported by Asa, many Hürthle cell tumors, whether benign or malignant, show papillary change. This is a pseudopapillary phenomenon, because Hürthle cells 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 from 1-11% of all papillary carcinomas. These tumors have a papillary architecture but are composed predominantly, or entirely, of Hürthle cells (Asa, 2004).

Mitochondrion-related alterations, such as mutations in mitochondrial DNA, also are 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 (Maximo, 2000), almost all Hürthle cells displayed a common deletion and/or somatic mitochondrial point mutations. Activating gene mutations encoding the thyrotropin receptor and the alpha subunit of the stimulatory G protein also are reported in some follicular carcinomas.

DNA content profiles after flow cytometry commonly are abnormal. Hürthle cell neoplasms, including histologically benign tumors, often are aneuploid. This finding parallels with nuclear atypia and anisocytosis. The demonstration of aneuploidy may be a marker for a particularly aggressive clinical behavior compared to euploid tumors.


Mortality/Morbidity: Hürthle cell cancer reportedly behaves in a more aggressive fashion than other well-differentiated thyroid cancers, with a tendency to higher incidence 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. Recurrence among patients with Hürthle cell carcinoma is considered to be incurable.

Race: Studies usually do not reflect racial differences; however, all races appear to be affected equally.

Sex: Females are affected more commonly than males, with a female-to-male ratio of approximately 2:1.

Age: The age range of patients presenting with this condition is 20-85 years. The mean age usually is 50-60 years, approximately 10 years older than other types of differentiated thyroid cancers.



Physical: The most common physical examination finding is a palpable single neck mass. Multiple masses also can be palpated.



Goiter, Diffuse Toxic
Goiter, Nontoxic
Goiter, Toxic Nodular
Graves Disease
Hashimoto Thyroiditis
Thyroid Lymphoma
Thyroid Nodule
Thyroid, Anaplastic Carcinoma
Thyroid, Follicular Carcinoma
Thyroid, Medullary Carcinoma
Thyroid, Papillary Carcinoma
Thyroiditis, Subacute

Other Problems to be Considered:

Hürthle cell adenoma (main differential diagnosis)
Follicular adenoma
Metastatic tumors to the thyroid
Thyroid cysts

Metastatic tumors of other Hürthle cell–harboring organs, particularly metastatic renal cell carcinoma and Hürthle cell tumors, originating from the following:

  • Salivary glands

  • Pharynx

  • Larynx

  • Trachea

  • Parathyroid gland

  • Esophagus

  • Pituitary

  • Liver


Lab Studies:

Imaging Studies:


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.

Papillary structures and intranuclear inclusions, features that are not ordinarily associated with Hürthle cell lesions, occasionally are 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 and/or vascular invasion 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 non-oncocytic follicular tumors. 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.

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. Such factors as tumor size, patient age, presence of metastases, and major capsular invasion (extensive capsular invasion in multiple sites) are considered in most classification systems during the evaluation of a patient with Hürthle cell carcinoma. 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).


Medical Care: Surgical treatment is the main treatment for patients with Hürthle cell carcinoma. Hürthle cell cancers traditionally are considered radioresistant; however, 10% of metastases take up radioiodine, compared with 75% of metastases from follicular carcinoma. Therefore, radioactive iodide treatment, which is the most useful nonsurgical therapy for patients with recurrent well-differentiated thyroid carcinoma, is not always useful for patients with Hürthle cell carcinoma, causing difficulty in treating recurrence.

Surgical Care:

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

Diet: No particular diet is recommended, but an iodide-free diet is recommended at least 1 week prior to scanning to minimize the interference.

Activity: Activity may be performed as tolerated.


The goals or pharmacotherapy are to reduce morbidity, induce remission, and prevent complications.

Drug Category: Thyroid hormones -- Levothyroxine treatment is started after the treatment dose of 131I is administered.
Drug Name
Levothyroxine (Synthroid, Levoxyl) -- In active form, influences growth and maturation of tissues. Involved in normal growth, metabolism, and development. Children require treatment with higher doses than adults.
Adult Dose2.2-2.8 mcg/kg/d PO
Pediatric DoseSuggested dosing:
1-12 months: 7-15 mcg/kg/d PO
1-5 years: 5-7 mcg/kg/d PO
5-10 years: 3-5 mcg/kg/d PO
10-18 years: 2-4 mcg/kg/d PO
ContraindicationsDocumented hypersensitivity; uncorrected adrenal insufficiency
InteractionsEstrogens may decrease response to thyroid hormone therapy in patients with nonfunctioning thyroid glands; activity of some beta-blockers may decrease when hypothyroid patient is converted to a euthyroid state
Pregnancy A - Safe in pregnancy
PrecautionsCaution in angina pectoris or cardiovascular disease; monitor thyroid status periodically


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