Laboratory Studies
A full set of thyroid function tests should be ordered, including the following:
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Thyroid-stimulating hormone (TSH)
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Thyroxine (T4)
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Triiodothyronine (T3)
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Free T4
In addition, the following antibody studies should be ordered:
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Antiperoxidase antibodies
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Antithyroglobulin antibodies
Imaging Studies
Imaging study findings are as follows:
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Thyroid uptake and scan: Typical finding is an area of decreased uptake, which corresponds to the tumor.
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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.
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MRI of the neck: MRI will provide more detailed information about the tumor and its relation to the other neck structures.
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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.
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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. [28]
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 neoplasia in 86% of cases [29] :
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Nonmacrofollicular architecture
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Absence of colloid
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Absence of inflammation
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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. [30]
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 for 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. [31]
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%). [31]
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). [32]
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 appropriately. In addition, 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.
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.
Hürthle cell carcinoma. A monomorphous cell population of Hürthle cells arranged in loosely cohesive clusters and single cells. The cells are polyhedral and have abundant granular cytoplasm with well-defined cell borders. The nuclei are enlarged and have a central prominent macronucleolus.
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 152 oncocytic Hürthle cell tumors (50 Hürthle cell adenomas, 70 Hürthle cell carcinomas, and 32 oncocytic variant of papillary carcinoma). In these tumors, the sensitivity of galectin-3 was 95.1%; of HBME-1, 53%; and of the combination of galectin-3 and HBME-1, 99%. However, the specificity for both markers was 88%, lower than for nononcocytic follicular tumors. [33]
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, 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.
Tumor, lymph node, metastases (TNM) staging system for papillary and follicular thyroid carcinoma.
See Thyroid Cancer Staging for additional information.
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Tumor, lymph node, metastases (TNM) staging system for papillary and follicular thyroid carcinoma.
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Hürthle cell carcinoma. A monomorphous cell population of Hürthle cells arranged in loosely cohesive clusters and single cells. The cells are polyhedral and have abundant granular cytoplasm with well-defined cell borders. The nuclei are enlarged and have a central prominent macronucleolus.
